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Sample records for cancer combined analysis

  1. Saliva analysis combining membrane protein purification with surface-enhanced Raman spectroscopy for nasopharyngeal cancer detection

    NASA Astrophysics Data System (ADS)

    Feng, Shangyuan; Lin, Duo; Lin, Juqiang; Huang, Zufang; Chen, Guannan; Li, Yongzeng; Huang, Shaohua; Zhao, Jianhua; Chen, Rong; Zeng, Haishan

    2014-02-01

    A method for saliva analysis combining membrane protein purification with silver nanoparticle-based surface-enhanced Raman spectroscopy (SERS) for non-invasive nasopharyngeal cancer detection was present in this paper. In this method, cellulose acetate membrane was used to obtain purified whole proteins from human saliva while removing other native saliva constituents and exogenous substances. The purified proteins were mixed with silver nanoparticle for SERS analysis. A diagnostic accuracy of 90.2% can be achieved by principal components analysis combined with linear discriminate analysis, for saliva samples obtained from patients with nasopharyngeal cancer (n = 62) and healthy volunteers (n = 30). This exploratory study demonstrated the potential for developing non-invasive, rapid saliva SERS analysis for nasopharyngeal cancer detection.

  2. Dynamic infrared imaging in identification of breast cancer tissue with combined image processing and frequency analysis.

    PubMed

    Joro, R; Lääperi, A-L; Soimakallio, S; Järvenpää, R; Kuukasjärvi, T; Toivonen, T; Saaristo, R; Dastidar, P

    2008-01-01

    Five combinations of image-processing algorithms were applied to dynamic infrared (IR) images of six breast cancer patients preoperatively to establish optimal enhancement of cancer tissue before frequency analysis. mid-wave photovoltaic (PV) IR cameras with 320x254 and 640x512 pixels were used. The signal-to-noise ratio and the specificity for breast cancer were evaluated with the image-processing combinations from the image series of each patient. Before image processing and frequency analysis the effect of patient movement was minimized with a stabilization program developed and tested in the study by stabilizing image slices using surface markers set as measurement points on the skin of the imaged breast. A mathematical equation for superiority value was developed for comparison of the key ratios of the image-processing combinations. The ability of each combination to locate the mammography finding of breast cancer in each patient was compared. Our results show that data collected with a 640x512-pixel mid-wave PV camera applying image-processing methods optimizing signal-to-noise ratio, morphological image processing and linear image restoration before frequency analysis possess the greatest superiority value, showing the cancer area most clearly also in the match centre of the mammography estimation. PMID:18666012

  3. NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis.

    PubMed

    Zhang, Jian; Qiu, Li-Xin; Wang, Zhong-Hua; Wang, Jia-Lei; He, Shuang-Shuang; Hu, Xi-Chun

    2010-10-01

    To derive a more precise estimation of the relationship between the slow or rapid acetylation resulting from N-acetyltransferase 2 (NAT2) polymorphisms and breast cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of association. The pooled ORs were performed for slow versus rapid acetylation genotypes. A total of 26 studies including 9,215 cases and 10,443 controls were included in the meta-analysis. Overall, no significantly elevated breast cancer risk was associated with NAT2 slow genotypes when all studies were pooled into the meta-analysis (OR = 1.026, 95% CI = 0.968-1.087). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR = 1.001, 95% CI = 0.938-1.068) or Asians (OR = 1.155, 95% CI = 0.886-1.506). When stratified by study design, statistically significantly elevated risk associated with NAT2 slow genotypes was only found among hospital-based studies (OR = 1.178, 95% CI = 1.037-1.339). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found in either premenopausal (OR = 1.053, 95% CI = 0.886-1.252) or postmenopausal women (OR = 0.965, 95% CI = 0.844-1.104). When stratified by cumulative smoking exposure, in the subgroup of smokers with high pack-years, NAT2 slow genotypes were significantly associated with increased breast cancer risk (OR = 1.400, 95% CI = 1.099-1.784). In conclusion, this meta-analysis suggested that there is overall lack of association between NAT2 genotypes and breast cancer risk, however, NAT2 polymorphisms when combining with heavy smoking history may contribute to breast cancer susceptibility. PMID:20180012

  4. Adoptive immunotherapy combined chemoradiotherapy for non-small-cell lung cancer: a meta-analysis.

    PubMed

    Qian, Haili; Wang, Haijuan; Guan, Xiuwen; Yi, Zongbi; Ma, Fei

    2016-06-01

    The aim of this study was to compare the efficacies between adoptive immunotherapy combined chemoradiotherapy and chemoradiotherapy alone in patients with non-small-cell lung cancer (NSCLC). The databases PubMed, EMBASE, and Cochrane database were searched to identify eligible clinical trials. Data analyses were carried out using a comprehensive meta-analysis program, version 2 software. A total of seven articles were finally included in the analysis. Meta-analyses showed that compared with chemoradiotherapy alone, adoptive immunotherapy combined with chemoradiotherapy could improve the 2-year overall survival [odds ratio (OR)=2.45, 95% confidence interval (CI): 1.60-3.75, P<0.001], but not 2-year progression-free survival (OR=1.81, 95% CI: 0.61-5.36, P=0.284). Specifically, early (OR=3.32, 95% CI: 1.38-7.95, P<0.01) but not advanced (OR=3.75, 95% CI: 0.96-14.68, P=0.057) NSCLC patients were likely to gain a large benefit from the adoptive immunotherapy. Most of the adoptive immunotherapy-induced adverse effects were self-limited, mainly including fever, shiver, nausea, fatigue, etc. and severe toxicities were not observed. Adoptive immunotherapy combined with chemoradiotherapy can delay the recurrence of NSCLC and improve survival in patients, where the benefits are even more significant in patients with early-stage NSCLC. PMID:26872311

  5. Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis

    PubMed Central

    Wettersten, Hiromi I.; Hakimi, A. Ari; Morin, Dexter; Bianchi, Cristina; Johnstone, Megan E.; Donohoe, Dallas R.; Trott, Josephine F.; Aboud, Omran Abu; Stirdivant, Steven; Neri, Bruce; Wolfert, Robert; Stewart, Benjamin; Perego, Roberto; Hsieh, James J.; Weiss, Robert H.

    2015-01-01

    Kidney cancer (or renal cell carcinoma [RCC]) is known as “the internist’s tumor” because it has protean systemic manifestations suggesting it utilizes complex, non-physiologic metabolic pathways. Given the increasing incidence of this cancer and its lack of effective therapeutic targets, we undertook an extensive analysis of human RCC tissue employing combined grade-dependent proteomics and metabolomics analysis to determine how metabolic reprogramming occurring in this disease allows it to escape available therapeutic approaches. After validation experiments in RCC cell lines that were wild-type or mutant for the VHL tumor suppressor, in characterizing higher grade tumors we found that the Warburg effect is relatively more prominent at the expense of the tricarboxylic acid cycle and oxidative metabolism in general. Further, we found that the glutamine metabolism pathway acts to inhibit reactive oxygen species, as evidenced by an upregulated glutathione pathway, while the β-oxidation pathway is inhibited leading to increased fatty acyl-carnitines. In support of findings from previous urine metabolomics analyses, we also documented tryptophan catabolism associated with immune suppression, which was highly represented in RCC compared to other metabolic pathways. Together, our results offer a rationale to evaluate novel anti-metabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC. PMID:25952651

  6. Combined blood/tissue analysis for cancer biomarker discovery: application to renal cell carcinoma.

    PubMed

    Johann, Donald J; Wei, Bih-Rong; Prieto, DaRue A; Chan, King C; Ye, Xiaying; Valera, Vladimir A; Simpson, R Mark; Rudnick, Paul A; Xiao, Zhen; Issaq, Haleem J; Linehan, W Marston; Stein, Stephen E; Veenstra, Timothy D; Blonder, Josip

    2010-03-01

    A method that relies on subtractive tissue-directed shot-gun proteomics to identify tumor proteins in the blood of a patient newly diagnosed with cancer is described. To avoid analytical and statistical biases caused by physiologic variability of protein expression in the human population, this method was applied on clinical specimens obtained from a single patient diagnosed with nonmetastatic renal cell carcinoma (RCC). The proteomes extracted from tumor, normal adjacent tissue and preoperative plasma were analyzed using 2D-liquid chromatography-mass spectrometry (LC-MS). The lists of identified proteins were filtered to discover proteins that (i) were found in the tumor but not normal tissue, (ii) were identified in matching plasma, and (iii) whose spectral count was higher in tumor tissue than plasma. These filtering criteria resulted in identification of eight tumor proteins in the blood. Subsequent Western-blot analysis confirmed the presence of cadherin-5, cadherin-11, DEAD-box protein-23, and pyruvate kinase in the blood of the patient in the study as well as in the blood of four other patients diagnosed with RCC. These results demonstrate the utility of a combined blood/tissue analysis strategy that permits the detection of tumor proteins in the blood of a patient diagnosed with RCC. PMID:20121140

  7. Near-infrared confocal micro-Raman spectroscopy combined with PCA-LDA multivariate analysis for detection of esophageal cancer

    NASA Astrophysics Data System (ADS)

    Chen, Long; Wang, Yue; Liu, Nenrong; Lin, Duo; Weng, Cuncheng; Zhang, Jixue; Zhu, Lihuan; Chen, Weisheng; Chen, Rong; Feng, Shangyuan

    2013-06-01

    The diagnostic capability of using tissue intrinsic micro-Raman signals to obtain biochemical information from human esophageal tissue is presented in this paper. Near-infrared micro-Raman spectroscopy combined with multivariate analysis was applied for discrimination of esophageal cancer tissue from normal tissue samples. Micro-Raman spectroscopy measurements were performed on 54 esophageal cancer tissues and 55 normal tissues in the 400-1750 cm-1 range. The mean Raman spectra showed significant differences between the two groups. Tentative assignments of the Raman bands in the measured tissue spectra suggested some changes in protein structure, a decrease in the relative amount of lactose, and increases in the percentages of tryptophan, collagen and phenylalanine content in esophageal cancer tissue as compared to those of a normal subject. The diagnostic algorithms based on principal component analysis (PCA) and linear discriminate analysis (LDA) achieved a diagnostic sensitivity of 87.0% and specificity of 70.9% for separating cancer from normal esophageal tissue samples. The result demonstrated that near-infrared micro-Raman spectroscopy combined with PCA-LDA analysis could be an effective and sensitive tool for identification of esophageal cancer.

  8. Comparative analysis of combined spectral and optical tomography methods for detection of skin and lung cancers

    NASA Astrophysics Data System (ADS)

    Zakharov, Valery P.; Bratchenko, Ivan A.; Artemyev, Dmitry N.; Myakinin, Oleg O.; Kornilin, Dmitry V.; Kozlov, Sergey V.; Moryatov, Alexander A.

    2015-02-01

    Malignant skin tumors of different types were studied in vivo using optical coherence tomography (OCT), backscattering (BS), and Raman spectroscopy (RS). A multimodal method is proposed for early cancer detection based on complex analysis of OCT images by their relative alteration of scattered-radiation spectral intensities between malignant and healthy tissues. An increase in average accuracy of diagnosis was observed for a variety of cancer types (9% sensitivity, 8% specificity) by a multimodal RS-BS-OCT system in comparison with any of the three methods used separately. The proposed approach equalizes the processing rates for all methods and allows for simultaneous imaging and classification of tumors.

  9. Computational analysis of image-based drug profiling predicts synergistic drug combinations: applications in triple-negative breast cancer.

    PubMed

    Brandl, Miriam B; Pasquier, Eddy; Li, Fuhai; Beck, Dominik; Zhang, Sufang; Zhao, Hong; Kavallaris, Maria; Wong, Stephen T C

    2014-12-01

    An imaged-based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi-drug therapies for the treatment of triple-negative breast cancer and other challenging malignancies. The identification of effective drug combinations for the treatment of triple-negative breast cancer (TNBC) was achieved by integrating high-content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA-approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule-targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib-induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumour activity of the combination vinblastine/ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumour growth without causing increased toxicity. Image-based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo, and has the potential to lead to the development of new therapeutic options in other hard-to-treat cancers. PMID:24997502

  10. Raman spectroscopy combined with principal component analysis and k nearest neighbour analysis for non-invasive detection of colon cancer

    NASA Astrophysics Data System (ADS)

    Li, Xiaozhou; Yang, Tianyue; Li, Siqi; Wang, Deli; Song, Youtao; Zhang, Su

    2016-03-01

    This paper attempts to investigate the feasibility of using Raman spectroscopy for the diagnosis of colon cancer. Serum taken from 75 healthy volunteers, 65 colon cancer patients and 60 post-operation colon cancer patients was measured in this experiment. In the Raman spectra of all three groups, the Raman peaks at 750, 1083, 1165, 1321, 1629 and 1779 cm-1 assigned to nucleic acids, amino acids and chromophores were consistently observed. All of these six Raman peaks were observed to have statistically significant differences between groups. For quantitative analysis, the multivariate statistical techniques of principal component analysis (PCA) and k nearest neighbour analysis (KNN) were utilized to develop diagnostic algorithms for classification. In PCA, several peaks in the principal component (PC) loadings spectra were identified as the major contributors to the PC scores. Some of the peaks in the PC loadings spectra were also reported as characteristic peaks for colon tissues, which implies correlation between peaks in PC loadings spectra and those in the original Raman spectra. KNN was also performed on the obtained PCs, and a diagnostic accuracy of 91.0% and a specificity of 92.6% were achieved.

  11. Optimal unified combination rule in application of Dempster-Shafer theory to lung cancer radiotherapy dose response outcome analysis.

    PubMed

    He, Yanyan; Hussaini, M Yousuff; Gong, Yutao U T; Xiao, Ying

    2016-01-01

     Our previous study demonstrated the application of the Dempster-Shafer theory of evidence to dose/volume/outcome data analysis. Specifically, it provided Yager's rule to fuse data from different institutions pertaining to radiotherapy pneumonitis versus mean lung dose. The present work is a follow-on study that employs the optimal unified combination rule, which optimizes data similarity among inde-pendent sources. Specifically, we construct belief and plausibility functions on the lung cancer radiotherapy dose outcome datasets, and then apply the optimal uni-fied combination rule to obtain combined belief and plausibility, which bound the probabilities of pneumonitis incidence. To estimate the incidence of pneumonitis at any value of mean lung dose, we use the Lyman-Kutcher-Burman (LKB) model to fit the combined belief and plausibility curves. The results show that the optimal unified combination rule yields a narrower uncertainty range (as represented by the belief-plausibility range) than Yager's rule, which is also theoretically proven. PMID:26894343

  12. Combining NMR and LC/MS Using Backward Variable Elimination: Metabolomics Analysis of Colorectal Cancer, Polyps, and Healthy Controls.

    PubMed

    Deng, Lingli; Gu, Haiwei; Zhu, Jiangjiang; Nagana Gowda, G A; Djukovic, Danijel; Chiorean, E Gabriela; Raftery, Daniel

    2016-08-16

    Both nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) play important roles in metabolomics. The complementary features of NMR and MS make their combination very attractive; however, currently the vast majority of metabolomics studies use either NMR or MS separately, and variable selection that combines NMR and MS for biomarker identification and statistical modeling is still not well developed. In this study focused on methodology, we developed a backward variable elimination partial least-squares discriminant analysis algorithm embedded with Monte Carlo cross validation (MCCV-BVE-PLSDA), to combine NMR and targeted liquid chromatography (LC)/MS data. Using the metabolomics analysis of serum for the detection of colorectal cancer (CRC) and polyps as an example, we demonstrate that variable selection is vitally important in combining NMR and MS data. The combined approach was better than using NMR or LC/MS data alone in providing significantly improved predictive accuracy in all the pairwise comparisons among CRC, polyps, and healthy controls. Using this approach, we selected a subset of metabolites responsible for the improved separation for each pairwise comparison, and we achieved a comprehensive profile of altered metabolite levels, including those in glycolysis, the TCA cycle, amino acid metabolism, and other pathways that were related to CRC and polyps. MCCV-BVE-PLSDA is straightforward, easy to implement, and highly useful for studying the contribution of each individual variable to multivariate statistical models. On the basis of these results, we recommend using an appropriate variable selection step, such as MCCV-BVE-PLSDA, when analyzing data from multiple analytical platforms to obtain improved statistical performance and a more accurate biological interpretation, especially for biomarker discovery. Importantly, the approach described here is relatively universal and can be easily expanded for combination with other analytical

  13. Screening biomarkers of bladder cancer using combined miRNA and mRNA microarray analysis.

    PubMed

    Jin, Ning; Jin, Xuefei; Gu, Xinquan; Na, Wanli; Zhang, Muchun; Zhao, Rui

    2015-08-01

    Biomarkers, such as microRNAs (miRNAs) may be useful for the diagnosis of bladder cancer. In order to understand the molecular mechanisms underlying bladder cancer, differentially expressed miRNAs (DE-miRNAs) and their target genes in bladder cancer were analyzed. In the present study, miRNA and mRNA expression profiles (GSE40355) were obtained from the Gene Expression Omnibus. These consisted of healthy bladder samples (n=8) and urothelial carcinoma samples (low-grade, n=8 and high-grade, n=8). DE-miRNAs and differentially expressed genes (DEGs) were identified using the limma package and the Benjamin and Hochberg method from the multtest package in R. Target genes of DE-miRNAs were screened. Associations between DEGs were investigated using STRING, and an interaction network was constructed using Cytoscape. Functional and pathway enrichment analyses were performed for DEGs from the interaction network. 87 DE-miRNAs and 2058 DEGs were screened from low-grade bladder cancer samples, and 40 DE-miRNAs and 2477 DEGs were screened from high-grade bladder cancer samples. DE-target genes were significantly associated with the regulation of cell apoptosis. Bladder cancer, non-small cell lung cancer and pancreatic cancer biological pathways were found to be enriched. The results of the present study demonstrated that E2F transcription factor 1, which is targeted by miR-106b, and cyclin-dependent kinase inhibitor 2A (CDKN2A) and V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog-2, which are targeted by miR-125b, participate in the bladder cancer pathway. In conclusion, DE-miRNAs in bladder cancer tissue samples and DE-targeted genes, such as miR-106b and CDKN2A, which were identified in the present study, may provide the basis for targeted therapy for breast cancer and enhance understanding of its pathogenesis. PMID:25955758

  14. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    PubMed

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies. PMID:27357488

  15. Assessing Combinational Drug Efficacy in Cancer Cells by Using Image-based Dynamic Response Analysis

    PubMed Central

    Sima, Chao; Hua, Jianping; Cypert, Milana; Miller, Tasha; Wilson-Robles, Heather M.; Trent, Jeffrey M.; Dougherty, Edward R.; Bittner, Michael L.

    2015-01-01

    The landscape of translational research has been shifting toward drug combination therapies. Pairing of drugs allows for more types of drug interaction with cells. In order to accurately and comprehensively assess combinational drug efficacy, analytical methods capable of recognizing these alternative reactions will be required to prioritize those drug candidates having better chances of delivering appreciable therapeutic benefits. Traditional efficacy measures are primarily based on the “extent” of drug inhibition, which is the percentage of cells being killed after drug exposure. Here, we introduce a second dimension of evaluation criterion, speed of killing, based on a live cell imaging assay. This dynamic response trajectory approach takes advantage of both “extent” and “speed” information and uncovers synergisms that would otherwise be missed, while also generating hypotheses regarding important mechanistic modes of drug action. PMID:26997864

  16. [Combination therapy of hypopharyngeal cancer].

    PubMed

    Miyahara, H

    1987-06-01

    Between 1978 and 1983, ninety-three patients with cancer of the hypopharynx were treated. They were evaluated as to sex, age, primary site, TNM classification, stage, habits of smoking and drinking, past history of irradiation, treatment modality and end results. Eighty-seven percent of the patients visited us at as late a stage as advanced stage III or IV, and were treated mainly by combined therapy involving irradiation and pharyngolaryngoesophagectomy. The 3-year and 5-year survival rates were 38.6% and 33.3%, respectively. After December 1983, 14 new patients with advanced disease including three with coervical esophageal cancer were treated with neo-adjuvant combination chemotherapy which included cisplatin, peplomycin, methotrexate, and bleomycin over two courses of therapy. The response rate (CR + PR) was high, being 82% for the primary tumor and 78% for the metastatic node. Histopathological effects of neo-adjuvant chemotherapy were studied in the resected specimens. The evaluation was based on the Ohboshi-Shimosato classification. The histological effects did not agree with the clinical effects. Grade II b change was evaluated mostly in CR cases and grade II a change was seen in PR cases. It thus seems that neo-adjuvant chemotherapy prior to surgery and/or radiation including cisplatin and other agents is very useful as a multidisciplinary treatment for cancer of the hypopharynx. PMID:3592715

  17. Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations.

    PubMed

    Corrigan, A; Walker, J L; Wickramasinghe, S; Hernandez, M A; Newhouse, S J; Folarin, A A; Lewis, C M; Sanderson, J D; Spicer, J; Marinaki, A M

    2014-10-01

    Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the Illumina Human Exome v1.1 BeadChip and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n=136). GGH rs11545078 was associated with a reduced incidence of grade ⩾3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade ⩾3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade ⩾3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity. PMID:24732178

  18. Monitoring cancer treatment response using photoacoustic and ultrasound spectral analysis in combination with oxygenation measurements (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hysi, Eno; May, Jonathan P.; Wirtzfeld, Lauren; Undzys, Elijus; Li, Shyh-Dar; Kolios, Michael C.

    2016-03-01

    At clinically-relevant depths, the frequency content of photoacoustic signals encodes information about the size, concentration and spatial distribution of non-resolvable blood vessels. This study evaluates whether photoacoustics can detect cancer therapy-induced vascular perturbations. Photoacoustic/ultrasound (PA/US) spectral analysis was combined with functional, PA-based oxygenation and power Doppler (PD) perfusion estimates to assess treatment response. Co-registered, in-vivo US/PA/PD imaging of mice bearing breast cancer tumors was performed pre-treatment and 30m/2h/5h/24h/7d post-treatment (VevoLAZR, Fujifilm VisualSonics). Hyperthermia treatment (1h, 43C) was performed after systemic injections of doxorubicin-loaded thermosensitive liposomes (TSL, n=13) or free doxorubicin (DOX, n=11). Response was classified according to 2h, PA-based oxygenation drop and endpoint (>9d), caliper-based volume reduction. At all time-points/wavelengths (750/850nm), the spectral-slope (SS) was computed from the normalized US/PA power spectra using depth-matched reference phantoms. The percent-vascularity (PV) was estimated for the animal with the largest oxygenation-drop at 2h. TLS-treated responders decreased their PA-SS by 1.9x @750nm and 5.8x @850nm 30m post-treatment and remained constant for 24h; tumor oxygenation followed the same trend. Non-responding SS remained unchanged for 24h. The 750nm SS was 18.7x lower than 850nm suggesting the TSL is sensitive vessel oxygenation. Responder PV decreased 100% when the 30m oxygenation dropped 15% and increased 7x when the 7d oxygenation increased 20%. DOX-responders exhibited similar trends to TSL-responders although the 750nm PA-SS was 1.6x smaller and post-treatment PV was 50% higher. The US-SS remained unchanged until 7d post-treatment suggesting its sensitivity to tumor cell-death. These findings suggest that PA spectral analysis has potential in monitoring cancer treatment response.

  19. Comparative study of CEA and CA19-9 in esophageal, gastric and colon cancers individually and in combination (ROC curve analysis)

    PubMed Central

    Bagaria, Bhawna; Sood, Sadhna; Sharma, Rameshwaram; Lalwani, Soniya

    2013-01-01

    Objective To determine the clinical serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), individually and in combination, for the diagnosis of 50 healthy subjects and 150 cases of esophageal, gastric, and colon cancers. Methods The sensitivities of the two markers were compared individually and in combination, with specificity set at 100%. Receiver operating characteristic (ROC) curves were plotted. Results Serum CEA levels were significantly higher in cancer patients than in the control group. The sensitivity of CEA was determined: in esophageal cancer, sensitivity=28%, negative predictive value (NPV)=61.72%, and AUC=0.742 
(SE=0.05), with a significance level of P<0.0001; in gastric cancer, sensitivity=30%, NPV=58.82%, and AUC=0.734 (SE=0.05), with a significance level of P<0.0001; in colon cancer, sensitivity=74%, NPV=79.36%, and AUC=0.856 
(SE=0.04), with a significance level of P<0.0001. The sensitivity of CA19-9 was also evaluated: in esophageal cancer, sensitivity=18%, NPV=54.94%, and AUC=0.573 (SE =0.05), with a significance level of P=0.2054. In gastric cancer, sensitivity=42%, NPV=63.29%, and AUC=0.679 (SE =0.05), with a significance level of P<0.0011. In colon cancer, sensitivity=26%, NPV=57.47%, and AUC=0.580 (SE =0.05), with a significance level of P=0.1670. The following were the sensitivities of CEA/CA19-9 combined: in esophageal cancer, sensitivity=42%, NPV=63.29%, SE=0.078 (95% CI: 0.0159-0.322); gastric cancer, sensitivity=58%, NPV=70.42%, SE=0.072 (95% CI: -0.0866-0.198); and colon cancer, sensitivity=72%, NPV=78.12%, SE=0.070 (95% CI: 0.137-0.415). Conclusion CEA exhibited the highest sensitivity for colon cancer, and CA19-9 exhibited the highest sensitivity for gastric cancer. Combined analysis indicated an increase in diagnostic sensitivity in esophageal and gastric cancer compared with that in colon cancer. PMID:24379990

  20. Evaluation of Breast Cancer Polyclonality by Combined Chromosome Banding and Comparative Genomic Hybridization Analysis1

    PubMed Central

    Teixeira, Manuel R; Tsarouha, Haroula; Kraggerud, Sigrid M; Pandis, Nikos; Dimitriadis, Euthymios; Andersen, Johan A; Lothe, Ragnhild A; Heim, Sverre

    2001-01-01

    Abstract Cytogenetically unrelated clones have been detected by chromosome banding analysis in many breast carcinomas. Because these karyotypic studies were performed on short-term cultured samples, it may be argued that in vitro selection occurred or that small clones may have arisen during culturing. To address this issue, we analyzed 37 breast carcinomas by G-banding and comparative genomic hybridization (CGH), a fluorescent in situ hybridization-based screening technique that does not require culturing or tumor metaphases. All but two of the 37 karyotypically abnormal cases presented copy number changes by CGH. The picture of genomic alterations revealed by the two techniques overlapped only partly. Sometimes the CGH analysis revealed genomic imbalances that belonged to cell populations not picked up by the cytogenetic analysis and in other cases, especially when the karyotypes had many markers and chromosomes with additional material of unknown origin, CGH gave a more reliable overall picture of the copy number gains and losses. However, besides sometimes revealing cell populations with balanced chromosome aberrations or unbalanced changes that nevertheless remained undetected by CGH, G-banding analysis was essential to understand how the genomic imbalances arose in the many cases in which both techniques detected the same clonal abnormalities. Furthermore, because CGH pictures only imbalances present in a significant proportion of the test sample, the very detection by this technique of imbalances belonging to apparently small, cytogenetically unrelated clones of cells proves that these clones must have been present in vivo. This constitutes compelling evidence that the cytogenetic polyclonality observed after short-term culturing of breast carcinomas is not an artifact. PMID:11494114

  1. Gemcitabine Compared With Gemcitabine and S-1 Combination Therapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

    PubMed

    Li, Doudou; Chen, Changhao; Zhou, Yu; Chen, Rufu; Fan, Xinxiang; Bi, Zhuofei; Li, Zhihua; Liu, Yimin

    2015-09-01

    Several reports suggest that gemcitabine (GEM) plus S-1 combination (GS) is associated to prolong the survival in patients with unresectable pancreatic cancer (PC). We conducted a systemic review and meta-analysis of studies comparing the safety and efficacy of GS versus GEM.Summary data from randomized trials and retrospective studies were searched in PubMed, EMBASE, Web of Science, and the Cochrane Library. Statistical analyses were conducted to calculate the hazard ratios (HRs) and relative risk (RR) with 95% confidence intervals (CIs) using random-effects models. Subgroup analyses based on the chemotherapy cycles were performed to explore the efficacy and toxicity for therapy. Sensitivity analyses were conducted by removing specific studies to assess the effects of study quality.Between January 2004 and August 2012, 4 RCTs and 2 retrospective studies including a total of 1025 cases were identified. The overall survival (OS) (HR: 0.82; 95% CI, 0.70-0.96; P = 0.01) and progression-free survival (PFS) (HR: 0.65; 95% CI, 0.55-0.77; P < 0.001) for the GS arm were significantly longer than the GEM arm. The differences in objective response rate (ORR) (RR: 1.24; 95% CI, 1.17-1.33; P < 0.001) and disease control rate (DCR) were also better in the GS arm (RR: 1.37; 95% CI, 1.19-1.59; P < 0.001). Grades 3 to 4 toxicities in both the groups were similar except neutropenia and diarrhea, which were more frequent in the GS arm (P < 0.001). In the subgroup analysis, the cycle for chemotherapy every 4 weeks has equivalent efficacy and less toxicity than regimens every 3 weeks in the GS arm.The current meta-analysis suggested that GEM significantly prolonged OS and PFS when added to S-1 combination in patients with unresectable PC. GS therapy also offers better ORR and DCR than GEM monotherapy and no unexpected toxicity was evident. PMID:26334891

  2. Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy

    PubMed Central

    Goltsov, Alexey; Deeni, Yusuf; Khalil, Hilal S.; Soininen, Tero; Kyriakidis, Stylianos; Hu, Huizhong; Langdon, Simon P.; Harrison, David J.; Bown, James

    2014-01-01

    The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming. PMID:24918976

  3. Shenqi Fuzheng Injection Combined with Chemotherapy for Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

    PubMed

    Lv, Yanhong; Zhang, Guijuan; Ma, Yi; Ma, Min; Liao, Rui; Xiang, Jingfang; Chen, Ruixue; Yan, Xianxin; Bie, Fengjie; Huang, Maojie; Liang, Shijie

    2015-01-01

    Purpose. To evaluate the therapeutic effectiveness and safety of shenqi fuzheng injection (SFI) in the associated chemotherapy of breast cancer. Methods. 1247 subjects were included in this study for meta-analysis with RevMan 5.3. Results. The clinical curative effective rate (OR = 2.03, 95% Cl [1.44, 2.86], P < 0.0001), grades of KPS (OR = 4.11, 95% Cl [2.74, 6.16], P < 0.00001), CD3(+) cells (MD = 7.05, 95% Cl [0.45, 13.64], P = 0.04) and CD4(+) cells (MD = 8.60, 95% Cl [2.67, 14.54], P = 0.004) and CD4/CD8(+) cells (MD = 0.35, 95% Cl [0.14, 0.56], P = 0.001), WBC (OR = 0.30, 95% Cl [0.20, 0.46], P ≤ 0.0001), PLT (OR = 0.36, 95% Cl [0.20, 0.67], P = 0.001), gastrointestinal reaction (OR = 0.21, 95% Cl [0.14, 0.32], P < 0.00001), and ECG (OR = 0.26, 95% Cl [0.13, 0.51], P < 0.0001) in the experimental group were superior to the control group. While there were no differences between two groups in CD8(+) (MD = 0.21, 95% Cl [-2.81, 3.23], P = 0.89), NK(+) (MD = 1.06, 95% Cl [-9.40, 11.53], P = 0.84), RBC (OR = 0.49, 95% Cl [0.14, 1.74], P = 0.27), liver function (OR = 0.59, 95% Cl [0.28, 1.24], P = 0.16), renal function (OR = 0.56, 95% Cl [0.13, 2.45], P = 0.44), and bone marrow suppression (OR = 0.50, 95% Cl [0.25, 1.01], P = 0.05). Conclusion. SFI combined with chemotherapy, to some extent, can improve the effectiveness and the security in the treatment of breast cancer; the mechanism may be related to the elevated immunity. PMID:26495018

  4. Modification of breast cancer risk according to age and menopausal status: A combined analysis of five population-based case-control studies

    PubMed Central

    Trentham-Dietz, Amy; Sprague, Brian L.; Hampton, John M.; Miglioretti, Diana L.; Nelson, Heidi D.; Titus, Linda J.; Egan, Kathleen M.; Remington, Patrick L.; Newcomb, Polly A.

    2014-01-01

    Purpose While several risk factors for breast cancer have been identified, studies have not consistently shown whether these factors operate more strongly at certain ages or for just pre- or postmenopausal women. We evaluated whether risk factors for breast cancer differ according to age or menopausal status. Methods Data from five population-based case-control studies conducted during 1988-2008 were combined and analyzed. Cases (N=23,959) and population controls (N=28,304) completed telephone interviews. Logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals and tests for interaction by age and menopausal status. Results Odds ratios for first-degree family history of breast cancer were strongest for younger women—reaching two-fold elevations—but were still statistically significantly elevated by 58-69% among older women. Obesity was inversely associated with breast cancer among younger women and positively associated with risk for older women (interaction P<0.0001). Recent alcohol intake was more strongly related to breast cancer risk among older women, although consumption of 3 or more drinks/day among younger women also was associated with elevated odd ratios (P<0.0001). Associations with benign breast disease and most reproductive/menstrual factors did not vary by age. Repeating analysis stratifying by menopausal status produced similar results. Conclusions With few exceptions, menstrual and lifestyle factors are associated with breast cancer risk regardless of age or menopausal status. Variation in the association of family history, obesity, and alcohol use with breast cancer risk by age and menopausal status may need to be considered when determining individual risk for breast cancer. PMID:24647890

  5. Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: Meta-analysis of randomized trials

    PubMed Central

    2010-01-01

    Background Hormone therapy plus radiotherapy significantly decreases recurrences and mortality of patients affected by locally advanced prostate cancer. In order to determine if difference exists according to the hormonal treatment duration, a literature-based meta-analysis was performed. Methods Relative risks (RR) were derived through a random-effect model. Differences in primary (biochemical failure, BF; cancer-specific survival, CSS), and secondary outcomes (overall survival, OS; local or distant recurrence, LR/DM) were explored. Absolute differences (AD) and the number needed to treat (NNT) were calculated. Heterogeneity, a meta-regression for clinic-pathological predictors and a correlation test for surrogates were conducted. Results Five trials (3,424 patients) were included. Patient population ranged from 267 to 1,521 patients. The longer hormonal treatment significantly improves BF (with significant heterogeneity) with an absolute benefit of 10.1%, and a non significant trend in CSS. With regard to secondary end-points, the longer hormonal treatment significantly decrease both the LR and the DM with an absolute difference of 11.7% and 11.5%. Any significant difference in OS was observed. None of the three identified clinico-pathological predictors (median PSA, range 9.5-20.35, Gleason score 7-10, 27-55% patients/trial, and T3-4, 13-77% patients/trial), did significantly affect outcomes. At the meta-regression analysis a significant correlation between the overall treatment benefit in BF, CSS, OS, LR and DM, and the length of the treatment was found (p≤0.03). Conclusions Although with significant heterogeneity (reflecting different patient' risk stratifications), a longer hormonal treatment duration significantly decreases biochemical, local and distant recurrences, with a trend for longer cancer specific survival. PMID:21143897

  6. Combined analysis of genome-wide expression and copy number profiles to identify key altered genomic regions in cancer

    PubMed Central

    2012-01-01

    Background Analysis of DNA copy number alterations and gene expression changes in human samples have been used to find potential target genes in complex diseases. Recent studies have combined these two types of data using different strategies, but focusing on finding gene-based relationships. However, it has been proposed that these data can be used to identify key genomic regions, which may enclose causal genes under the assumption that disease-associated gene expression changes are caused by genomic alterations. Results Following this proposal, we undertake a new integrative analysis of genome-wide expression and copy number datasets. The analysis is based on the combined location of both types of signals along the genome. Our approach takes into account the genomic location in the copy number (CN) analysis and also in the gene expression (GE) analysis. To achieve this we apply a segmentation algorithm to both types of data using paired samples. Then, we perform a correlation analysis and a frequency analysis of the gene loci in the segmented CN regions and the segmented GE regions; selecting in both cases the statistically significant loci. In this way, we find CN alterations that show strong correspondence with GE changes. We applied our method to a human dataset of 64 Glioblastoma Multiforme samples finding key loci and hotspots that correspond to major alterations previously described for this type of tumors. Conclusions Identification of key altered genomic loci constitutes a first step to find the genes that drive the alteration in a malignant state. These driver genes can be found in regions that show high correlation in copy number alterations and expression changes. PMID:23095915

  7. Combined Cancer Immunotherapy Against Aurora Kinase A.

    PubMed

    Kaštánková, Iva; Poláková, Ingrid; Dušková, Martina; Šmahel, Michal

    2016-05-01

    Aurora kinase A (AURKA) is a centrosomal protein that is overexpressed in a number of human malignancies and can contribute to tumor progression. As we used this protein as a target of DNA immunization, we increased its immunogenicity by the addition of the PADRE helper epitope and decreased its potential oncogenicity by mutagenesis of the kinase domain. For in vitro analysis of induced immune responses in mice, we identified the Aurka220-228 nonapeptide representing an H-2K epitope. As DNA vaccination against the Aurka self-antigen by a gene gun did not show any antitumor effect, we combined DNA immunization with anti-CD25 treatment that depletes mainly regulatory T cells. Whereas 1 anti-CD25 dose injected before DNA vaccination did not enhance the activation of Aurka-specific splenocytes, 3 doses administered on days of immunizations augmented about 10-fold immunity against Aurka. However, an opposite effect was found for antitumor immunity-only 1 anti-CD25 dose combined with DNA vaccination reduced tumor growth. Moreover, the administration of 3 doses of anti-CD25 antibody alone accelerated tumor growth. Analysis of tumor-infiltrating cells showed that 3 anti-CD25 doses not only efficiently depleted regulatory T cells but also activated helper T cells and CD3CD25 cells. Next, we found that blockade of the PD-1 receptor initiated 1 week after the first immunization was necessary for significant inhibition of tumor growth with therapeutic DNA vaccination against Aurka combined with depletion of CD25 cells. Our results suggest that combined cancer immunotherapy should be carefully evaluated to achieve the optimal antitumor effect. PMID:27070447

  8. Meta-Analysis of Oxaliplatin-Based Chemotherapy Combined With Traditional Medicines for Colorectal Cancer: Contributions of Specific Plants to Tumor Response.

    PubMed

    Chen, Menghua; May, Brian H; Zhou, Iris W; Xue, Charlie C L; Zhang, Anthony L

    2016-03-01

    This meta-analysis evaluates the clinical evidence for the addition of traditional medicines (TMs) to oxaliplatin-based regimens for colorectal cancer (CRC) in terms of tumor response rate (TRR). Eight electronic databases were searched for randomized controlled trials of oxaliplatin-based chemotherapy combined with TMs compared to the same oxaliplatin-based regimen. Data on TRR from 42 randomized controlled trials were analyzed using Review Manager 5.1. Studies were conducted in China or Japan. Publication bias was not evident. The meta-analyses suggest that the combination of the TMs with oxaliplatin-based regimens increased TRR in the palliative treatment of CRC (risk ratio [RR] 1.31 [1.20-1.42], I(2) = 0%). Benefits were evident for both injection products (RR 1.36 [1.18-1.57], I(2) = 0%) and orally administered TMs (RR 1.27 [1.15-1.41], I(2) = 0%). Further sensitivity analysis of specific plant-based TMs found that Paeonia, Curcuma, and Sophora produced consistently higher contributions to the RR results. Compounds in each of these TMs have shown growth-inhibitory effects in CRC cell-line studies. Specific combinations of TMs appeared to produce higher contributions to TRR than the TMs individually. Notable among these was the combination of Hedyotis, Astragalus, and Scutellaria. PMID:26254190

  9. Paclitaxel efficacy and toxicity in older women with metastatic breast cancer: combined analysis of CALGB 9342 and 9840

    PubMed Central

    Lichtman, S. M.; Hurria, A.; Cirrincione, C. T.; Seidman, A. D.; Winer, E.; Hudis, C.; Cohen, H. J.; Muss, H. B.

    2012-01-01

    Background: Two Cancer and Leukemia Group B (CALGB) studies were utilized to determine the efficacy and tolerability of paclitaxel (Taxol) in older patients with metastatic breast cancer. Patients and methods: CALGB 9840 evaluated weekly paclitaxel (80 mg/m2) versus paclitaxel every 3 weeks (175 mg/m2); CALGB 9342 evaluated three doses of paclitaxel as follows: 175, 210 and 250 mg/m2 each over 3 h every 3 weeks. Of the 1048 patients, paclitaxel was used first line in 57%. The groups: (i) <55 years (45%), (ii) 55–64 years (29%), and (iii) ≥65 years (26%). Results: Tumor response was also similar among age groups. First-line therapy (P = 0.0001) and better performance status (PS) (P = 0.018) were significantly related to higher response. Age did not significantly relate to overall survival (OS) or progression-free survival (PFS). First-line therapy, better PS, estrogen receptor positive status and a fewer number of metastatic sites were significantly related to improved OS and PFS. The grade ≥3 toxic effects that increased linearly with age were leucopenia (P = 0.0099), granulocytopenia (P = 0.022), anorexia (P = 0.028), bilirubin elevation (P = 0.0035) and neurotoxicity (P < 0.0001). Patients over 65 years receiving second-line therapy had the shortest time to neurotoxicity. Conclusions: Older women with breast cancer derive similar efficacy from treatment with paclitaxel as younger women. Older women are at increased risk for specific toxic effects. PMID:21693770

  10. Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study

    PubMed Central

    Goodfellow, Paul J.; Billingsley, Caroline C.; Lankes, Heather A.; Ali, Shamshad; Cohn, David E.; Broaddus, Russell J.; Ramirez, Nilsa; Pritchard, Colin C.; Hampel, Heather; Chassen, Alexis S.; Simmons, Luke V.; Schmidt, Amy P.; Gao, Feng; Brinton, Louise A.; Backes, Floor; Landrum, Lisa M.; Geller, Melissa A.; DiSilvestro, Paul A.; Pearl, Michael L.; Lele, Shashikant B.; Powell, Matthew A.; Zaino, Richard J.; Mutch, David

    2015-01-01

    Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease. PMID:26552419

  11. The Cancer Genome Atlas ovarian cancer analysis

    Cancer.gov

    An analysis of genomic changes in ovarian cancer has provided the most comprehensive and integrated view of cancer genes for any cancer type to date. Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Re

  12. Oxaliplatin-based chemotherapy combined with traditional medicines for neutropenia in colorectal cancer: A meta-analysis of the contributions of specific plants.

    PubMed

    Chen, Menghua; May, Brian H; Zhou, Iris W; Sze, Daniel Man-Yuen; Xue, Charlie C; Zhang, Anthony L

    2016-09-01

    This review assessed the effects on chemotherapy induced neutropenia (CIN) of combining oxaliplatin regimens with traditional plant-based medicines (TMs) in the management of colorectal cancer (CRC). 32 RCTs (2224 participants) were included. Meta-analysis showed reduced incidence of grade 3/4 CIN (RR 0.45[0.31, 0.65], I(2)=0%). No studies reported serious adverse events or reduction in tumour response rates associated with concurrent use of oxaliplatin and TM. Due to small sample sizes and risk of bias, these results should be interpreted with caution. Analyses of sub-groups of studies that used similar TM interventions assessed the relative contributions of individual plant-based ingredients to the results. Astragalus, Codonopsis, Atractylodes, Poria and Coix, in various combinations were consistently associated with reduced CIN incidence when administered orally. Experimental studies of these plants have reported reduced myelosuppression and/or enhanced immune response. Further studies of these plants may lead to the development of interventions to supplement conventional CIN treatment. PMID:27497028

  13. Mammalian target of rapamycin (mTOR) inhibitors and combined chemotherapy in breast cancer: a meta-analysis of randomized controlled trials

    PubMed Central

    Qiao, Longwei; Liang, Yuting; Mira, Ranim R; Lu, Yaojuan; Gu, Junxia; Zheng, Qiping

    2014-01-01

    The mammalian target of rapamycin (mTOR) inhibitor, in combination with other chemotherapeutic drugs, has been used for treatment of breast cancer that develops resistance to endocrine therapy. However, the efficacy and safety need further evaluation. Here, we report a meta-analysis of randomized controlled trials (RCT) in breast cancer patients undergoing chemotherapy using steroid (exemestane) or nonsteroid (letrozole) aromatase inhibitors with or without mTOR inhibitors (everolimus). The overall response rate (ORR), progression-free survival (PFS), clinical benefi;t rate with 95% confidence interval (CI), and the major toxicities/adverse effects were analyzed. Data were extracted from twelve studies that meet the selection criteria. Among these, six studies that enrolled 3693 women received treatment of everolimus plus exemestane, or placebo with exemestane. The results showed that everolimus plus exemestane significantly increased the ORR relative risk (relative risk = 9.18, 95% CI = 5.21-16.15), PFS hazard ratio (hazard ratio = 0.44, 95% CI = 0.41-0.48), and clinical benefi;t rate (relative risk = 1.92, 95% CI 1.69-2.17) compared to placebo control, while the risks of stomatitis, rash, hyperglycemia, diarrhea, fatigue, anorexia and pneumonitis also increased. Three studies that enrolled 715 women who received everolimus as neoadjuvant therapy were analyzed. Compared to chemotherapy with placebo, chemotherapy plus everolimus did not increase the ORR relative risk (relative risk = 0.90, 95% CI = 0.77-1.05). Meanwhile, two other studies that enrolled 2104 women examined the efficacy of temsirolimus (or placebo control) plus letrozole. The results indicated that emsirolimus plus letrozole did not increase the ORR relative risk and clinical benefi;t rate (p > 0.05). Together, these data suggest that the combined mTOR inhibitor (everolimus) plus endocrine therapy (exemestane) is superior to endocrine therapy alone. As a neoadjuvant, everolimus did not increase the

  14. [Systematic review and Meta-analysis of Shenqi Fuzheng injection combined with first-line chemotherapy for non-small cell lung cancer].

    PubMed

    Hao, Teng-teng; Xie, Yan-ming; Liao, Xing; Wang, Jing

    2015-10-01

    The paper is to systematically evaluate the effect and safety of Shenqi Fuzheng injection (SFI) combined with first-line chemotherapy for non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on Shenqi Fuzheng injection (SFI) combined with first-line chemotherapy (experiment group) and chemotherapy alone group ( control group) were electronically retrieved from Medline, EMbase, Clinical Trials, Cochrane Library, CBM, CNKI, VIP, and Wanfang Data base. All trials were assessed for quality according to the Cochrane Reviewer's Handbook for Systematic Reviews of Intervention and then Meta-analysis was performed withRevMan5. 2 Software. A total of 43 RCTs (3433 patients) were included after screening and selecting. Results of Meta-analysis showed that: Objective remission rate (ORR): ORR of experimental group was about 20% higher than that of control group [RR = 1.23, 95% CI (1.11,1.35), P < 0.0001]. Disease control rate (DCR):DCR of SFI combined with first-line chemotherapy was 11% higher than that of first-line chemotherapy alone [RR = 1.11, 95% CI (1.07, 1.16), P < 0.000 01]. Life quality evaluated by Kosovan performance status (KPS) showed that: life quality improvement rate of experimental group was about twice of that in control group [RR = 2.02, 95% CI (1.81, 2.26), P < 0.000 01]. Toxic and side reaction analysis showed that: the incidence of side reactions in experimental group was about 50% lower than that in control group [RR = 0.59, 95% CI (0.53, 0.66), P < 0.000 01]. Immune function test showed that: the function of experimental group was 3.2 (standard deviations) times greater than that of control group [MD = 3.23, 95% CI (2.86, 3.60), P < 0.000 01]. We can see that SFI combined with first-line chemotherapy for NSCLC can increase objective efficacy, improve life quality, decrease toxic and side reactionsinduced by chemotherapy, and improve the immune functions. As most of the included studies in this systematic evaluation had poor quality

  15. Efficacy and tolerability of oral oxycodone and oxycodone/naloxone combination in opioid-naïve cancer patients: a propensity analysis

    PubMed Central

    Lazzari, Marzia; Greco, Maria Teresa; Marcassa, Claudio; Finocchi, Simona; Caldarulo, Clarissa; Corli, Oscar

    2015-01-01

    Background World Health Organization step III opioids are required to relieve moderate-to-severe cancer pain; constipation is one of the most frequent opioid-induced side effects. A fixed combination, prolonged-release oxycodone/naloxone (OXN), was developed with the aim of reducing opioid-related gastrointestinal side effects. The objective of this study was to compare the efficacy and safety of prolonged-release oxycodone (OXY) alone to OXN in opioid-naïve cancer patients with moderate-to-severe pain. Methods Propensity analysis was utilized in this observational study, which evaluated the efficacy, safety, and quality of life. Results Out of the 210 patients recruited, 146 were matched using propensity scores and included in the comparative analysis. In both groups, pain intensity decreased by ≈3 points after 60 days, indicating comparable analgesic efficacy. Responder rates were similar between groups. Analgesia was achieved and maintained with similarly low and stable dosages over time (12.0–20.4 mg/d for OXY and 11.5–22.0 mg/d for OXN). Bowel Function Index (BFI) and laxative use per week improved from baseline at 30 days and 60 days in OXN recipients (−16, P<0.0001 and −3.5, P=0.02, respectively); BFI worsened in the OXY group. The overall incidence of drug-related adverse events was 28.9% in the OXY group and 8.2% in the OXN group (P<0.01); nausea and vomiting were two to five times less frequent with OXN. Quality of life improved to a significantly greater extent in patients receiving OXN compared to OXY (increase in Short Form-36 physical component score of 7.1 points vs 3.2 points, respectively; P<0.001). Conclusion In patients with chronic cancer pain, OXN provided analgesic effectiveness that is similar to OXY, with early and sustained benefits in tolerability. The relationship between responsiveness to OXN and clinical characteristics is currently being investigated. PMID:26586937

  16. Combination of phytochemicals as adjuvants for cancer therapy.

    PubMed

    Ho, John W S; Cheung, Matt W M

    2014-01-01

    Newer treatments of advanced human cancer are based on combination of cancer drugs that have different mechanism of actions yet the combination strategy may potentiate the anti-cancer effects and cytotoxicity. Recent studies suggest that cancer growth can be inhibited more effectively by combination of phytochemicals that affect different pathways. The apoptotic activity can be modulated by intrinsic and extrinsic molecules. The combination of anti-tumor phytochemicals can be more effective in modulating different signaling pathways associated with tumor cell growth which is the common target for anti-tumor action. Combinations of cytotoxic anti-tumor agents and inhibitors from phytochemicals are believed to act together producing inhibitory mechanisms on cancer growth. This combination strategy shows promise on cancer therapy. However, the combination of phytochemicals in cancer therapy needs to be further investigated to develop a better treatment strategy. Recent patents on anti-tumor phytochemicals are reviewed in this article. PMID:24942759

  17. Human Lung Cancer Risks from Radon – Part III - Evidence of Influence of Combined Bystander and Adaptive Response Effects on Radon Case-Control Studies - A Microdose Analysis

    PubMed Central

    Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

    2012-01-01

    Since the publication of the BEIR VI (1999) report on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, in particular the potentially deleterious Bystander Effect (BE) and the potentially beneficial Adaptive Response radio-protection (AR). The case-control radon lung cancer risk data of the pooled 13 European countries radon study (Darby et al 2005, 2006) and the 8 North American pooled study (Krewski et al 2005, 2006) have been evaluated. The large variation in the odds ratios of lung cancer from radon risk is reconciled, based on the large variation in geological and ecological conditions and variation in the degree of adaptive response radio-protection against the bystander effect induced lung damage. The analysis clearly shows Bystander Effect radon lung cancer induction and Adaptive Response reduction in lung cancer in some geographical regions. It is estimated that for radon levels up to about 400 Bq m−3 there is about a 30% probability that no human lung cancer risk from radon will be experienced and a 20% probability that the risk is below the zero-radon, endogenic spontaneous or perhaps even genetically inheritable lung cancer risk rate. The BEIR VI (1999) and EPA (2003) estimates of human lung cancer deaths from radon are most likely significantly excessive. The assumption of linearity of risk, by the Linear No-Threshold Model, with increasing radon exposure is invalid. PMID:22942874

  18. Arsenic and its combinations in cancer therapeutics.

    PubMed

    Prajapati, Vandana; Kale, Raosaheb K; Singh, Rana P

    2011-06-01

    Arsenic is a metalloid that is considered to be a paradox in terms of its role both as a carcinogen and as a therapeutic agent. Chronic exposure to arsenic in drinking water has been linked with the development of various pathological conditions including cancer. Nevertheless, the therapeutic potential of arsenic and its derivatives in a variety of diseases have been exploited in the past. However, its role and mechanism of action as a therapeutic agent still remain an active area of research and investigation. Our ongoing work also suggests varied responses in cancer cells exposed to lower versus higher concentrations of arsenic. Furthermore, the arsenic combinations with chemopreventive or anticancer agents have been observed to sensitize the cell for cell-cycle arrest and cell death. Here, we have provided the account of recent updates on the mechanism of action of arsenic and its derivatives that lead to various disorders, and its role as a therapeutic agent both as a single agent as well as in combination chemotherapy. PMID:22822509

  19. Combination immunotherapy and photodynamic therapy for cancer

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel

    2006-02-01

    Cancer is a leading cause of death among modern people largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with minimal toxicity towards normal tissue. This is best accomplished by priming the body's immune system to recognize the tumor antigens so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species leading to vascular shutdown and tumor cell death. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens using PDT and immunostimulating treatments are likely to even further enhance post-PDT immunity. These immunostimulants are likely to include products derived from pathogenic microorganisms that are effectively recognized by Toll-like receptors and lead to upregulation of transcription factors for cytokines and inflammatory mediators. The following cascade of events causes activation of macrophages, dendritic and natural killer cells. Exogenous cytokine administration can be another way to increase PDT-induced immunity as well as treatment with a low dose of cyclophosphamide that selectively reduces T-regulatory cells. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.

  20. A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials.

    PubMed

    Xu, Liang; Wu, Xiaobo; Hu, Chun; Zhang, Zhiying; Zhang, Le; Liang, Shujing; Xu, Yingchun; Zhang, Fengchun

    2016-01-01

    Nowadays, the philosophy of treating metastatic breast cancer (MBC) is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015) comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS), and the secondary end points were the progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicities. The pooled hazard ratio (HR) and pooled risk ratio (RR) were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84-0.96, P=0.002), PFS (HR 0.81, 95% CI 0.76-0.88, P<0.001), and ORR (RR 1.72, 95% CI 1.34-2.21, P<0.001). Notably, subgroup analysis failed to favor the targeted agent-based combination in terms of OS (HR 1.08, 95% CI 0.89-1.31, P=0.365), PFS (HR 1.09, 95% CI 0.88-1.35, P=0.433), and ORR (RR 1.60, 95% CI 0.69-3.71, P=0.278) compared with single agent. In addition, although more hematological and gastrointestinal toxicities were observed in the doublet agents group, they were acceptable and manageable. Taken together, when compared with single-agent therapy, doublet agents should be considered a treatment option because of the superior efficacy and the manageable safety profile for the prior anthracycline- and taxane-treated MBC patients. PMID:27445497

  1. A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials

    PubMed Central

    Xu, Liang; Wu, Xiaobo; Hu, Chun; Zhang, Zhiying; Zhang, Le; Liang, Shujing; Xu, Yingchun; Zhang, Fengchun

    2016-01-01

    Nowadays, the philosophy of treating metastatic breast cancer (MBC) is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015) comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS), and the secondary end points were the progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicities. The pooled hazard ratio (HR) and pooled risk ratio (RR) were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84–0.96, P=0.002), PFS (HR 0.81, 95% CI 0.76–0.88, P<0.001), and ORR (RR 1.72, 95% CI 1.34–2.21, P<0.001). Notably, subgroup analysis failed to favor the targeted agent-based combination in terms of OS (HR 1.08, 95% CI 0.89–1.31, P=0.365), PFS (HR 1.09, 95% CI 0.88–1.35, P=0.433), and ORR (RR 1.60, 95% CI 0.69–3.71, P=0.278) compared with single agent. In addition, although more hematological and gastrointestinal toxicities were observed in the doublet agents group, they were acceptable and manageable. Taken together, when compared with single-agent therapy, doublet agents should be considered a treatment option because of the superior efficacy and the manageable safety profile for the prior anthracycline- and taxane-treated MBC patients. PMID:27445497

  2. Combined magnetic and gravity analysis

    NASA Technical Reports Server (NTRS)

    Hinze, W. J.; Braile, L. W.; Chandler, V. W.; Mazella, F. E.

    1975-01-01

    Efforts are made to identify methods of decreasing magnetic interpretation ambiguity by combined gravity and magnetic analysis, to evaluate these techniques in a preliminary manner, to consider the geologic and geophysical implications of correlation, and to recommend a course of action to evaluate methods of correlating gravity and magnetic anomalies. The major thrust of the study was a search and review of the literature. The literature of geophysics, geology, geography, and statistics was searched for articles dealing with spatial correlation of independent variables. An annotated bibliography referencing the Germane articles and books is presented. The methods of combined gravity and magnetic analysis techniques are identified and reviewed. A more comprehensive evaluation of two types of techniques is presented. Internal correspondence of anomaly amplitudes is examined and a combined analysis is done utilizing Poisson's theorem. The geologic and geophysical implications of gravity and magnetic correlation based on both theoretical and empirical relationships are discussed.

  3. [Studies on Cancer Diagnosis by Using Spectroscopy Combined with Chemometrics].

    PubMed

    Zhang, Zhuo-yong

    2015-09-01

    Studies on cancer diagnosis using various spectroscopic methods combined with chemometrics are briefly reviewed. Elemental contents in serum samples were determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES), bidirectional associative memory (BAM) networks were used to establish diagnosis models for the relationships between elemental contents and lung cancer, liver cancer, and stomach cancer, respectively. Near infrared spectroscopy (NIRS) is a non-destructive detection technology. Near infrared spectra of endometrial carcinoma samples were determined and spectral features were extracted by chemoometric methods, a fuzzy rule-based expert system (FuRES) was used for establishing diagnosis model, satisfactory results were obtained. We also proposed a novel variable selection method based on particle swarm optimization (PSO) for near infrared spectra of endometrial carcinoma samples. Spectra with optimized variable were then modeled by support victor machine (SVM). Terahertz technology is an emerging technology for non-destructive detection, which has some unique characteristics. Terahertz time domain spectroscopy (THz-TDS) was used for cervical carcinoma measurement. Absorption coefficients were calculated from the measured time domain spectra and then processed with derivative, orthogonal signal correction (PC-OSC) to reduce interference components, and then fuzzy rule-based expert system (FuRES), fuzzy optimal associative memory (FOAM), support victor machine (SVM), and partial least squares discriminant analysis (PLS-DA) were used for diagnosis model establishment. The above results provide useful information for cancer occurring and development, and provide novel approaches for early stage diagnosis of various cancers. PMID:26669135

  4. A Combined Measure of Procedural Volume and Outcome to Assess Hospital Quality of Colorectal Cancer Surgery, a Secondary Analysis of Clinical Audit Data

    PubMed Central

    Kolfschoten, Nikki E.; Marang-van de Mheen, Perla J.; Wouters, Michel W. J. M.; Eddes, Eric-Hans; Tollenaar, Rob A. E. M.; Stijnen, Theo; Kievit, Job

    2014-01-01

    Objective To identify, on the basis of past performance, those hospitals that demonstrate good outcomes in sufficient numbers to make it likely that they will provide adequate quality of care in the future, using a combined measure of volume and outcome (CM-V&O). To compare this CM-V&O with measures using outcome-only (O-O) or volume-only (V-O), and verify 2010-quality of care assessment on 2011 data. Design Secondary analysis of clinical audit data. Setting The Dutch Surgical Colorectal Audit database of 2010 and 2011, the Netherlands. Participants 8911 patients (test population, treated in 2010) and 9212 patients (verification population, treated in 2011) who underwent a resection of primary colorectal cancer in 89 Dutch hospitals. Main Outcome Measures Outcome was measured by Observed/Expected (O/E) postoperative mortality and morbidity. CM-V&O states 2 criteria; 1) outcome is not significantly worse than average, and 2) outcome is significantly better than substandard, with ‘substandard care’ being defined as an unacceptably high O/E threshold for mortality and/or morbidity (which we set at 2 and 1.5 respectively). Results Average mortality and morbidity in 2010 were 4.1 and 24.3% respectively. 84 (94%) hospitals performed ‘not worse than average’ for mortality, but only 21 (24%) of those were able to prove they were also ‘better than substandard’ (O/E<2). For morbidity, 42 hospitals (47%) met the CM-V&O. Morbidity in 2011 was significantly lower in these hospitals (19.8 vs. 22.8% p<0.01). No relationship was found between hospitals' 2010 performance on O-O en V-O, and the quality of their care in 2011. Conclusion CM-V&O for morbidity can be used to identify hospitals that provide adequate quality and is associated with better outcomes in the subsequent year. PMID:24558418

  5. Checkpoint blockade in combination with cancer vaccines.

    PubMed

    Morse, Michael A; Lyerly, H Kim

    2015-12-16

    Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study. PMID:26482147

  6. Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria.

    PubMed

    Turner, Natalie; Wong, Hui-Li; Templeton, Arnoud; Tripathy, Sagarika; Whiti Rogers, Te; Croxford, Matthew; Jones, Ian; Sinnathamby, Mathuranthakan; Desai, Jayesh; Tie, Jeanne; Bae, Susie; Christie, Michael; Gibbs, Peter; Tran, Ben

    2016-02-01

    In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil-to-lymphocyte ratio (NLR) >5, as calculated from pre-operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non-significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence-free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high-risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5-year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer. PMID:26270488

  7. Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Li, Qin; Yan, Han; Zhao, Pengfei; Yang, Yifan; Cao, Bangwei

    2015-01-01

    Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68–0.84, P < 0.001; HR 0.75, 95% CI: 0.69–0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs. PMID:26503902

  8. Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

    PubMed

    Li, Qin; Yan, Han; Zhao, Pengfei; Yang, Yifan; Cao, Bangwei

    2015-01-01

    Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68-0.84, P < 0.001; HR 0.75, 95% CI: 0.69-0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs. PMID:26503902

  9. Treatment of liver cancer of middle and advanced stages using ultrasound-guided percutaneous ethanol injection combined with radiofrequency ablation: A clinical analysis

    PubMed Central

    SUN, XUE; LI, RU; ZHANG, BOTAO; YANG, YUEJIE; CUI, ZHIFEI

    2016-01-01

    Liver cancer is a malignancy of the digestive system and has a high morbidity and mortality rate. Local intervention has become a viable option in identifying liver treatment. The aim of the present study was to analyze the clinical effects of treating liver cancer in middle and advanced stages using ultrasound-guided percutaneous ethanol injection (PEI) in tumors combined with radiofrequency ablation (RFA). A total of 100 patients with stage III–IV liver cancers were selected to participate in the study. Patients were divided into groups. In group A, treatment was initiated with PEI and after 1–2 weeks RFA was applied while in group B treatment was initiated with RFA and after 1–2 weeks PEI was applied. Patients in group C received PEI and RFA simultaneously. The clinical effects in the 3 groups were compared after 6-month follow ups. The volume of tumor ablation necrosis in group A was significantly greater than that in the groups B and C, while the size was significantly smaller compared to groups B and C after ablation. For group A, the complete ablation rate was significantly higher than that in groups B and C, and the differences were statistically significant (P<0.05). Liver damage indices, including raising levels of glutamic-pyruvic transaminase and total bilirubin, were significantly decreased in group A (P<0.05). The survival rate in group A was also significantly higher than in groups B and C (P<0.05). In conclusion, for patients with liver cancer in middle and advanced stages, the treatment method using PEI followed by RFA was more beneficial in terms of improving the tumor ablation rate, alleviating liver damages and increasing survival rates. PMID:26998128

  10. Retrospective analysis of high intensity focused ultrasound combined with S-1 in the treatment of metastatic pancreatic cancer after failure of gemcitabine.

    PubMed

    Li, Xiaoping; Wang, Kun; Zheng, Leizhen; Meng, Zhiqiang

    2016-01-01

    The purpose of this study was to verify the efficacy and safety of high intensity focused ultrasound therapy (HIFU) combined with S-1 in the treatment of metastatic pancreatic cancer after failure of gemcitabine (GEM). In total, 120 patients with GEM-refractory PC who received HIFU and S-1 between Aug 2012 and December 2014 were randomly assigned to 2 groups. The patients in group A (n = 61) received HIFU in combination with S-1 and those in group B (n = 59) were given S-1 alone. S-1 was administered orally twice a day on days 1-14. Cycles were repeated every 21 days. The follow up time was 3~19 months in both groups. The median overall survival (OS) time and progression free survival (PFS) were analysed by Kaplan-Meier method and Logrank test. The pain remission rate of the two groups was compared by χ(2) test. Patient characteristics and prognostic factors were compared. Patient characteristics did not significantly differ between the 2 groups. Median OS was significantly longer in group A (10.3 months) than in group B (6.6 months, P = 0.000). Median PFS was also significantly longer in group A than in group B (5.1 months vs 2.3 months, P = 0.000). Meanwhile, the pain remission rate was markedly higher in group A than in group B (57% vs. 20%, P = 0.000). There were mild side effects and no significant difference was observed between the two groups. The treatment effect was independently associated with a good outcome. HIFU in combination with S-1 might be effective and well tolerated as salvage chemotherapy in the treatment for metastatic pancreatic cancer. PMID:27073725

  11. Retrospective analysis of high intensity focused ultrasound combined with S-1 in the treatment of metastatic pancreatic cancer after failure of gemcitabine

    PubMed Central

    Li, Xiaoping; Wang, Kun; Zheng, Leizhen; Meng, Zhiqiang

    2016-01-01

    The purpose of this study was to verify the efficacy and safety of high intensity focused ultrasound therapy (HIFU) combined with S-1 in the treatment of metastatic pancreatic cancer after failure of gemcitabine (GEM). In total, 120 patients with GEM-refractory PC who received HIFU and S-1 between Aug 2012 and December 2014 were randomly assigned to 2 groups. The patients in group A (n = 61) received HIFU in combination with S-1 and those in group B (n = 59) were given S-1 alone. S-1 was administered orally twice a day on days 1-14. Cycles were repeated every 21 days. The follow up time was 3~19 months in both groups. The median overall survival (OS) time and progression free survival (PFS) were analysed by Kaplan-Meier method and Logrank test. The pain remission rate of the two groups was compared by χ2 test. Patient characteristics and prognostic factors were compared. Patient characteristics did not significantly differ between the 2 groups. Median OS was significantly longer in group A (10.3 months) than in group B (6.6 months, P = 0.000). Median PFS was also significantly longer in group A than in group B (5.1 months vs 2.3 months, P = 0.000). Meanwhile, the pain remission rate was markedly higher in group A than in group B (57% vs. 20%, P = 0.000). There were mild side effects and no significant difference was observed between the two groups. The treatment effect was independently associated with a good outcome. HIFU in combination with S-1 might be effective and well tolerated as salvage chemotherapy in the treatment for metastatic pancreatic cancer. PMID:27073725

  12. Combinational strategies of metformin and chemotherapy in cancers.

    PubMed

    Zhang, Hui-Hui; Guo, Xiu-Li

    2016-07-01

    Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well-tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review. PMID:27118574

  13. The role of induction and adjuvant chemotherapy in combination with concurrent chemoradiotherapy for nasopharyngeal cancer: a Bayesian network meta-analysis of published randomized controlled trials

    PubMed Central

    Yu, Hongliang; Gu, Dayong; He, Xia; Gao, Xianshu; Bian, Xiuhua

    2016-01-01

    Whether the addition of induction chemotherapy (IC) or adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locally advanced nasopharyngeal cancer is unknown. A Bayesian network meta-analysis was performed to investigate the efficacy of CCRT, IC + CCRT, and CCRT + AC on locally advanced nasopharyngeal cancer. The overall survival (OS) with hazard ratios (HRs) and locoregional recurrence rates (LRRs) and distant metastasis rates (DMRs) with risk ratios (RRs) were investigated. After a comprehensive database search, eleven studies involving 2,626 assigned patients were included in this network meta-analysis. Compared with CCRT alone, IC + CCRT resulted in no significant improvement in OS or LRR and a marginal improvement in DMR (OS: HR =0.67, 95% credible interval (CrI) 0.32–1.18; LRR: RR =1.79, 95% CrI 0.80–3.51; DMR: RR =1.79, 95% CrI 0.24–1.04) and CCRT + AC exhibited no beneficial effects on any of the endpoints of OS, LRR, or DMR (OS: HR =0.99, 95% CrI 0.64–1.43; LRR: RR =0.78, 95% CrI 0.43–1.32; DMR: RR =0.85, 95% CrI 0.57–1.24). As a conclusion, for locally advanced nasopharyngeal cancer, no significant differences in the treatment efficacies of CCRT, IC + CCRT, and CCRT + AC were found, with the exception of a marginally significant improvement in distant control observed following IC + CCRT compared with CCRT alone. PMID:26793000

  14. Evolving synergistic combinations of targeted immunotherapies to combat cancer.

    PubMed

    Melero, Ignacio; Berman, David M; Aznar, M Angela; Korman, Alan J; Pérez Gracia, José Luis; Haanen, John

    2015-08-01

    Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients. PMID:26205340

  15. Combination oral contraceptives and cancer risk.

    PubMed

    Gast, K; Snyder, T

    1990-07-01

    Substantial evidence exists to suggest that the use of oral contraceptives alters the risk for some types of cancer. Use of oral contraceptives for one year or more will reduce the risk of endometrial cancer and epithelial ovarian cancer by 50%, with the protective effect lasting for at least 10 years. The risk for developing cervical cancer in women who have used oral contraceptives appears to be slightly increased, although two independent studies actually found a protective effect associated with oral contraceptive use. The protective effect was probably related to the increased screening frequency found in oral contraceptive users and not related to a biologically protective effect. Therefore, women should be encouraged to undergo regular Pap tests. Data regarding breast cancer, in general, show no increased risk associated with oral contraceptive use. The latency associated with the development of breast cancer does not allow a definitive conclusion, and further study will be required. Oral contraceptives appear to increase the risk for developing benign hepatocellular adenoma, but not hepatocellular carcinoma. PMID:2202849

  16. Survival benefit and safety of the combinations of FOLFOXIRI ± bevacizumab versus the combinations of FOLFIRI ± bevacizumab as first-line treatment for unresectable metastatic colorectal cancer: a meta-analysis

    PubMed Central

    Xu, Wei; Kuang, Meng; Gong, Yang; Cao, Chunxiang; Chen, Jinfei; Tang, Cuiju

    2016-01-01

    Background The survival of patients with metastatic colorectal cancer (mCRC) could be improved with exposure to three active drugs, irinotecan, fluorouracil/leucovorin, and oxaliplatin, irrespective of their sequence. However, only 50%–80% of patients can be exposed to all the three drugs in a sequential strategy with two-drug combinations. We carried out this systematic assessment to compare the survival benefit and safety of FOLFOXIRI (irinotecan, fluorouracil/leucovorin, and oxaliplatin) ± bevacizumab (with or without bevacizumab) versus FOLFIRI (irinotecan and fluorouracil/leucovorin) ± bevacizumab (with or without bevacizumab) as first-line treatment for unresectable mCRC. Methods PubMed and EMBASE were searched for original articles written in English and published before December 2015. A total of 1,035 patients from three randomized controlled trials were included. Results Our results demonstrated that overall survival (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.73–0.97), progression-free survival (HR, 0.69; 95% CI, 0.59–0.81), and overall response rate (odds ratio, 1.96; 95% CI, 1.28–2.98) were significantly improved in the FOLFOXIRI ± bevacizumab arm compared to the FOLFIRI ± bevacizumab arm. Significantly higher incidences of neutropenia, anemia, diarrhea, stomatitis, and neuropathy were observed in the FOLFOXIRI ± bevacizumab arm. Conclusion Current evidence shows that the combination of FOLFOXIRI ± bevacizumab significantly improves the overall survival, progression-free survival, and overall response rate of patients with mCRC, with an increased but manageable toxicity, compared with the combinations of FOLFIRI ± bevacizumab. The combination of FOLFOXIRI ± bevacizumab should be considered as a treatment option for these patients under the premise of reasonable selection of target population. PMID:27536147

  17. The microarray gene profiling analysis of glioblastoma cancer cells reveals genes affected by FAK inhibitor Y15 and combination of Y15 and temozolomide.

    PubMed

    Huang, Grace; Ho, Baotran; Conroy, Jeffrey; Liu, Song; Qiang, Hu; Golubovskaya, Vita

    2014-01-01

    Focal adhesion is known to be highly expressed and activated in glioma cells. Recently, we demonstrated that FAK autophosphorylation inhibitor, Y15 significantly decreased tumor growth of DBTRG and U87 cells, especially in combination with temozolomide. In the present report, we performed gene expression analysis in these cells to reveal genes affected by Y15, temozolomide and combination of Y15 and temozolomide. We tested the effect of Y15 on gene expression by Illumina Human HT12v4 microarray assay and detected 8087 and 6555 genes, which were significantly either up- or down-regulated by Y15-treatment in DBTRG and U87 cells, respectively (p<0.05). Moreover, DBTRG and U87 cells treated with Y15 changed expression of 1332 and 462 genes more than 1.5 fold, p<0.05, respectively and had 237 common genes affected by Y15. The common genes up-regulated by Y15 included GADD45A, HSPA6 (heat-shock 70); DUSP1, DUSP 5 (dual-phosphatase 5); CDKN1A (p21) and common down-regulated genes included kinesins, such as KIF11, 14, 20A, 20B; topoisomerase II, TOP2A; cyclin F; cell cycle protein: BUB1; PARP1, POLA1. In addition, we detected genes affected by temozolomide and by combination of Y15 and temozolomide treatment in U87 cells. Among genes up-regulated by Y15 and temozolomide more significantly than by each agent alone were: COX7B; interferon, gamma-inducible transcript: IFI16; DDIT4; GADD45G and down-regulated: KIF3A, AKT1; ABL; JAK1, GLI3 and ALDH1A3. Thus, microarray gene expression analysis can be effective in establishing genes affected in response to FAK inhibitor alone and in response to combination of Y15 with temozolomide that is important for glioblastoma therapy. PMID:23387973

  18. Nanoparticle Based Combination Treatments for Targeting Multiple Hallmarks of Cancer

    PubMed Central

    VanDyke, D; Kyriacopulos, P; Yassini, B; Wright, A; Burkhart, E; Jacek, S; Pratt, M; Peterson, CR; Rai, P

    2016-01-01

    Treatment of cancer remains one of the most challenging tasks facing the healthcare system. Cancer affects the lives of millions of people and is often fatal. Current treatment methods include surgery, chemotherapy, radiation therapies or some combinations of these. However, recurrence is a major problem. These treatments can be invasive with severe side effects. Inefficacies in treatments are a result of the complex and variable biology of cancerous cells. Malignant tumor cells and normal functioning cells share many of the same biological characteristics but the main difference is that in cancer cells there is in an overuse and over expression of these biological characteristics. These pertinent characteristics can be grouped into eight hallmarks, as illustrated by Hanahan and Weinberg. These characteristics include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. In order to provide a noninvasive, effective treatment, delivery methods must be explored in order to transport cytotoxic agents used for targeting the hallmarks of cancer in a safer and more effective fashion. The use of nanoparticles as drug delivery carriers provides an effective method in which multiple cytotoxic agents can be safely delivered to cancer tissue to simultaneously target multiple hallmarks. By targeting multiple hallmarks of cancer at once, the efficacy of cancer treatments could be improved drastically. This review explores the uses and efficacy of combination therapies using nanoparticles that can simultaneously target multiple hallmarks of cancer. PMID:27547592

  19. CHEMOTHERAPY: A new standard combination for recurrent ovarian cancer?

    PubMed Central

    Bast, Robert C.; Markman, Maurie

    2010-01-01

    Ovarian cancer that recurs more than 6 months following primary chemotherapy can respond to many different drugs, but retreatment with a combination of carboplatin and paclitaxel has become a standard of care. A combination of pegylated liposomal doxorubicin and carboplatin may provide a slightly but significantly greater therapeutic index than carboplatin and paclitaxel. PMID:20877420

  20. Drug combination may be highly effective in recurrent ovarian cancer

    Cancer.gov

    Significant improvement with the use of a combination drug therapy for recurrent ovarian cancer was reported at the annual meeting of the American Society of Clinical Oncology meeting in Chicago. The trial compared the activity of a combination of the dru

  1. Vitamin D in combination cancer treatment

    PubMed Central

    Ma, Yingyu; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    As a steroid hormone that regulates mineral homeostasis and bone metabolism, 1α, 25-dihydroxycholecalciferol (calcitriol) also has broad spectrum anti-tumor activities as supported by numerous epidemiological and experimental studies. Calcitriol potentiates the anti-tumor activities of multiple chemotherapeutics agents including DNA-damaging agents cisplatin, carboplatin and doxorubicin; antimetabolites 5-fluorouracil, cytarabine, hydroxyurea, cytarabine and gemcitabine; and microtubule-disturbing agents paclitaxel and docetaxel. Calcitriol elicits anti-tumor effects mainly through the induction of cancer cell apoptosis, cell cycle arrest, differentiation, angiogenesis and the inhibition of cell invasiveness by a number of mechanisms. Calcitriol enhances the cytotoxic effects of gamma irradiation and certain antioxidants and naturally derived compounds. Inhibition of calcitriol metabolism by 24-hydroxylase promotes growth inhibition effect of calcitriol. Calcitriol has been used in a number of clinical trials and it is important to note that sufficient dose and exposure to calcitriol is critical to achieve anti-tumor effect. Several trials have demonstrated that safe and feasible to administer high doses of calcitriol through intermittent regimen. Further well designed clinical trials should be conducted to better understand the role of calcitriol in cancer therapy. PMID:20842231

  2. Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Botrel, Tobias Engel Ayer; Clark, Otávio; Lima Pompeo, Antônio Carlos; Horta Bretas, Francisco Flávio; Sadi, Marcus Vinicius; Ferreira, Ubirajara; Borges dos Reis, Rodolfo

    2016-01-01

    Objective Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). Results The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group

  3. Two drugs are better than one. A short history of combined therapy of ovarian cancer

    PubMed Central

    Gajek, Arkadiusz; Marczak, Agnieszka

    2014-01-01

    Combined therapy of ovarian cancer has a long history. It has been applied for many years. The first drug which was commonly combined with other chemotherapeutics was cisplatin. It turned out to be effective given together with alkylating agents as well as with taxanes. Another drug which is often the basis of first-line therapy is doxorubicin. The use of traditional chemotherapy is often limited due to side effects. This is why new drugs, targeted specifically at cancer cells (e.g. monoclonal antibodies or epidermal growth factor receptor inhibitors), offer a welcome addition when used in combination with conventional anticancer agents. Drugs applied in combination should be synergistic or at least additive. To evaluate the type of interaction between drugs in a plausible sequence, isobolographic analysis is used. This method allows one to assess whether the two agents could make an efficient combination, which might improve the therapy of ovarian cancer. PMID:26793017

  4. Biochip analysis of prostate cancer.

    PubMed

    Fan, M Q; Wang, P X; Feng, J Y; Xiao, Y; Huang, C B

    2014-01-01

    Microarray expression analysis was used to forecast the roles of differentially co-expressed genes (DCG) and DCG and links in the pathogenesis of prostate cancer. In addition, we demonstrate that the relationship between transcriptional factors (TFs) and their targets can be considered a key factor in determining the difference between primary and metastatic prostate cancer. Regulatory impact factors were adopted to calculate the impact of TF. We identified 5 TFs and 29 target genes important in the transition between normal prostate and primary prostate cancer and 2 TFs and 7 target genes important in the transition between primary and metastatic prostate cancer. These results suggest that it may be possible to predict the clinical behavior of prostate cancer based on gene expression analysis. PMID:24446298

  5. Genetic variants in DNA repair pathways and risk of upper aerodigestive tract cancers: combined analysis of data from two genome-wide association studies in European populations.

    PubMed

    Babron, Marie-Claude; Kazma, Rémi; Gaborieau, Valérie; McKay, James; Brennan, Paul; Sarasin, Alain; Benhamou, Simone

    2014-07-01

    DNA repair pathways are good candidates for upper aerodigestive tract cancer susceptibility because of their critical role in maintaining genome integrity. We have selected 13 pathways involved in DNA repair representing 212 autosomal genes. To assess the role of these pathways and their associated genes, two European data sets from the International Head and Neck Cancer Epidemiology consortium were pooled, totaling 1954 cases and 3121 controls, with documented demographic, lifetime alcohol and tobacco consumption information. We applied an innovative approach that tests single nucleotide polymorphism (SNP)-sets within DNA repair pathways and then within genes belonging to the significant pathways. We showed an association between the polymerase pathway and oral cavity/pharynx cancers (P-corrected = 4.45 × 10(-) (2)), explained entirely by the association with one SNP, rs1494961 (P = 2.65 × 10(-) (4)), a missense mutation V306I in the second exon of HELQ gene. We also found an association between the cell cycle regulation pathway and esophagus cancer (P-corrected = 1.48 × 10(-) (2)), explained by three SNPs located within or near CSNK1E gene: rs1534891 (P = 1.27 × 10(-) (4)), rs7289981 (P = 3.37 × 10(-) (3)) and rs13054361 (P = 4.09 × 10(-) (3)). As a first attempt to investigate pathway-level associations, our results suggest a role of specific DNA repair genes/pathways in specific upper aerodigestive tract cancer sites. PMID:24658182

  6. Therapeutic cancer vaccines and combination immunotherapies involving vaccination

    PubMed Central

    Nguyen, Trang; Urban, Julie; Kalinski, Pawel

    2014-01-01

    Recent US Food and Drug Administration approvals of Provenge® (sipuleucel-T) as the first cell-based cancer therapeutic factor and ipilimumab (Yervoy®/anticytotoxic T-lymphocyte antigen-4) as the first “checkpoint blocker” highlight recent advances in cancer immunotherapy. Positive results of the clinical trials evaluating additional checkpoint blocking agents (blockade of programmed death [PD]-1, and its ligands, PD-1 ligand 1 and 2) and of several types of cancer vaccines suggest that cancer immunotherapy may soon enter the center stage of comprehensive cancer care, supplementing surgery, radiation, and chemotherapy. This review discusses the current status of the clinical evaluation of different classes of therapeutic cancer vaccines and possible avenues for future development, focusing on enhancing the magnitude and quality of cancer-specific immunity by either the functional reprogramming of patients’ endogenous dendritic cells or the use of ex vivo-manipulated dendritic cells as autologous cellular transplants. This review further discusses the available strategies aimed at promoting the entry of vaccination-induced T-cells into tumor tissues and prolonging their local antitumor activity. Finally, the recent improvements to the above three modalities for cancer immunotherapy (inducing tumor-specific T-cells, prolonging their persistence and functionality, and enhancing tumor homing of effector T-cells) and rationale for their combined application in order to achieve clinically effective anticancer responses are addressed. PMID:27471705

  7. Epigenetic therapy in gastrointestinal cancer: the right combination.

    PubMed

    Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita

    2016-07-01

    Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224

  8. Epigenetic therapy in gastrointestinal cancer: the right combination

    PubMed Central

    Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita

    2016-01-01

    Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224

  9. Combination Drug Delivery Approaches in Metastatic Breast Cancer

    PubMed Central

    Lee, Jun H.; Nan, Anjan

    2012-01-01

    Disseminated metastatic breast cancer needs aggressive treatment due to its reduced response to anticancer treatment and hence low survival and quality of life. Although in theory a combination drug therapy has advantages over single-agent therapy, no appreciable survival enhancement is generally reported whereas increased toxicity is frequently seen in combination treatment especially in chemotherapy. Currently used combination treatments in metastatic breast cancer will be discussed with their challenges leading to the introduction of novel combination anticancer drug delivery systems that aim to overcome these challenges. Widely studied drug delivery systems such as liposomes, dendrimers, polymeric nanoparticles, and water-soluble polymers can concurrently carry multiple anticancer drugs in one platform. These carriers can provide improved target specificity achieved by passive and/or active targeting mechanisms. PMID:22619725

  10. Combined Label-Free Quantitative Proteomics and microRNA Expression Analysis of Breast Cancer Unravel Molecular Differences with Clinical Implications.

    PubMed

    Gámez-Pozo, Angelo; Berges-Soria, Julia; Arevalillo, Jorge M; Nanni, Paolo; López-Vacas, Rocío; Navarro, Hilario; Grossmann, Jonas; Castaneda, Carlos A; Main, Paloma; Díaz-Almirón, Mariana; Espinosa, Enrique; Ciruelos, Eva; Fresno Vara, Juan Ángel

    2015-06-01

    Better knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor-positive (ER(+)) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER(+) and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention. PMID:25883093

  11. Partnership to Explore New Drug Combination for Pancreatic Cancer | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer Scientists at NCI and Frederick National Laboratory for Cancer Research (FNLCR) are partnering with the Lustgarten Foundation to test whether a vitamin D derivative will make a difference when combined with a conventional anticancer drug in treating tumors of the pancreas.

  12. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    SciTech Connect

    Wairagu, Peninah M.; Park, Kwang Hwa; Kim, Jihye; Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il; Jung, Soon-Hee; Yong, Suk-Joong; Jeong, Yangsik

    2014-05-09

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

  13. Clinically Meaningful Differences in Patient-Reported Outcomes With Amifostine in Combination With Chemoradiation for Locally Advanced Non-Small-Cell Lung Cancer: An Analysis of RTOG 9801

    SciTech Connect

    Sarna, Linda Swann, Suzanne; Langer, Corey; Werner-Wasik, Maria; Nicolaou, Nicos; Komaki, Ritsuko; Machtay, Mitchell; Byhardt, Roger; Wasserman, Todd; Movsas, Benjamin

    2008-12-01

    Purpose: The purpose of this study is to analyze changes in quality of life (QOL) and symptoms from pretreatment to 6 weeks posttreatment in a Phase III randomized study (Radiation Therapy Oncology Group 9801) of amifostine (AM) vs. no AM in patients with Stages II-III non-small-cell lung cancer receiving paclitaxel and carboplatin as induction and then concurrently with hyperfractionated radiation therapy (RT). Methods and Materials: One hundred thirty-eight patients with baseline and 6-week posttreatment QOL data were analyzed. There were no significant differences in baseline demographics between those who did and did not have QOL data. The QOL and symptoms were assessed by using the European Organization for Research and Treatment of Cancer (EORTC) Global QOL and Pain subscales and the EORTC-Lung Cancer-13 symptom tool. Clinically relevant changes in QOL were characterized by 10-point differences in individual scores pre/post treatment. A daily diary of patient-rated difficulty swallowing and a weekly physician-rated dysphagia log (using National Cancer Institute Common Toxicity Criteria) were completed during treatment. Weight loss was monitored. Differences in outcomes were examined according to smoking status, alcohol use, and sex. Results: Patients receiving AM reported significantly greater pain reduction after chemoradiation (34% vs. no AM, 21%), less difficulty swallowing during chemoradiation, and less weight loss than patients not receiving AM. However, physician-rated assessments of dysphagia were not significantly different by treatment arm. There were no other significant changes in QOL or symptoms according to treatment arm, smoking status, alcohol use, or sex. Conclusions: Patient evaluations of difficulty swallowing and pain suggest benefits from AM use that are distinct from clinician-rated assessments.

  14. Meta-analysis in cancer genetics.

    PubMed

    Pabalan, Noel A

    2010-01-01

    Genetic association studies report potentially conflicting findings which meta-analysis seeks to quantify and objectively summarize. Attributing cancer to a single gene variant requires large sample sizes, which may strain resources in a primary study. Properly used, meta-analysis is a powerful tool for resolving discrepancies in genetic association studies given the exponential increase in sample sizes when data are combined. The several steps involved in this methodology require careful attention to critical issues in meta-analysis, heterogeneity and publication bias, evaluation of which can be graphical or statistical. Overall summary effects of a meta-analysis may or may not reflect similar associations when the component studies are sub grouped. Overall associations and that of the subgroups are evaluated for tenability using sensitivity analysis. The low association between a polymorphism and cancer is offset by detectable changes in cancer incidence in the general population making them an important issue from a public health point of view. Asian meta-analytic publications in cancer genetics come from six countries with an output that number from one to two. The exception is China, whose publication output has increased exponentially since 2008. PMID:20593927

  15. Mass segmentation using a combined method for cancer detection

    PubMed Central

    2011-01-01

    Background Breast cancer is one of the leading causes of cancer death for women all over the world and mammography is thought of as one of the main tools for early detection of breast cancer. In order to detect the breast cancer, computer aided technology has been introduced. In computer aided cancer detection, the detection and segmentation of mass are very important. The shape of mass can be used as one of the factors to determine whether the mass is malignant or benign. However, many of the current methods are semi-automatic. In this paper, we investigate fully automatic segmentation method. Results In this paper, a new mass segmentation algorithm is proposed. In the proposed algorithm, a fully automatic marker-controlled watershed transform is proposed to segment the mass region roughly, and then a level set is used to refine the segmentation. For over-segmentation caused by watershed, we also investigated different noise reduction technologies. Images from DDSM were used in the experiments and the results show that the new algorithm can improve the accuracy of mass segmentation. Conclusions The new algorithm combines the advantages of both methods. The combination of the watershed based segmentation and level set method can improve the efficiency of the segmentation. Besides, the introduction of noise reduction technologies can reduce over-segmentation. PMID:22784625

  16. RAD51 135G→C Modifies Breast Cancer Risk among BRCA2 Mutation Carriers: Results from a Combined Analysis of 19 Studies

    PubMed Central

    Antoniou, Antonis C. ; Sinilnikova, Olga M. ; Simard, Jacques ; Léoné, Mélanie ; Dumont, Martine ; Neuhausen, Susan L. ; Struewing, Jeffery P. ; Stoppa-Lyonnet, Dominique ; Barjhoux, Laure ; Hughes, David J. ; Coupier, Isabelle ; Belotti, Muriel ; Lasset, Christine ; Bonadona, Valérie ; Bignon, Yves-Jean ; Rebbeck, Timothy R. ; Wagner, Theresa ; Lynch, Henry T. ; Domchek, Susan M. ; Nathanson, Katherine L. ; Garber, Judy E. ; Weitzel, Jeffrey ; Narod, Steven A. ; Tomlinson, Gail ; Olopade, Olufunmilayo I. ; Godwin, Andrew ; Isaacs, Claudine ; Jakubowska, Anna ; Lubinski, Jan ; Gronwald, Jacek ; Górski, Bohdan ; Byrski, Tomasz ; Huzarski, Tomasz ; Peock, Susan ; Cook, Margaret ; Baynes, Caroline ; Murray, Alexandra ; Rogers, Mark ; Daly, Peter A. ; Dorkins, Huw ; Schmutzler, Rita K. ; Versmold, Beatrix ; Engel, Christoph ; Meindl, Alfons ; Arnold, Norbert ; Niederacher, Dieter ; Deissler, Helmut ; Spurdle, Amanda B. ; Chen, Xiaoqing ; Waddell, Nicola ; Cloonan, Nicole ; Kirchhoff, Tomas ; Offit, Kenneth ; Friedman, Eitan ; Kaufmann, Bella ; Laitman, Yael ; Galore, Gilli ; Rennert, Gad ; Lejbkowicz, Flavio ; Raskin, Leon ; Andrulis, Irene L. ; Ilyushik, Eduard ; Ozcelik, Hilmi ; Devilee, Peter ; Vreeswijk, Maaike P. G. ; Greene, Mark H. ; Prindiville, Sheila A. ; Osorio, Ana ; Benítez, Javier ; Zikan, Michal ; Szabo, Csilla I. ; Kilpivaara, Outi ; Nevanlinna, Heli ; Hamann, Ute ; Durocher, Francine ; Arason, Adalgeir ; Couch, Fergus J. ; Easton, Douglas F. ; Chenevix-Trench, Georgia 

    2007-01-01

    RAD51 is an important component of double-stranded DNA–repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5′ untranslated region (UTR) of RAD51, 135G→C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G→C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25–2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83–1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91–1.51) among heterozygotes and 3.18 (95% CI 1.39–7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G→C variant affects RAD51 splicing within the 5′ UTR. Thus, 135G→C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers. PMID:17999359

  17. Precision medicine and personalized breast cancer: combination pertuzumab therapy

    PubMed Central

    Reynolds, Kerry; Sarangi, Sasmit; Bardia, Aditya; Dizon, Don S

    2014-01-01

    Trastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer. PMID:24715764

  18. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

    PubMed Central

    Simpson, Guy R; Relph, Kate; Harrington, Kevin; Melcher, Alan; Pandha, Hardev

    2016-01-01

    Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.

  19. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances.

    PubMed

    Simpson, Guy R; Relph, Kate; Harrington, Kevin; Melcher, Alan; Pandha, Hardev

    2016-01-01

    Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena. PMID:27579292

  20. Convergence analysis of combinations of different methods

    SciTech Connect

    Kang, Y.

    1994-12-31

    This paper provides a convergence analysis for combinations of different numerical methods for solving systems of differential equations. The author proves that combinations of two convergent linear multistep methods or Runge-Kutta methods produce a new convergent method of which the order is equal to the smaller order of the two original methods.

  1. Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

    PubMed Central

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-01-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy. PMID:25656384

  2. Combination cancer immunotherapies tailored to the tumour microenvironment.

    PubMed

    Smyth, Mark J; Ngiow, Shin Foong; Ribas, Antoni; Teng, Michele W L

    2016-03-01

    Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments. PMID:26598942

  3. The Effect of ShenQi FuZheng Injection in Combination with Chemotherapy versus Chemotherapy Alone on the Improvement of Efficacy and Immune Function in Patients with Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

    PubMed Central

    dedong, Cao; huilin, Xu; Anbing, He; Ximing, Xu; wei, Ge

    2016-01-01

    Objective To evaluate the effect of ShenQi FuZheng Injection (SFI) on cellular immunity and clinical efficacy in patients with advanced non small cell lung cancer(NSCLC) when combined with chemotherapy. Methods Electronic databases including EMBASE, PUBMED, the conference proceedings of the American Society of Clinical Oncology (ASCO), Cochrane, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biological Medical disc(CBM) were searched, until July, 2015. The randomized controlled clinical studies reporting results of efficacy and immune function were collected according to the inclusion criteria. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and Revman 5 software was used for data analysis. Results Fifteen studies including 1006 cases of advanced NSCLC were included based on the inclusion criteria. The results of meta-analysis showed that there were significant differences in percentages of CD3+ cells (SMD = 13.48; 95%CI: 8.11–18.85; p<0.01), CD4+ cells (SMD = 10.78; 95%CI, 6.38–15.18; p<0.01), NK [WMD = 8.59, 95% CI(3.97, 13.21), p = 0.003], and ratio of CD4+/ CD8+ (SMD = 0.32; 95%: 0.28–0.36; p<0.01) between SFI combination group and control group, whereas the difference was not significant in CD8+ (SMD = -1.44; 95%CI, -4.53–1.65; p = 0.36). Funnel plot, Begg's rank correlation test and Egger's linear regression analysis indicated that there was significant publication bias across studies. Conclusion SFI is effective to improve the efficacy of chemotherpay and function of cellular immunity in NSCLC patients, however, high quality RCTs are needed to further confirm the findings. PMID:27015629

  4. Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.

    PubMed

    Schwartz, Harvey; Scroggins, Brad; Zuehlke, Abbey; Kijima, Toshiki; Beebe, Kristin; Mishra, Alok; Neckers, Len; Prince, Thomas

    2015-09-01

    The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas. PMID:26070366

  5. Combination of Intravesical Chemotherapy and Bacillus Calmette-Guerin Versus Bacillus Calmette-Guerin Monotherapy in Intermediate- and High-risk Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-analysis.

    PubMed

    Cui, Jianfeng; Wang, Wenbo; Chen, Shouzhen; Chen, Pengxiang; Yang, Yue; Guo, Yunliang; Zhu, Yaofeng; Chen, Fan; Shi, Benkang

    2016-01-01

    Urothelial carcinoma of the bladder has become a major cause of morbidity, mortality, and health-related costs. There is still no standard instillation therapy against bladder cancer. A meta-analysis was conducted to evaluate the efficacy and toxicity of adding chemotherapy to Bacillus Calmette-Guerin (BCG) in intermediate- and high-risk nonmuscle invasive bladder cancer (NMIBC).All randomized controlled trials (RCTs) that evaluated the efficacy of combination therapy and BCG monotherapy for intermediate- and high-risk NMIBC were comprehensively searched. Relevant databases, including PubMed, Embase, Cochrane Central Register of Controlled trials databases, and American Society of Clinical Oncology (http://www.asco.org/ASCO), the clinical trial registration website (ClinicalTrials.gov), and relevant trials from the references of selected studies were searched from initial state up to June 6, 2015. Random-effects model was used to estimate hazard ratios (HRs) statistics. All statistical analyses were performed by STATA (version 13.0, College Station, TX).Seven studies, including 1373 patients with intermediate- and high-risk NMIBC, were identified. For disease-free survival, the pooled HRs from all studies was 0.69 (95% confidence interval [CI], 0.48-1.00; P = 0.048). The disease-free survival benefit was more apparent among patients with intermediate-risk NMIBC (P = 0.002) or Ta/T1 with/without carcinoma in situ (P < 0.01). In subgroup analysis, a significant reduction in recurrence was found in studies that explored the influence of a perioperative single dose instillation compared with delayed BCG monotherapy (HR = 0.60; 95% CI, 0.38-0.92; P = 0.021). No significant difference was found for progression-free survival (HR = 0.78; 95% CI, 0.43-1.44; P = 0.435).Patients with intermediate- and high-risk NMIBC who underwent combination therapy achieved lower rates of recurrence than those who underwent BCG therapy alone. No difference in

  6. Methods for Cancer Epigenome Analysis

    PubMed Central

    Nagarajan, Raman P.; Fouse, Shaun D.; Bell, Robert J.A.; Costello, Joseph F.

    2014-01-01

    Accurate detection of epimutations in tumor cells is crucial for understanding the molecular pathogenesis of cancer. Alterations in DNA methylation in cancer are functionally important and clinically relevant, but even this well-studied area is continually re-evaluated in light of unanticipated results, including a strong connection between aberrant DNA methylation in adult tumors and polycomb group profiles in embryonic stem cells, cancer-associated genetic mutations in epigenetic regulators such as DNMT3A and TET family genes, and the discovery of abundant 5-hydroxymethylcytosine, a product of TET proteins acting on 5-methylcytosine, in human tissues. The abundance and distribution of covalent histone modifications in primary cancer tissues relative to normal cells is a largely uncharted area, although there is good evidence for a mechanistic role of cancer-specific alterations in epigenetic marks in tumor etiology, drug response and tumor progression. Meanwhile, the discovery of new epigenetic marks continues, and there are many useful methods for epigenome analysis applicable to primary tumor samples, in addition to cancer cell lines. For DNA methylation and hydroxymethylation, next-generation sequencing allows increasingly inexpensive and quantitative whole-genome profiling. Similarly, the refinement and maturation of chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) has made possible genome-wide mapping of histone modifications, open chromatin and transcription factor binding sites. Computational tools have been developed apace with these epigenome methods to better enable the accuracy and interpretation of the data from the profiling methods. PMID:22956508

  7. CPAP: Cancer Panel Analysis Pipeline.

    PubMed

    Huang, Po-Jung; Yeh, Yuan-Ming; Gan, Ruei-Chi; Lee, Chi-Ching; Chen, Ting-Wen; Lee, Cheng-Yang; Liu, Hsuan; Chen, Shu-Jen; Tang, Petrus

    2013-10-01

    Targeted sequencing using next-generation sequencing technologies is currently being rapidly adopted for clinical sequencing and cancer marker tests. However, no existing bioinformatics tool is available for the analysis and visualization of multiple targeted sequencing datasets. In the present study, we use cancer panel targeted sequencing datasets generated by the Life Technologies Ion Personal Genome Machine Sequencer as an example to illustrate how to develop an automated pipeline for the comparative analyses of multiple datasets. Cancer Panel Analysis Pipeline (CPAP) uses standard output files from variant calling software to generate a distribution map of SNPs among all of the samples in a circular diagram generated by Circos. The diagram is hyperlinked to a dynamic HTML table that allows the users to identify target SNPs by using different filters. CPAP also integrates additional information about the identified SNPs by linking to an integrated SQL database compiled from SNP-related databases, including dbSNP, 1000 Genomes Project, COSMIC, and dbNSFP. CPAP only takes 17 min to complete a comparative analysis of 500 datasets. CPAP not only provides an automated platform for the analysis of multiple cancer panel datasets but can also serve as a model for any customized targeted sequencing project. PMID:23893859

  8. Response of Breast Cancer Cells and Cancer Stem Cells to Metformin and Hyperthermia Alone or Combined

    PubMed Central

    Lee, Hyemi; Park, Heon Joo; Park, Chang-Shin; Oh, Eun-Taex; Choi, Bo-Hwa; Williams, Brent; Lee, Chung K.; Song, Chang W.

    2014-01-01

    Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5–10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44high/CD24low cells of MCF-7 cells and, CD44high/CD24high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia. PMID:24505341

  9. Sequences and Combinations of Multifaceted Therapy In Advanced Prostate Cancer

    PubMed Central

    Vaishampayan, Ulka

    2015-01-01

    Purpose of Review Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for use in advanced prostate cancer. The next wave of investigations is focused on development of combinations and optimal sequences of the currently available agents. The focus of this review paper is to provide an update on clinical developments in advanced prostate cancer occurring within the past year, and to highlight the ongoing investigations of promising novel targets and compounds. Recent Findings The clinical use of enzalutamide prior to chemotherapy, demonstrated improvement in progression free survival (PFS) and overall survival (OS) as compared to placebo in metastatic castrate resistant prostate cancer (CRPC). This report of the PREVAIL trial led to the FDA approval of this agent. Novel agents such as cabozantinib and custirsen that had shown promising results in phase II trials, revealed disappointing results in the phase III setting. The breakthrough report, of the ability of the ARV-7 mutation, detected in circulating tumor cells, to predict lack of response to abiraterone or enzalutamide, and the remarkable responses of poly ADP ribose polymerase (PARP) inhibitors in prostate cancer with BRCA1/2 mutations, have elevated hopes of a bright future in the biomarker driven therapeutic arena. Summary As the clinical application of the recently approved multifaceted therapies widens, trials addressing optimal sequences and combinations are gaining importance. In addition, exploring the utility of therapies in the hormone naïve or non-metastatic settings is an area of active investigation. Early use of available agents, optimal sequencing and aid of biomarkers to guide therapeutic choices will make the achievement of lifetime remissions in advanced prostate cancer a reachable goal. PMID:25811344

  10. Combination treatment of tamoxifen with risperidone in breast cancer.

    PubMed

    Yeh, Wei-Lan; Lin, Hui-Yi; Wu, Hung-Ming; Chen, Dar-Ren

    2014-01-01

    Tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. Tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. Risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients, providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer. PMID:24886861

  11. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin

    PubMed Central

    Kai, Masaya; Kanaya, Noriko; Wu, Shang V.; Mendez, Carlos; Nguyen, Duc; Luu, Thehang

    2015-01-01

    The aim of this study is to investigate the efficacy of combining a histone deacetylase inhibitor (LBH589) and a breast cancer stem cells (BCSC)-targeting agent (salinomycin) as a novel combination therapy for triple-negative breast cancer (TNBC). We performed in vitro studies using the TNBC cell lines to examine the combined effect. We used the mammosphere and ALDE-FLUOR assays to estimate BCSC self-renewal capacity and distribution of BCSCs, respectively. Synergistic analysis was performed using CalcuSyn software. For in vivo studies, aldehyde dehydrogenase 1 ALDH1-positive cells were injected into non-obese diabetic/severe combined immunodeficiency gamma (NSG) mice. After tumor formation, mice were treated with LBH589, salinomycin, or in combination. In a second mouse model, HCC1937 cells were first treated with each treatment and then injected into NSG mice. For mechanistic analysis, immunohistochemistry and Western blot analysis were performed using cell and tumor samples. HCC1937 cells displayed BCSC properties including self-renewal capacity, an ALDH1-positive cell population, and the ability to form tumors. Treatment of HCC1937 cells with LBH589 and salinomycin had a potent synergistic effect inhibiting TNBC cell proliferation, ALDH1-positive cells, and mammosphere growth. In xenograft mouse models treated with LBH589 and salinomycin, the drug combination effectively and synergistically inhibited tumor growth of ALDH1-positive cells. The drug combination exerted its effects by inducing apoptosis, arresting the cell cycle, and regulating epithelial–mesenchymal transition (EMT). Combination of LBH589 and salinomycin has a synergistic inhibitory effect on TNBC BCSCs by inducing apoptosis, arresting the cell cycle, and regulating EMT; with no apparent associated severe toxicity. This drug combination could therefore offer a new targeted therapeutic strategy for TNBC and warrants further clinical study in patients with TNBC. PMID:25904215

  12. Multifunctional nanoparticle systems for combined chemoand photothermal cancer therapy

    NASA Astrophysics Data System (ADS)

    Wang, Hai; Zhao, Yu-Liang; Nie, Guang-Jun

    2013-06-01

    Hyperthermia has long been considered as an adjuvant therapy for treating various diseases. Cancer treatment exploiting hyperthermia shows great clinical potential for a wide range of tumors. Importantly, the efficacy of hyperthermal therapy has recently been enhanced by the development of functional nanomaterials. The unique physicochemical properties of nanomaterials afford the specific localization of hyperthermia to primary tumors and early-stage cancers. In particular, due to their high rate of light-to-heat conversion and their capacity to be activated by tissue-penetrating electromagnetic radiation, near-infrared (NIR) light-absorbing plasmonic nanomaterials have attracted considerable attention as candidates for noninvasive photothermal therapy. The purpose of this article is to provide a overview on the current development in multifunctional nanomaterials capable of combined hyperthermia-chemotherapy delivery.

  13. Robust Automatic Breast Cancer Staging Using A Combination of Functional Genomics and Image-Omics

    PubMed Central

    Su, Hai; Shen, Yong; Xing, Fuyong; Qi, Xin; Hirshfield, Kim M.; Yang, Lin; Foran, David J.

    2016-01-01

    Breast cancer is one of the leading cancers worldwide. Precision medicine is a new trend that systematically examines molecular and functional genomic information within each patient's cancer to identify the patterns that may affect treatment decisions and potential outcomes. As a part of precision medicine, computer-aided diagnosis enables joint analysis of functional genomic information and image from pathological images. In this paper we propose an integrated framework for breast cancer staging using image-omics and functional genomic information. The entire biomedical imaging informatics framework consists of image-omics extraction, feature combination, and classification. First, a robust automatic nuclei detection and segmentation is presented to identify tumor regions, delineate nuclei boundaries and calculate a set of image-based morphological features; next, the low dimensional image-omics is obtained through principal component analysis and is concatenated with the functional genomic features identified by a linear model. A support vector machine for differentiating stage I breast cancer from other stages are learned. We experimentally demonstrate that compared with a single type of representation (image-omics), the combination of image-omics and functional genomic feature can improve the classification accuracy by 3%. PMID:26737959

  14. In silico identification of breast cancer genes by combined multiple high throughput analyses.

    PubMed

    Shen, Dejun; He, Jianbo; Chang, Helena R

    2005-02-01

    that the combined multiple high throughput analyses is an effective data mining strategy in cancer gene identification. This approach may improve the usage of public available genomic data through strategic data mining of high throughput analysis. PMID:15647832

  15. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy.

    PubMed

    Khalil, Danny N; Smith, Eric L; Brentjens, Renier J; Wolchok, Jedd D

    2016-05-01

    In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended. PMID:26977780

  16. Polymeric-gold nanohybrids for combined imaging and cancer therapy.

    PubMed

    Topete, Antonio; Alatorre-Meda, Manuel; Villar-Alvarez, Eva M; Carregal-Romero, Susana; Barbosa, Silvia; Parak, Wolfgang J; Taboada, Pablo; Mosquera, Víctor

    2014-08-01

    Here, the use of folic acid (FA)-functionalized, doxorubicin (DOXO)/superparamagnetic iron oxide nanoparticles (SPION)-loaded poly(lactic-co-glycolic acid) (PLGA)-Au porous shell nanoparticles (NPs) as potential nanoplatforms is reported for targeted multimodal chemo- and photothermal therapy combined with optical and magnetic resonance imaging in cancer. These polymeric-gold nanohybrids (PGNH) are produced by a seeded-growth method using chitosan as an electrostatic "glue" to attach Au seeds to DOXO/SPION-PLGA NPs. In order to determine their potential as theranostic nanoplatforms, their physicochemical properties, cellular uptake, and photothermal and chemotherapeutic efficiencies are tested in vitro using a human cervical cancer (HeLa) cell line. The present NPs show a near-infrared (NIR)-light-triggered release of cargo molecules under illumination and a great capacity to induce localized cell death in a well-focused region. The functionalization of the PGNH NPs with the targeting ligand FA improves their internalization efficiency and specificity. Furthermore, the possibility to guide the PGNH NPs to cancer cells by an external magnetic field is also proven in vitro, which additionally increases the cellular uptake and therapeutic efficiency. PMID:24764284

  17. Sex Differences in Outcome with Bevacizumab Therapy: Analysis of Patients with Advanced-Stage Non-Small-Cell Lung Cancer Treated with or without Bevacizumab in Combination with Paclitaxel and Carboplatin in the Eastern Cooperative Oncology Group Trial 4599

    PubMed Central

    Brahmer, Julie R.; Dahlberg, Suzanne E.; Gray, Robert J.; Schiller, Joan H.; Perry, Michael C.; Sandler, Alan; Johnson, David H.

    2010-01-01

    Introduction E4599 compared carboplatin and paclitaxel with (PCB) or without (PC) bevacizumab in patients with advanced stage non-small cell lung cancer. Bevacizumab improved overall survival. However, an unplanned subset analysis did not show a survival benefit for females treated with bevacizumab. Methods Known prognostic factors and toxicities were compared by sex. Proportional hazards models of survival with multiple factor combinations were used to adjust for treatment effect. Results The analysis includes 850 patients. The median survival for males was 8.7 months (PC) versus 11.7 months (PCB) (P=0.001) and 13.1 months (PC) versus 13.3 months (PCB) for females (P=0.87). Progression free survival and response rate was 6.3 months and 29% on the PCB arm for males, and 6.2 months and 41% for females, (p>0.05). Progression free survival and response rate was 4.3 months and 16% on the PC arm for males, and 5.3 months and 14% for females, (p>0.05). No significant demographic differences were seen between the two arms for males (M), whereas fewer females (F) on the PCB arm had liver metastasis (PCB 11.7% vs. PC 23.2%, p=0.003). Adverse events with a sex difference on the PCB arm included severe hypertension (M 4.2%, F 9.9%, p=0.02), constipation (M 1.4%, F 4.7%, p=0.05), and abdominal pain (M 0.9%, F 5.2%, p=0.01). In the proportional hazards model adjusting for the other factors, the test for a sex by treatment interaction was not significant (p=0.09). Conclusions Multiple factors may contribute to the apparent sex-specific differences in efficacy of bevacizumab noted in this study. PMID:21079521

  18. Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case-control studies using bi-dimensional spline models.

    PubMed

    Dal Maso, Luigino; Torelli, Nicola; Biancotto, Elisa; Di Maso, Matteo; Gini, Andrea; Franchin, Gianni; Levi, Fabio; La Vecchia, Carlo; Serraino, Diego; Polesel, Jerry

    2016-04-01

    The synergistic effect of tobacco smoking and alcohol consumption on the risk of head and neck cancers has been mainly investigated as a cross-product of categorical exposure, thus leading to loss of information. We propose a bi-dimensional logistic spline model to investigate the interacting dose-response relationship of two continuous exposures (i.e., ethanol intake and tobacco smoking) on the risk of head and neck cancers, representing results through three-dimensional graphs. This model was applied to a pool of hospital-based case-control studies on head and neck cancers conducted in Italy and in the Vaud Swiss Canton between 1982 and 2000, including 1569 cases and 3147 controls. Among never drinkers and for all levels of ethanol intake, the risk of head and neck cancers steeply increased with increasing smoking intensity, starting from 1 cigarette/day. The risk associated to ethanol intake increased with incrementing exposure among smokers, and a threshold effect at approximately 50 g/day emerged among never smokers. Compared to abstainers from both tobacco and alcohol consumption, the combined exposure to ethanol and/or cigarettes led to a steep increase of cancer risk up to a 35-fold higher risk (95 % confidence interval 27.30-43.61) among people consuming 84 g/day of ethanol and 10 cigarettes/day. The highest risk was observed at the highest levels of alcohol and tobacco consumption. Our findings confirmed a combined effect of tobacco smoking and alcohol drinking on head and neck cancers risk, providing evidence that bi-dimensional spline models could be a feasible and flexible method to explore the pattern of risks associated to two interacting continuous-exposure variables. PMID:25855002

  19. Arctigenin in combination with quercetin synergistically enhances the anti-proliferative effect in prostate cancer cells

    PubMed Central

    Wang, Piwen; Phan, Tien; Gordon, David; Chung, Seyung; Henning, Susanne M.; Vadgama, Jaydutt V.

    2014-01-01

    Scope We investigated whether a combination of two promising chemopreventive agents arctigenin and quercetin increases the anti-carcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Methods and results Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of arctigenin and quercetin alone or in combination for 48h. The anti-proliferative activity of arctigenin was 10-20 fold stronger than quercetin in both cell lines. Their combination synergistically enhanced the anti-proliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arctigenin demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. Conclusion The combination of arctigenin and quercetin, that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer. PMID:25380086

  20. Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia

    PubMed Central

    Setiawan, Veronica Wendy; Schumacher, Fredrick; Prescott, Jennifer; Haessler, Jeffrey; Malinowski, Jennifer; Wentzensen, Nicolas; Yang, Hannah; Chanock, Stephen; Brinton, Louise; Hartge, Patricia; Lissowska, Jolanta; Park, S.Lani; Cheng, Iona; Bush, William S.; Crawford, Dana C.; Ursin, Giske; Horn-Ross, Pamela; Bernstein, Leslie; Lu, Lingeng; Risch, Harvey; Yu, Herbert; Sakoda, Lori C.; Doherty, Jennifer; Chen, Chu; Jackson, Rebecca; Yasmeen, Shagufta; Cote, Michele; Kocarnik, Jonathan M.; Peters, Ulrike; Kraft, Peter; De Vivo, Immaculata; Haiman, Christopher A.; Kooperberg, Charles; Le Marchand, Loic

    2014-01-01

    Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry were combined using fixed-effect meta-analysis to evaluate the association between each SNP and endometrial cancer risk. A Bonferroni-corrected P value of 2.35×10−4 was used to determine statistical significance of the associations. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer [meta-analysis odds ratio = 0.87 (per copy of the C allele), 95% confidence interval = 0.81, 0.93; P = 7.37×10−5] with no evidence of heterogeneity across studies (P heterogeneity = 0.66). This pleiotropic analysis is the first to suggest TET2 as a susceptibility locus for endometrial cancer. PMID:24832084

  1. [Current Progress and Feasibility of Using Molecular-Targeted Agent Combinations for Metastatic Colorectal Cancer].

    PubMed

    Masuishi, Toshiki; Muro, Kei

    2016-04-01

    The efficacy of molecular-targeted agent combinations for the treatment of metastatic colorectal cancer has become increasingly evident over recent years, although none of these combinations have been recognized yet as a standard therapy. The intention here is to provide a synopsis of current progress in this developing area by reviewing existing publications and ongoing clinical trials. While bevacizumab plus anti-EGFR agents exhibit detrimental effects in first-line setting , a combination of bevacizumab with erlotinib has been suggested as an effective maintenance therapy. Dabrafenib plus panitumumab in combination with trametinib and encorafenib plus cetuximab in combination with alpelisib, are very promising combination treatments and are currently being developed in clinical trials for patients with BRAF mutant-type tumors. An earlier nonclinical trial suggested that a combination of panitumumab plus trametinib was effective in patients who were resistant to anti- EGFR agents but developing KRAS- or NRAS-mutated tumors. The HERACLES trial further indicated that a combination of trastuzumab and lapatinib showed promising antitumor effects in patients with emerging HER2 amplification. Other reports suggest that irinotecan and cetuximab in combination with tivantinib were more effective than a combination of irinotecan and cetuximab alone for patients with MET amplification, although further research is needed for this application, as results were based upon the analysis of subgroups. It is clear that data arising from both primary research and clinical trials support the combined use of molecular-targeted drugs in the treatment of metastatic colorectal cancer. As clinical trials progress, it is likely that such treatment combinations will become recognized as standard therapies. PMID:27220786

  2. Astragalus-containing Traditional Chinese Medicine, with and without prescription based on syndrome differentiation, combined with chemotherapy for advanced non-small-cell lung cancer: a systemic review and meta-analysis

    PubMed Central

    Wang, S.F.; Wang, Q.; Jiao, L.J.; Huang, Y.L.; Garfield, D.; Zhang, J.; Xu, L.

    2016-01-01

    Objective Traditional Chinese Medicine (tcm) is used in China as part of the treatment for non-small-cell lung cancer (nsclc) and often includes prescription of herbal therapy based on syndrome differentiation. Studies of various Astragalus-based Chinese medicines combined with platinum-based chemotherapy in the treatment of lung cancer are popular in East Asia, particularly in China. The aim of the present study was to perform a systematic review and meta-analysis comparing platinum-based chemotherapy alone with platinum-based chemotherapy plus Astragalus-based Chinese botanicals, with and without prescription based on syndrome differentiation, as first-line treatment for advanced nsclc. Methods We searched the Chinese Biomedical Literature database, the China National Knowledge Internet, the VIP Chinese Science and Technology Periodicals Database, PubMed, embase, the Cochrane databases, and abstracts presented at meetings of the American Society of Clinical Oncology, the World Conference on Lung Cancer, the European Society for Medical Oncology, and the Chinese Society of Clinical Oncology for all eligible studies. Endpoints were overall survival; 1-year, 2-year, and 3-year survival rates; performance status; overall response rate; and grade 3 or 4 adverse events. Subgroup analyses based on herbal formulae individualized using syndrome differentiation or on oral or injection patent medicines were performed using the Stata software application (version 11.0: StataCorp LP, College Station, TX, U.S.A.) and a fixed-effects or random-effects model in case of heterogeneity. Results are expressed as a hazard ratio (hr) or relative risk (rr), with corresponding 95% confidence intervals (cis). Results Seventeen randomized studies with scores on the Jadad quality scale of 2 or more, representing 1552 patients, met the inclusion criteria. Compared with platinum-based chemotherapy alone, the addition of Astragalus-based tcm to chemotherapy was associated with significantly

  3. Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.

    PubMed

    Weiss, Andrea; Ding, Xianting; van Beijnum, Judy R; Wong, Ieong; Wong, Tse J; Berndsen, Robert H; Dormond, Olivier; Dallinga, Marchien; Shen, Li; Schlingemann, Reinier O; Pili, Roberto; Ho, Chih-Ming; Dyson, Paul J; van den Bergh, Hubert; Griffioen, Arjan W; Nowak-Sliwinska, Patrycja

    2015-07-01

    Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases. PMID:25824484

  4. Combined Chemotherapy with Mitomycin C, Folinic Acid, and 5-Fluorouracil (MiFoFU) as Salvage Treatment for Patients with Liver Metastases from Breast Cancer — a Retrospective Analysis

    PubMed Central

    Eichbaum, Michael H.R.; Gast, Anne-Sybil; Bruckner, Thomas; Schneeweiss, Andreas; Sohn, Christof

    2008-01-01

    Summary Background The aim of this study was to analyze the activity and tolerability of a combined chemotherapy with mitomycin C, folinic acid, and 5-fluorouracil (MiFoFU) in patients with hepatic metastases from breast cancer, and in particular in patients with impaired liver function. Patients and Methods We retrospectively studied the charts of 44 patients who were treated with a MiFoFU combination therapy because of progressive metastatic breast cancer. Predominant site of metastases was the liver. Primary endpoints were response and time to progression (TTP); secondary endpoints were overall survival (OS) and tolerability. Results Median age prior to treatment was 59 years. A median of 6 treatment cycles were administered per patient. Clinical benefit rate amounted to 64%. A mean TTP of 9 months and a mean OS of 14 months were found. Main clinical signs of nonhematological toxicity were stomatitis, nausea, and diarrhea. Grade III/IV hematotoxicity was seen in only 9 patients. 16 patients showed clinical signs of liver dysfunction. A clinical benefit could be achieved in 8 of these patients. Conclusion MiFoFU combination chemotherapy is a well-tolerated treatment alternative in the palliative therapy of patients with liver metastases from breast cancer. Particularly in patients with hepatic dysfunction, this regimen seems to represent a helpful treatment option. PMID:21076607

  5. Analysis of fractals with combined partition

    NASA Astrophysics Data System (ADS)

    Dedovich, T. G.; Tokarev, M. V.

    2016-03-01

    The space—time properties in the general theory of relativity, as well as the discreteness and non-Archimedean property of space in the quantum theory of gravitation, are discussed. It is emphasized that the properties of bodies in non-Archimedean spaces coincide with the properties of the field of P-adic numbers and fractals. It is suggested that parton showers, used for describing interactions between particles and nuclei at high energies, have a fractal structure. A mechanism of fractal formation with combined partition is considered. The modified SePaC method is offered for the analysis of such fractals. The BC, PaC, and SePaC methods for determining a fractal dimension and other fractal characteristics (numbers of levels and values of a base of forming a fractal) are considered. It is found that the SePaC method has advantages for the analysis of fractals with combined partition.

  6. Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo.

    PubMed

    Gomez-Gutierrez, Jorge G; Nitz, Jonathan; Sharma, Rajesh; Wechman, Stephen L; Riedinger, Eric; Martinez-Jaramillo, Elvis; Sam Zhou, Heshan; McMasters, Kelly M

    2016-01-01

    Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial. PMID:26561948

  7. Analysis of drug combinations: current methodological landscape

    PubMed Central

    Foucquier, Julie; Guedj, Mickael

    2015-01-01

    Combination therapies exploit the chances for better efficacy, decreased toxicity, and reduced development of drug resistance and owing to these advantages, have become a standard for the treatment of several diseases and continue to represent a promising approach in indications of unmet medical need. In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest. Research in this field has resulted in a large number of papers and revealed several issues. Here, we propose an overview of the current methodological landscape concerning the study of combination effects. First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect-based approaches and dose–effect-based approaches, and introduced in light of their respective practical advantages and limitations. Then, we discuss six main common methodological issues that scientists have to face at each step of the development of new combination therapies. In particular, in the absence of a reference methodology suitable for all biomedical situations, the analysis of drug combinations should benefit from a collective, appropriate, and rigorous application of the concepts and methods reviewed here. PMID:26171228

  8. Unique Molecular Landscapes in Cancer: Implications for Individualized, Curated Drug Combinations

    PubMed Central

    Wheler, Jennifer; Lee, J. Jack; Kurzrock, Razelle

    2014-01-01

    With increasing lysophisticated technologies in molecular biology and ‘omic’ platforms to analyze patients’ tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next generation sequencing (NGS); amongst 57 consecutive patients, no two had the same molecular portfolio (1). Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a ‘mismatch’ between our traditional clinical trials system that selects patients based on common characteristics in order to evaluate a drug (drug-centric approach), and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach). PMID:25326492

  9. [Cancer Genome Atlas Pan-cancer Analysis Project].

    PubMed

    Zhang, Kun; Wang, Hong

    2015-04-01

    Cancer can exhibit different forms depending on the site of origin, cell types, the different forms of genetic mutations which also affect cancer therapeutic effect. Although many genes have been demonstrated to change a direct result of the change in phenotype, however, many cancers lineage complex molecular mechanisms are still not fully elucidated. Therefore, The Cancer Genome Atlas (TCGA) Research Network analyzed a large human tumors, in order to find the molecular changes in DNA, RNA, protein and epigenetic level, The results contain a wealth of data provides us with an opportunity for common, personality and new ideas throughout the cancer lineages form a whole description. Pan-cancer genome program first compares the 12 kinds of cancer types. Analysis of different tumor molecular changes and their functions, will tell us how effective treatment method is applied to a similar phenotype of the tumor. PMID:25936886

  10. A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines.

    PubMed

    Shi, Yi; Sun, Lin; Chen, Ge; Zheng, Dongyan; Li, Li; Wei, Wanguo

    2015-12-01

    Breast cancer is one of the most significant causes of female cancer death worldwide. Paclitaxel, an extensively used breast cancer chemotherapeutic has limited success due to drug resistance. 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small molecule pharmacological inhibitor of telomerase activity, can inhibit human cancer cell proliferation as well. Thus, to enhance breast cancer treatment efficacy, we studied the combination of BIBR1532 and paclitaxel in breast cancer cell lines. Cell viability assays revealed that BIBR1532 or paclitaxel alone inhibited proliferation in a dose-dependent manner, and combining the drugs synergistically induced growth inhibition in all breast cell lines tested independent of their p53, ER, and HER2 status. The drug combination also synergistically inhibited colony formation of MCF-7 cells in a dose-dependent manner. Annexin V-PI staining and Western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that BIBR1532 in combination with paclitaxel was more potent than either agent alone in promoting MCF-7 cell apoptosis. Cell cycle analysis indicated that BIBR1532 induced a G1 phase arrest and paclitaxel arrested cells at the G2/M phase. The drug combination dramatically blocked S cells from entering the G2/M phase. Our results suggest the potential of telomerase inhibition as an effective breast cancer treatment and that used in conjunction with paclitaxel; it may potentiate tumor cytotoxicity. PMID:25916999

  11. Elevation of Plasma TGF-{beta}1 During Radiation Therapy Predicts Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer: A Combined Analysis From Beijing and Michigan

    SciTech Connect

    Zhao Lujun; Wang Luhua Ji Wei; Wang Xiaozhen; Zhu Xiangzhi; Hayman, James A.; Kalemkerian, Gregory P.; Yang Weizhi; Brenner, Dean; Lawrence, Theodore S.; Kong, F.-M.

    2009-08-01

    Purpose: To test whether radiation-induced elevations of transforming growth factor-{beta}1 (TGF-{beta}1) during radiation therapy (RT) correlate with radiation-induced lung toxicity (RILT) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the ability of mean lung dose (MLD) to improve the predictive power. Methods and Materials: Eligible patients included those with Stage I-III NSCLC treated with RT with or without chemotherapy. Platelet-poor plasma was obtained pre-RT and at 4-5 weeks (40-50 Gy) during RT. TGF-{beta}1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint was {>=} Grade 2 RILT. Mann-Whitney U test, logistic regression, and chi-square were used for statistical analysis. Results: A total of 165 patients were enrolled in this study. The median radiation dose was 60 Gy, and the median MLD was 15.3 Gy. Twenty-nine patients (17.6%) experienced RILT. The incidence of RILT was 46.2% in patients with a TGF-{beta}1 ratio > 1 vs. 7.9% in patients with a TGF-{beta}1 ratio {<=} 1 (p < 0.001), and it was 42.9% if MLD > 20 Gy vs. 17.4% if MLD {<=} 20 Gy (p = 0.024). The incidence was 4.3% in patients with a TGF-{beta}1 ratio {<=} 1 and MLD {<=} 20 Gy, 47.4% in those with a TGF-{beta}1 ratio >1 or MLD > 20 Gy, and 66.7% in those with a TGF-{beta}1 ratio >1 and MLD > 20 Gy (p < 0.001). Conclusions: Radiation-induced elevation of plasma TGF-{beta}1 level during RT is predictive of RILT. The combination of TGF- {beta}1 and MLD may help stratify the patients for their risk of RILT.

  12. Cancers in Australia in 2010 attributable to and prevented by the use of combined oral contraceptives

    PubMed Central

    Jordan, Susan J; Wilson, Louise F; Nagle, Christina M; Green, Adele C; Olsen, Catherine M; Bain, Christopher J; Pandeya, Nirmala; Whiteman, David C; Webb, Penelope M

    2015-01-01

    Objectives To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to combined oral contraceptive pill (OCP) use. Methods We estimated the population attributable fraction (PAF) for cancers causally associated with combined OCP use (breast, cervix), and the proportion of endometrial and ovarian cancers prevented (prevented fraction [PF]). We used standard formulae incorporating prevalence of combined OCP use in the Australian population, relative risks of cancer associated with this exposure and cancer incidence. Results An estimated 105 breast and 52 cervical cancers (0.7% and 6.4% of each cancer, respectively) in Australia in 2010 were attributable to current use of combined OCP. Past combined OCP use was estimated to have prevented 1,032 endometrial and 308 ovarian cancers in 2010, reducing the number of cancers that would otherwise have occurred by 31% and 19%, respectively. Conclusions A small proportion of breast and cervical cancers is attributable to combined OCP use; OCP use is likely to have prevented larger numbers of endometrial and ovarian cancers. Implications Women seeking contraceptive advice should be told of potential adverse effects, but should also be told that – along with reproductive health benefits – combined OCP use can reduce long-term risks of ovarian and endometrial cancers. PMID:26437729

  13. Identification of cancer cells by a combination of FTIR spectroscopy and PET

    NASA Astrophysics Data System (ADS)

    Steiner, Gerald; Richter, Tom; Salzer, Reiner; Bergmann, Ralf; Rodig, Heike; Johannsen, Bernd

    2000-03-01

    A combination of FTIR spectroscopy and positron emission tomography (PET) is shown to provide new information on tissue. Here we give a first demonstration on the potential of this combination in discriminating tumor tissue from healthy tissue. Examples are taken of cancer grown in muscle tissue in mice. Immediately before thin sections of the cancer tissue were prepared, a radiotracer was injected in the living mouse. Subsequently a native section was immobilized on a CaF2 window and an autoradiographic image was recorded from that immobilized section. FTIR maps of the thin sections were obtained by using an infrared microscopy equipped with computerized XY stage and MCT detector. Principal component analysis was chosen for chemometric evaluation of the spectra. Evaluated data were reassembled into 2D maps and compared with the corresponding PET image.

  14. Nanomechanical analysis of cells from cancer patients

    NASA Astrophysics Data System (ADS)

    Cross, Sarah E.; Jin, Yu-Sheng; Rao, Jianyu; Gimzewski, James K.

    2007-12-01

    Change in cell stiffness is a new characteristic of cancer cells that affects the way they spread. Despite several studies on architectural changes in cultured cell lines, no ex vivo mechanical analyses of cancer cells obtained from patients have been reported. Using atomic force microscopy, we report the stiffness of live metastatic cancer cells taken from the body (pleural) fluids of patients with suspected lung, breast and pancreas cancer. Within the same sample, we find that the cell stiffness of metastatic cancer cells is more than 70% softer, with a standard deviation over five times narrower, than the benign cells that line the body cavity. Different cancer types were found to display a common stiffness. Our work shows that mechanical analysis can distinguish cancerous cells from normal ones even when they show similar shapes. These results show that nanomechanical analysis correlates well with immunohistochemical testing currently used for detecting cancer.

  15. Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

    PubMed Central

    Onay, Ummiye V; Aaltonen, Kirsimari; Briollais, Laurent; Knight, Julia A; Pabalan, Noel; Kilpivaara, Outi; Andrulis, Irene L; Blomqvist, Carl; Nevanlinna, Heli; Ozcelik, Hilmi

    2008-01-01

    Background Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription. Methods In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins. Results Here, we have shown that the high enzymatic activity genotype of CCND1High (AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMTMedium (MetVal) and the high enzymatic activity of COMTHigh (ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMTHigh (ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: 2.22, 95%CI (1.49–3.28)] and Finland [OR: 1.73, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity. Conclusion Using

  16. Effects of Serum Triglycerides on Prostate Cancer and Breast Cancer Risk: A Meta-Analysis of Prospective Studies.

    PubMed

    Ma, Hong-Qun; Cui, Lian-Hua; Li, Cheng-Cheng; Yu, Zhuang; Piao, Jin-Mei

    2016-10-01

    Epidemiological studies show conflicting results regarding the link between serum triglyceride and the risk of prostate cancer and breast cancer. Therefore, we performed a meta-analysis of prospective studies to clarify this association. We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) database to identify relevant prospective studies of the relationship between serum triglyceride and prostate cancer and breast cancer risk. Study-specific estimates adjusting for potential confounders were combined to evaluate a summary relative risks (RRs) and 95% confidence intervals (95% CIs) using a fixed- or random-effects model. A total of 11 prospective studies (619,410 subjects and 15,691 incident prostate cancer patients) and 8 prospective studies (590,878 subjects and 12,177 incident breast cancer patients) were respectively included in our meta-analysis to assess the associations of serum triglyceride with prostate cancer and breast cancer risk. The pooled adjusted RR estimates for prostate cancer and breast cancer for the highest versus the lowest exposure levels of serum triglycerides were 0.95 (95% CI: 0.87-1.04) and 0.94 (95% CI: 0.87-1.00), respectively. Additionally, a dose-response analysis revealed that serum levels of triglycerides were not associated with the risk of prostate cancer and breast cancer. We found that serum triglyceride was not related to the risk of prostate cancer and breast cancer. PMID:27618148

  17. Multifunctional hybrid materials for combined photo and chemotherapy of cancer.

    PubMed

    Botella, Pablo; Ortega, Ilida; Quesada, Manuel; Madrigal, Roque F; Muniesa, Carlos; Fimia, Antonio; Fernández, Eduardo; Corma, Avelino

    2012-08-21

    Combined chemo and photothermal therapy in in vitro testing has been achieved by means of multifunctional nanoparticles formed by plasmonic gold nanoclusters with a protecting shell of porous silica that contains an antitumor drug. We propose a therapeutic nanoplatform that associates the optical activity of small gold nanoparticles aggregates with the cytotoxic activity of 20(S)-camptothecin simultaneously released for the efficient destruction of cancer cells. For this purpose, a method was used for the controlled assembly of gold nanoparticles into stable clusters with a tailored absorption cross-section in the vis/NIR spectrum, which involves aggregation in alkaline medium of 15 nm diameter gold colloids protected with a thin silica layer. Clusters were further encapsulated in an ordered homogeneous mesoporous silica coating that provides biocompatibility and stability in physiological fluids. After internalization in 42-MG-BA human glioma cells, these protected gold nanoclusters were able to produce effective photothermolysis under femtosecond pulse laser irradiation of 790 nm. Cell death occurred by combination of a thermal mechanism and mechanical disruption of the membrane cell due to induced generation of micrometer-scale bubbles by vaporizing the water inside the channels of the mesoporous silica coating. Moreover, the incorporation of 20(S)-camptothecin within the pores of the external shell, which was released during the process, provoked significant cell death increase. This therapeutic model could be of interest for application in the treatment and suppression of non-solid tumors. PMID:22555652

  18. Immunotherapy of Cancer by IL-12-based Cytokine Combinations

    PubMed Central

    Subleski, Jeff J.; Wigginton, Jon M.; Wiltrout, Robert H.

    2008-01-01

    Cancer is a multi-faceted disease comprising complex interactions between neoplastic and normal cells. Over the past decade, there has been considerable progress in defining the molecular, cellular and environmental contributions to the pathophysiology of tumor development. Despite these advances, the conventional treatment of patients still generally involves surgery, radiotherapy and/or chemotherapy and the clinical outcome for many of these efforts remains unsatisfactory. Recent studies have highlighted the feasibility of using immunotherapeutic approaches that seek to enhance host immune responses to developing tumors. These strategies include immunomodulatory cytokines, with tumor necrosis factor (TNF) alpha, type I or type II Interferons (IFNs), Interleukins (IL)-2, IL-12, IL-15 and IL-18 being among the most potent inducers of anti-tumor activity in a variety of pre-clinical studies. More recently, some exciting new cytokines have been characterized, such as IL-21, IL-23, IL-27, and their immunomodulatory and anti-tumor effects in vitro and in vivo suggest that they may have considerable promise for future immunotherapy protocols. The promise of cytokine therapy does indeed derive from the identification of these novel cytokines, but even more fundamentally, the field is greatly benefiting from the ever-expanding amount of pre-clinical data that convincingly demonstrate synergistic and/or novel biological effects that may be achieved through the use of several combinations of cytokines with complementary immune-stimulating capabilities. One cytokine in particular, IL-12, holds considerable promise by virtue of the fact that it plays a central role in regulating both innate and adaptive immune responses, can by itself induce potent anti-cancer effects, and synergizes with several other cytokines for increased immunoregulatory and anti-tumor activities. This review will discuss the anti-tumor activity of IL-12, with a special emphasis on its ability to

  19. Proteomics Analysis of Bladder Cancer Exosomes*

    PubMed Central

    Welton, Joanne L.; Khanna, Sanjay; Giles, Peter J.; Brennan, Paul; Brewis, Ian A.; Staffurth, John; Mason, Malcolm D.; Clayton, Aled

    2010-01-01

    Exosomes are nanometer-sized vesicles, secreted by various cell types, present in biological fluids that are particularly rich in membrane proteins. Ex vivo analysis of exosomes may provide biomarker discovery platforms and form non-invasive tools for disease diagnosis and monitoring. These vesicles have never before been studied in the context of bladder cancer, a major malignancy of the urological tract. We present the first proteomics analysis of bladder cancer cell exosomes. Using ultracentrifugation on a sucrose cushion, exosomes were highly purified from cultured HT1376 bladder cancer cells and verified as low in contaminants by Western blotting and flow cytometry of exosome-coated beads. Solubilization in a buffer containing SDS and DTT was essential for achieving proteomics analysis using an LC-MALDI-TOF/TOF MS approach. We report 353 high quality identifications with 72 proteins not previously identified by other human exosome proteomics studies. Overrepresentation analysis to compare this data set with previous exosome proteomics studies (using the ExoCarta database) revealed that the proteome was consistent with that of various exosomes with particular overlap with exosomes of carcinoma origin. Interrogating the Gene Ontology database highlighted a strong association of this proteome with carcinoma of bladder and other sites. The data also highlighted how homology among human leukocyte antigen haplotypes may confound MASCOT designation of major histocompatability complex Class I nomenclature, requiring data from PCR-based human leukocyte antigen haplotyping to clarify anomalous identifications. Validation of 18 MS protein identifications (including basigin, galectin-3, trophoblast glycoprotein (5T4), and others) was performed by a combination of Western blotting, flotation on linear sucrose gradients, and flow cytometry, confirming their exosomal expression. Some were confirmed positive on urinary exosomes from a bladder cancer patient. In summary, the

  20. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

    PubMed

    Wang, Tao; Narayanaswamy, Radhika; Ren, Huilan; Torchilin, Vladimir P

    2016-06-01

    Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types. PMID:27259361

  1. [Treatment outcomes of colon cancer surgery combined with radical lymphadenectomy].

    PubMed

    Lipská, L; Visokai, V; Mrácek, M; Levý, M

    2008-05-01

    The authors analyzed a group of 1281 subjects with colorectal cancer operated and followed up in a single institution from I/1992 to VIII/2007. Colon carcinoma patients were assessed separately (C18). Patients with rectal and rectosigmoid tumors are not included in the presentation. A total of 846 patients were operated for colon carcinomas. In 546 subjects, radical R0 resections were achieved. In the R0 group, the male/female ratio is 315/231, age 29-94 years, the mean age of 69 years. The R0 group stratification by TNM classification was: I 17.8%, II 49.6%, III 24.0%, IV 8.1%, TNMx 0.5%. Irrespective of the TNM staging, three-year, five-year and ten-year survival rates were 80%, 71%, and 51%, resp. The median survival time was 9.85 years. Postoperative morality was 5.5%, morbidity 29.8%, anastomic leak occured in 5.7%. Systematic lymph node dissection up to the apical level, had been gradually introduced as an integral part of the R0 surgery. The aim of the study is to analyze outcomes of the colon carcinoma surgical management, combined with radical lymphadenectomy. Furthermore, effects of the extensive procedure on the postoperative morbidity and moratility rates are analyzed as well. PMID:18595540

  2. Human epithelial cancer cells studied using combined AFM-IR absorption nanoimaging

    NASA Astrophysics Data System (ADS)

    Kennedy, Eamonn; Al-Majomaie, Rasoul; Zerulla, Dominic; Al-Rubeai, Mohammed; Rice, James H.

    2014-05-01

    Several recent studies have described the use of infrared (IR) nanoimaging for non-invasive chemical discrimination of subcellular features and intracellular exogenous agents. In this work we outline a number of improvements in both quantitative IR nanoimage analysis and optical system improvements which enable recovery of nanoscale subcellular chemical localization with improved chemical precision. Additionally, we demonstrate how a combination of IR absorption nanoimaging and topographic data can produce subcellular chemical density and complexity maps, which can illustrate several cellular features of interest, including the label free localization of nuclei for both healthy and cancerous cell lines with sub 40nm accuracy. As many cell processes related to disease are governed by the position and dynamics of subcellular features, we present the ability to map biochemical inhomogeneity of cancer cells at nanoscale resolution as a means to explore the subcellular biomechanics underlying carcinogenesis.

  3. The Cancer Genome Atlas Pan-Cancer analysis project.

    PubMed

    Weinstein, John N; Collisson, Eric A; Mills, Gordon B; Shaw, Kenna R Mills; Ozenberger, Brad A; Ellrott, Kyle; Shmulevich, Ilya; Sander, Chris; Stuart, Joshua M

    2013-10-01

    The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. PMID:24071849

  4. Combination of Molecular Alterations and Smoking Intensity Predicts Bladder Cancer Outcome: A Report from the Los Angeles Cancer Surveillance Program

    PubMed Central

    Mitra, Anirban P.; Castelao, Jose E.; Hawes, Debra; Tsao-Wei, Denice D.; Jiang, Xuejuan; Shi, Shan-Rong; Datar, Ram H.; Skinner, Eila C.; Stein, John P.; Groshen, Susan; Yu, Mimi C.; Ross, Ronald K.; Skinner, Donald G.; Cortessis, Victoria K.; Cote, Richard J.

    2012-01-01

    Background Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort. Methods Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. “Smoking intensity” quantified the impact of duration and daily frequency of smoking. Results Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P<0.001). Apaf-1, E-cadherin and p53 were prognostic for outcome (P=0.005, 0.014 and 0.032, respectively); E-cadherin remained prognostic following multivariable analysis (P=0.040). Combined alterations in all nine biomarkers were prognostic by univariable (P<0.001) and multivariable (P=0.006) analysis. A multivariable model that included all nine biomarkers and smoking intensity had greater accuracy in predicting prognosis than models comprising of standard clinicopathological covariates without or with smoking intensity (P<0.001 and P=0.018, respectively). Conclusions Apaf-1, E-cadherin and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the nine-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters

  5. Combination of integrin siRNA and irradiation for breast cancer therapy

    SciTech Connect

    Cao Qizhen; Cai Weibo; Li Tianfang; Yang Yong; Chen Kai; Xing Lei; Chen Xiaoyuan . E-mail: shawchen@stanford.edu

    2006-12-22

    Up-regulation of integrin {alpha}{sub v}{beta}{sub 3} has been shown to play a key role in tumor angiogenesis and metastasis. In this study, we evaluated the role of integrin {alpha}{sub v}{beta}{sub 3} in breast cancer cell resistance to ionizing irradiation (IR) and tested the anti-tumor efficacy of combining integrin {alpha}{sub v} siRNA and IR. Colonogenic survival assay, cell proliferation, apoptosis, and cell cycle analysis were carried out to determine the treatment effect of siRNA, IR, or combination of both on MDA-MB-435 cells (integrin {alpha}{sub v}{beta}{sub 3}-positive). Integrin {alpha}{sub v}{beta}{sub 3}-negative MCF-7 cells exert more radiosensitivity than MDA-MB-435 cells. IR up-regulates integrin {alpha}{sub v}{beta}{sub 3} expression in MDA-MB-435 cells and integrin {alpha}{sub v} siRNA can effectively reduce both {alpha}{sub v} and {alpha}{sub v}{beta}{sub 3} integrin expression, leading to increased radiosensitivity. Integrin {alpha}{sub v} siRNA also promotes IR-induced apoptosis and enhances IR-induced G2/M arrest in cell cycle progression. This study, with further optimization, may provide a simple and highly efficient treatment strategy for breast cancer as well as other integrin {alpha}{sub v}{beta}{sub 3}-positive cancer types.

  6. Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer12

    PubMed Central

    Qiao, Yuanyuan; Feng, Felix Y.; Wang, Yugang; Cao, Xuhong; Han, Sumin; Wilder-Romans, Kari; Navone, Nora M.; Logothetis, Christopher; Taichman, Russell S.; Keller, Evan T.; Palapattu, Ganesh S.; Alva, Ajjai S.; Smith, David C.; Tomlins, Scott A.; Chinnaiyan, Arul M.; Morgan, Todd M.

    2016-01-01

    A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status (+ or −), which identified MET expression as markedly increased in AR− samples. In vitro, AR signaling inhibition in AR+ CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR+ CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR− disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR− prostate cancer. PMID:26806347

  7. Combining Static Analysis and Model Checking for Software Analysis

    NASA Technical Reports Server (NTRS)

    Brat, Guillaume; Visser, Willem; Clancy, Daniel (Technical Monitor)

    2003-01-01

    We present an iterative technique in which model checking and static analysis are combined to verify large software systems. The role of the static analysis is to compute partial order information which the model checker uses to reduce the state space. During exploration, the model checker also computes aliasing information that it gives to the static analyzer which can then refine its analysis. The result of this refined analysis is then fed back to the model checker which updates its partial order reduction. At each step of this iterative process, the static analysis computes optimistic information which results in an unsafe reduction of the state space. However we show that the process converges to a fired point at which time the partial order information is safe and the whole state space is explored.

  8. Combined CDKN1A/TP53 mutation in bladder cancer is a therapeutic target.

    PubMed

    Liu, Yang; Kwiatkowski, David J

    2015-01-01

    Invasive bladder cancer has high morbidity and nearly uniform mortality when metastatic, with no therapeutic improvement in many years. Although chemotherapy combined with Chk1 inhibition has been investigated in several cancer types in which TP53 mutation is seen, this combination treatment approach has not been studied in bladder cancer. Recently, cancer genome sequencing efforts have identified CDKN1A (p21) mutations at 14% frequency in invasive bladder cancer, co-occurring half the time with TP53 mutations. We hypothesized that combined CDKN1A-TP53 loss would make bladder cancer sensitive to combined treatment with gemcitabine and Chk1 inhibitor. Here, we show that TP53-CDKN1A double-mutant bladder cancer cell lines, 647V and RT-112, have a remarkable increase in p-Chk1 levels and G2-M arrest in response to gemcitabine treatment, with a heightened sensitivity to combination treatment with gemcitabine and either Chk1 inhibitor PF477736 or AZD7762, in comparison with other bladder cancer cell lines (either TP53 or p21 deficient). In addition, CDKN1A restoration in p21-deficient bladder cancer cells significantly reduced their sensitivity to combined treatment by protecting them from DNA damage and apoptosis. Furthermore, xenograft studies using RT-112 showed a significant synergistic effect of combined gemcitabine-PF477736 treatment on tumor growth. Our findings suggest that TP53/CDKN1A double-mutant bladder cancer cells have a unique dependence on Chk1 activity for the G2-M cell-cycle checkpoint in response to chemotherapy-induced DNA damage. This combination or others involving genotoxic agents and Chk kinase inhibitors is a promising therapeutic approach for bladder cancer with these mutations. PMID:25349305

  9. Combined CDKN1A/TP53 mutation in bladder cancer is a therapeutic target

    PubMed Central

    Liu, Yang; Kwiatkowski, David J.

    2014-01-01

    Invasive bladder cancer has high morbidity and nearly uniform mortality when metastatic, with no therapeutic improvement in many years. Although chemotherapy combined with Chk1 inhibition has been investigated in several cancer types in which TP53 mutation is seen, this combination treatment approach has not been studied in bladder cancer. Recently cancer genome sequencing efforts have identified CDKN1A (p21) mutations at 14% frequency in invasive bladder cancer, co-occurring half the time with TP53 mutations. We hypothesized that combined CDKN1A – TP53 loss would make bladder cancer sensitive to combined treatment with gemcitabine and Chk1 inhibitor. Here, we show that TP53/CDKN1A double mutant bladder cancer cell lines, 647V and RT-112, have a remarkable increase in p-Chk1 levels and G2/M arrest in response to gemcitabine treatment, with a heightened sensitivity to combination treatment with gemcitabine and either Chk1 inhibitor PF477736 or AZD7762, in comparison to other bladder cancer cell lines (either TP53 or p21 deficient). In addition, CDKN1A restoration in p21-deficient bladder cancer cells significantly reduced their sensitivity to combined treatment by protecting them from DNA damage and apoptosis. Furthermore, xenograft studies using RT-112 showed a significant synergistic effect of combined gemcitabine - PF477736 treatment on tumor growth. Our findings suggest that TP53/CDKN1A double mutant bladder cancer cells have a unique dependence on Chk1 activity for the G2/M cell cycle checkpoint in response to chemotherapy-induced DNA damage. This combination or others involving genotoxic agents-Chk kinase inhibitors is a promising therapeutic approach for bladder cancer with these mutations. PMID:25349305

  10. Combining capecitabine and bevacizumab in metastatic breast cancer: a comprehensive review.

    PubMed

    Miles, David; Zielinski, Christoph; Martin, Miguel; Vrdoljak, Eduard; Robert, Nicholas

    2012-03-01

    Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine-bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine-bevacizumab combination therapy. PMID:22257791

  11. Methods for Selection of Cancer Patients and Predicting Efficacy of Combination Therapy | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Lung Cancer Biomarkers Group of the National Cancer Institute (NCI) seeks parties interested in collaborative research to further co-develop methods for selecting cancer patients for combination therapy.

  12. Pathway and network analysis of cancer genomes.

    PubMed

    2015-07-01

    Genomic information on tumors from 50 cancer types cataloged by the International Cancer Genome Consortium (ICGC) shows that only a few well-studied driver genes are frequently mutated, in contrast to many infrequently mutated genes that may also contribute to tumor biology. Hence there has been large interest in developing pathway and network analysis methods that group genes and illuminate the processes involved. We provide an overview of these analysis techniques and show where they guide mechanistic and translational investigations. PMID:26125594

  13. Pathway and Network Analysis of Cancer Genomes

    PubMed Central

    Haider, Syed; Wu, Guanming; Shibata, Tatsuhiro; Vazquez, Miguel; Mustonen, Ville; Gonzalez-Perez, Abel; Pearson, John; Sander, Chris; Raphael, Benjamin J.; Marks, Debora S.; Ouellette, B.F. Francis; Valencia, Alfonso; Bader, Gary D.; Boutros, Paul C.; Stuart, Joshua M.; Linding, Rune; Lopez-Bigas, Nuria; Stein, Lincoln D.

    2016-01-01

    Genomic information on tumors from 50 cancer types catalogued by The International Cancer Genome Consortium (ICGC) shows that only few well-studied driver genes are frequently mutated, in contrast to many infrequently mutated genes that may also contribute to tumor biology. Hence there has been large interest in developing pathway and network analysis methods that group genes and illuminate the processes involved. We provide an overview of these analysis techniques and show where they guide mechanistic and translational investigations. PMID:26125594

  14. Resveratrol–zinc combination for prostate cancer management

    PubMed Central

    Singh, Chandra K; Pitschmann, Anna; Ahmad, Nihal

    2014-01-01

    Zinc, an essential trace element, plays a critical role in cell signaling, and defect(s) in zinc homeostasis may contribute to adverse physiological and pathological conditions, including cancer. Zinc is present in healthy prostate at a very high concentration, where it is required for important prostatic functions. However, zinc levels are significantly diminished in cancerous tissue, and intracellular zinc level is inversely correlated with prostate cancer progression. During neoplastic transformation, zinc-accumulating, citrate-producing normal prostate cells are metabolically transformed to citrate oxidizing cells that lose the ability to accumulate zinc. Interestingly, zinc has been shown to function as chemopreventive agent against prostate cancer, albeit at high doses, which may lead to many adverse effects. Therefore, novel means to enhance bioaccumulation of sufficient zinc in prostate cells via increasing zinc transport could be useful against prostate cancer. On the basis of available evidence, we present a possibility that the grape antioxidant resveratrol, when given with zinc, may lead to retuning the zinc homeostasis in prostate, thereby abolishing or reversing malignancy. If experimentally verified in in vivo model(s) of prostate cancer, such as transgenic mouse models, this may lead to novel means toward management of prostate cancer and other conditions with compromised zinc homeostasis. PMID:24866157

  15. Resveratrol-zinc combination for prostate cancer management.

    PubMed

    Singh, Chandra K; Pitschmann, Anna; Ahmad, Nihal

    2014-01-01

    Zinc, an essential trace element, plays a critical role in cell signaling, and defect(s) in zinc homeostasis may contribute to adverse physiological and pathological conditions, including cancer. Zinc is present in healthy prostate at a very high concentration, where it is required for important prostatic functions. However, zinc levels are significantly diminished in cancerous tissue, and intracellular zinc level is inversely correlated with prostate cancer progression. During neoplastic transformation, zinc-accumulating, citrate-producing normal prostate cells are metabolically transformed to citrate oxidizing cells that lose the ability to accumulate zinc. Interestingly, zinc has been shown to function as chemopreventive agent against prostate cancer, albeit at high doses, which may lead to many adverse effects. Therefore, novel means to enhance bioaccumulation of sufficient zinc in prostate cells via increasing zinc transport could be useful against prostate cancer. On the basis of available evidence, we present a possibility that the grape antioxidant resveratrol, when given with zinc, may lead to retuning the zinc homeostasis in prostate, thereby abolishing or reversing malignancy. If experimentally verified in in vivo model(s) of prostate cancer, such as transgenic mouse models, this may lead to novel means toward management of prostate cancer and other conditions with compromised zinc homeostasis. PMID:24866157

  16. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors

    PubMed Central

    Kleponis, Jennifer; Skelton, Richard; Zheng, Lei

    2015-01-01

    Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing. PMID:26487965

  17. Changes in PSA Kinetics Predict Metastasis-Free Survival in Men with PSA-Recurrent Prostate Cancer Treated with Non-Hormonal Agents: Combined Analysis of 4 Phase II Trials

    PubMed Central

    Antonarakis, Emmanuel S.; Zahurak, Marianna L.; Lin, Jianqing; Keizman, Daniel; Carducci, Michael A.; Eisenberger, Mario A.

    2011-01-01

    Background Several phase II trials in men with non-castrate PSA-recurrent prostate cancer have assessed the impact of novel non-hormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS). Methods We performed a retrospective post hoc analysis of 146 men treated in four phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n=39), imatinib (a tyrosine kinase inhibitor; n=25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n=22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n=60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation. Results After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P=.05), baseline PSA slope (P=.01), on-study change in PSADT (P=.02), and on-study change in PSA slope (P=.03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% CI 34.6–not reached) and 28.9 months (95% CI 13.5–68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively. Conclusions This hypothesis-generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically-recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate endpoint for screening new agents in these patients. PMID:21960118

  18. Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone.

    PubMed

    Merouani, A; Davidson, S A; Schrier, R W

    1997-01-01

    To investigate the increased nephrotoxicity of taxol and cisplatin combination chemotherapy in gynecologic cancers as compared to cisplatin alone, the medical records of 25 patients with gynecological cancers were reviewed for evaluation of nephrotoxicity after chemotherapy treatment. The data included age, serum creatinine, calculated creatinine clearance, initial and cumulative dose of cisplatin and taxol, primary site of the cancer, renal ultrasound and hydration protocols. Renal function was evaluated before, during and 6 months after chemotherapy. Renal dysfunction was defined as a greater than 25% decrease in creatinine clearance. Comparing 11 patients treated with taxol and cisplatin versus 14 treated with cisplatin alone, there was a significant difference in effect on renal function. Nine of 11 patients (81%) treated with the combination chemotherapy had a greater than 25% decrease in creatinine clearance while only 4 of the 14 patients (29%) treated with cisplatin alone had such a decrease in creatinine clearance (p < 0.004). The patients treated with the combination chemotherapy, however, received a higher dose of cisplatin (80.4 vs. 66.4 mg/m2, p < 0.02) and were treated longer (6.7 vs. 4.3 months, p < 0.002). Nevertheless, when the patients were matched for age, initial dose and cumulative dose of cisplatin, a higher frequency of nephrotoxicity persisted in patients treated with taxol and cisplatin as compared to cisplatin alone (72 as compared to 20%, p < 0.02). The patients in both groups were comparably hydrated; prerenal failure and urinary tract obstruction were excluded in all patients. Six months after completion of chemotherapy, a significantly lower creatinine clearance was still observed in patients treated with taxol and cisplatin combination therapy (46 vs. 76 ml/min, p < 0.01). In summary, a retrospective analysis of renal function in patients with gynecological cancers showed an increased nephrotoxicity in patients treated with taxol and

  19. Combination Therapy Shows Promise for Treating Advanced Breast Cancer

    Cancer.gov

    Adding the drug everolimus (Afinitor®) to exemestane helped postmenopausal women whose advanced breast cancer had stopped responding to hormonal therapy live about 4 months longer without the disease progressing than women who received exemestane alone.

  20. A CASE STUDY OF CANCER DATA SET COMBINATIONS FOR PCBs

    EPA Science Inventory

    Results of several animal bioassays have demonstrated the carcinogenic potential of polychlorinated biphenyl (PCB) mixtures. Although PCBs are no longer manufactured, cancer risk assessment for PCBs remains an important issue because of continued potential human exposure from man...

  1. Combining Chemotherapy with Bevacizumab Improves Outcomes for Ovarian Cancer Patients

    Cancer.gov

    Results from two phase III randomized clinical trials suggest that, at least for some patients with ovarian cancer, adding the antiangiogenesis agent bevacizumab to chemotherapy increases the time to disease progression and may improve survival.

  2. Breast cancer histopathology image analysis: a review.

    PubMed

    Veta, Mitko; Pluim, Josien P W; van Diest, Paul J; Viergever, Max A

    2014-05-01

    This paper presents an overview of methods that have been proposed for the analysis of breast cancer histopathology images. This research area has become particularly relevant with the advent of whole slide imaging (WSI) scanners, which can perform cost-effective and high-throughput histopathology slide digitization, and which aim at replacing the optical microscope as the primary tool used by pathologist. Breast cancer is the most prevalent form of cancers among women, and image analysis methods that target this disease have a huge potential to reduce the workload in a typical pathology lab and to improve the quality of the interpretation. This paper is meant as an introduction for nonexperts. It starts with an overview of the tissue preparation, staining and slide digitization processes followed by a discussion of the different image processing techniques and applications, ranging from analysis of tissue staining to computer-aided diagnosis, and prognosis of breast cancer patients. PMID:24759275

  3. Microfluidic platform combining droplets and magnetic tweezers: application to HER2 expression in cancer diagnosis

    PubMed Central

    Ferraro, Davide; Champ, Jérôme; Teste, Bruno; Serra, Marco; Malaquin, Laurent; Viovy, Jean-Louis; de Cremoux, Patricia; Descroix, Stephanie

    2016-01-01

    The development of precision medicine, together with the multiplication of targeted therapies and associated molecular biomarkers, call for major progress in genetic analysis methods, allowing increased multiplexing and the implementation of more complex decision trees, without cost increase or loss of robustness. We present a platform combining droplet microfluidics and magnetic tweezers, performing RNA purification, reverse transcription and amplification in a fully automated and programmable way, in droplets of 250nL directly sampled from a microtiter-plate. This platform decreases sample consumption about 100 fold as compared to current robotized platforms and it reduces human manipulations and contamination risk. The platform’s performance was first evaluated on cell lines, showing robust operation on RNA quantities corresponding to less than one cell, and then clinically validated with a cohort of 21 breast cancer samples, for the determination of their HER2 expression status, in a blind comparison with an established routine clinical analysis. PMID:27157697

  4. Microfluidic platform combining droplets and magnetic tweezers: application to HER2 expression in cancer diagnosis

    NASA Astrophysics Data System (ADS)

    Ferraro, Davide; Champ, Jérôme; Teste, Bruno; Serra, Marco; Malaquin, Laurent; Viovy, Jean-Louis; de Cremoux, Patricia; Descroix, Stephanie

    2016-05-01

    The development of precision medicine, together with the multiplication of targeted therapies and associated molecular biomarkers, call for major progress in genetic analysis methods, allowing increased multiplexing and the implementation of more complex decision trees, without cost increase or loss of robustness. We present a platform combining droplet microfluidics and magnetic tweezers, performing RNA purification, reverse transcription and amplification in a fully automated and programmable way, in droplets of 250nL directly sampled from a microtiter-plate. This platform decreases sample consumption about 100 fold as compared to current robotized platforms and it reduces human manipulations and contamination risk. The platform’s performance was first evaluated on cell lines, showing robust operation on RNA quantities corresponding to less than one cell, and then clinically validated with a cohort of 21 breast cancer samples, for the determination of their HER2 expression status, in a blind comparison with an established routine clinical analysis.

  5. Microfluidic platform combining droplets and magnetic tweezers: application to HER2 expression in cancer diagnosis.

    PubMed

    Ferraro, Davide; Champ, Jérôme; Teste, Bruno; Serra, Marco; Malaquin, Laurent; Viovy, Jean-Louis; de Cremoux, Patricia; Descroix, Stephanie

    2016-01-01

    The development of precision medicine, together with the multiplication of targeted therapies and associated molecular biomarkers, call for major progress in genetic analysis methods, allowing increased multiplexing and the implementation of more complex decision trees, without cost increase or loss of robustness. We present a platform combining droplet microfluidics and magnetic tweezers, performing RNA purification, reverse transcription and amplification in a fully automated and programmable way, in droplets of 250nL directly sampled from a microtiter-plate. This platform decreases sample consumption about 100 fold as compared to current robotized platforms and it reduces human manipulations and contamination risk. The platform's performance was first evaluated on cell lines, showing robust operation on RNA quantities corresponding to less than one cell, and then clinically validated with a cohort of 21 breast cancer samples, for the determination of their HER2 expression status, in a blind comparison with an established routine clinical analysis. PMID:27157697

  6. Capture and Release of Cancer Cells by Combining On-Chip Purification and Off-Chip Enzymatic Treatment.

    PubMed

    Yu, Xiaolei; Wang, Bingrui; Zhang, Nangang; Yin, Changqing; Chen, Hao; Zhang, Lingling; Cai, Bo; He, Zhaobo; Rao, Lang; Liu, Wei; Wang, Fu-Bing; Guo, Shi-Shang; Zhao, Xing-Zhong

    2015-11-01

    As "liquid biopsies", circulating tumor cells (CTCs) have been thought to hold significant insights for cancer diagnosis and treatment. Despite the advances of microfluidic techniques that improve the capture of CTCs to a certain extent, recovering the captured CTCs with enhanced purity at the same time remains a challenge. Here, by combining on-chip purification and off-chip enzymatic treatment, we demonstrate a two-stage strategy to enhance the purity of captured cancer cells from blood samples. The on-chip purification introduces a stirring flow to increase the capture sensitivity and decrease nonspecifically bounded cells. The off-chip enzymatic treatment enables the cancer cells to be released from the attached magnetic beads, further improving the purity and enabling next reculture. For the proof-of-concept study, spiked cancer cells are successfully obtained from unprocessed whole blood with high recovery rate (∼68%) and purity (∼61%), facilitating subsequent RNA expression analysis. PMID:26488449

  7. Changes in body composition of cancer patients following combined nutritional support

    SciTech Connect

    Cohn, S.H.; Vartsky, D.; Vaswani, A.N.; Sawitsky, A.; Rai, K.; Gartenhaus, W.; Yasumura, S.; Ellis, K.J.

    1982-01-01

    The effects of combined nutritional support (parenteral, enteral, and oral) were measured in cancer patients unable to maintain normal alimentation.Changes in body composition were quantified by measurement of total body levels of nitrogen, potassium, water, and fat. The protein-calorie intake of the patients was also evaluated by dietary survey (4-day recall). Standard anthropometric and biochemical measurements for nutritional assessment were obtained for comparison. The dietary evaluation indicated that the dietary supplementation for all patients was more than adequate to meet their energy requirements. Determination of body composition indicated that change in body weight was equal to the sum of the changes in body protein, total body water, and total body fat. Information on the nature of the tissue gained was obtained by comparison of body composition data with the ratio of protein:water:lean body mass for normal tissue. The mean gain of protein in the cancer patients was quite small (0.3-0.6 kg). The main change in body weight appeared to be the result of gains in body water and body fat. The total body nitrogen to potassium ratio served to define the extent of tissue anabolism following hyperalimentation. The ratio dropped in the cancer patients following hyperalimentation toward the value of the control subjects on ad libitum diets. Total body nitrogen was determined by prompt gamma neutron activation analysis, total body potassium by whole-body counting. (JMT)

  8. Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells

    PubMed Central

    Chen, Pin-jia; Huang, Guo-bin; Li, Bin; Zheng, De-qing; Yu, Xiu-rong; Luo, Xiao-yong

    2014-01-01

    Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer. PMID

  9. Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis.

    PubMed

    Akladios, Fady N; Andrew, Scott D; Parkinson, Christopher J

    2015-07-01

    Cancer cell resistance to chemotherapy is still a heavy burden that impairs the response of many cancer patients to conventional chemotherapy. Using drug combinations is one therapeutic approach to overcome the developing resistance to any one drug. Oxidative stress is now a generally regarded hallmark of cancer that can be one approach to selectively target cancer cells while sparing normal cells. With the aim of increasing oxidative stress in cancer cells to a lethal set point, we have generated and combined several series of redox active compounds that act at different points of the cellular oxidative cascade. The premise of such combinations is to deplete of endogenous antioxidant defence proteins (e.g., Glutathione) while concomitantly increasing the generation of ROS via metal redox recycling and Fenton chemistry which eventually leads to the disruption of cellular redox homeostasis and induction of cell death. Through this approach, we have identified highly synergistic combinations of two distinctive classes of compounds (Azines and Copper(II) complexes of 2-pyridyl ketone thiosemicarbazones) which are capable of eliminating cancer cells without concomitant increase in toxicity toward normal cells. In one of our most potent combinations, a combination index (CI) value of 0.056 was observed, representing a 17 fold enhancement in activity beyond additive effects. Such new combination regimen of redox active compounds can be one step closer to potentially safer low dose chemotherapy. PMID:26022081

  10. Combination of Fenretinide and Selenite Inhibits Proliferation and Induces Apoptosis in Ovarian Cancer Cells

    PubMed Central

    Liu, Jie; Li, Jia; Zhang, Jian-Fang; Xin, Xiao-Yan

    2013-01-01

    The combination of fenretinide and selenite on ovarian cancer cells was investigated to assess its effects on proliferation and ability to induce apoptosis. Our results showed that fenretinide and selenite in combination significantly suppress the proliferation of ovarian cancer cells and induced apoptosis (including reactive oxygen species generation, and the loss of mitochondrial membrane potential) compared with either drug used alone. The caspase3/9-dependent pathway was triggered significantly in combination treatment, and moreover, the AMPK pathway also mediated the apoptosis induction in fenretinide and selenite combination. Fenretinide and selenite combination treatment was demonstrated to suppress tumor growth in vivo, this drug combination has been thus found to have an enhanced anti-tumor effect on ovarian cancers cells. PMID:24192821

  11. Universes Collide: Combining Immunotherapy with Targeted Therapy for Cancer

    PubMed Central

    Wargo, Jennifer A.; Cooper, Zachary A.; Flaherty, Keith T.

    2014-01-01

    There have been significant advances in the past several years with regard to targeted therapy and immunotherapy for cancer. This is highlighted in melanoma, where treatment with targeted therapy (against the BRAF oncogene) results in responses in the majority of patients, though duration of response is limited. In contrast, treatment with immunotherapy results in a lower response rate, but ones that tend to be more durable. Insights regarding mechanisms of response and potential synergy between these treatment strategies for melanoma are a focus of this review, with opportunities to extend these insights to the treatment of other cancers. PMID:25395294

  12. Synergistic antitumor effects of liposomal honokiol combined with cisplatin in colon cancer models.

    PubMed

    Cheng, Niang; Xia, Tian; Han, Ying; He, Qing Jun; Zhao, Rong; Ma, Jun Rong

    2011-09-01

    Honokiol, a novel antitumor agent, may induce apoptosis and inhibit the growth of vascular endothelium in a number of tumor cell lines and xenograft models. It has been proposed that the antitumor effects of chemotherapy may be increased in combination with an antiangiogenesis agent as an anticancer strategy. In the present study, we examined the potential of honokiol to increase the antitumor effect of cisplatin (DDP) when the agent and drug were combined in murine CT26 colon cancer models, and investigated the underlying mechanism. Liposomal honokiol (LH) was prepared, and female BALB/c mice were administered LH at various doses to determine the optimum doses for honokial. Evaluation of cell apoptosis was analyzed using flow cytometry. Honokiol was encapsulated with liposome to improve its water insolubility. In vitro, LH inhibited the proliferation of CT26 cells via apoptosis and significantly enhanced the DPP-induced apoptosis of CT26 cells. In vivo, the systemic administration of LH plus DDP resulted in the inhibition of subcutaneous tumor growth beyond the effects observed with either LH or DDP alone. This growth reduction was associated with elevated levels of apoptosis (TUNEL staining) and reduced endothelial cell density (CD31 staining) compared with either treatment alone. Collectively, these findings indicate that LH may augment the induction of apoptosis in CT26 cells in vitro and in vivo, and this combined treatment has exhibited synergistic suppression in tumor progression according to the synergistic analysis. The present study may be significant to future exploration of the potential application of the combined approach in the treatment of colon cancer. PMID:22866157

  13. Effect of Combined Treatment Using Wilfortrine and Paclitaxel in Liver Cancer and Related Mechanism

    PubMed Central

    Li, Shuzhen; Zheng, Lei

    2016-01-01

    Background Liver cancer is a common malignant tumor with high mortality. Currently, effective medicines against liver cancer are still lacking. Paclitaxel is a wide-spectrum anti-tumor agent, while wilfortrine has been shown to have an inhibitory effect on the proliferation of liver cancer cells. This study thus investigated the potential effect of paclitaxel combined with wilfortrine on cultured liver cancer cells and related mechanisms, in order to provide evidence for pathogenesis and treatment of liver cancer. Material/Methods Liver cancer cell line HpeG2 was divided into control, paclitaxel, wilfortrine, and combined treatment groups. Cell proliferation was tested by MTT, while invasion was detected in Transwell chamber assay. Apoptotic protein Bcl-2 and Bax expression levels were further quantified using real-time PCR and Western blotting. Results Both of those 2 drugs can effectively inhibit cancer cell proliferation, depress invasion ability, increase Bcl-2 expression, and elevate Bax expression levels (p<0.05 in all cases). The combined therapy had better treatment efficacy compared to either of those drugs alone (p<0.05). Conclusions The combined treatment using wilfortrine and paclitaxel can inhibit proliferation and invasion of liver cancer cells via down-regulating Bcl-2 and up-regulating Bax, with better efficacy than single use of either drug. PMID:27043783

  14. Combined Use of Metformin and Everolimus Is Synergistic in the Treatment of Breast Cancer Cells.

    PubMed

    Wang, Yunshan; Wei, Junmin; Li, Li; Fan, Cong; Sun, Ying

    2014-01-01

    Everolimus inhibits mammalian target of rapamycin (mTOR) and leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'-monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. Histopathological and biochemical studies of breast cancer show frequent dysregulation of the AMPK and the mTOR pathway. Therefore, we investigated the efficacy of the mTOR inhibitor everolimus and metformin in the treatment of breast cancer cells. This study evaluated the in vitro and in vivo effects of everolimus alone or in combination with metformin on breast cancer cells. MTT assay was used to quantify the inhibitory effect of the drugs on breast cancer cells in vitro. SCID mice injected with HCC1428 cells followed by different treatments were used to assess the in vivo efficacy of different agents. Data showed that the combination of everolimus and metformin exerted synergistic inhibitory effects on the growth of breast cancer cells both in culture and in a mouse xenograft model. Further, this combination abrogated S6 and 4EBP1phosphorylation. Collectively, we suggest that the combination of everolimus and metformin may be an effective regimen for treatment of breast cancer, hence warranting further evaluation of the combination in the clinic. PMID:26351208

  15. Role of Taxane and Anthracycline Combination Regimens in the Management of Advanced Breast Cancer

    PubMed Central

    Zheng, Ruinian; Han, Shuai; Duan, Chongyang; Chen, Kexu; You, Zhijian; Jia, Jun; Lin, Shunhuan; Liang, Liming; Liu, Aixue; Long, Huidong; Wang, Senming

    2015-01-01

    Abstract The clinical benefits provided by using combined taxanes and anthracyclines in first-line chemotherapy for metastatic breast carcinoma (MBC) remain uncertain. This meta-analysis compares the benefits of using a combination of anthracyclines along with taxanes versus using single-agent-based chemotherapeutic regimens in the treatment of MBC. Relevant clinical trials as well as abstracts from articles presented at major cancer conferences were searched in various databases including PubMed, Embase, and Cochrane Library. The relevant studies had a primary endpoint of overall survival (OS) and secondary endpoints that included progression-free survival (PFS), time-to-treatment failure (TTF), time to progression (TTP), objective response rate (ORR), disease control rate (DCR), and safety. The hazard ratios of OS, PFS, TTF, and TTP, the odds ratios of ORR and DCR, and the risk ratios (RRs) for grades 1–2 and 3–4 toxicities were extracted from the retrieved studies and analyzed using various statistical methods. Meta-analytic estimates were derived from a random-effect model. Fifteen trials were included in the final meta-analysis, and the results suggest that chemotherapy with combined anthracyclines and taxanes does not significantly improve the OS of MBC patients when compared with the OS achieved using separate taxane or anthracycline-based regimens. Compared with taxane-based regimens, combined taxane along with anthracycline regimens failed to significantly improve TTP, ORR, or DCR, but did significantly improve TTP and ORR when compared with anthracycline-based regimens. Furthermore, both individual taxane-based and anthracycline-based regimens produced fewer toxic reactions compared to combined taxane along with anthracycline regimens. Taxane-based regimens had lower RRs for side effects of neutropenia, infection/febrile neutropenia, nausea, and vomiting, whereas patients receiving anthracycline-based regimens had lower RRs for neutropenia, infection

  16. Quantitative Analysis of Human Cancer Cell Extravasation Using Intravital Imaging.

    PubMed

    Willetts, Lian; Bond, David; Stoletov, Konstantin; Lewis, John D

    2016-01-01

    Metastasis, or the spread of cancer cells from a primary tumor to distant sites, is the leading cause of cancer-associated death. Metastasis is a complex multi-step process comprised of invasion, intravasation, survival in circulation, extravasation, and formation of metastatic colonies. Currently, in vitro assays are limited in their ability to investigate these intricate processes and do not faithfully reflect metastasis as it occurs in vivo. Traditional in vivo models of metastasis are limited by their ability to visualize the seemingly sporadic behavior of where and when cancer cells spread (Reymond et al., Nat Rev Cancer 13:858-870, 2013). The avian embryo model of metastasis is a powerful platform to study many of the critical steps in the metastatic cascade including the migration, extravasation, and invasion of human cancer cells in vivo (Sung et al., Nat Commun 6:7164, 2015; Leong et al., Cell Rep 8, 1558-1570, 2014; Kain et al., Dev Dyn 243:216-28, 2014; Leong et al., Nat Protoc 5:1406-17, 2010; Zijlstra et al., Cancer Cell 13:221-234, 2008; Palmer et al., J Vis Exp 51:2815, 2011). The chicken chorioallantoic membrane (CAM) is a readily accessible and well-vascularized tissue that surrounds the developing embryo. When the chicken embryo is grown in a shell-less, ex ovo environment, the nearly transparent CAM provides an ideal environment for high-resolution fluorescent microcopy approaches. In this model, the embryonic chicken vasculature and labeled cancer cells can be visualized simultaneously to investigate specific steps in the metastatic cascade including extravasation. When combined with the proper image analysis tools, the ex ovo chicken embryo model offers a cost-effective and high-throughput platform for the quantitative analysis of tumor cell metastasis in a physiologically relevant in vivo setting. Here we discuss detailed procedures to quantify cancer cell extravasation in the shell-less chicken embryo model with advanced fluorescence

  17. Cancer therapy improvement with mesoporous silica nanoparticles combining targeting, drug delivery and PDT.

    PubMed

    Gary-Bobo, Magali; Hocine, Ouahiba; Brevet, David; Maynadier, Marie; Raehm, Laurence; Richeter, Sébastien; Charasson, Virginie; Loock, Bernard; Morère, Alain; Maillard, Philippe; Garcia, Marcel; Durand, Jean-Olivier

    2012-02-28

    The synthesis of mesoporous silica nanoparticles (MSN) covalently encapsulating fluoresceine or a photosensitizer, functionalized with galactose on the surface is described. Confocal microscopy experiments demonstrated that the uptake of galactose-functionalized MSN by colorectal cancer cells was mediated by galactose receptors leading to the accumulation of the nanoparticles in the endosomal and lysosomal compartments. The MSN functionalized with a photosensitizer and galactose were loaded with the anti-cancer drug camptothecin. Those MSN combining drug delivery and photodynamic therapy were tested on three cancer cell lines and showed a dramatic enhancement of cancer cell death compared to separate treatments. PMID:22178618

  18. Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression

    PubMed Central

    2009-01-01

    Background It is well recognized that colorectal cancer does not frequently metastasize to bone. The aim of this retrospective study was to establish whether colorectal cancer ever bypasses other organs and metastasizes directly to bone and whether the presence of lung lesions is superior to liver as a better predictor of the likelihood and timing of bone metastasis. Methods We performed a retrospective analysis on patients with a clinical diagnosis of colon cancer referred for staging using whole-body 18F-FDG PET and CT or PET/CT. We combined PET and CT reports from 252 individuals with information concerning patient history, other imaging modalities, and treatments to analyze disease progression. Results No patient had isolated osseous metastasis at the time of diagnosis, and none developed isolated bone metastasis without other organ involvement during our survey period. It took significantly longer for colorectal cancer patients to develop metastasis to the lungs (23.3 months) or to bone (21.2 months) than to the liver (9.8 months). Conclusion: Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare, perhaps more rare than we previously thought. Our findings suggest that resistant metastasis to the lungs predicts potential disease progression to bone in the colorectal cancer population better than liver metastasis does. PMID:19664211

  19. Nonsteroidal antiinflammatory drugs and bladder cancer: a pooled analysis.

    PubMed

    Daugherty, Sarah E; Pfeiffer, Ruth M; Sigurdson, Alice J; Hayes, Richard B; Leitzmann, Michael; Schatzkin, Arthur; Hollenbeck, Albert R; Silverman, Debra T

    2011-04-01

    Case-control studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) decreases bladder cancer risk, but few cohort studies have evaluated this association. The authors investigated NSAID use and bladder cancer in 3 large prospective studies (NIH-AARP Diet and Health Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and U.S. Radiologic Technologists Study). Frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using self-administered questionnaires. Study-specific hazard ratios and 95% confidence intervals were estimated using Cox regression models and were combined using a fixed-effects meta-analytic model. Data from all studies were aggregated, and aggregated hazard ratios were estimated. The analysis included 508,842 individuals, with 2,489 incident cases of bladder cancer. A reduction in risk was observed for individuals who reported regular use (>2 times/week) of nonaspirin NSAIDs compared with those who reported no use (hazard ratio (HR) = 0.92, 95% confidence interval (CI): 0.81, 1.04). The risk reduction was limited to nonsmokers (HR = 0.58, 95% CI: 0.41, 0.83) (P(trend) = 0.008) (P(interaction) = 0.02). No association was observed between regular aspirin use and bladder cancer risk (HR = 1.04, 95% CI: 0.94, 1.15). Results suggest that nonaspirin NSAIDs, but not aspirin, are associated with a reduction in risk of bladder cancer, particularly for nonsmokers. PMID:21367875

  20. A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib

    PubMed Central

    YERLIKAYA, AZMI; ERDOĞAN, ELIF; OKUR, EMRAH; YERLIKAYA, ŞERIFE; SAVRAN, BIRCAN

    2016-01-01

    Glucose-regulated protein 78 kDa/binding immunoglobulin protein (GRP78/BIP) is a well-known endoplasmic reticulum (ER) chaperone protein regulating ER stress by facilitating protein folding, assembly and Ca2+ binding. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics. Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study first examined the dose- and time-dependent effects of bortezomib on GRP78 expression levels in the highly metastatic mouse breast cancer 4T1 cell line using western blot analysis. The analysis results revealed that GRP78 levels were significantly increased by bortezomib at a dose as low as 10 nM. Time-dependent experiments indicated that the accumulation of GRP78 was initiated after a 24 h incubation period following the addition of 10 nM bortezomib. Subsequently, the present study determined the half maximal inhibitory concentration of intracellular calcium chelator BAPTA-AM (13.6 µM) on 4T1 cells. The combination effect of BAPTA-AM and bortezomib on the 4T1 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and WST-1 assays and an iCELLigence system. The results revealed that the combination of 10 nM bortezomib + 5 µM BAPTA-AM is more cytotoxic compared with monotherapies, including 10 nM bortezomib, 1 µM BAPTA-AM and 5 µM BAPTA-AM. In addition, the present results revealed that bortezomib + BAPTA-AM combination causes cell death through the induction of apoptosis. The present results also revealed that bortezomib + BAPTA-AM combination-induced apoptosis is associated with a clear increase in the phosphorylation of stress-activated protein kinase/Jun amino-terminal kinase SAPK/JNK. Overall, the present results suggest that bortezomib and BAPTA-AM combination therapy may be a novel therapeutic strategy for breast cancer treatment

  1. Combination strategies to enhance the potency of monocyte-derived dendritic cell-based cancer vaccines.

    PubMed

    Fecek, Ronald J; Storkus, Walter J

    2016-10-01

    Dendritic cells (DCs) are potent inducers of adaptive immunity and their clinical use in cancer vaccine formulations remains an area of active translational and clinical investigation. Although cancer vaccines applied as monotherapies have had a modest history of clinical success, there is great enthusiasm for novel therapeutic strategies combining DC-based cancer vaccines with agents that 'normalize' immune function in the tumor microenvironment (TME). Broadly, these combination vaccines are designed to antagonize/remove immunosuppressive networks within the TME that serve to limit the antitumor action of vaccine-induced T cells and/or to condition the TME to facilitate the recruitment and optimal function and durability of vaccine-induced T cells. Such combination regimens are expected to dramatically enhance the clinical potency of DC-based cancer vaccine platforms. PMID:27605069

  2. [R0 Resection of Locally Advanced Pancreatic Cancer after Combination Chemotherapy with Gemcitabine and S-1].

    PubMed

    Kametaka, Hisashi; Makino, Hironobu; Fukada, Tadaomi; Seike, Kazuhiro; Koyama, Takashi; Hasegawa, Akio

    2015-11-01

    A 68-year-old female was referred to our institution in October 2014 for additional therapy for cancer of the head of the pancreas. Utilizing a computed tomography scan, he was initially diagnosed with locally advanced unresectable cancer because of massive invasion to the superior mesenteric artery (SMA). Combination chemotherapy consisting of gemcitabine and S-1 was administrated for 10 months. Since the tumor was remarkably reduced after chemotherapy, pancreaticoduodenectomy combined with portal vein resection was performed. Since the histopathological findings indicated few residual cancer tissues, our chemotherapy was considered dramatically effective. The postoperative course was uneventful and the patient remains well and without any recurrences 14 months after the surgery. We therefore report a case of locally unresectable pancreatic cancer, which achieved R0 resection after combination chemotherapy with gemcitabine and S-1. PMID:26805123

  3. Effect of ketamine combined with butorphanol on emergence agitation of postoperative patients with gastric cancer

    PubMed Central

    Lin, Liang; Liu, Shuncui; Chen, Zhenyi; Lin, Shaoli

    2016-01-01

    Background This study aimed to investigate the effect of ketamine combined with butorphanol on emergence agitation (EA) in postoperative gastric cancer patients. Materials and methods A total of 150 patients with gastric cancer were included and divided into group B (1 mg butorphanol before anesthesia induction, n=50), group K (1 mg/kg ketamine, n=50), and group C (1 mg butorphanol combined with 1 mg/kg ketamine, n=50). Mean arterial pressure (MAP) and heart rate (HR) at the end of operation, just before extubation (T0) and at 0 minute (T1), 5 minutes (T2), and 30 minutes (T3) after extubation were compared. Statistical analysis of recovery time, extubation time, time in postanesthesia care unit, and EA incidence and adverse reactions were performed. Results There were no differences among groups with respect to MAP and HR at T0 and T1 (P>0.05). Compared with patients in group C, significant reduction of MAP and HR were observed in groups K and B at T2 and T3 (P<0.05), while no differences were found between group K and group B (P>0.05). Recovery time, extubation time, time in postanesthesia care unit, and incidence of EA in group C were significantly less than those in groups K and B (P<0.05), but no differences were observed between group K and group B (P>0.05). Total incidence of adverse reactions were significantly increased in group K compared to those in groups C and B (P<0.05). Conclusion Injection of ketamine combined with butorphanol before anesthesia induction was more effective than injection of ketamine or butorphanol separately in the prevention of EA. PMID:27217761

  4. Spatial Analysis of Colorectal Cancer in Iran.

    PubMed

    Pakzad, Reza; Moudi, Asieh; Pournamdar, Zahra; Pakzad, Iraj; Mohammadian-Hashejani, Abdollah; Momenimovahed, Zohre; Salehiniya, Hamid; Towhidi, Farhad; Makhsosi, Behnam Reza

    2016-01-01

    Colorectal cancer is one of the most common cancers. Due to demographic changes, it is predicted that the incidence of this cancer will increase. Variations of its incidence rate among geographical areas are due to various contributing factors. Since there have been a lack of studies on this topic in our country, the present assessment of spatial patterns of colorectal cancer incidence in Iran was performed. In this ecological study, the new cases of colon cancer were extracted from Cancer Registry Center report of the Health Deputy of Iran in 2009. The reported incidences of the disease were standardized on the basis of the World Health Organization population and the direct method. Then the data were inserted into the GIS software, and finally, using the analysis of hot spots (Getis-Ord Gi) high-risk areas were drawn. Provinces that are higher or lower than the national average (1.9 SD) were considered hot spots or cold spots, significant at the level of 0.05. A total of 6,210 cases of colorectal cancer were registered in Iran in 2009, of which 3,727 were in men and 2,783 in women (age-standardized rates of 11.3 and 10.9 per 100,000 population, respectively). The results showed that in central and northern Iran including Isfahan, Qom, Tehran, Qazvin and Mazandaran significant hot spots in men were present (p <0.05). In women also we have high incidence in northern and central states: Mazandaran province (p<0.01) and the province of Tehran (p<0.05) had higher incidences than the national average and were apparent as significant hot spots. Analysis of the spatial distribution of colorectal cancer showed significant differences between different areas pointing to the necessity for further epidemiological studies into the etiology and early detection. PMID:27165208

  5. The combination of tetraiodothyroacetic acid and cetuximab inhibits cell proliferation in colorectal cancers with different K-ras status.

    PubMed

    Lee, Yee-Shin; Chin, Yu-Tang; Yang, Yu-Chen S H; Wei, Po-Li; Wu, Han-Chung; Shih, Ai; Lu, Yueh-Tong; Pedersen, Jens Z; Incerpi, Sandra; Liu, Leroy F; Lin, Hung-Yun; Davis, Paul J

    2016-07-01

    Thyroid hormone induces cancer cell proliferation through its cell surface receptor integrin αvβ3. Acting via integrin αvβ3, the deaminated T4 analog tetraiodothyroacetic acid (tetrac), and its nanoparticle formulation nano-diamino-tetrac (NDAT) could inhibit cell proliferation and xenograft growth. In this study, we investigated the T4 effects on proliferation in colorectal cancer cell lines based on the proliferation marker expressions at both mRNA and protein levels. The effects of tetrac/NDAT, the monoclonal anti-EGFR antibody cetuximab, and their combinations on colorectal cancer cell proliferation were examined according to the relevant gene expression profiles and cell count analysis. The results showed that T4 significantly enhanced PCNA, Cyclin D1 and c-Myc levels in both K-ras wild type HT-29 and mutant HCT 116 cells. In HCT 116 cells, the combination of NDAT and cetuximab significantly suppressed the mRNA expressions of proliferative genes PCNA, Cyclin D1, c-Myc and RRM2 raised by T4 compared to cetuximab alone. In addition, T4-suppressed mRNA expressions of pro-apoptotic genes p53 and RRM2B could be significantly elevated by the combination of NDAT and cetuximab compared to cetuximab alone. In the K-ras mutant HCT 116 cells, but not in the K-ras wild type COLO 205 cells, the combinations of tetrac/NDAT and cetuximab significantly reduced cell proliferation compared to cetuximab alone. In conclusion, T4 promoted colorectal cancer cell proliferation which could be repressed by tetrac and NDAT. The combinations of tetrac/NDAT and cetuximab potentiated cetuximab actions in K-ras mutant colorectal cancer cells. PMID:26980146

  6. Lung cancer in HIV-infected patients in the combination antiretroviral treatment era

    PubMed Central

    Moltó, José; Sirera, Guillem; Clotet, Bonaventura

    2015-01-01

    The advent of combination antiretroviral treatment (cART) has been followed by a decrease in HIV-associated morbidity and mortality, but also by an apparent increase in the incidence of non-AIDS-defining cancers (NADCs). The risk of lung cancer is substantially higher in HIV-infected patients than in the general population, in part due to aging and tobacco use, and it is the most frequent NADC. The management of lung cancer in HIV-infected patients has some peculiarities that need to be taken into account. This review focuses on the epidemiology, risk factors, and clinical management of lung cancer in HIV-infected patients. In addition, screening tools and future perspectives are also discussed. Keywords Lung cancer; non-AIDS-defining cancers (NADCs); HIV infection; antiretroviral treatment PMID:26798577

  7. SHIELDING ANALYSIS FOR PORTABLE GAUGING COMBINATION SOURCES

    SciTech Connect

    J. TOMPKINS; L. LEONARD; ET AL

    2000-08-01

    Radioisotopic decay has been used as a source of photons and neutrons for industrial gauging operations since the late 1950s. Early portable moisture/density gauging equipment used Americium (Am)-241/Beryllium (Be)/Cesium (Cs)-137 combination sources to supply the required nuclear energy for gauging. Combination sources typically contained 0.040 Ci of Am-241 and 0.010 Ci of CS-137 in the same source capsule. Most of these sources were manufactured approximately 30 years ago. Collection, transportation, and storage of these sources once removed from their original device represent a shielding problem with distinct gamma and neutron components. The Off-Site Source Recovery (OSR) Project is planning to use a multi-function drum (MFD) for the collection, shipping, and storage of AmBe sources, as well as the eventual waste package for disposal. The MFD is an approved TRU waste container design for DOE TRU waste known as the 12 inch Pipe Component Overpack. As the name indicates, this drum is based on a 12 inch ID stainless steel weldment approximately 25 inch in internal length. The existing drum design allows for addition of shielding within the pipe component up to the 110 kg maximum pay load weight. The 12 inch pipe component is packaged inside a 55-gallon drum, with the balance of the interior space filled with fiberboard dunnage. This packaging geometry is similar to the design of a DOT 6M, Type B shipping container.

  8. A combined prognostic serum IL-8 and IL-6 classifier for stage 1 lung cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

    PubMed Central

    Ryan, Bríd M.; Pine, Sharon R.; Chaturvedi, Anil K.; Caporaso, Neil; Harris, Curtis C.

    2014-01-01

    Hypothesis The advent of LDCT for lung cancer screening will likely lead to an increase in the detection of stage I lung cancer. Presently, these patients are primarily treated with surgery alone and ~ 30% will develop recurrence and die. Biomarkers that can identify patients for whom adjuvant chemotherapy would be a benefit could significantly reduce both patient morbidity and mortality. Herein, we sought to build a prognostic inflammatory-based classifier for stage I lung cancer. Methods We performed a retrospective analysis of 548 European American lung cancer cases prospectively enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) study. CRP, IL-6, IL-8, TNFα and IL-1β were measured using an ultrasensitive electrochemiluminescence immunoassay in serum samples collected at the time of study entry. Results IL-6 and IL-8 were each associated with significantly shorter survival (HR, 1.33; 95% CI, 1.08–1.64, P=0.007) (HR, 1.3; 95% CI, 1.09–1.67, P=0.005), respectively). Moreover, a combined classifier of IL-6 and IL-8 were significantly associated with poor outcome in stage I lung cancer patients (HR, 3.39; 95% C.I. 1.54 – 7.48, P=0.002) and in stage 1 patients with ≥30 pack-years of smoking (HR, 3.15; 95% C.I. 1.54 – 6.46, P=0.002). Conclusions These results further support the association between inflammatory markers and lung cancer outcome and suggest that a combined serum IL-6/IL-8 classifier could be a useful tool for guiding therapeutic decisions in stage I lung cancer patients. PMID:25170636

  9. Atomic-Based-Combined-Cycle Analysis

    NASA Technical Reports Server (NTRS)

    Han, Sam; Bai, Don; Schmidt, George

    2000-01-01

    Atomic-based-combined-cycle (ABCC) engine combines an air-breathing ramjet engine with an atomic reactor to increase the mission-averaged specific impulse and thereby increasing the dry-mass ratio. ABCC engine is similar to RBCC engine except that energy needed for the propulsive power is derived from nuclear reaction rather than chemical combustion used in the RBCC engine. The potential performance improvement of an ABCC engine over a RBCC engine comes from two factors. Firstly, the energy density of nuclear reaction is several order of magnitudes higher than the chemical combustion. Secondly, hydrogen can produce much higher nozzle exit velocity because of its small molecular weight. A one-dimensional, transient numerical model was used to analyze a generic scramjet engine and it is used as a baseline to evaluate an imaginary ABCC engine performance. A nuclear reactor is treated as a black box energy source that replaces the role of the primary rocket and the chemical combustion chamber in a RBCC engine. Hydrogen is heated by the reactor and accelerated to produce high-speed ejection velocity. The ejection velocity up 10,000 m/sec is theoretically possible because of high energy density from the reactor and large gas constant of the hydrogen. Oxygen contained in the entrained air reacts with hydrogen and produces propulsive power for ejector mode operation. To provide enough thrust for initial acceleration, relatively large amount of hydrogen must be pumped through the reactor. Amount of oxygen contained in the entrained air may not be sufficient to burn all hydrogen and consequently combustion could occur at the end of exit nozzle. It is assumed that this combustion process is constant-pressure combustion at 1.0 atmospheric pressure and thus not affects the nozzle exit condition.

  10. Atomic-Based-Combined-Cycle Analysis

    NASA Technical Reports Server (NTRS)

    Han, Samuel S.

    1999-01-01

    Atomic-based-combined-cycle (ABCC) engine combines an air-breathing ramjet engine with an atomic reactor to increase the mission-averaged specific impulse and thereby increasing the dry-mass ratio. ABCC engine is similar to RBCC engine except that energy needed for the propulsive power is derived from nuclear reaction rather than chemical combustion used in the RBCC engine. The potential performance improvement of an ABCC engine over a RBCC engine comes from two factors. Firstly, the energy density of nuclear reaction is several order of magnitudes higher than the chemical combustion. Secondly, hydrogen can produce much higher nozzle exit velocity because of its small molecular weight. A one-dimensional, transient numerical model was used to analyze a generic RBCC engine and it is used as a baseline to evaluate an imaginary ABCC engine performance. A nuclear reactor is treated as a black box energy source that replaces the role of the primary rocket and the chemical combustion chamber in a RBCC engine. The performance of a generic ABCC engine along a flight path (q0 =10 (exp 3) lbf per square ft) shows that the mission averaged-specific impulse is about twice larger than RBCC engine and the dry mass-ratio is about 50% larger. Results of the present ABCC engine performance are based on the assumptions that the flow passage of working fluids is identical to that of RBCC engine and that a nuclear reactor is treated as an energy black box. Preliminary heat transfer calculation shows that the rate of heat transfer to the working fluids is within the limit of turbulent convective heat transfer regimes. The flow passage of realistic ABCC engine must be known for a better prediction of ABCC engine performance. Also, critical heat transfer calculations must be performed for the ejector mode and ramjet mode operations. This is possible only when the details of a reactor configuration are available.

  11. Recent Advances in Delivery of Drug-Nucleic Acid Combinations for Cancer Treatment

    PubMed Central

    Li, Jing; Wang, Yan; Zhu, Yu; Oupický, David

    2013-01-01

    Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations. PMID:23624358

  12. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions

    PubMed Central

    Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S. Tomlinson

    2016-01-01

    Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

  13. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions.

    PubMed

    Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S Tomlinson

    2016-01-01

    Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

  14. Pathway-based analysis of breast cancer

    PubMed Central

    Song, Dong; Cui, Miao; Zhao, Gang; Fan, Zhimin; Nolan, Katherine; Yang, Ying; Lee, Peng; Ye, Fei; Zhang, David Y

    2014-01-01

    Introduction: Although HER2 and ER pathways are predominant pathways altered in breast cancer, it is now well accepted that many other signaling pathways are also involved in the pathogenesis of breast cancer. The understanding of these additional pathways may assist in identifying new therapeutic approaches for breast cancer. Methods: 13 invasive ductal carcinoma tissues and 5 benign breast tissues were analyzed for the mRNA expression level of 1243 cancer pathway-related genes using SmartChip (WaferGen, CA), a real-time PCR-base method. In addition, the levels of 131 cancer pathway-related proteins and phosphoproteins in 33 paired breast cancers were measured using our innovative Protein Pathway Array. Results: Out of 1,243 mRNAs, 68.7% (854) were detected in breast cancer and 395 mRNAs were statistically significant (fold change >2) between benign and cancer tissues. Of these mRNAs, 105 only expressed in breast cancer tissues and 33 mRNAs only expressed in normal breast tissues. Out of 131 proteins and phosphoproteins, 68% (89) were detected in cancer tissues and 57 proteins were significantly differentiated between tumor and normal tissues. Interestingly, only 3 genes (CDK6, Vimentin and SLUG) showed decreases in both protein and mRNA. Six proteins (BCL6, CCNE1, PCNA, PDK1, SRC and XIAP) were differentially expressed between tumor and normal tissues but no differences were observed at mRNA levels. Analyses of mRNA and protein data using Ingenuity Pathway Analysis showed more than 15 pathways were altered in breast cancer and 6 of which were shared between mRNAs and proteins, including p53, IL17, HGF, NGF, PTEN and PI3K/AKT pathways. Conclusions: There is a broad dysregulation of various pathways in breast cancer both at protein levels and mRNA levels. It is important to note that mRNA expression does not correlate with protein level, suggesting different regulation mechanisms between proteins and mRNAs. PMID:24936222

  15. Traditional Chinese patent medicines for cancer treatment in China: a nationwide medical insurance data analysis

    PubMed Central

    Wu, Min; Lu, Peng; Shi, Luwen; Li, Shao

    2015-01-01

    Based on the nationwide survey into inpatients' utilization of the health service covered by China's urban basic medical insurance from 2008 to 2010, we analyzed the use rate, cancer profile and combined use of anticancer Chinese patent medicines (CPMs) on 51,382 insured cancer patients by using statistical, bi-clustering and network methods. We found that 42.4% of 51,382 cancer patients used 33 anticancer CPMs, and 51.7% used 71 anticancer Western medicines (WMs). The CPMs were most often used in lung (52%) and nasopharynx (52%) cancer patients, and least in bladder cancer (21%) and leukemia of unspecified cell type (21%) patients. The cost per patient for all 33 anticancer CPMs was 2069RMB, lower than that of the WMs (3458RMB). The cancer profile of commonly used CPMs and WMs for the top 17 cancers (>500 sampled patients) were provided, indicating anticancer CPMs had a broad spectrum of cancers and lacked selectivity in cancer treatment (CPM mean CV = 49%; WM mean CV = 152%). Moreover, 24.8% of the cancer patients used both CPMs and WMs, and CPM-WM combined use networks were constructed for four major cancers. This first nationwide analysis revealed the use characteristics and herb-drug combined use patterns of insurance covered anticancer CPMs in China. The study offers valuable information to guide future studies of the precision, safety and standard use of CPMs. PMID:26513017

  16. Combination of structural reliability and interval analysis

    NASA Astrophysics Data System (ADS)

    Qiu, Zhiping; Yang, Di; Elishakoff, Isaac

    2008-02-01

    In engineering applications, probabilistic reliability theory appears to be presently the most important method, however, in many cases precise probabilistic reliability theory cannot be considered as adequate and credible model of the real state of actual affairs. In this paper, we developed a hybrid of probabilistic and non-probabilistic reliability theory, which describes the structural uncertain parameters as interval variables when statistical data are found insufficient. By using the interval analysis, a new method for calculating the interval of the structural reliability as well as the reliability index is introduced in this paper, and the traditional probabilistic theory is incorporated with the interval analysis. Moreover, the new method preserves the useful part of the traditional probabilistic reliability theory, but removes the restriction of its strict requirement on data acquisition. Example is presented to demonstrate the feasibility and validity of the proposed theory.

  17. Enhanced anticancer effect of ABT-737 in combination with naringenin on gastric cancer cells

    PubMed Central

    ZHANG, HAIYANG; ZHONG, XIA; ZHANG, XIAO; SHANG, DEYA; ZHOU, YI; ZHANG, CHUNQING

    2016-01-01

    Gastric cancer is the second leading cause of cancer-associated mortality and is a frequently occurring cancer worldwide. Multiple drug resistance of gastric cancer cells leads to the poor prognosis. In addition, overexpression of anti-apoptotic protein B-cell lymphoma (Bcl)-2 have been demonstrated in various cancer cells and is closely associated with drug resistance and poor prognosis. Naringenin is a flavonoid that has antimutagenic and anticarcinogenic activities in numerous cancer types. In the present study, naringenin and a Bcl-2 inhibitor, ABT-737, were used to investigate their combinative anticancer effect in the SGC7901 gastric cancer cell line. The results revealed that naringenin and ABT-737 were able to inhibit SGC7901 cell growth and colony formation, alone or in combination. Furthermore, the combination of these drugs was found to further increase the cleavage of caspase-3 and poly ADP-ribose polymerase. Naringenin and ABT-737 also decreased Akt activation and increased p53 expression, suggesting the involvement of these pathways in the inhibition of gastric cell growth. PMID:26893664

  18. Imaging nonmelanoma skin cancers with combined ultrasound-photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Sunar, Ulas; Rohrbach, Daniel J.; Morgan, Janet; Zeitouni, Natalie

    2013-03-01

    PDT has become a treatment of choice especially for the cases with multiple sites and large areas. However, the efficacy of PDT is limited for thicker and deeper tumors. Depth and size information as well as vascularity can provide useful information to clinicians for planning and evaluating PDT. High-resolution ultrasound and photoacoustic imaging can provide information regarding skin structure and vascularity. We utilized combined ultrasound-photoacoustic microscopy for imaging a basal cell carcinoma (BCC) tumor pre-PDT and the results indicate that combined ultrasound-photoacoustic imaging can be useful tool for PDT planning by providing both structural and functional contrasts.

  19. The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

    PubMed

    Ge, Yanxiu; Ma, Yakun; Li, Lingbing

    2016-10-01

    Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. PMID:27400243

  20. Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid

    SciTech Connect

    Eitsuka, Takahiro; Tatewaki, Naoto; Nishida, Hiroshi; Kurata, Tadao; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2014-10-24

    Highlights: • δ-Tocotrienol (δ-T3) and ferulic acid (FA) synergistically inhibit cancer cell growth. • The combination of δ-T3 and FA induces G1 arrest by up-regulating p21. • The synergy is attributed to an increase in the cellular concentration of δ-T3 by FA. - Abstract: Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly δ-tocotrienol (δ-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of δ-T3 and FA markedly reduced cell proliferation relative to δ-T3 alone, and FA had no effect when used alone. Although δ-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of δ-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of δ-T3 by FA. Our results suggest that the combination of δ-T3 and FA may present a new strategy for cancer prevention and therapy.

  1. Optical pathology of human brain metastasis of lung cancer using combined resonance Raman and spatial frequency spectroscopies

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; Pu, Yang; Cheng, Gangge; Zhou, Lixin; Chen, Jun; Zhu, Ke; Alfano, Robert R.

    2016-03-01

    Raman spectroscopy has become widely used for diagnostic purpose of breast, lung and brain cancers. This report introduced a new approach based on spatial frequency spectra analysis of the underlying tissue structure at different stages of brain tumor. Combined spatial frequency spectroscopy (SFS), Resonance Raman (RR) spectroscopic method is used to discriminate human brain metastasis of lung cancer from normal tissues for the first time. A total number of thirty-one label-free micrographic images of normal and metastatic brain cancer tissues obtained from a confocal micro- Raman spectroscopic system synchronously with examined RR spectra of the corresponding samples were collected from the identical site of tissue. The difference of the randomness of tissue structures between the micrograph images of metastatic brain tumor tissues and normal tissues can be recognized by analyzing spatial frequency. By fitting the distribution of the spatial frequency spectra of human brain tissues as a Gaussian function, the standard deviation, σ, can be obtained, which was used to generate a criterion to differentiate human brain cancerous tissues from the normal ones using Support Vector Machine (SVM) classifier. This SFS-SVM analysis on micrograph images presents good results with sensitivity (85%), specificity (75%) in comparison with gold standard reports of pathology and immunology. The dual-modal advantages of SFS combined with RR spectroscopy method may open a new way in the neuropathology applications.

  2. Theragnosis-based combined cancer therapy using doxorubicin-conjugated microRNA-221 molecular beacon.

    PubMed

    Lee, Jonghwan; Choi, Kyung-Ju; Moon, Sung Ung; Kim, Soonhag

    2016-01-01

    Recently, microRNA (miRNA or miR) has emerged as a new cancer biomarker because of its high expression level in various cancer types and its role in the control of tumor suppressor genes. In cancer studies, molecular imaging and treatment based on target cancer markers have been combined to facilitate simultaneous cancer diagnosis and therapy. In this study, for combined therapy with diagnosis of cancer, we developed a doxorubicin-conjugated miR-221 molecular beacon (miR-221 DOXO MB) in a single platform composed of three different nucleotides: miR-221 binding sequence, black hole quencher 1 (BHQ1), and doxorubicin binding site. Imaging of endogenous miR-221 was achieved by specific hybridization between miR-221 and the miR-221 binding site in miR-221 DOXO MB. The presence of miR-221 triggered detachment of the quencher oligo and subsequent activation of a fluorescent signal of miR-221 DOXO MB. Simultaneous cancer therapy in C6 astrocytoma cells and nude mice was achieved by inhibition of miRNA-221 function that downregulates tumor suppressor genes. The detection of miR-221 expression and inhibition of miR-221 function by miR-221 DOXO MB provide the feasibility as a cancer theragnostic probe. Furthermore, a cytotoxic effect was induced by unloading of doxorubicin intercalated into miR-221 DOXO MB inside cells. Loss of miR-221 function and cytotoxicity induced by the miR-221 DOXO MB provides combined therapeutic efficacy against cancers. This method could be used as a new theragnostic probe with enhanced therapy to detect and inhibit many cancer-related miRNAs. PMID:26454049

  3. Differential action on cancer and normal tissue by adrenochrome monoaminoguanidine methanesulfonate and cytochrome C combined with radiotherapy

    SciTech Connect

    Nakatsugawa, S. ); Sugahara, T. )

    1994-06-15

    The possibility that radioprotective effects on potent natural killer (NK) cells by adrenochrome monoaminoguanidine methanesulfonate (AMM) + cytochrome C during radiotherapy (RT) for lung cancer might result in the radiosensitization of human lung cancer cells in vivo is examined. Human lung cancer xenografts in the right hind legs of KSN mice (10 weeks old) were locally irradiated with 20 Gy of X ray. AMM (10 mg/kg/day) and/or cytochrome C (CCC) (5 mg/kg/day) were given intraperitoneally immediately before or after RT, followed by daily administration for 4 days. Natural killer activities of host splenocytes were also tested with the standard [sup 51]Cr releasing assay with YAC-1 cells as target cells. In a clinical study, 65 patients with lung cancer were treated with more than 50 Gy of RT with or without combination with AMM + CCC, OK-432 or AMM + CCC + OK-432. Before and after RT, lymphocyte subsets in the peripheral blood were examined with dichromatic analysis using an Ortho Spectrum IIIFCM system and fluorescent MABs. In this study, the change in the absolute number of each subset was investigated. AMM + cytochrome C augumented NK activity in KSN nude mice, protected potent NK cells in patients with lung cancer against RT and sensitized the human lung cancer xenografts to RT. AMM + cytochrome C may have potential as a differential modulator of radiosensitivity of normal tissues and of tumors. 8 refs., 2 figs., 1 tab.

  4. Content analysis of cancer blog posts*

    PubMed Central

    Kim, Sujin

    2009-01-01

    Objectives: The efficacy of user-defined subject tagging and software-generated subject tagging for describing and organizing cancer blog contents was explored. Methods: The Technorati search engine was used to search the blogosphere for cancer blog postings generated during a two-month period. Postings were mined for relevant subject concepts, and blogger-defined tags and Text Analysis Portal for Research (TAPoR) software–defined tags were generated for each message. Descriptive data were collected, and the blogger-defined tags were compared with software-generated tags. Three standard vocabularies (Opinion Templates, Basic Resource, and Medical Subject Headings [MeSH] Resource) were used to assign subject terms to the blogs, with results compared for efficacy in information retrieval. Results: Descriptive data showed that most of the studied cancer blogs (80%) contained fewer than 500 words each. The numbers of blogger-defined tags per posting (M = 4.49 per posting) were significantly smaller than the TAPoR keywords (M = 23.55 per posting). Both blogger-defined subject tags and software-generated subject tags were often overly broad or overly narrow in focus, producing less than effective search results for those seeking to extract information from cancer blogs. Conclusions: Additional exploration into methods for systematically organizing cancer blog postings is necessary if blogs are to become stable and efficacious information resources for cancer patients, friends, families, or providers. PMID:19851489

  5. Combination Therapy of Lactobacillus plantarum Supernatant and 5-Fluouracil Increases Chemosensitivity in Colorectal Cancer Cells.

    PubMed

    An, JaeJin; Ha, Eun-Mi

    2016-08-28

    Colorectal cancer (CRC) is the third most common cancer in the world. Although 5-fluorouracil (5-FU) is the representative chemotherapy drug for colorectal cancer, it has therapeutic limits due to its chemoresistant characteristics. Colorectal cancer cells can develop into cancer stem cells (CSCs) with self-renewal potential, thereby causing malignant tumors. The human gastrointestinal tract contains a complex gut microbiota that is essential for the host's homeostasis. Recently, many studies have reported correlations between gut flora and the onset, progression, and treatment of CRC. The present study confirms that the most representative symbiotic bacteria in humans, Lactobacillus plantarum (LP) supernatant (SN), selectively inhibit the characteristics of 5-FU-resistant colorectal cancer cells (HT-29 and HCT- 116). LP SN inhibited the expression of the specific markers CD44, 133, 166, and ALDH1 of CSCs. The combination therapy of LP SN and 5-FU inhibited the survival of CRCs and led to cell death by inducing caspase-3 activity. The combination therapy of LP SN and 5-FU induced an anticancer mechanism by inactivating the Wnt/β-catenin signaling of chemoresistant CRC cells, and reducing the formation and size of colonospheres. In conclusion, our results show that LP SN can enhance the therapeutic effect of 5-FU for colon cancer, and reduce colorectal cancer stem-like cells by reversing the development of resistance to anticancer drugs. This implies that probiotic substances may be useful therapeutic alternatives as biotherapeutics for chemoresistant CRC. PMID:27221111

  6. Prediction of Candidate Drugs for Treating Pancreatic Cancer by Using a Combined Approach

    PubMed Central

    Dong, Xinran; Li, Ying; Yang, Bo; Tian, Weidong; Wang, Xiaoqin

    2016-01-01

    Pancreatic cancer is the leading cause of death from solid malignancies worldwide. Currently, gemcitabine is the only drug approved for treating pancreatic cancer. Developing new therapeutic drugs for this disease is, therefore, an urgent need. The C-Map project has provided a wealth of gene expression data that can be mined for repositioning drugs, a promising approach to new drug discovery. Typically, a drug is considered potentially useful for treating a disease if the drug-induced differential gene expression profile is negatively correlated with the differentially expressed genes in the target disease. However, many of the potentially useful drugs (PUDs) identified by gene expression profile correlation are likely false positives because, in C-Map, the cultured cell lines to which the drug is applied are not derived from diseased tissues. To solve this problem, we developed a combined approach for predicting candidate drugs for treating pancreatic cancer. We first identified PUDs for pancreatic cancer by using C-Map-based gene expression correlation analyses. We then applied an algorithm (Met-express) to predict key pancreatic cancer (KPC) enzymes involved in pancreatic cancer metabolism. Finally, we selected candidates from the PUDs by requiring that their targets be KPC enzymes or the substrates/products of KPC enzymes. Using this combined approach, we predicted seven candidate drugs for treating pancreatic cancer, three of which are supported by literature evidence, and three were experimentally validated to be inhibitory to pancreatic cancer celllines. PMID:26910401

  7. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases. PMID:27431631

  8. Risk of cancer with combined oral contraceptive use among Iranian women.

    PubMed

    Vaisy, Afasaneh; Lotfinejad, Shirin; Zhian, Faegh

    2014-01-01

    Oral contraceptive use is the most common type of contraception. More than 300 million women worldwide take oral contraceptives every day. However, there is a concern about the relationship with the incidence of cancer. This analytical retrospective study aimed to investigate the relationship between the incidence of cervical and breast cancers and oral contraceptive use in 128 Iranian patients with cervical cancer, 235 with breast cancer and equal numbers of controls. Data were collected through interviews with an organized set of questions. Details were also extracted from patient files. Data were analyzed using Student's t-test, chi-square and Fisher's exact tests, and Pearson's correlation analysis. The result revealed correlations between both cervical and breast cancers and history of contraceptive pills use. While cervical cancer significantly correlated with duration of use of pills, breast cancer had significant correlations with the type of oral contraceptive and age at first use. No significant relationships were found between the two types of cancer and age at discontinuation of oral contraceptives, patterns of use, and intervals from the last use. The use of oral contraceptives may triple the incidence of cervical cancer and doubles the incidence of breast cancer. Therefore, performing Pap smears every six months and breast cancer screening are warranted for long-term oral contraceptive users. PMID:25081657

  9. Combination Chemotherapy With or Without Vismodegib in Treating Patients With Advanced Stomach Cancer or Gastroesophageal Junction Cancer

    ClinicalTrials.gov

    2015-12-16

    Adenocarcinoma of the Gastroesophageal Junction; Adenocarcinoma of the Stomach; Recurrent Gastric Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Gastric Cancer

  10. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.

    PubMed

    Liang, Han; Cheung, Lydia W T; Li, Jie; Ju, Zhenlin; Yu, Shuangxing; Stemke-Hale, Katherine; Dogruluk, Turgut; Lu, Yiling; Liu, Xiuping; Gu, Chao; Guo, Wei; Scherer, Steven E; Carter, Hannah; Westin, Shannon N; Dyer, Mary D; Verhaak, Roeland G W; Zhang, Fan; Karchin, Rachel; Liu, Chang-Gong; Lu, Karen H; Broaddus, Russell R; Scott, Kenneth L; Hennessy, Bryan T; Mills, Gordon B

    2012-11-01

    Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. PMID:23028188

  11. Antiproliferative and Proapoptotic Effects of Crocin Combined with Hyperthermia on Human Breast Cancer Cells.

    PubMed

    Mostafavinia, Seyedeh Elham; Khorashadizadeh, Mohsen; Hoshyar, Reyhane

    2016-07-01

    We investigated the suppressive effects of crocin alone and in combination with hyperthermia (HT) on proliferation of breast cancer cells. Cell viability, colony formation ability, and apoptosis were assessed by 3-(4,5-dimetylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT), soft agar, Hoechst 33258 staining, and percentage of lactate dehydrogenase (LDH) release methods, respectively. The mRNA levels Hsp27, Hsp70, Hsp90, Bax, and Bcl-2 were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Hsp70 and Hsp90 proteins were determined using enzyme-linked immunosorbent assay (ELISA) technique. Crocin in combination with HT significantly inhibited the proliferation of cancer cells in a dose- and time-dependent manner. There was a degree of synergism in the combined treatment. However, crocin did not show the high cytotoxic effect on normal cells. This treatment decreased colony formation of cancer cells up to 94%. Changed nuclear morphology and increased LDH indicated that crocin combined with HT has a more apoptotic effect than crocin alone. Furthermore, in treated cells Bax/Bcl-2 ratio markedly increased, whereas expression of heat-induced genes decreased. Also, the Hsp70 and Hsp90 proteins decreased in the treated cells. Our study indicated that combination of crocin and HT has strong antiproliferative and apoptotic activities against breast cancer cells. Hence, it is suggested that more studies are warranted to apply crocin as a possible, safe, and promising anticancer agent in cancer. PMID:27003728

  12. Combined Modality Therapy Including Intraoperative Electron Irradiation for Locally Recurrent Colorectal Cancer

    SciTech Connect

    Haddock, Michael G.; Miller, Robert C.; Nelson, Heidi; Pemberton, John H.; Dozois, Eric J.; Alberts, Steven R.; Gunderson, Leonard L.

    2011-01-01

    Purpose: To evaluate survival, relapse patterns, and prognostic factors in patients with colorectal cancer relapse treated with curative-intent therapy, including intraoperative electron radiation therapy (IOERT). Methods and Materials: From April 1981 through January 2008, 607 patients with recurrent colorectal cancer received IOERT as a component of treatment. IOERT was preceded or followed by external radiation (median dose, 45.5 Gy) in 583 patients (96%). Resection was classified as R0 in 227 (37%), R1 in 224 (37%), and R2 in 156 (26%). The median IOERT dose was 15 Gy (range, 7.5-30 Gy). Results: Median overall survival was 36 months. Five- and 10-year survival rates were 30% and 16%, respectively. Survival estimates at 5 years were 46%, 27%, and 16% for R0, R1, and R2 resection, respectively. Multivariate analysis revealed that R0 resection, no prior chemotherapy, and more recent treatment (in the second half of the series) were associated with improved survival. The 3-year cumulative incidence of central, local, and distant relapse was 12%, 23%, and 49%, respectively. Central and local relapse were more common in previously irradiated patients and in those with subtotal resection. Toxicity Grade 3 or higher partially attributable to IOERT was observed in 66 patients (11%). Neuropathy was observed in 94 patients (15%) and was more common with IOERT doses exceeding 12.5 Gy. Conclusions: Long-term survival and disease control was achievable in patients with locally recurrent colorectal cancer. Continued evaluation of curative-intent, combined-modality therapy that includes IOERT is warranted in this high-risk population.

  13. The Efficacy of Combining Antiangiogenic Agents with Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer Who Failed First-Line Chemotherapy: A Systematic Review and Meta-Analysis

    PubMed Central

    Yang, Bijun; Zhang, Yaxiong; Kang, Shiyang; Zhou, Ting; Hong, Shaodong; Qin, Tao; Hu, Zhihuang; Fang, Wenfeng; Huang, Yan; Zhang, Li

    2015-01-01

    Background The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients. Methods We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients. Results Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02). Conclusions This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy. PMID:26034985

  14. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging

    PubMed Central

    Glasgow, Micah D. K.; Chougule, Mahavir B.

    2016-01-01

    Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug’s therapeutic effectiveness while reducing adverse side effects associated with high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an “active” molecular marker targeted approach would be beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging. PMID:26554150

  15. Combining polarimetry and spectropolarimetry techniques in diagnostics of cancer changes in biological tissues

    NASA Astrophysics Data System (ADS)

    Yermolenko, Sergey; Ivashko, Pavlo; Gruia, Ion; Gruia, Maria; Peresunko, Olexander; Zelinska, Natalia; Voloshynskyi, Dmytro; Fedoruk, Olexander; Zimnyakov, Dmitry; Alonova, Marina

    2015-02-01

    The aim of the study is combining polarimetry and spectropolarimetry techniques for identifying the changes of opticalgeometrical structure in different kinds of biotissues with solid tumours. It is researched that a linear dichroism appears in biotissues (human esophagus, muscle tissue of rats, human prostate tissue, cervical smear) with cancer diseases, magnitude of which depends on the type of the tissue and on the time of cancer process development.

  16. Radiotherapy Combined With Androgen Deprivation for Bone Oligometastases After Primary Curative Radiotherapy for Prostate Cancer

    PubMed Central

    Wu, Jun-Xin; Lin, Li-Mei; He, Jun-Yan; Hong, Liang; Li, Jin-Luan

    2016-01-01

    Abstract To evaluate the effects and toxicity of radiotherapy (RT) combined with androgen deprivation (AD) for bone oligometastases after primary curative RT for prostate cancer (PCa). We retrospectively analyzed 30 consecutively treated PCa patients with bone oligometastases from April 2005 to July 2014. All patients underwent RT combined with AD for oligometastatic bones after curative RT for PCa. Measured outcomes included overall survival (OS) rate, local control (LC), progression-free survival (PFS), pain relief, and toxicities. Statistical analysis was performed with SPSS17.0. The median follow-up was 32.5 months (range, 0.6–50.3). The 3-year PFS and OS rates were 22.8% (95% CI, 13.4–37.5%) and 69% (95% CI, 51.7–81.1%), respectively. The number of bone oligometastases and RT schedule were found to be significantly associated with OS on univariate analysis (P < 0.05, respectively). The 3-year OS for patients with 1 and >1 metastases was 78.8% versus 42.2%, respectively (P = 0.037). The long-course RT was associated with better 3-year OS compared with short-course (76.4% vs 44.1%, P = 0.03). A total of 15 (83.3%, 15/18) patients achieved pain relief. No grade 3 toxicity was observed. Long-course RT combined with ADT was effective and well-tolerated in PCa patients with bone oligometastases after curative RT for PCa. Further randomized controlled trials are needed to corroborate the findings. PMID:26871838

  17. Combining immunological and androgen-directed approaches: an emerging concept in prostate cancer immunotherapy

    PubMed Central

    Antonarakis, Emmanuel S.; Drake, Charles G.

    2012-01-01

    Purpose of review The autologous antigen-presenting cell immunotherapy, sipuleucel-T, was the first and remains the only US Food and Drug Administration-approved immunotherapy for prostate cancer. In this article, we will summarize recent clinical data on several additional immune-directed strategies, some of which have now entered phase 3 trials. Recent findings Multiple studies are now testing sipuleucel-T in different disease settings and/or in combination with conventional and novel hormonal therapies. In addition, a poxviral-based vaccine has shown promise in early-phase clinical studies and has now entered phase 3 testing in men with metastatic prostate cancer. Next, a DNA vaccine has been evaluated in men with biochemically recurrent prostate cancer and has shown early signs of clinical efficacy. Finally, several studies are evaluating the role of immune checkpoint blockade using ipilimumab in pivotal phase 3 trials in prostate cancer patients with advanced disease, as well as in earlier phase studies in combination with androgen ablation. Summary The abundance of new treatment options for men with advanced prostate cancer will challenge the role of immunotherapy in these patients. Future progress may rely on optimal combination and sequencing of various immunotherapies with androgen-directed approaches as well as with other standard prostate cancer therapies, an effort which is now just beginning. PMID:22410456

  18. Drug Combinations in Preoperative Chemoradiation for Rectal Cancer.

    PubMed

    Glynne-Jones, Rob; Carvalho, Carlos

    2016-07-01

    Preoperative radiotherapy has an accepted role in reducing the risk of local recurrence in locally advanced resectable rectal cancer, particularly when the circumferential resection margin is breached or threatened, according to magnetic resonance imaging. Fluoropyrimidine-based chemoradiation can obtain a significant down-sizing response and a curative resection can then be achieved. Approximately, 20% of the patients can also obtain a pathological complete response, which is associated with less local recurrences and increased survival. Patients who achieve a sustained complete clinical response may also avoid radical surgery. In unresectable or borderline resectable tumors, around 20% of the patients still fail to achieve a sufficient down-staging response with the current chemoradiation schedules. Hence, investigators have aspired to increase pathological complete response rates, aiming to improve curative resection rates, enhance survival, and potentially avoid mutilating surgery. However, adding additional cytotoxic or biological agents have not produced dramatic improvements in outcome and often led to excess surgical morbidity and higher levels of acute toxicity, which effects on compliance and in the global efficacy of chemoradiation. PMID:27238473

  19. Deciphering intratumor heterogeneity using cancer genome analysis.

    PubMed

    Ryu, Daeun; Joung, Je-Gun; Kim, Nayoung K D; Kim, Kyu-Tae; Park, Woong-Yang

    2016-06-01

    Intratumor heterogeneity within individual cancer tissues underlies the numerous phenotypes of cancer. Tumor subclones ultimately affect therapeutic outcomes due to their distinct molecular features. Drug-resistant subclones are present at a low frequency in tissues at the time of biopsy, but can also arise as a result of acquired somatic mutations. A number of different approaches have been utilized to understand the nature of intratumor heterogeneity. Clonal analysis using whole exome or genome sequencing data can help monitor subclones in the context of tumor progression. Multiregional biopsies permit the molecular characterization of subclones within tumors. Deep sequencing has also provided researchers with the ability to measure the low allele fraction variant within a small number of cells. Ultimately, single-cell sequencing will enable the identification of every minor population within a tumor microenvironment. In the clinical context, the ability to identify and monitor the subclonal architecture of a tumor is valuable for the development of precise cancer therapeutic methods. PMID:27126234

  20. Sparse principal component analysis in cancer research

    PubMed Central

    Hsu, Ying-Lin; Huang, Po-Yu; Chen, Dung-Tsa

    2015-01-01

    A critical challenging component in analyzing high-dimensional data in cancer research is how to reduce the dimension of data and how to extract relevant features. Sparse principal component analysis (PCA) is a powerful statistical tool that could help reduce data dimension and select important variables simultaneously. In this paper, we review several approaches for sparse PCA, including variance maximization (VM), reconstruction error minimization (REM), singular value decomposition (SVD), and probabilistic modeling (PM) approaches. A simulation study is conducted to compare PCA and the sparse PCAs. An example using a published gene signature in a lung cancer dataset is used to illustrate the potential application of sparse PCAs in cancer research. PMID:26719835

  1. Quantitative DNA methylation analysis of candidate genes in cervical cancer.

    PubMed

    Siegel, Erin M; Riggs, Bridget M; Delmas, Amber L; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID:25826459

  2. Quantitative DNA Methylation Analysis of Candidate Genes in Cervical Cancer

    PubMed Central

    Siegel, Erin M.; Riggs, Bridget M.; Delmas, Amber L.; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D.

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97–1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID:25826459

  3. Targeted near infrared hyperthermia combined with immune stimulation for optimized therapeutic efficacy in thyroid cancer treatment

    PubMed Central

    Zhou, Le; Zhang, Mengchao; Fu, Qingfeng; Li, Jingting; Sun, Hui

    2016-01-01

    Treatment of thyroid cancer has incurred much focus because of its high prevalency. As a new strategy treating thyroid cancer, hyperthermia takes several advantages compared with surgery or chemotherapy, including minimal invasion, low systematic toxicity and the ability to enhance the immunogenicity of cancer cells with the expression Hsp70 which serves as Toll-like receptors-4 (TLR-4 agonist). However, Hsp70 as a molecular chaperone can protect cells from heat induced apoptosis and therefore compromise the tumor killing effect of hyperthermia. In this study, to solve this problem, a combined hyperthermia therapy was employed to treat thyroid cancer. We prepared a probe with the tumor targeting agent AG to monitor thyroid tumor issue and generate heat to kill tumor cells in vivo. At the same time Quercetin (inhibitor of HSP70) and lipopolysaccharide (LPS) (agonist of TLR-4) were used for the combined hyperthermia therapy. The results showed that compared with free IR820, AG modification facilitated much enhanced cellular uptake and greatly pronounced tumor targeting ability. The combined therapy exhibited the most remarkable tumor inhibition compared with the single treatments both in vitro and in vivo. These findings verified that the new therapeutic combination could significantly improve the effect of hyperthermia and shed light on a novel clinical strategy in thyroid cancer treatment. PMID:26769848

  4. Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment.

    PubMed

    Vandana, Mallaredy; Sahoo, Sanjeeb K

    2015-08-01

    Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard, we have synthesized Pem-PEG-Gem, wherein pemetrexed (Pem) and gemcitabine (Gem) are conjugated to a heterobifunctional polyethylene glycol (PEG) polymer for the effective treatment of Non-Small Cell Lung Cancer (NSCLC). Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC. PMID:25968494

  5. Two combined photosensitizers: a goal for more effective photodynamic therapy of cancer.

    PubMed

    Acedo, P; Stockert, J C; Cañete, M; Villanueva, A

    2014-01-01

    Photodynamic therapy (PDT) is a clinically approved therapeutic modality for the treatment of diseases characterized by uncontrolled cell proliferation, mainly cancer. It involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species upon irradiation with light, leading to tumor regression. Here a synergistic cell photoinactivation is reported based on the simultaneous administration of two PSs, zinc(II)-phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N-methylpyridyl)porphine (TMPyP) in three cell lines (HeLa, HaCaT and MCF-7), using very low doses of PDT. We detected changes from predominant apoptosis (without cell detachment) to predominant necrosis, depending on the light dose used (2.4 and 3.6 J/cm(2), respectively). Analysis of changes in cytoskeleton components (microtubules and F-actin), FAK protein, as well as time-lapse video microscopy evidenced that HeLa cells were induced to undergo apoptosis, without losing adhesion to the substrate. Moreover, 24 h after intravenous injection into tumor-bearing mice, ZnPc and TMPyP were preferentially accumulated in the tumor area. PDT with combined treatment produced significant retardation of tumor growth. We believe that this combined and highly efficient strategy (two PSs) may provide synergistic curative rates regarding conventional photodynamic treatments (with one PS alone). PMID:24625981

  6. Two combined photosensitizers: a goal for more effective photodynamic therapy of cancer

    PubMed Central

    Acedo, P; Stockert, J C; Cañete, M; Villanueva, A

    2014-01-01

    Photodynamic therapy (PDT) is a clinically approved therapeutic modality for the treatment of diseases characterized by uncontrolled cell proliferation, mainly cancer. It involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species upon irradiation with light, leading to tumor regression. Here a synergistic cell photoinactivation is reported based on the simultaneous administration of two PSs, zinc(II)-phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N-methylpyridyl)porphine (TMPyP) in three cell lines (HeLa, HaCaT and MCF-7), using very low doses of PDT. We detected changes from predominant apoptosis (without cell detachment) to predominant necrosis, depending on the light dose used (2.4 and 3.6 J/cm2, respectively). Analysis of changes in cytoskeleton components (microtubules and F-actin), FAK protein, as well as time-lapse video microscopy evidenced that HeLa cells were induced to undergo apoptosis, without losing adhesion to the substrate. Moreover, 24 h after intravenous injection into tumor-bearing mice, ZnPc and TMPyP were preferentially accumulated in the tumor area. PDT with combined treatment produced significant retardation of tumor growth. We believe that this combined and highly efficient strategy (two PSs) may provide synergistic curative rates regarding conventional photodynamic treatments (with one PS alone). PMID:24625981

  7. Safety Study of MGA271 in Combination With Pembrolizumab in Refractory Cancer

    ClinicalTrials.gov

    2016-05-03

    Melanoma; Head and Neck Cancer; Non Small Cell Lung Cancer; Mesothelioma; Urethelial Carcinoma; Clear Cell Renal Cell Carcinoma; Ovarian Cancer; Thyroid Cancer; Triple Negative Breast Cancer; Pancreatic Cancer; Colon Cancer; Soft Tissue Sarcoma; Prostate Cancer

  8. Safety Study of MGA271 in Combination With Ipilimumab in Refractory Cancer

    ClinicalTrials.gov

    2016-05-03

    Melanoma; Head and Neck Cancer; Non Small Cell Lung Cancer; Mesothelioma; Urothelial Carcinoma; Clear Cell Renal Cell Carcinoma; Ovarian Cancer; Thyroid Cancer; Triple Negative Breast Cancer; Pancreatic Cancer; Colon Cancer; Soft Tissue Sarcoma; Prostate Cancer

  9. Combination of drug-conjugated SWCNT nanocarriers for efficient therapy of cancer stem cells in a breast cancer animal model.

    PubMed

    Al Faraj, Achraf; Shaik, Asma Sultana; Ratemi, Elaref; Halwani, Rabih

    2016-03-10

    Targeting breast cancer and more specifically cancer stem cell (CSC) subpopulation, responsible for tumor growth, resistance and self-renewal, using combination of therapeutic drugs selectively delivered via biocompatible nanocarriers, provides a novel approach for effective therapy. Here, we propose to evaluate the potential therapeutic efficacy of combining Paclitaxel and Salinomycin drugs actively targeted to both breast cancer and CSCs in xenograft murine model after conjugation with biocompatible CD44 antibody conjugated SWCNTs via hydrazone linker allowing pH-responsive release mechanism near the acidic tumor microenvironment. Both in vitro investigations on MDA-MB-231, sorted CSC negative or CSC positive fractions and in vivo evaluations on tumor-bearing mice using noninvasive bioluminescence and magnetic resonance imaging confirmed the enhanced therapeutic effect of the combined therapy compared to treatment with individual drug-conjugated nanocarriers or free drug suspensions. Thus, confirmed the great promise of the developed SWCNTs drug delivery system for effective breast cancer treatment by targeting and eradicating both whole tumor cells and CSCs populations. PMID:26827662

  10. [Combination chemotherapy with VP-16 in the treatment of lung cancer and malignant lymphoma].

    PubMed

    Hosomi, Y; Shibuya, M

    2001-10-01

    Many investigators have reported the dose and schedule of VP-16 administration, but as yet they remain undetermined. VP-16 is one of the most active agents for several carcinomas and usually administered intravenously over 3 to 5 consecutive days in combination with other agents. Although, the development of new drugs recently reduces the use of VP-16 administration, VP-16 is still an important drug for the treatment of lung cancer and malignant lymphoma. In this paper, the combination therapy with VP-16, especially in the treatment of lung cancer and malignant lymphoma, are reviewed. PMID:11681241

  11. Combination Regimens of Radiation Therapy and Therapeutic Cancer Vaccines: Mechanisms and Opportunities

    PubMed Central

    Garnett-Benson, Charlie; Hodge, James W.; Gameiro, Sofia R.

    2014-01-01

    Radiation therapy is widely used with curative or palliative intent in the clinical management of multiple cancers. Although mainly aimed at direct tumor cell killing, mounting evidence suggests that radiation can alter the tumor to become an immunostimulatory milieu. Data suggest that the immunogenic effects of radiation can be exploited to promote synergistic antitumor effects in combination with immunotherapeutic agents. Here we review concepts associated with the immunogenic consequences of radiation therapy, and highlight how preclinical findings are translating into clinical benefit for patients receiving combination regimens of radiation therapy and therapeutic cancer vaccines. PMID:25481266

  12. Gene expression profiling analysis of ovarian cancer

    PubMed Central

    YIN, JI-GANG; LIU, XIAN-YING; WANG, BIN; WANG, DAN-YANG; WEI, MAN; FANG, HUA; XIANG, MEI

    2016-01-01

    As a gynecological oncology, ovarian cancer has high incidence and mortality. To study the mechanisms of ovarian cancer, the present study analyzed the GSE37582 microarray. GSE37582 was downloaded from Gene Expression Omnibus and included data from 74 ovarian cancer cases and 47 healthy controls. The differentially-expressed genes (DEGs) were screened using linear models for microarray data package in R and were further screened for functional annotation. Next, Gene Ontology and pathway enrichment analysis of the DEGs was conducted. The interaction associations of the proteins encoded by the DEGs were searched using the Search Tool for the Retrieval of Interacting Genes, and the protein-protein interaction (PPI) network was visualized by Cytoscape. Moreover, module analysis of the PPI network was performed using the BioNet analysis tool in R. A total of 284 DEGs were screened, consisting of 145 upregulated genes and 139 downregulated genes. In particular, downregulated FBJ murine osteosarcoma viral oncogene homolog (FOS) was an oncogene, while downregulated cyclin-dependent kinase inhibitor 1A (CDKN1A) was a tumor suppressor gene and upregulated cluster of differentiation 44 (CD44) was classed as an ‘other’ gene. The enriched functions included collagen catabolic process, stress-activated mitogen-activated protein kinases cascade and insulin receptor signaling pathway. Meanwhile, FOS (degree, 15), CD44 (degree, 9), B-cell CLL/lymphoma 2 (BCL2; degree, 7), CDKN1A (degree, 7) and matrix metallopeptidase 3 (MMP3; degree, 6) had higher connectivity degrees in the PPI network for the DEGs. These genes may be involved in ovarian cancer by interacting with other genes in the module of the PPI network (e.g., BCL2-FOS, BCL2-CDKN1A, FOS-CDKN1A, FOS-CD44, MMP3-MMP7 and MMP7-CD44). Overall, BCL2, FOS, CDKN1A, CD44, MMP3 and MMP7 may be correlated with ovarian cancer. PMID:27347159

  13. Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention.

    PubMed

    Xiao, Hang; Yang, Chung S

    2008-09-01

    Statins and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for lowering cholesterol and anti-inflammation, respectively. Recently, their potential roles as cancer chemopreventive agents have been subject to intensive studies. Human trials have not provided conclusive results on the protective effects of statins against different cancers, while more convincing results have been observed for cancer preventive effects of NSAIDs, especially on colorectal cancer. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs is to use them in combination, which may produce synergy and lower the dose required for each agent. This strategy is of particular interest for potential use of low doses of statins and NSAIDs on a long-term basis for cancer chemoprevention; increased risks for gastrointestinal and cardiovascular side effects associated with the use of NSAIDs have been observed in colorectal cancer chemopreventive trials. This article reviews the evidence for the cancer preventive actions of statins and NSAIDs, as well as their possible synergistic action and the mechanisms involved. PMID:18548583

  14. Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection

    PubMed Central

    2013-01-01

    Background Although mammary cancer (MC) is the most common malignant neoplasia in women, the mortality for this cancer has decreased principally because of early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause MC regression, doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use is limited due to the rapid development of chemoresistance and to the cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced experimental models of MC. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. Methods Here, we analyzed the effect of I2 in combination with DOX treatment in female Sprague Dawley rats with MNU-induced MC. In the first experiment (short) animals were treated with the therapeutic DOX dose (16 mg/kg) or with lower doses (8 and 4 mg/Kg), in each case with and without 0.05% I2 in drinking water. Iodine treatment began on day 0, a single dose of DOX was injected (ip) on day 2, and the analysis was carried out on day 7. In the second experiment (long) animals with and without iodine supplement were treated with one or two injections of 4 mg/kg DOX (on days 0 and 14) and were analyzed on day 56. Results At all DOX doses, the short I2 treatment induced adjuvant antineoplastic effects (decreased tumor size and proliferating cell nuclear antigen level) with significant protection against body weight loss and cardiotoxicity (creatine kinase MB, cardiac lipoperoxidation, and heart damage). With long-term I2, mammary tumor tissue became more sensitive to DOX, since a single injection of the lowest dose of DOX (4 mg/Kg) was enough to stop tumor progression and a second DOX4 injection on day 14 caused a significant and rapid decrease in tumor size, decreased the expression of chemoresistance markers (Bcl2 and survivin), and increased

  15. An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine

    PubMed Central

    Liu, Yin; Fei, Teng; Zheng, Xiaoqi; Brown, Myles; Zhang, Peng; Liu, X. Shirley; Wang, Haiyun

    2016-01-01

    An individual tumor harbors multiple molecular alterations that promote cell proliferation and prevent apoptosis and differentiation. Drugs that target specific molecular alterations have been introduced into personalized cancer medicine, but their effects can be modulated by the activities of other genes or molecules. Previous studies aiming to identify multiple molecular alterations for combination therapies are limited by available data. Given the recent large scale of available pharmacogenomic data, it is possible to systematically identify multiple biomarkers that contribute jointly to drug sensitivity, and to identify combination therapies for personalized cancer medicine. In this study, we used pharmacogenomic profiling data provided from two independent cohorts in a systematic in silico investigation of perturbed genes cooperatively associated with drug sensitivity. Our study predicted many pairs of molecular biomarkers that may benefit from the use of combination therapies. One of our predicted biomarker pairs, a mutation in the BRAF gene and upregulated expression of the PIM1 gene, was experimentally validated to benefit from a therapy combining BRAF inhibitor and PIM1 inhibitor in lung cancer. This study demonstrates how pharmacogenomic data can be used to systematically identify potentially cooperative genes and provide novel insights to combination therapies in personalized cancer medicine. PMID:26916442

  16. An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine.

    PubMed

    Liu, Yin; Fei, Teng; Zheng, Xiaoqi; Brown, Myles; Zhang, Peng; Liu, X Shirley; Wang, Haiyun

    2016-01-01

    An individual tumor harbors multiple molecular alterations that promote cell proliferation and prevent apoptosis and differentiation. Drugs that target specific molecular alterations have been introduced into personalized cancer medicine, but their effects can be modulated by the activities of other genes or molecules. Previous studies aiming to identify multiple molecular alterations for combination therapies are limited by available data. Given the recent large scale of available pharmacogenomic data, it is possible to systematically identify multiple biomarkers that contribute jointly to drug sensitivity, and to identify combination therapies for personalized cancer medicine. In this study, we used pharmacogenomic profiling data provided from two independent cohorts in a systematic in silico investigation of perturbed genes cooperatively associated with drug sensitivity. Our study predicted many pairs of molecular biomarkers that may benefit from the use of combination therapies. One of our predicted biomarker pairs, a mutation in the BRAF gene and upregulated expression of the PIM1 gene, was experimentally validated to benefit from a therapy combining BRAF inhibitor and PIM1 inhibitor in lung cancer. This study demonstrates how pharmacogenomic data can be used to systematically identify potentially cooperative genes and provide novel insights to combination therapies in personalized cancer medicine. PMID:26916442

  17. Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines

    PubMed Central

    Ávila-Arroyo, Sonia; Nuñez, Gema Santamaría; García-Fernández, Luis Francisco

    2015-01-01

    Purpose Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells. Methods We have evaluated the in vitro synergistic effect of combinations of trabectedin and three different PARP inhibitors (veliparib, olaparib, and iniparib) in four breast cancer cell lines, each presenting a different BRCA1 genetic background. Antiproliferative activity, DNA damage, cell cycle perturbations and poly(ADP-ribosyl)ation were assessed by MTT assay, comet assay, flow cytometry and western blot, respectively. Results The combination of trabectedin and olaparib was synergistic in all the breast cancer cell lines tested. Our data indicated that the synergy persisted regardless of the BRCA1 status of the tumor cells. Combination treatment was associated with a strong accumulation of double-stranded DNA breaks, G2/M arrest, and apoptotic cell death. Synergistic effects were not observed when trabectedin was combined with veliparib or iniparib. Conclusion Collectively, our results indicate that the combination of trabectedin and olaparib induces an artificial synthetic lethality effect that can be used to kill breast cancer cells, independent of BRCA1 status. PMID:26770239

  18. Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer cell lines

    PubMed Central

    Polanski, R; Vincent, J; Polanska, U M; Petreus, T; Tang, E K Y

    2015-01-01

    The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis generated broad excitement and development of TRAIL receptor agonists (TRA) as potential cancer therapy. Studies demonstrating the synergistic combination effect of SMAC mimetics and TRA further suggested potentially effective treatment in multiple tumour settings. However, predictive biomarkers allowing identification of patients that could respond to treatment are lacking. Here, we described a high throughput combination screen conducted across a panel of 31 breast cancer cell lines in which we observed highly synergistic activity between TRAIL and the inhibitors of apoptosis proteins (IAP) inhibitor (IAPi) AZD5582 in ~30% of cell lines. We detected no difference in the expression levels of the IAPi or TRAIL-targeted proteins or common modulators of the apoptotic pathway between the sensitive and resistant cell lines. Synergistic combination effect of AZD5582 and TRAIL correlated with sensitivity to TRAIL, but not to AZD5582 as a single agent. TRAIL treatment led to significantly greater activity of Caspase-8 in sensitive than in resistant cell lines (P=0.002). The majority (12/14) of AZD5582+TRAIL-resistant cell lines retained a functional cell death pathway, as they were sensitive to AZD5582+TNFα combination treatment. This suggested that failure of the TRAIL receptor complex to transduce the death signal to Caspase-8 underlies AZD5582+TRAIL resistance. We developed a 3D spheroid assay and demonstrated its suitability for the ex vivo analysis of the Caspase-8 activity as a predictive biomarker. Altogether, our study demonstrated a link between the functionality of the TRAIL receptor pathway and the synergistic activity of the IAPi+TRA combination treatment. It also provided a rationale for development of the Caspase-8 activity assay as a functional predictive biomarker that could allow better prediction of the response to IAPi

  19. Combination of Anti-IGF-1R Antibody A12 and Ionizing Radiation in Upper Respiratory Tract Cancers

    SciTech Connect

    Riesterer, Oliver; Yang Qiuan; Raju, Uma; Torres, Mylin; Molkentine, David; Patel, Nalini; Valdecanas, David; Milas, Luka; Ang, K. Kian

    2011-03-15

    Purpose: The IGF1/IGF-1R signaling pathway has emerged as a potential determinant of radiation resistance in human cancer cell lines. Therefore we investigated the potency of monoclonal anti-IGF-1R antibody, A12, to enhance radiation response in upper respiratory tract cancers. Methods and Materials: Cell lines were assessed for IGF-1R expression and IGF1-dependent response to A12 or radiation using viability and clonogenic cancer cell survival assays. In vivo response of tumor xenografts to 10 or 20 Gy and A12 (0.25-2 mg x 3) was assessed using growth delay assays. Combined treatment effects were also analyzed by immunohistochemical assays for tumor cell proliferation, apoptosis, necrosis, and vascular endothelial growth factor expression at Days 1 and 6 after start of treatment. Results: A12 enhanced the radiosensitivity of HN5 and FaDu head-and-neck carcinomas in vitro (p < 0.05) and amplified the radioresponse of FaDu xenografts in a dose-dependent manner, with enhancement factors ranging from 1.2 to 1.8 (p < 0.01). Immunohistochemical analysis of FaDu xenografts demonstrated that A12 inhibited tumor cell proliferation (p < 0.05) and vascular endothelial growth factor expression. When A12 was combined with radiation, this resulted in apoptosis induction that persisted until 6 days from the start of treatment and in increased necrosis at Day 1 (p < 0.01, respectively). Combined treatment with A12 and radiation resulted in additive or subadditive growth delay in H460 or A549 xenografts, respectively. Conclusions: The results of this study strengthen the evidence for investigating how anti-IGF-1R strategies can be integrated into radiation and radiation-cetuximab regimen in the treatment of cancer of the upper aerodigestive tract cancers.

  20. Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium

    PubMed Central

    Cook, Michael B.; Guénel, Pascal; Gapstur, Susan M.; van den Brandt, Piet A.; Michels, Karin B.; Casagrande, John T.; Cooke, Rosie; Van Den Eeden, Stephen K.; Ewertz, Marianne; Falk, Roni T.; Gaudet, Mia M.; Gkiokas, George; Habel, Laurel A.; Hsing, Ann W.; Johnson, Kenneth; Kolonel, Laurence N.; La Vecchia, Carlo; Lynge, Elsebeth; Lubin, Jay H.; McCormack, Valerie A.; Negri, Eva; Olsson, Håkan; Parisi, Dominick; Petridou, Eleni Th.; Riboli, Elio; Sesso, Howard D.; Swerdlow, Anthony; Thomas, David B.; Willett, Walter C.; Brinton, Louise A.

    2015-01-01

    Background The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. Methods The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) odds ratios (OR) and 95% confidence intervals (CI), which were then combined using fixed effects meta-analysis. Results Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one sub-analysis of very high recent alcohol consumption (>60 grams/day) was tentatively associated with male breast cancer (ORunexposed referent=1.29, 95%CI:0.97–1.71; OR>0–<7 g/day referent=1.36, 95%CI:1.04–1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. Conclusions In this analysis of the Male Breast Cancer Pooling Project we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. Impact Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. PMID:25515550

  1. Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set and Network Analysis

    PubMed Central

    Lee, Won Jun; Kim, Sang Cheol; Yoon, Jung-Ho; Yoon, Sang Jun; Lim, Johan; Kim, You-Sun; Kwon, Sung Won; Park, Jeong Hill

    2016-01-01

    Generally, cancer stem cells have epithelial-to-mesenchymal-transition characteristics and other aggressive properties that cause metastasis. However, there have been no confident markers for the identification of cancer stem cells and comparative methods examining adherent and sphere cells are widely used to investigate mechanism underlying cancer stem cells, because sphere cells have been known to maintain cancer stem cell characteristics. In this study, we conducted a meta-analysis that combined gene expression profiles from several studies that utilized tumorsphere technology to investigate tumor stem-like breast cancer cells. We used our own gene expression profiles along with the three different gene expression profiles from the Gene Expression Omnibus, which we combined using the ComBat method, and obtained significant gene sets using the gene set analysis of our datasets and the combined dataset. This experiment focused on four gene sets such as cytokine-cytokine receptor interaction that demonstrated significance in both datasets. Our observations demonstrated that among the genes of four significant gene sets, six genes were consistently up-regulated and satisfied the p-value of < 0.05, and our network analysis showed high connectivity in five genes. From these results, we established CXCR4, CXCL1 and HMGCS1, the intersecting genes of the datasets with high connectivity and p-value of < 0.05, as significant genes in the identification of cancer stem cells. Additional experiment using quantitative reverse transcription-polymerase chain reaction showed significant up-regulation in MCF-7 derived sphere cells and confirmed the importance of these three genes. Taken together, using meta-analysis that combines gene set and network analysis, we suggested CXCR4, CXCL1 and HMGCS1 as candidates involved in tumor stem-like breast cancer cells. Distinct from other meta-analysis, by using gene set analysis, we selected possible markers which can explain the biological

  2. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer.

    PubMed

    Kirk, Jason S; Schaarschuch, Kevin; Dalimov, Zafardjan; Lasorsa, Elena; Ku, ShengYu; Ramakrishnan, Swathi; Hu, Qiang; Azabdaftari, Gissou; Wang, Jianmin; Pili, Roberto; Ellis, Leigh

    2015-02-20

    Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development. PMID:25605014

  3. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer

    PubMed Central

    Lasorsa, Elena; Ku, ShengYu; Ramakrishnan, Swathi; Hu, Qiang; Azabdaftari, Gissou; Wang, Jianmin; Pili, Roberto; Ellis, Leigh

    2015-01-01

    Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development. PMID:25605014

  4. Ferulic acid in combination with PARP inhibitor sensitizes breast cancer cells as chemotherapeutic strategy.

    PubMed

    Choi, Young Eun; Park, Eunmi

    2015-03-13

    Homologous-recombination (HR)-dependent repair defective cells are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Combinations of defective HR pathway and PARP inhibitors have been an effective chemotherapeutic modality. We previously showed that knockdown of the WD40-repeat containing protein, Uaf1, causes an HR repair defect in mouse embryo fibroblast cells and therefore, increases sensitivity to PARP inhibitor, ABT-888. Similarly, here, we show that ferulic acid reduces HR repair, inhibits RAD 51 foci formation, and accumulates γ-H2AX in breast cancer cells. Moreover, ferulic acid, when combined with ABT-888, renders breast cancer cells become hypersensitive to ABT-888. Our study indicates that ferulic acid in combination with ABT-888 treatment may serve as an effective combination chemotherapeutic agent as a natural bioactive compound. PMID:25677620

  5. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis

    PubMed Central

    Gu, Dongsheng; Liu, Hailan; Su, Gloria H.; Zhang, Xiaoli; Chin-Sinex, Helen; Hanenberg, Helmut; Mendonca, Marc S.; Shannon, Harlan E.; Chiorean, E. Gabriela; Xie, Jingwu

    2013-01-01

    Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of pancreatic cancer patients. PMID:23468532

  6. Ameliorative potential of fluoxetine/raloxifene combination on experimentally induced breast cancer.

    PubMed

    Kabel, Ahmed M; Elkhoely, Abeer A

    2016-04-01

    Breast cancer is one of the most common types of malignancies in females worldwide. Targeting the estrogen receptors alone with raloxifene (RAL) reduces the incidence of estrogen receptor positive tumors. Fluoxetine (FLX) is one of selective serotonin reuptake inhibitors that was proven to have anticancer properties. Our aim was to detect the effects of RAL/FLX combination on experimentally induced breast cancer. Eighty female Wistar rats were divided into four equal groups: 7,12-Dimethyl Benzanthracene (DMBA) induced breast cancer group, DMBA+RAL, DMBA+FLX and DMBA+RAL+FLX. Tumor volume, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-β1) were determined in the tumor tissues. Parts of the tumor were subjected to histopathological examination. RAL or FLX alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tissue MDA, TNF-α, IL-6 and TGF-β1 and alleviated the histopathological and immunohistochemical changes compared to DMBA group. In conclusion, RAL/FLX combination had a better effect than each of RAL or FLX alone against DMBA-induced breast cancer in rats which may represent a new therapeutic modality for management of breast cancer. PMID:26881735

  7. HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy

    PubMed Central

    Lin, Tzu-yin; Guo, Wenchang; Long, Qilai; Ma, Aihong; Liu, Qiangqiang; Zhang, Hongyong; Huang, Yee; Chandrasekaran, Siddarth; Pan, Chongxian; Lam, Kit S.; Li, Yuanpei

    2016-01-01

    Photodynamic therapy (PDT) is a promising non-invasive therapeutic modality that has been proposed for treating prostate cancer, but the procedure is associated with limited efficacy, tumor recurrence and photo-toxicity. In the present study, we proposed to develop a novel multifunctional nano-platform for targeted delivery of heat, reactive oxygen species (ROS) and heat shock protein 90 (Hsp90) inhibitor simultaneously for combination therapy against prostate cancer. This new nano-platform combines two newly developed entities: 1) a unique organic and biocompatible nanoporphyrin-based drug delivery system that can generate efficient heat and ROS simultaneously with light activation at the tumor sites for dual-modal photothermal- and photodynamic- therapy (PTT/PDT), and 2) new nano-formulations of Hsp90 inhibitors that can decrease the levels of pro-survival and angiogenic signaling molecules induced by phototherapy, therefore, further sensitizing cancer cells to phototherapy. Furthermore, the nanoparticles have activatable near infrared (NIR) fluorescence for optical imaging to conveniently monitor the real-time drug delivery in both subcutaneous and orthotopic mouse models bearing prostate cancer xenograft. This novel multifunctional nano-platform has great potential to improve the care of prostate cancer patients through targeted combination therapy. PMID:27375782

  8. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells

    PubMed Central

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A. Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-01-01

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial. PMID:26958811

  9. [Combined radiation therapy and androgen deprivation in the management of prostate cancer: Where do we stand?].

    PubMed

    Bellefqih, S; Hadadi, K; Mezouri, I; Maghous, A; Marnouche, E; Andaloussi, K; Elmarjany, M; Sifat, H; Mansouri, H; Benjaafar, N

    2016-04-01

    Radiotherapy and androgen deprivation therapy play a major role in the management of prostate cancer. Indeed, radiotherapy and hormone therapy are combined in a neoadjuvant and concomitant setting for intermediate risk cancers but also in an adjuvant setting in high risk or locally advanced prostate cancer. The benefice of this association was suggested by preclinical studies and demonstrated later by several randomized trials. However, as these trials were conducted before the era of dose escalation the role of androgen deprivation therapy in this case is less clear. Moreover, as hormonal therapy can lead to a significant morbidity and a decrement in quality of life its indications must be carefully weighed especially in case of intermediate risk cancer witch represent a heterogeneous group with distinct prognostic subgroups. PMID:26969245

  10. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice

    PubMed Central

    2009-01-01

    Background Ginsenoside Rg3, a saponin extracted from ginseng, inhibits angiogenesis. The combination of low-dose chemotherapy and anti-angiogenic inhibitors suppresses growth of experimental tumors more effectively than conventional therapy or anti-angiogenic agent alone. The present study was designed to evaluate the efficacy of low-dose gemcitabine combined with ginsenoside Rg3 on angiogenesis and growth of established Lewis lung carcinoma in mice. Methods C57L/6 mice implanted with Lewis lung carcinoma were randomized into the control, ginsenoside Rg3, gemcitabine and combination group. The quality of life and survival of mice were recorded. Tumor volume, inhibitive rate and necrosis rate were estimated. Necrosis of tumor and signals of blood flow as well as dynamic parameters of arterial blood flow in tumors such as peak systolic velocity (PSV) and resistive index (RI) were detected by color Doppler ultrasound. In addition, expression of vascular endothelial cell growth factor (VEGF) and CD31 were observed by immunohistochemstry, and microvessel density (MVD) of the tumor tissues was assessed by CD31 immunohistochemical analysis. Results Quality of life of mice in the ginsenoside Rg3 and combination group were better than in the control and gemcitabine group. Combined therapy with ginsenoside Rg3 and gemcitabine not only enhanced efficacy on suppression of tumor growth and prolongation of the survival, but also increased necrosis rate of tumor significantly. In addition, the combination treatment could obviously decrease VEGF expression and MVD as well as signals of blood flow and PSV in tumors. Conclusion Ginsenoside Rg3 combined with gemcitabine may significantly inhibit angiogenesis and growth of lung cancer and improve survival and quality of life of tumor-bearing mice. The combination of chemotherapy and anti-angiogenic drugs may be an innovative and promising therapeutic strategy in the experimental treatment of human lung cancer. PMID:19624862

  11. Ultrasmall Biocompatible WO3- x Nanodots for Multi-Modality Imaging and Combined Therapy of Cancers.

    PubMed

    Wen, Ling; Chen, Ling; Zheng, Shimin; Zeng, Jianfeng; Duan, Guangxin; Wang, Yong; Wang, Guanglin; Chai, Zhifang; Li, Zhen; Gao, Mingyuan

    2016-07-01

    Ultrasmall biocompatible WO3 - x nanodots with an outstanding X-ray radiation sensitization effect are prepared, and demonstrated to be applicable for multi-modality tumor imaging through computed tomography and photoacoustic imaging (PAI), and effective cancer treatment combining both photothermal therapy and radiation therapy. PMID:27136070

  12. Recent Advances in Upconversion Nanoparticles-Based Multifunctional Nanocomposites for Combined Cancer Therapy.

    PubMed

    Tian, Gan; Zhang, Xiao; Gu, Zhanjun; Zhao, Yuliang

    2015-12-16

    Lanthanide-doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous-wave near-infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue-penetration ability and high signal-to-noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging-guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co-delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs-based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs-based composites. The future prospects and challenges in this emerging field will be also discussed. PMID:26505885

  13. Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

    PubMed Central

    Ahrens, Theresa D; Timme, Sylvia; Hoeppner, Jens; Ostendorp, Jenny; Hembach, Sina; Follo, Marie; Hopt, Ulrich T; Werner, Martin; Busch, Hauke; Boerries, Melanie; Lassmann, Silke

    2015-01-01

    Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach. PMID:25923331

  14. Overexpression of fatty acid synthase in human urinary bladder cancer and combined expression of the synthase and Ki-67 as a predictor of prognosis of cancer patients.

    PubMed

    Sugino, Takashi; Baba, Keiichi; Hoshi, Nobuo; Aikawa, Ken; Yamaguchi, Osamu; Suzuki, Toshimitsu

    2011-09-01

    To investigate the status of fatty acid synthase (FAS) in bladder tumors and evaluate its prognostic significance, we immunohistochemically examined the expression of FAS in normal urothelium, carcinoma in situ (CIS), and urothelial carcinoma (UC) in cystectomized bladder. In normal urothelium, only the surface layer expressed FAS, whereas the protein was detected in the basal layer or whole layer of CIS and UC in every specimen. Of the clinicopathological factors in UC, pathological tumor (pT) stage and histological grade were significantly correlated to FAS expression (P = 0.002, P < 0.0001, respectively). Univariate analysis for disease-specific survival indicated that the combination scores of FAS and Ki-67 expression, which were not associated with each other, was a more predictive variable than the individual score of each protein expression. Kaplan-Meier analysis showed that high combination scores of both proteins were significantly associated with poor prognosis (P = 0.04). In conclusion, FAS expression can be a biomarker for tumor aggressiveness and loss of differentiation of bladder cancer, and the evaluation of its expression level in combination with Ki-67 labeling index may be a precise predictor for poor prognosis of cancer patients. PMID:21922386

  15. Fatal Breast Cancer Risk in Relation to Use of Unopposed Estrogen and Combined Hormone Therapy

    PubMed Central

    Pocobelli, Gaia; Newcomb, Polly A.; Li, Christopher I.; Cook, Linda S.; Barlow, William E.; Weiss, Noel S.

    2014-01-01

    Background Use of combined hormone therapy (CHT) is associated with increased breast cancer incidence, but it is unclear whether this translates into increased breast cancer mortality. Methods We conducted a population-based nested case-control study in Saskatchewan, Canada, where a population-based prescription drug database has existed since 1975. We evaluated fatal breast cancer risk in relation to recency and duration of use of CHT and unopposed estrogen hormone therapy (EHT). Results A total of 1,288 cases and 12,535 controls were included in the analyses. Exclusive use of EHT was not associated with fatal breast cancer risk, either overall or within categories of recency or duration (odds ratio (OR) for current versus never use=1.1; 95% CI (confidence interval), 0.8–1.3). Use of CHT (includes women who had also used EHT) was also not associated with fatal breast cancer risk (OR for current versus never use=0.9; 95% CI, 0.7–1.3), except for a suggestion of an increased risk with current long-term use. Conclusion Consistent with prior studies, we observed no increased risk of fatal breast cancer associated with use of EHT. To date only a few studies have evaluated fatal breast cancer risk in relation to use of CHT, and collectively the results are inconsistent. PMID:24671356

  16. Combined fibrinogen concentration and neutrophil-lymphocyte ratio as a prognostic marker of gastric cancer

    PubMed Central

    ARIGAMI, TAKAAKI; UENOSONO, YOSHIKAZU; MATSUSHITA, DAISUKE; YANAGITA, SHIGEHIRO; UCHIKADO, YASUTO; KITA, YOSHIAKI; MORI, SHINICHIRO; KIJIMA, YUKO; OKUMURA, HIROSHI; MAEMURA, KOSEI; ISHIGAMI, SUMIYA; NATSUGOE, SHOJI

    2016-01-01

    Certain patients with early gastric cancer succumb to recurrent disease and cancer-associated complications. The key cause of recurrence is challenging to determine, since clinical blood markers that are able to predict the tumor properties of gastric cancer are limited. The present study investigated the fibrinogen concentration and neutrophil-lymphocyte ratio (NLR) in blood specimens from patients with gastric cancer, and assessed the clinical applicability of combining the fibrinogen concentration with the NLR (CFS-NLR) as a prognostic marker of gastric cancer. The present study consisted of 275 patients with gastric cancer, who were divided into three groups: Those possessing hyperfibrinogenemia (≥305 mg/dl) and a high NLR (≥2.34; CFS-NLR 2 group); those possessing either hyperfibrinogenemia or a high NLR (CFS-NLR 1 group); or those that possessed neither abnormality (CFS-NLR 0 group). The CFS-NLR was significantly associated with the depth of tumor invasion, lymph node metastasis, lymphovascular invasion and tumor stage (P<0.0001). The prognostic differences among the three groups were significant (P=0.0016). Therefore, the CFS-NLR may be a potentially useful blood marker for predicting tumor progression and the prognosis of patients with gastric cancer. PMID:26893776

  17. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal

    PubMed Central

    Gao, Jianjiong; Aksoy, Bülent Arman; Dogrusoz, Ugur; Dresdner, Gideon; Gross, Benjamin; Sumer, S. Onur; Sun, Yichao; Jacobsen, Anders; Sinha, Rileen; Larsson, Erik; Cerami, Ethan; Sander, Chris; Schultz, Nikolaus

    2014-01-01

    The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics. PMID:23550210

  18. Pan-Cancer Analysis for Studying Cancer Stage using Protein Expression Data

    PubMed Central

    Mishra, Sameer; Kaddi, Chanchala D.; Wang, May D.

    2016-01-01

    Pan-cancer analyses attempt to discover similar features among multiple cancers in order to identify fundamental patterns common to cancer development and progression. Pan-cancer analysis at the level of protein expression is particularly important because protein expression is more immediately related to patient phenotype than genomic or transcriptomic data. This study aims to analyze differentially expressed (DE) proteins between early and advanced cases of multiple cancer types through the usage of reverse-phase protein array data. The relevance of these proteins is further investigated by developing predictive models using K-nearest neighbor and linear discriminant analysis classifiers. The results of this study suggest that a pan-cancer analysis may be highly complementary to standard analysis of an individual cancer for identifying biologically relevant DE proteins, and can assist in developing effective predictive models for cancer progression. PMID:26738195

  19. Pan-cancer subtyping in a 2D-map shows substructures that are driven by specific combinations of molecular characteristics.

    PubMed

    Taskesen, Erdogan; Huisman, Sjoerd M H; Mahfouz, Ahmed; Krijthe, Jesse H; de Ridder, Jeroen; van de Stolpe, Anja; van den Akker, Erik; Verheagh, Wim; Reinders, Marcel J T

    2016-01-01

    The use of genome-wide data in cancer research, for the identification of groups of patients with similar molecular characteristics, has become a standard approach for applications in therapy-response, prognosis-prediction, and drug-development. To progress in these applications, the trend is to move from single genome-wide measurements in a single cancer-type towards measuring several different molecular characteristics across multiple cancer-types. Although current approaches shed light on molecular characteristics of various cancer-types, detailed relationships between patients within cancer clusters are unclear. We propose a novel multi-omic integration approach that exploits the joint behavior of the different molecular characteristics, supports visual exploration of the data by a two-dimensional landscape, and inspection of the contribution of the different genome-wide data-types. We integrated 4,434 samples across 19 cancer-types, derived from TCGA, containing gene expression, DNA-methylation, copy-number variation and microRNA expression data. Cluster analysis revealed 18 clusters, where three clusters showed a complex collection of cancer-types, squamous-cell-carcinoma, colorectal cancers, and a novel grouping of kidney-cancers. Sixty-four samples were identified outside their tissue-of-origin cluster. Known and novel patient subgroups were detected for Acute Myeloid Leukemia's, and breast cancers. Quantification of the contributions of the different molecular types showed that substructures are driven by specific (combinations of) molecular characteristics. PMID:27109935

  20. Pan-cancer subtyping in a 2D-map shows substructures that are driven by specific combinations of molecular characteristics

    PubMed Central

    Taskesen, Erdogan; Huisman, Sjoerd M. H.; Mahfouz, Ahmed; Krijthe, Jesse H.; de Ridder, Jeroen; van de Stolpe, Anja; van den Akker, Erik; Verheagh, Wim; Reinders, Marcel J. T.

    2016-01-01

    The use of genome-wide data in cancer research, for the identification of groups of patients with similar molecular characteristics, has become a standard approach for applications in therapy-response, prognosis-prediction, and drug-development. To progress in these applications, the trend is to move from single genome-wide measurements in a single cancer-type towards measuring several different molecular characteristics across multiple cancer-types. Although current approaches shed light on molecular characteristics of various cancer-types, detailed relationships between patients within cancer clusters are unclear. We propose a novel multi-omic integration approach that exploits the joint behavior of the different molecular characteristics, supports visual exploration of the data by a two-dimensional landscape, and inspection of the contribution of the different genome-wide data-types. We integrated 4,434 samples across 19 cancer-types, derived from TCGA, containing gene expression, DNA-methylation, copy-number variation and microRNA expression data. Cluster analysis revealed 18 clusters, where three clusters showed a complex collection of cancer-types, squamous-cell-carcinoma, colorectal cancers, and a novel grouping of kidney-cancers. Sixty-four samples were identified outside their tissue-of-origin cluster. Known and novel patient subgroups were detected for Acute Myeloid Leukemia’s, and breast cancers. Quantification of the contributions of the different molecular types showed that substructures are driven by specific (combinations of) molecular characteristics. PMID:27109935

  1. Combined brachytherapy and external beam radiation: an effective approach for palliation in esophageal cancer

    PubMed Central

    Lewis, Shirley; Agarwal, Jai Prakash; Mishra, Shagun; Mehta, Shaesta; Patil, Prachi

    2015-01-01

    Purpose Palliation of dysphagia is a challenge in advanced esophageal cancer. The addition of external beam radiotherapy (EBRT) to intraluminal brachytherapy (ILBT) has shown significant improvement in dysphagia relief and symptom scores. The aim of the present study was to evaluate the efficacy of combined use of ILBT and EBRT. Material and methods The medical records of 148 patients with advanced/metastatic esophageal cancer were screened from January 2008 to April 2014, and 74 patients were found eligible for the analysis. All patients received two fractions of 8 Gy each of ILBT, followed by EBRT. Patients were assessed for the symptom scores of dysphagia, odynophagia, regurgitation, and chest pain and weight was recorded periodically. Results For a median follow-up of 6 months, the median OS was 9.5 months (95% CI: 7.5-10.5). The median dysphagia free survival was 6 months (95% CI: 4.8-7.1). The scores for dysphagia significantly improved after completion of 1st ILBT (p = 0.000), 2nd ILBT (p = 0.000), and at 3 months after EBRT compared to ILBT (p = 0.02). Overall 47% had improvement in dysphagia scores and 35% maintained the improvement of scores till last follow up. There was significant improvement in weight after completion of ILBT (p = 0.001) and at 3 months after completion of EBRT (p = 0.00). Twenty nine (39%) patients required nasogastric (NGT) insertions and 12 (16%) needed hospitalization for supportive care. 36.4% had complications in the form of stricture (27%), fistula (5.4%), and bleeding (4%). Conclusions Palliative radiotherapy is an effective alternative for palliation of dysphagia with improvement in symptom scores being evident and sustained. The results of this clinical audit were comparable with those from the trial setting. PMID:26816502

  2. Nanoparticulate delivery of novel drug combination regimens for the chemoprevention of colon cancer

    PubMed Central

    KANTHAMNENI, NAVEEN; CHAUDHARY, ABHISHEK; WANG, JEFFREY; PRABHU, SUNIL

    2010-01-01

    The purpose of this work was to assess synergistic inhibitory responses of a novel chemopreventive combination regimen of drugs namely, aspirin in combination with calcium and folic acid on two human colon cancer cell lines, HT-29 and SW-480. Subsequently, based on positive responses, nanotechnology-based formulations were developed for the targeted delivery of these combinatorial regimens to the colon for the chemoprevention of colon cancer. Additionally, conventional drug formulations using controlled release polymers chitosan, pectin and hydroxypropyl methylcellulose (HPMC) were tested for release of the drugs, for comparison purposes. Chemopreventive combination regimens demonstrated significant synergistic efficacy in both cell lines from XTT assay studies, when compared to the effects of individual agents. Approximately 45% decrease in cell viability for aspirin (15 mM) and calcium (30 mM) mixtures was observed in HT-29 cell lines, compared to ~55% decrease by the same combination in SW-480 cell lines. With combinations of aspirin (5 mM) and folic acid (1.5 mM), HT-29 cells demonstrated a 30% decrease in cell viability compared to ~38% decrease in the SW-480 cell line. Overall, all drug combinations demonstrated significant synergistic responses in the cell lines tested with the SW-480 cell line being more significantly affected by the drug regimens than the HT-29 cell line. Drug encapsulated nanoparticles demonstrated a spherical morphology, <125 nm average particle size (aspirin and folic acid) of nanoparticles and encapsulation efficiencies in the range of 80–91%. Drug release from nanoparticles was controlled with ~60% of the original amount released over a 96 h period. Conventional formulations exhibited faster kinetics of drug release when compared to the PLGA nanoparticles. Overall, the cell line studies demonstrate, for the first time, the ability of novel chemopreventive combinations to inhibit the growth of colon cancer cells whereas the

  3. Growth inhibitory effects of Phyllanthus niruri extracts in combination with cisplatin on cancer cell lines

    PubMed Central

    Araújo Júnior, Raimundo Fernandes; Soares, Luiz Alberto Lira; da Costa Porto, Cínthia Raquel; de Aquino, Ranniere Gurgel Furtado; Guedes, Hugo Gonçalo; Petrovick, Pedro Ros; de Souza, Tatiane Pereira; Araújo, Aurigena Antunes; Guerra, Gerlane Coelho Bernardo

    2012-01-01

    AIM:To investigate the cytotoxic effects of spray-dried extracts of Phyllanthus niruri in combination with cisplatin on two cancer cell lines. METHODS: Colorectal carcinoma (HT29) and human hepatocellular carcinoma (HepG2) cells were treated with spray-dried extracts of Phyllanthus niruri (SDEPN) either alone or in combination with cisplatin at different concentrations (0.5 mg/mL and 1 mg/mL) for 4 h and 24 h. To verify and quantify cancer cells treated with these products as well as identify the cell cycle stage and cell viability, we stained the cells with propidium iodide and assessed them by flow cytometry. The percentage of cells in different cell cycle phases was quantified and data were expressed as histograms. Significant differences between groups were determined using analysis of variance and Bonferroni’s test, as indicated. A value of P < 0.05 was considered to be statistically significant. RESULTS: SDEPN had significantly different cytotoxic effects on HT29 (2.81 ± 0.11 vs 3.51 ± 1.13, P > 0.05) and HepG2 (5.07 ± 0.3 vs 15.9 ± 1.04, P < 0.001) cells when compared to control cells for 4 h. SDEPN also had significantly different cytotoxic effects on HT29 (1.91 ± 0.57 vs 4.53 ± 1.22, P > 0.05) and HepG2 (14.56 ± 1.6 vs 35.67 ± 3.94, P < 0.001) cells when compared to control cells for 24 h. Both cell lines were killed by cisplatin in a dose-dependent manner compared to control cells (HepG2 cells for 4 h: 10.78 ± 1.58 vs 53.89 ± 1.53, P < 0.001; 24 h: 8.9 ± 1.43 vs 62.78 ± 1.87, P < 0.001 and HT29 cells for 4 h: 9.52 ± 0.913 vs 49.86 ± 2.89, P < 0.001; 24 h: 11.78 ± 1.05 vs 53.34 ± 2.65, P < 0.001). In HT29 cells, pretreatment with SDEPN and subsequent treatment with cisplatin resulted in a greater number of cells being killed (12.78 ± 1.01 vs 93.76 ± 1.6, P < 0.001). HepG2 cells showed significant cell killing with treatment with SDEPN when combined with cisplatin (12.87 ± 2.78 vs 78.8 ± 3.02, P < 0.001). CONCLUSION: SDEPN is

  4. A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells

    PubMed Central

    Borges, Sahra; Döppler, Heike R.

    2014-01-01

    The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer. PMID:24510012

  5. Combination of E2F-1 promoter-regulated oncolytic adenovirus and cytokine-induced killer cells enhances the antitumor effects in an orthotopic rectal cancer model.

    PubMed

    Yan, Yang; Xu, Yingxin; Zhao, Yunshan; Li, Li; Sun, Peiming; Liu, Hailiang; Fan, Qinghao; Liang, Kai; Liang, Wentao; Sun, Huiwei; Du, Xiaohui; Li, Rong

    2014-02-01

    Due to the anatomical structure of the rectum, the treatment of rectal cancer remains challenging. Ad-E2F, an oncolytic adenovirus containing the E2F-1 promoter, can selectively replicate within and kill cancer cells derived from solid tumors. Thus, this virus provides a novel approach for the treatment of rectal cancer. Given the poor efficacy and possible adverse reactions that arise from the use of oncolytic virus alone and the results of our analysis of the efficacy of Ad-E2F in the treatment of rectal cancer, we investigated the use of oncolytic adenovirus in combination with adoptive immunotherapy using cytokine-induced killer (CIK) cells as a therapeutic treatment for rectal cancer. Our results illustrated that E2F-1 gene expression is higher in rectal cancer tissue than in normal tissue. Furthermore, the designed oncolytic adenovirus Ad-E2F is capable of selectively killing colorectal cell lines but has no significant effect on CIK cells. The results of in vitro and in vivo experiments demonstrated that combined therapy with Ad-E2F and CIK cells produce stronger antitumor effects than the administration of Ad-E2F or CIK cells alone. For low rectal cancers that are suitable for intratumoral injection, local injections of oncolytic viruses in combination with CIK cell-based adoptive immunotherapy may be suitable as a novel comprehensive therapeutic approach. PMID:24037896

  6. Workshop on immunotherapy combinations. Society for Immunotherapy of Cancer annual meeting Bethesda, November 3, 2011.

    PubMed

    Martinez Forero, Ivan; Okada, Hideho; Topalian, Suzanne L; Gajewski, Thomas F; Korman, Alan J; Melero, Ignacio

    2012-01-01

    Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and "perceived" business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace. PMID

  7. Multifunctional superparamagnetic iron oxide nanoparticles for combined chemotherapy and hyperthermia cancer treatment

    NASA Astrophysics Data System (ADS)

    Quinto, Christopher A.; Mohindra, Priya; Tong, Sheng; Bao, Gang

    2015-07-01

    Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43 °C, sufficient to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy.Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could

  8. Optical spectra analysis for breast cancer diagnostics

    NASA Astrophysics Data System (ADS)

    Belkov, S. A.; Kochemasov, G. G.; Lyubynskaya, T. E.; Maslov, N. V.; Nuzhny, A. S.; da Silva, L. B.; Rubenchik, A.

    2011-11-01

    Minimally invasive probe and optical biopsy system based on optical spectra recording and analysis seem to be a promising tool for early diagnostics of breast cancer. Light scattering and absorption spectra are generated continuously as far as the needle-like probe with one emitting and several collecting optical fibers penetrates through the tissues toward to the suspicious area. That allows analyzing not only the state of local site, but also the structure of tissues along the needle trace. The suggested method has the advantages of automated on-line diagnosing and minimal tissue destruction and in parallel with the conventional diagnostic procedures provides the ground for decision-making. 165 medical trials were completed in Nizhny Novgorod Regional Oncology Centre, Russia. Independent diagnoses were the results of fine biopsy and histology. Application of wavelet expansion and clasterization techniques for spectra analysis revealed several main spectral types for malignant and benign tumors. Automatic classification algorithm demonstrated specificity ˜90% and sensitivity ˜91%. Large amount of information, fuzziness in criteria and data noisiness make neural networks to be an attractive analytic tool. The model based on three-layer perceptron was tested over the sample of 29 `cancer' and 29 `non-cancer' cases and demonstrated total separation.

  9. High-Throughput Testing of Novel-Novel Combination Therapies for Cancer: An Idea Whose Time Has Come.

    PubMed

    Scarlett, Uciane K; Chang, Dennis C; Murtagh, Thomas J; Flaherty, Keith T

    2016-09-01

    Combination therapies are essential to address the genetic complexity, plasticity, and heterogeneity of tumors and to overcome resistance mechanisms that confound single-agent approaches, and are a paradigm that became well established in the era of conventional cytotoxic chemotherapies. Today, we are well equipped to address many of the scientific, clinical, and collaboration challenges that have existed historically; however, the pace of testing rational combinations is modest. Our analysis shows that the volume of clinical trials testing multiple investigational pipeline agents ("novel-novel" combinations) is dismally low, as out of approximately 1,500 phase I to III investigational combination trials initiated in 2014-2015, only 80 were for novel-novel combinations, and only 9 of those involved more than one company. The Collaborative Novel-Novel Combination Therapies (CoNNCT) initiative aims to alleviate this bottleneck by developing a new, faster paradigm for early investigation of scientifically informed, novel-novel drug combinations. The initiative kicked off on March 7, 2016, when representatives from top academic centers, biopharma, nonprofits, the FDA, and other groups gathered to define an actionable path forward. Cancer Discov; 6(9); 956-62. ©2016 AACR. PMID:27587468

  10. Californium-252 Brachytherapy Combined With External-Beam Radiotherapy for Cervical Cancer: Long-Term Treatment Results

    SciTech Connect

    Lei Xin; Qian Chengyuan; Qing Yi; Zhao Kewei; Yang Zhengzhou; Dai Nan; Zhong Zhaoyang; Tang Cheng; Li Zheng; Gu Xianqing; Zhou Qian; Feng Yan; Xiong Yanli; Shan Jinlu; Wang Dong

    2011-12-01

    Purpose: To observe, by retrospective analysis, the curative effects and complications due to californium-252 ({sup 252}Cf) neutron intracavitary brachytherapy (ICBT) combined with external-beam radiotherapy (EBRT) in the treatment of cervical cancer. Methods and Materials: From February 1999 to December 2007, 696 patients with cervical cancer (Stages IB to IIIB) were treated with {sup 252}Cf-ICBT in combination of EBRT. Of all, 31 patients were at Stage IB, 104 at IIA, 363 at IIB, 64 at IIIA, and 134 at IIIB. Californium-252 ICBT was delivered at 7-12 Gy per insertion per week, with a total dose of 29-45 Gy to reference point A in three to five insertions. The whole pelvic cavity was treated with 8-MV X-ray external irradiation at 2 Gy per fraction, four times per week. After 16-38 Gy of external irradiation, the center of the whole pelvic field was blocked with a 4-cm-wide lead shield, with a total external irradiation dose of 44-56 Gy. The total treatment course was 5 to 6 weeks. Results: Overall survival rate at 3 and 5 years for all patients was 76.0% and 64.9%, respectively. Disease-free 3- and 5-year survival rates of patients were 71.2% and 58.4%, respectively. Late complications included vaginal contracture and adhesion, radiation proctitis, radiation cystitis, and inflammatory bowel, which accounted for 5.8%, 7.1%, 6.2%, and 4.9%, respectively. Univariate analysis results showed significant correlation of stage, age, histopathologic grade, and lymph node status with overall survival. Cox multiple regression analysis showed that the independent variables were stage, histopathologic grade, tumor size, and lymphatic metastasis in all patients. Conclusion: Results of this series suggest that the combined use of {sup 252}Cf-ICBT with EBRT is an effective method for treatment of cervical cancer.

  11. Combined Treatment Effects of Radiation and Immunotherapy: Studies in an Autochthonous Prostate Cancer Model

    SciTech Connect

    Wada, Satoshi; Harris, Timothy J.; Tryggestad, Erik; Yoshimura, Kiyoshi; Zeng, Jing; Yen, Hung-Rong; Getnet, Derese; Grosso, Joseph F.; Bruno, Tullia C.; De Marzo, Angelo M.; and others

    2013-11-15

    Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.

  12. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

    PubMed Central

    Mohni, Kareem N.; Thompson, Petria S.; Luzwick, Jessica W.; Glick, Gloria G.; Pendleton, Christopher S.; Lehmann, Brian D.; Pietenpol, Jennifer A.; Cortez, David

    2015-01-01

    The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic. PMID:25965342

  13. Spectral characteristic analysis of lung cancer serum

    NASA Astrophysics Data System (ADS)

    Li, Xiao Zhou; Jin, Huiqiang; Liu, Huasheng; Ding, Jianhua; Lin, Junxiu

    2001-10-01

    Spectral changes of lung cancer serum in the process of tumor evolution were investigated in this study. We kept close watch on the tumor progression of a group of patients, and measured their serum spectra using 488.0nm and 514.5nm excitation of an Ar-ion laser once a week. There was no apparent change observed in fluorescence spectrum in different period. However, the relative intensity of three Raman peaks (mode A, B and C) decreased every week later. For quantitative analysis of such changes, a parameter Ir (relative intensity of C Raman peak) was introduced and Ir-value was calculated. Calculation showed that Ir-value was degressive with tumor evolution, but (beta) (Ir5145 /Ir4880) varied irregularly. To the end, no Raman peak was observed. We assumed that three Raman peaks were derived from beta carotene. It indicated that the content of beta carotene decreased with the aggravation of lung cancer.

  14. Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

    PubMed

    Kawajiri, Hidemi; Takashima, Tsutomu; Kashiwagi, Shinichiro; Noda, Satoru; Onoda, Naoyoshi; Hirakawa, Kosei

    2015-01-01

    Overexpression of HER2 - found in approximately 15-20% of all breast cancers - is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer. PMID:25494663

  15. Synergistic antitumor activity of gemcitabine combined with triptolide in pancreatic cancer cells

    PubMed Central

    QIAO, ZHIXIN; HE, MIN; HE, MU; LI, WEIJING; WANG, XUANLIN; WANG, YANBING; KUAI, QIYUAN; LI, CHANGLAN; REN, SUPING; YU, QUN

    2016-01-01

    Pancreatic cancer is a fatal human malignancy associated with an exceptionally poor prognosis. Novel therapeutic strategies are urgently required to treat this disease. In addition to immunosuppressive activity, triptolide possesses strong antitumor activity and synergistically enhances the antitumor activities of conventional chemotherapeutic drugs in preclinical models of pancreatic cancer. The present study investigated the antitumor effects of triptolide in pancreatic cancer cells, either in combination with gemcitabine, or alone. The pancreatic cancer BxPC-3 and PANC-1 cell lines were treated with triptolide, which resulted in time- and dose-dependent growth arrest. When incorporated into a sequential schedule, triptolide synergistically increased gemcitabine-induced cell growth inhibition and apoptosis, in addition to the cooperative regulation of B-cell lymphoma 2 family proteins and loss of mitochondrial membrane potential. Furthermore, triptolide enhanced gemcitabine-induced S phase arrest and DNA double-strand breaks, possibly through checkpoint kinase 1 suppression. The results of the present study suggest that triptolide has therapeutic potential for the treatment of pancreatic cancer, particularly when administered in combination with gemcitabine. PMID:27123146

  16. Enhancing cancer clonality analysis with integrative genomics

    PubMed Central

    2015-01-01

    Introduction It is understood that cancer is a clonal disease initiated by a single cell, and that metastasis, which is the spread of cancer from the primary site, is also initiated by a single cell. The seemingly natural capability of cancer to adapt dynamically in a Darwinian manner is a primary reason for therapeutic failures. Survival advantages may be induced by cancer therapies and also occur as a result of inherent cell and microenvironmental factors. The selected "more fit" clones outmatch their competition and then become dominant in the tumor via propagation of progeny. This clonal expansion leads to relapse, therapeutic resistance and eventually death. The goal of this study is to develop and demonstrate a more detailed clonality approach by utilizing integrative genomics. Methods Patient tumor samples were profiled by Whole Exome Sequencing (WES) and RNA-seq on an Illumina HiSeq 2500 and methylation profiling was performed on the Illumina Infinium 450K array. STAR and the Haplotype Caller were used for RNA-seq processing. Custom approaches were used for the integration of the multi-omic datasets. Results Reported are major enhancements to CloneViz, which now provides capabilities enabling a formal tumor multi-dimensional clonality analysis by integrating: i) DNA mutations, ii) RNA expressed mutations, and iii) DNA methylation data. RNA and DNA methylation integration were not previously possible, by CloneViz (previous version) or any other clonality method to date. This new approach, named iCloneViz (integrated CloneViz) employs visualization and quantitative methods, revealing an integrative genomic mutational dissection and traceability (DNA, RNA, epigenetics) thru the different layers of molecular structures. Conclusion The iCloneViz approach can be used for analysis of clonal evolution and mutational dynamics of multi-omic data sets. Revealing tumor clonal complexity in an integrative and quantitative manner facilitates improved mutational

  17. Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells.

    PubMed

    Motawi, Tarek M K; Sadik, Nermin A H; Fahim, Sally A; Shouman, Samia A

    2015-05-25

    Imatinib mesylate (IM), a tyrosine kinase inhibitor, is used as targeted cancer therapy. However, mono-targeting by IM does not always achieve full tumor eradication and thus it is recommended to combine IM with other anticancer agents. Clotrimazole (CLT) is an antifungal azole derivative with promising anticancer effects due to inhibiting the activity of glycolytic enzymes. The present study aimed to evaluate the effect of combining CLT with IM on breast cancer cell line in an attempt to establish effective new combination. T47D human breast cancer cell line was treated with different concentrations of IM and/or CLT for 48 h. IM-CLT interaction was determined by isobologram equation and combination index. Cell viability was confirmed by measuring LDH activity. As indicators of glycolysis inhibition, the expression of hexokinase-2 (HK-2) and 6-phosphofructo-1-kinase (PFK-1) plus the activity of intracellular lactate dehydrogenase (LDH) and pyruvate kinase (PK) were determined. In addition, glucose consumption and adenosine triphosphate (ATP) production were measured. Moreover, nitric oxide (NO), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α (HIF-α) were also determined as they are modulators for glycolysis. This study demonstrated that IM or CLT synergistically inhibited cell growth in T47D as shown by combination and dose reduction indices. The combination of 15 μM IM and 20 μM CLT significantly decreased glucose consumption, activity of both PK and intracellular LDH, while increased leaked LDH, VEGF and NO in the medium compared to each drug alone. Furthermore the combination decreased gene expression of HK-2, PFK-1 and ATP content compared to the control. In conclusion, the synergistic effect of CLT on IM cytotoxicity in T47D cell line maybe mediated through inhibition of glycolysis and increasing both NO and VEGF. Further studies are required to confirm the efficiency and safety of this combination. PMID:25863232

  18. Combination of Potassium Pentagamavunon-0 and Doxorubicin Induces Apoptosis and Cell Cycle Arrest and Inhibits Metastasis in Breast Cancer Cells.

    PubMed

    Putri, Herwandhani; Jenie, Riris Istighfari; Handayani, Sri; Kastian, Ria Fajarwati; Meiyanto, Edy

    2016-01-01

    A salt compound of a curcumin analogue, potassium pentagamavunon-0 (K PGV-0) has been synthesized to improve solubility of pentagamavunon-0 which has been proven to have anti-proliferative effects on several cancer cells. The purpose of this study was to investigate cytotoxic activity and metastasis inhibition by K PGV- 0 alone and in combination with achemotherapeutic agent, doxorubicin (dox), in breast cancer cells. Based on MTT assay analysis, K PGV-0 showed cytotoxic activity in T47D and 4T1 cell lines with IC50 values of 94.9 μM and 49.0±0.2 μM, respectively. In general, K PGV-0+dox demonstrated synergistic effects and decreased cell viability up to 84.7% in T47D cells and 62.6% in 4T1 cells. Cell cycle modulation and apoptosis induction were examined by flow cytometry. K PGV-0 and K PGV-0+dox caused cell accumulation in G2/M phase and apoptosis induction. Regarding cancer metastasis, while K PGV-0 alone did not show any inhibition of 4T1 cell migration, K PGV-0+dox exerted inhibition. K PGV-0 and its combination with dox inhibited the activity of MMP-9 which has a pivotal role in extracellular matrix degradation. These results show that a combination of K PGV-0 and doxorubicin inhibits cancer cell growth through cell cycling, apoptosis induction, and inhibition of cell migration and MMP-9 activity. Therefore, K PGV-0 may have potential for development as a co-chemotherapeutic agent. PMID:27268651

  19. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations

    PubMed Central

    Castel, David; Moshe, Itai; Mazal, Inbal; Cohen, Osher; Avivi, Camila; Rosenblatt, Kineret; Aviel-Ronen, Sarit; Schiby, Ginette; Yahalom, Joachim; Amariglio, Ninette; Pfeffer, Raphael; Lawrence, Yaacov; Toren, Amos; Rechavi, Gideon; Paglin, Shoshana

    2016-01-01

    Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)–a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors. PMID:27196668

  20. nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer.

    PubMed

    Megerdichian, Christine; Olimpiadi, Yuliya; Hurvitz, Sara A

    2014-06-01

    Taxanes are highly active chemotherapeutic agents used in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-Paclitaxel is a biologically interactive, solvent-free, 130-nm-sized albumin-bound paclitaxel, developed to avoid the Cremophor vehicle used in solvent-based paclitaxel. Based on a pivotal phase 3 study, nab-paclitaxel was shown to be safely infused at a significantly higher dose of paclitaxel than the doses used with standard paclitaxel therapy, and had a shorter infusion time, no premedication, and higher response rates. It is now approved in the United States for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, and has demonstrated promising efficacy and favorable tolerability. Recently, several phase 2 and 3 studies have suggested a role for nab-paclitaxel in combination with biologically targeted agents for the treatment of early- and late-stage breast cancer. This review will discuss the findings of clinical trials evaluating nab-paclitaxel in combination with biologically targeted therapeutic agents for breast cancer in the neoadjuvant, adjuvant, and metastatic settings. PMID:24560997

  1. Prolonged complete response following gemcitabine-erlotinib combined therapy in advanced pancreatic cancer

    PubMed Central

    CZARNECKA, ANNA M.; KORZEŃ, PIOTR; NOWAK-DEMENT, ANNA; KUKWA, WOJCIECH; KORNILUK, JAN; SZCZYLIK, CEZARY

    2016-01-01

    Pancreatic cancer is one of the most lethal types of malignant solid tumor and is typically associated with a poor prognosis. The majority of patients are diagnosed with advanced-stage disease, therefore, the median survival period is <6 months. Recently, a number of basic research projects and clinical trials were undertaken with the aim of improving treatment outcomes in pancreatic cancer; however, only one agent, erlotinib, passed the clinical trials. Erlotinib is an inhibitor of epidermal growth factor receptor, which when overexpressed in cancer, promotes angiogenesis, cell proliferation and inhibits apoptosis. The US Food and Drug Administration and European Medicines Agency approved erlotinib in combination with gemcitabine for the first-line treatment of advanced pancreatic cancer. To the best of our knowledge, the current study is the first to report a case of pancreatic cancer treated with this regimen alone to achieve a complete response (CR). A 40-year-old male with a medical history of chronic pancreatitis and hypertension was diagnosed with medically inoperable adenocarcinoma of the pancreas. Following palliative surgery, the patient began palliative gemcitabine and erlotinib chemotherapy. After three months, this treatment strategy resulted in a CR, as determined by imaging studies. Therapy was discontinued after 14 months due to the development of peritoneal metastases and the patient was referred for treatment with the folinic acid, 5-fluorouracil, irinotecan and oxaliplatin regimen. A CR is rarely reported in pancreatic cancer, however, a treatment strategy of gemcitabine and erlotinib may induce rapid regression of advanced-stage disease. PMID:26893699

  2. Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

    PubMed Central

    Jelveh, Salomeh; Chithrani, Devika B.

    2011-01-01

    The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. PMID:24212654

  3. Integrated analysis of germline and somatic variants in ovarian cancer.

    PubMed

    Kanchi, Krishna L; Johnson, Kimberly J; Lu, Charles; McLellan, Michael D; Leiserson, Mark D M; Wendl, Michael C; Zhang, Qunyuan; Koboldt, Daniel C; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F; Wyczalkowski, Matthew A; Larson, David E; Schmidt, Heather K; Miller, Christopher A; Fulton, Robert S; Spellman, Paul T; Mardis, Elaine R; Druley, Todd E; Graubert, Timothy A; Goodfellow, Paul J; Raphael, Benjamin J; Wilson, Richard K; Ding, Li

    2014-01-01

    We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways. PMID:24448499

  4. Integrated Analysis of Germline and Somatic Variants in Ovarian Cancer

    PubMed Central

    Kanchi, Krishna L.; Johnson, Kimberly J.; Lu, Charles; McLellan, Michael D.; Leiserson, Mark D.M.; Wendl, Michael C.; Zhang, Qunyuan; Koboldt, Daniel C.; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F.; Wyczalkowski, Matthew A.; Larson, David E.; Schmidt, Heather K.; Miller, Christopher A.; Fulton, Robert S.; Spellman, Paul T.; Mardis, Elaine R.; Druley, Todd E.; Graubert, Timothy A.; Goodfellow, Paul J.; Raphael, Benjamin J.; Wilson, Richard K.; Ding, Li

    2014-01-01

    We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyze germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2, and PALB2. Additionally, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B, and MLL3). Evidence for loss of heterozygosity was found in 100% and 76% of cases with germline BRCA1 and BRCA2 truncations respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 237 candidate functional germline truncation and missense variants, including 2 pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK, and MLL pathways. PMID:24448499

  5. Prognostic impact of progesterone receptor status combined with body mass index in breast cancer patients treated with adjuvant aromatase inhibitor

    PubMed Central

    OHARA, MASAHIRO; AKIMOTO, ETSUSHI; NOMA, MIDORI; MATSUURA, KAZUO; DOI, MIHOKO; KAGAWA, NAOKI; ITAMOTO, TOSHIYUKI

    2015-01-01

    Aromatase inhibitors have played a central role in endocrine therapy for the treatment of estrogen receptor (ER)-positive breast cancer in postmenopausal patients. However, prognostic factors for recurrence following such treatment have not been identified. The current study aimed to validate the prognostic value of endocrine-related progesterone receptor (PgR) status combined with body mass index (BMI). Among 659 consecutive patients with primary breast cancer who underwent curative surgery between 2002 and 2012, 184 postmenopausal patients with ER-positive (ER+) and human epidermal growth factor receptor type 2-negative (HER2-) breast cancer who were treated with adjuvant aromatase inhibitor therapy were assessed. The patients were assigned to groups based on BMI, according to the WHO cut-off value: ≥25 kg/m2 (high, H) or <25 kg/m2 (low, L). Positive nodal status, negative PgR status, BMI-H and a high Ki-67 labeling index (≥20%) were found to be significantly associated with a short recurrence-free interval (RFI) upon univariate analysis (P=0.048, 0.007, 0.027, and 0.012, respectively). The patients were further grouped based on their combined PgR/BMI status. The RFI was significantly shorter in the PgR- and/or BMI-H group compared with that of the PgR+/BMI-L group (P=0.012). Multivariate analysis revealed PgR- tumors and/or BMI-H and positive nodal status to be independent prognostic factors (P=0.012 and 0.020, respectively). The present findings indicate that PgR/BMI status may serve as a practical tool in the management of ER+ and HER2- breast cancer in patients treated with adjuvant aromatase inhibitors. PMID:26722327

  6. Combination of aloe-emodin with radiation enhances radiation effects and improves differentiation in human cervical cancer cells.

    PubMed

    Luo, Jinghua; Yuan, Yong; Chang, Pengyu; Li, Dawei; Liu, Zhiqiang; Qu, Yaqin

    2014-08-01

    The aim of the present study was to investigate the effects of aloe-emodin (AE) on the radiosensitivity and differentiation of HeLa human cervical cancer cells. Cell proliferation was assessed in the HeLa cervical cancer cell line by a methylthiazolyldiphenyl-tetrazolium bromide assay. Radiosensitivity was determined by a colony‑forming assay. Flow cytometry was used for analysis of cell cycle distribution and apoptosis. The expression of γ-H2AX and cyclin B was assessed by western blotting. Alkaline phosphatase (ALP) activity was measured by an ALP activity kit. It was demonstrated that AE inhibited the proliferation of HeLa cells in a concentration- and time-dependent manner, induced G2/M and S phase cell cycle arrest and enhanced the radiosensitivity of HeLa cells. The combination of AE and radiation induced apoptosis, upregulated cyclin B and γ-H2AX expression and further improved ALP activity compared with treatment with AE or radiation alone. AE enhanced the radiosensitivity of HeLa human cervical cancer cells in vitro, inhibited the proliferation of HeLa cells, induced G2/M phase cell cycle arrest and, in combination with radiation, induced the apoptosis and improved the differentiation of HeLa cells. PMID:24920336

  7. Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth.

    PubMed

    Pathania, Rajneesh; Ramachandran, Sabarish; Mariappan, Gurusamy; Thakur, Priyanka; Shi, Huidong; Choi, Jeong-Hyeon; Manicassamy, Santhakumar; Kolhe, Ravindra; Prasad, Puttur D; Sharma, Suash; Lokeshwar, Bal L; Ganapathy, Vadivel; Thangaraju, Muthusamy

    2016-06-01

    Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSC), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Furthermore, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer. Cancer Res; 76(11); 3224-35. ©2016 AACR. PMID:27197203

  8. Combination of circulating tumor cells with serum carcinoembryonic antigen enhances clinical prediction of non-small cell lung cancer.

    PubMed

    Chen, Xi; Wang, Xu; He, Hua; Liu, Ziling; Hu, Ji-Fan; Li, Wei

    2015-01-01

    Circulating tumor cells (CTCs) have emerged as a potential biomarker in the diagnosis, prognosis, treatment, and surveillance of lung cancer. However, CTC detection is not only costly, but its sensitivity is also low, thus limiting its usage and the collection of robust data regarding the significance of CTCs in lung cancer. We aimed to seek clinical variables that enhance the prediction of CTCs in patients with non-small cell lung cancer (NSCLC). Clinical samples and pathological data were collected from 169 NSCLC patients. CTCs were detected by CellSearch and tumor markers were detected using the Luminex xMAP assay. Univariate analyses revealed that histology, tumor stage, tumor size, invasiveness, tumor grade and carcinoembryonic antigen (CEA) were associated with the presence of CTCs. However, the level of CTCs was not associated with the degree of nodal involvement (N) or tumor prognostic markers Ki-67, CA125, CA199, Cyfra21-1, and SCCA. Using logistic regression analysis, we found that the combination of CTCs with tumor marker CEA has a better disease prediction. Advanced stage NSCLC patients with elevated CEA had higher numbers of CTCs. These data suggest a useful prediction model by combining CTCs with serum CEA in NSCLC patients. PMID:25996878

  9. Combination of Circulating Tumor Cells with Serum Carcinoembryonic Antigen Enhances Clinical Prediction of Non-Small Cell Lung Cancer

    PubMed Central

    He, Hua; Liu, Ziling; Hu, Ji-Fan; Li, Wei

    2015-01-01

    Circulating tumor cells (CTCs) have emerged as a potential biomarker in the diagnosis, prognosis, treatment, and surveillance of lung cancer. However, CTC detection is not only costly, but its sensitivity is also low, thus limiting its usage and the collection of robust data regarding the significance of CTCs in lung cancer. We aimed to seek clinical variables that enhance the prediction of CTCs in patients with non-small cell lung cancer (NSCLC). Clinical samples and pathological data were collected from 169 NSCLC patients. CTCs were detected by CellSearch and tumor markers were detected using the Luminex xMAP assay. Univariate analyses revealed that histology, tumor stage, tumor size, invasiveness, tumor grade and carcinoembryonic antigen (CEA) were associated with the presence of CTCs. However, the level of CTCs was not associated with the degree of nodal involvement (N) or tumor prognostic markers Ki-67, CA125, CA199, Cyfra21-1, and SCCA. Using logistic regression analysis, we found that the combination of CTCs with tumor marker CEA has a better disease prediction. Advanced stage NSCLC patients with elevated CEA had higher numbers of CTCs. These data suggest a useful prediction model by combining CTCs with serum CEA in NSCLC patients. PMID:25996878

  10. Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review

    PubMed Central

    Chen, Shihong; Huang, Ying; O'Barr, Stephen A.; Wong, Rebecca A.; Chow, Moses Sing Sum

    2014-01-01

    Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer. PMID:24876866

  11. Clinical Evaluation and Cost-Effectiveness Analysis of Serum Tumor Markers in Lung Cancer

    PubMed Central

    Wang, Rong; Wang, Guoqing; Zhang, Nan; Li, Xue; Liu, Yunde

    2013-01-01

    The detection of serum tumor markers is valuable for the early diagnosis of lung cancer. Tumor markers are frequently used for the management of cancer patients. However, single markers are less efficient but marker combinations increase the cost, which is troublesome for clinics. To find an optimal serum marker combination panel that benefits the patients and the medical management system as well, four routine lung cancer serum markers (SCCA, NSE, CEA, and CYFRA21-1) were evaluated individually and in combination. Meanwhile, the costs and effects of these markers in clinical practice in China were assessed by cost-effectiveness analysis. As expected, combinations of these tumor markers improved their sensitivity for lung cancer and different combination panels had their own usefulness. NSE + CEA + CYFRA21-1 was the optimal combination panel with highest Youden's index (0.64), higher sensitivity (75.76%), and specificity (88.57%), which can aid the clinical diagnosis of lung cancer. Nevertheless, the most cost-effective combination was SCCA + CEA, which can be used to screen the high-risk group. PMID:24167812

  12. Combination Chemotherapy and Bevacizumab With or Without RO4929097 in Treating Patients With Metastatic Colorectal Cancer

    ClinicalTrials.gov

    2013-10-07

    Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  13. Combination Chemotherapy and Bevacizumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Colorectal Cancer

    ClinicalTrials.gov

    2013-01-24

    Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage III Colon Cancer; Stage III Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer

  14. A Novel Electrochemical Microfluidic Chip Combined with Multiple Biomarkers for Early Diagnosis of Gastric Cancer

    NASA Astrophysics Data System (ADS)

    Xie, Yao; Zhi, Xiao; Su, Haichuan; Wang, Kan; Yan, Zhen; He, Nongyue; Zhang, Jingpu; Chen, Di; Cui, Daxiang

    2015-12-01

    Early diagnosis is very important to improve the survival rate of patients with gastric cancer and to understand the biology of cancer. In order to meet the clinical demands for early diagnosis of gastric cancer, we developed a disposable easy-to-use electrochemical microfluidic chip combined with multiple antibodies against six kinds of biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), Helicobacter pylori CagA protein (H.P.), P53oncoprotein (P53), pepsinogen I (PG I), and PG-II). The six kinds of biomarkers related to gastric cancer can be detected sensitively and synchronously in a short time. The specially designed three electrodes system enables cross-contamination to be avoided effectively. The linear ranges of detection of the electrochemical microfluidic chip were as follows: 0.37-90 ng mL-1 for CEA, 10.75-172 U mL-1 for CA19-9, 10-160 U L-1 for H.P., 35-560 ng mL-1 for P53, 37.5-600 ng mL-1 for PG I, and 2.5-80 ng mL-1for PG II. This method owns better sensitivity compared with enzyme-linked immunosorbent assay (ELISA) results of 394 specimens of gastric cancer sera. Furthermore, we established a multi-index prediction model based on the six kinds of biomarkers for predicting risk of gastric cancer. In conclusion, the electrochemical microfluidic chip for detecting multiple biomarkers has great potential in applications such as early screening of gastric cancer patients, and therapeutic evaluation, and real-time dynamic monitoring the progress of gastric cancer in near future.

  15. Analysis of framelets for breast cancer diagnosis.

    PubMed

    Thivya, K S; Sakthivel, P; Venkata Sai, P M

    2016-01-27

    Breast cancer is the second threatening tumor among the women. The effective way of reducing breast cancer is its early detection which helps to improve the diagnosing process. Digital mammography plays a significant role in mammogram screening at earlier stage of breast carcinoma. Even though, it is very difficult to find accurate abnormality in prevalent screening by radiologists. But the possibility of precise breast cancer screening is encouraged by predicting the accurate type of abnormality through Computer Aided Diagnosis (CAD) systems. The two most important indicators of breast malignancy are microcalcifications and masses. In this study, framelet transform, a multiresolutional analysis is investigated for the classification of the above mentioned two indicators. The statistical and co-occurrence features are extracted from the framelet decomposed mammograms with different resolution levels and support vector machine is employed for classification with k-fold cross validation. This system achieves 94.82% and 100% accuracy in normal/abnormal classification (stage I) and benign/malignant classification (stage II) of mass classification system and 98.57% and 100% for microcalcification system when using the MIAS database. PMID:26409529

  16. Internet cancer support groups: a feminist analysis.

    PubMed

    Im, Eun-Ok; Chee, Wonshik; Tsai, Hsiu-Min; Lin, Li-Chen; Cheng, Ching-Yu

    2005-01-01

    Internet Cancer Support Groups (ICSGs) are an emerging form of support group on Internet specifically for cancer patients. Previous studies have indicated the effectiveness of ICSGs as a research setting or a data-collection method. Yet recent studies have also indicated that ICSGs tend to serve highly educated, high-income White males who tend to be at an early stage of cancer. In this article, a total of 317 general ICSGs and 229 ethnic-specific ICSGs searched through Google.com, Yahoo.com, Msn.com, AOL.com, and ACOR.org are analyzed from a feminist perspective. The written records of group discussions and written memos by the research staff members were also analyzed using content analysis. The idea categories that emerged about these groups include (a) authenticity issues; (b) ethnicity and gender issues; (c) intersubjectivity issues; and (d) potential ethical issues. The findings suggest that (a) researchers adopt multiple recruitment strategies through various Internet sites and/or real settings; (b) researchers raise their own awareness of the potential influences of the health-related resources provided by ICSGs and regularly update their knowledge related to the federal and state standards and/or policies related to ICSGs; and (c) researchers consider adopting a quota-sampling method. PMID:15681976

  17. New potential chemotherapy for ovarian cancer - Combined therapy with WP 631 and epothilone B.

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Marczak, Agnieszka

    2016-04-15

    Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment. PMID:26944437

  18. Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer

    PubMed Central

    Karnak, David; Engelke, Carl G.; Parsels, Leslie A.; Kausar, Tasneem; Wei, Dongping; Robertson, Jordan R.; Marsh, Katherine B.; Davis, Mary A.; Zhao, Lili; Maybaum, Jonathan; Lawrence, Theodore S.; Morgan, Meredith A.

    2014-01-01

    Purpose While the addition of radiation to chemotherapy improves survival in patients with locally advanced pancreatic cancer, more effective therapies are urgently needed. Thus, we investigated the radiosensitizing efficacy of the novel drug combination of Wee1 and PARP1/2 [poly (ADP-ribose) polymerase 1/2] inhibitors (AZD1775 and olaparib, respectively) in pancreatic cancer. Experimental Design Radiosensitization of AsPC-1 or MiaPaCa-2 human pancreatic cancer cells was assessed by clonogenic survival and tumor growth assays. Mechanistically, the effects of AZD1775, olaparib, and radiation on cell cycle, DNA damage (γH2AX) and HRR (homologous recombination repair) were determined. Results Treatment of AsPC-1 and MiaPaCa-2 cells with either AZD1775 or olaparib caused modest radiosensitization while treatment with the combination significantly increased radiosensitization. Radiosensitization by the combination of AZD1775 and olaparib was associated with G2 checkpoint abrogation and persistent DNA damage. In addition, AZD1775 inhibited HRR activity and prevented radiation-induced Rad51 focus formation. Finally, in vivo, in MiaPaCa-2-derived xenografts, olaparib did not radiosensitize, while AZD1775 produced moderate, yet significant, radiosensitization (P<0.05). Importantly, the combination of AZD1775 and olaparib produced highly significant radiosensitization (P<0.0001) evidenced by a 13-day delay in tumor volume doubling (vs radiation alone) and complete eradication of 20% of tumors. Conclusions Taken together, these results demonstrate the efficacy of combined inhibition of Wee1 and PARP inhibitors for radiosensitizing pancreatic cancers and support the model that Wee1 inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization through inhibition of HRR and abrogation of the G2 checkpoint, ultimately resulting in unrepaired, lethal DNA damage and radiosensitization. PMID:25117293

  19. The effect of neuraxial anesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis

    PubMed Central

    Weng, Meilin; Chen, Wankun; Hou, Wenting; Li, Lihong; Ding, Ming; Miao, Changhong

    2016-01-01

    Several animal and observational studies have evaluated the effects of neuraxial anesthesia on the recurrence and survival of cancer surgery; studies reported benefit, whereas others did not. To provide further evidence that neuraxial anesthesia(combined with or without general anesthesia (GA))may be associated with reduced cancer recurrence and long-term survival after cancer surgery, we conducted this meta-analysis. A total of 21 studies were identified and analyzed, based on searches conducted using PubMed, Web of Science, EMBASE database and the Cochrane Database of Systematic Reviews. After data abstraction, adjusted hazard ratios (HR) with 95% confidence intervals (CIs) were used to assess the impact of neuraxial anesthesia (combined with or without GA) and GA on oncological outcomes after cancer surgery. For overall survival (OS), a potential association between neuraxial anesthesia and improved OS (HR 0.853, CI 0.741-0.981, P = 0.026, the random-effects model) was observed compared with GA. Specifically, we found a positive association between neuraxial anesthesia and improved OS in colorectal cancer (HR 0.653, CI 0.430-0.991, P = 0.045, the random-effects model). For recurrence-free survival (RFS), a significant association between neuraxial anesthesia and improved RFS (HR 0.846, CI 0.718-0.998, P = 0.047, the random-effects model) was detected compared with GA. Our meta-analysis suggests that neuraxial anesthesia may be associated with improved OS in patients with cancer surgery, especially for those patients with colorectal cancer. It also supports a potential association between neuraxial anesthesia and a reduced risk of cancer recurrence. More prospective studies are needed to elucidate whether the association between neuraxial use and survival is causative. PMID:26918830

  20. Irinotecan Compared With Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer

    ClinicalTrials.gov

    2013-05-01

    Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IIIA Colon Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  1. Combined effect of polymorphisms in Rad51 and Xrcc3 on breast cancer risk and chromosomal radiosensitivity.

    PubMed

    Vral, A; Willems, P; Claes, K; Poppe, B; Perletti, Gianpaolo; Thierens, H

    2011-01-01

    Enhanced in vitro chromosomal radiosensitivity (CRS) has been proposed as a marker for low-penetrance gene mutations predisposing to breast cancer (BC). Since the double strand break (DSB) is the most detrimental form of DNA damage induced by ionizing radiation, it is possible that mutations in genes encoding proteins involved in DSB repair affect breast cancer risk. The purpose of the present study was to examine whether five single nucleotide polymorphisms (SNPs) in Rad51 and Xrcc3 (rs1801320, rs1801321, rs1799796, rs861539 and rs1799794) exhibited an association with breast cancer susceptibility in a Belgian population of BC patients with a known or putative genetic predisposition. We also ascertained whether a relationship exists between the occurrence of the variant alleles of these variations and in vitro CRS. Blood samples were obtained from BC patients and from the control population that included healthy female individuals. Variations in the 5' UTR of Rad51 and Xrcc3 were genotyped, and statistical analysis was performed. The results showed that low-penetrant variations in Rad51 and Xrcc3, two proteins belonging to the homologous recombination DSB repair pathway, may modify BC risk in patients already carrying a pathological mutation in the highly penetrant BC genes BRCA1 and BRCA2. Combined risk genotype analysis revealed that Rad51 SNPs enhance BC risk in BRCA2 patients, whereas Xrcc3 SNPs significantly enhance BC risk in carriers of BRCA1 mutations and in patients with hereditary BC. When four putative risk genotypes of Rad51 and Xrcc3 were combined, positive significant odds ratios were obtained in the entire patient population and in patients with a hereditary history of disease. Although obtained from a limited number of patients, our data are supportive of a polygenic model whereby combinations of weak variations are responsible for an enhanced BC risk by acting jointly with high-penetrant mutations in BRCA1 or BRCA2. PMID:21725594

  2. Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment

    PubMed Central

    Larson, Nate; Yang, Jiyuan; Ray, Abhijit; Cheney, Darwin L.; Ghandehari, Hamidreza; Kopeček, Jindřich

    2013-01-01

    The synthesis, characterization, and in vitro evaluation of a combination delivery of multiblock poly(N-2-hydroxypropyl)methacrylamide (HPMA), gemcitabine (GEM) and paclitaxel (PTX) conjugates is described in this study. Multiblock copolymer conjugates of a large molecular weight (Mw > 200 kDa) were studied and compared to traditional, small molecular weight (Mw < 45 kDa) conjugates. Stability of the conjugates in different pH was assessed, and their cytotoxicity in combination toward A2780 human ovarian cancer cells was evaluated by combination index analysis. Treatment duration (4 and 72 h) and sequence of addition were explored. In addition, an HPMA copolymer conjugate with both GEM and PTX in the side chains was evaluated in a similar manner and compared to a physical mixture of individual conjugates. Conjugates with narrow molecular weight distribution (Mw/Mn < 1.1) were obtained via RAFT polymerization, and drug loadings of between 5.5 and 9.2 wt% were achieved. Conjugates demonstrated moderate stability with less than 65% release over 24 h at pH 7.4, and near complete drug release in the presence of the lysosomal enzyme cathepsin B in 3 h. In combination, the cytotoxic effects of a mixture of the conjugates were primarily additive. Synergistic effects were observed when A2780 human ovarian cancer cells were treated simultaneously for 4 h with multiblock conjugates (CI < 0.7). When both GEM and PTX were conjugated to the same copolymer backbone, moderate antagonism (CI 1.3–1.6) was observed. These results demonstrate that multiblock HPMA copolymer–GEM and –PTX conjugates, when delivered as a mixture of individual agents, are promising for the treatment of ovarian cancer. PMID:23827653

  3. Cancer Nursing Education: Literature Review and Documentary Analysis.

    ERIC Educational Resources Information Center

    Langton, Helen; Blunden, Gillian; Hek, Gill

    The knowledge and skills needed by cancer nurses and the content and strategies of England's existing cancer nursing education programs were examined. The study included a comprehensive literature review and an analysis of course documents from selected English National Board-approved post-qualifying cancer nursing and palliative care courses…

  4. Combination Chemotherapy Followed by Bone Marrow Transplantation in Treating Patients With Rare Cancer

    ClinicalTrials.gov

    2013-06-20

    Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Head and Neck Cancer; Kidney Cancer; Liver Cancer; Lymphoma; Neuroblastoma; Ovarian Cancer; Retinoblastoma; Sarcoma; Testicular Germ Cell Tumor

  5. Cancer treatment by photodynamic therapy combined with NK-cell-line-based adoptive immunotherapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Sun, Jinghai

    1998-05-01

    Treatment of solid cancers by photodynamic therapy (PDT) triggers a strong acute inflammatory reaction localized to the illuminated malignant tissue. This event is regulated by a massive release of various potent mediators which have a profound effect not only on local host cell populations, but also attract different types of immune cells to the treated tumor. Phagocytosis of PDT-damaged cancerous cells by antigen presenting cells, such as activated tumor associated macrophages, enables the recognition of even poorly immunogenic tumors by specific immune effector cells and the generation of immune memory populations. Because of its inflammatory/immune character, PDT is exceptionally responsive to adjuvant treatments with various types of immunotherapy. Combining PDT with immuneactivators, such as cytokines or other specific or non-specific immune agents, rendered marked improvements in tumor cures with various cancer models. Another clinically attractive strategy is adoptive immunotherapy, and the prospects of its use in conjunction with PDT are outlined.

  6. Core-shell nanoparticle-based peptide therapeutics and combined hyperthermia for enhanced cancer cell apoptosis.

    PubMed

    Shah, Birju P; Pasquale, Nicholas; De, Gejing; Tan, Tao; Ma, Jianjie; Lee, Ki-Bum

    2014-09-23

    Mitochondria-targeting peptides have garnered immense interest as potential chemotherapeutics in recent years. However, there is a clear need to develop strategies to overcome the critical limitations of peptides, such as poor solubility and the lack of target specificity, which impede their clinical applications. To this end, we report magnetic core-shell nanoparticle (MCNP)-mediated delivery of a mitochondria-targeting pro-apoptotic amphipathic tail-anchoring peptide (ATAP) to malignant brain and metastatic breast cancer cells. Conjugation of ATAP to the MCNPs significantly enhanced the chemotherapeutic efficacy of ATAP, while the presence of targeting ligands afforded selective delivery to cancer cells. Induction of MCNP-mediated hyperthermia further potentiated the efficacy of ATAP. In summary, a combination of MCNP-mediated ATAP delivery and subsequent hyperthermia resulted in an enhanced effect on mitochondrial dysfunction, thus resulting in increased cancer cell apoptosis. PMID:25133971

  7. An observation on combined use of chemotherapy and traditional Chinese medicine to relieve cancer pain.

    PubMed

    Lin, C; Lin, X; Yang, J

    1996-12-01

    We have treated 50 patients with stage III, VI malignant tumors confirmed by pathology. The patients were divided into two groups. One group was treated by combination of chemotherapy and traditional Chinese medicine (treatment group); the other only by chemotherapy (control group). The effect of cancer treatment was evaluated according to the criteria of WHO. The results showed that the effective rate was 80% in treatment group and 52% in control group. The pain relieving rate was 68% in treatment group and 40% in control group (P < 0.01). This fact demonstrates that the application of traditional Chinese medicine can invigorate blood circulation, eliminate blood stasis, soften hardness and dissolve the mass, nourish blood and increase vigor. This kind of application can not only enhance the effect of cancer treatment but also increase the cancer pain relieving rate. PMID:9389100

  8. Cancer and occupational exposure to inorganic lead compounds: a meta-analysis of published data.

    PubMed Central

    Fu, H; Boffetta, P

    1995-01-01

    OBJECTIVES--To review and summarise the epidemiological evidence on the carcinogenicity of occupational exposure to inorganic lead. METHODS--Case-control and cohort studies were reviewed and combined for meta-analysis. Fixed and random effect methods were used to estimate the summary effects. RESULTS--The combined results show a significant excess risk of overall cancer, stomach cancer, lung cancer, and bladder cancer, with relative risk ratios (RRs) and 95% confidence intervals (95% CIs) in the meta-analysis of 1.11 (1.05-1.17), 1.33 (1.18-1.49), 1.29 (1.10-1.50), and 1.41 (1.16-1.71) respectively. The RR (95% CI) for kidney cancer was also high, but did not reach significance (1.19 (0.96-1.48)). A separate analysis of studies of heavily exposed workers provided slightly increased RRs for cancers of the stomach (1.50) and lung (1.42). CONCLUSIONS--The findings from the workers with heavy exposure to lead provided some evidence to support the hypothesis of an association between stomach and lung cancer and exposure to lead. The main limitation of the present analysis is that the excess risks do not take account of potential confounders, because little information was available for other occupational exposures, smoking, and dietary habits. To some extent, the risk of lung cancer might be explained by confounders such as tobacco smoking and exposure to other occupational carcinogens. The excess risk of stomach cancer may also be explained, at least in part, by non-occupational factors. For bladder and kidney cancers, the excess risks are only suggestive of a true effect because of possible publication bias. PMID:7757170

  9. Combining Multi-modal Features for Social Media Analysis

    NASA Astrophysics Data System (ADS)

    Nikolopoulos, Spiros; Giannakidou, Eirini; Kompatsiaris, Ioannis; Patras, Ioannis; Vakali, Athena

    In this chapter we discuss methods for efficiently modeling the diverse information carried by social media. The problem is viewed as a multi-modal analysis process where specialized techniques are used to overcome the obstacles arising from the heterogeneity of data. Focusing at the optimal combination of low-level features (i.e., early fusion), we present a bio-inspired algorithm for feature selection that weights the features based on their appropriateness to represent a resource. Under the same objective of optimal feature combination we also examine the use of pLSA-based aspect models, as the means to define a latent semantic space where heterogeneous types of information can be effectively combined. Tagged images taken from social sites have been used in the characteristic scenarios of image clustering and retrieval, to demonstrate the benefits of multi-modal analysis in social media.

  10. Cyber security analysis testbed : combining real, emulation, and simulation.

    SciTech Connect

    Villamarin, Charles H.; Eldridge, John M.; Van Leeuwen, Brian P.; Urias, Vincent E.

    2010-07-01

    Cyber security analysis tools are necessary to evaluate the security, reliability, and resilience of networked information systems against cyber attack. It is common practice in modern cyber security analysis to separately utilize real systems of computers, routers, switches, firewalls, computer emulations (e.g., virtual machines) and simulation models to analyze the interplay between cyber threats and safeguards. In contrast, Sandia National Laboratories has developed novel methods to combine these evaluation platforms into a hybrid testbed that combines real, emulated, and simulated components. The combination of real, emulated, and simulated components enables the analysis of security features and components of a networked information system. When performing cyber security analysis on a system of interest, it is critical to realistically represent the subject security components in high fidelity. In some experiments, the security component may be the actual hardware and software with all the surrounding components represented in simulation or with surrogate devices. Sandia National Laboratories has developed a cyber testbed that combines modeling and simulation capabilities with virtual machines and real devices to represent, in varying fidelity, secure networked information system architectures and devices. Using this capability, secure networked information system architectures can be represented in our testbed on a single, unified computing platform. This provides an 'experiment-in-a-box' capability. The result is rapidly-produced, large-scale, relatively low-cost, multi-fidelity representations of networked information systems. These representations enable analysts to quickly investigate cyber threats and test protection approaches and configurations.

  11. Optimizing matching and analysis combinations for estimating causal effects.

    PubMed

    Colson, K Ellicott; Rudolph, Kara E; Zimmerman, Scott C; Goin, Dana E; Stuart, Elizabeth A; Laan, Mark van der; Ahern, Jennifer

    2016-01-01

    Matching methods are common in studies across many disciplines. However, there is limited evidence on how to optimally combine matching with subsequent analysis approaches to minimize bias and maximize efficiency for the quantity of interest. We conducted simulations to compare the performance of a wide variety of matching methods and analysis approaches in terms of bias, variance, and mean squared error (MSE). We then compared these approaches in an applied example of an employment training program. The results indicate that combining full matching with double robust analysis performed best in both the simulations and the applied example, particularly when combined with machine learning estimation methods. To reduce bias, current guidelines advise researchers to select the technique with the best post-matching covariate balance, but this work finds that such an approach does not always minimize mean squared error (MSE). These findings have important implications for future research utilizing matching. To minimize MSE, investigators should consider additional diagnostics, and use of simulations tailored to the study of interest to identify the optimal matching and analysis combination. PMID:26980444

  12. Analysis of the combined maglev levitation, propulsion, and guidance system

    SciTech Connect

    He, J.L.; Coffey, H.T.; Rote, D.M.

    1995-03-01

    An analysis of a Japanese maglev system that uses only one set of coils in the guideway for combined levitation, propulsion, and guidance functions is presented. This preliminary study, using the dynamic circuit approach, indicates that the system is very promising.

  13. Optimizing matching and analysis combinations for estimating causal effects

    NASA Astrophysics Data System (ADS)

    Colson, K. Ellicott; Rudolph, Kara E.; Zimmerman, Scott C.; Goin, Dana E.; Stuart, Elizabeth A.; Laan, Mark Van Der; Ahern, Jennifer

    2016-03-01

    Matching methods are common in studies across many disciplines. However, there is limited evidence on how to optimally combine matching with subsequent analysis approaches to minimize bias and maximize efficiency for the quantity of interest. We conducted simulations to compare the performance of a wide variety of matching methods and analysis approaches in terms of bias, variance, and mean squared error (MSE). We then compared these approaches in an applied example of an employment training program. The results indicate that combining full matching with double robust analysis performed best in both the simulations and the applied example, particularly when combined with machine learning estimation methods. To reduce bias, current guidelines advise researchers to select the technique with the best post-matching covariate balance, but this work finds that such an approach does not always minimize mean squared error (MSE). These findings have important implications for future research utilizing matching. To minimize MSE, investigators should consider additional diagnostics, and use of simulations tailored to the study of interest to identify the optimal matching and analysis combination.

  14. Optimizing matching and analysis combinations for estimating causal effects

    PubMed Central

    Colson, K. Ellicott; Rudolph, Kara E.; Zimmerman, Scott C.; Goin, Dana E.; Stuart, Elizabeth A.; Laan, Mark van der; Ahern, Jennifer

    2016-01-01

    Matching methods are common in studies across many disciplines. However, there is limited evidence on how to optimally combine matching with subsequent analysis approaches to minimize bias and maximize efficiency for the quantity of interest. We conducted simulations to compare the performance of a wide variety of matching methods and analysis approaches in terms of bias, variance, and mean squared error (MSE). We then compared these approaches in an applied example of an employment training program. The results indicate that combining full matching with double robust analysis performed best in both the simulations and the applied example, particularly when combined with machine learning estimation methods. To reduce bias, current guidelines advise researchers to select the technique with the best post-matching covariate balance, but this work finds that such an approach does not always minimize mean squared error (MSE). These findings have important implications for future research utilizing matching. To minimize MSE, investigators should consider additional diagnostics, and use of simulations tailored to the study of interest to identify the optimal matching and analysis combination. PMID:26980444

  15. A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer

    PubMed Central

    Delaney, Joe R.; Patel, Chandni; McCabe, Katelyn E.; Lu, Dan; Davis, Mitzie-Ann; Tancioni, Isabelle; von Schalscha, Tami; Bartakova, Alena; Haft, Carley; Schlaepfer, David D.; Stupack, Dwayne G.

    2015-01-01

    Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC. PMID:26418751

  16. Facile Approach To Construct Ternary Cocktail Nanoparticles for Cancer Combination Therapy.

    PubMed

    Huang, Ping; Ao, Junping; Zhou, Linzhu; Su, Yue; Huang, Wei; Zhu, Xinyuan; Yan, Deyue

    2016-07-20

    Drug combinations have been widely used in cancer treatment. However, it remains a formidable challenge to deliver three or more therapeutic agents in one nanoparticle with a precise and tunable molar ratio because of differences in pharmacokinetics and biodistribution of various anticancer drugs. Herein, we reported a facile approach to construct ternary cocktail nanoparticles, which are composed of three different anticancer drugs, such as gemcitabine, chlorambucil, and irinotecan, through the molecular coassembly of two amphiphilic drug-drug conjugates. The component of these nanoparticles can be simply adjusted by changing the feed ratio of two amphiphilic drug-drug conjugates in the coassembly process. Without the help of any drug carriers, they can self-deliver, release three drugs synchronally, and obtain the optimal synergistic therapeutic effect. This facile strategy may open a new way for cancer combination therapy. PMID:27206493

  17. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer

    PubMed Central

    Thurn, K Ted; Thomas, Scott; Moore, Amy; Munster, Pamela N

    2011-01-01

    Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach. PMID:21345145

  18. Modeling Combined Chemotherapy and Particle Therapy for Locally Advanced Pancreatic Cancer

    PubMed Central

    Durante, Marco; Tommasino, Francesco; Yamada, Shigeru

    2015-01-01

    Pancreatic ductal adenocarcinoma is the only cancer for which deaths are predicted to increase in 2014 and beyond. Combined radiochemotherapy protocols using gemcitabine and hypofractionated X-rays are ongoing in several clinical trials. Recent results indicate that charged particle therapy substantially increases local control of resectable and unresectable pancreas cancer, as predicted from previous radiobiology studies considering the high tumor hypoxia. Combination with chemotherapy improves the overall survival (OS). We compared published data on X-ray and charged particle clinical results with or without adjuvant chemotherapy calculating the biological effective dose. We show that chemoradiotherapy with protons or carbon ions results in 1 year OS significantly higher than those obtained with other treatment schedules. Further hypofractionation using charged particles may result in improved local control and survival. A comparative clinical trial using the standard X-ray scheme vs. the best current standard with carbon ions is crucial and may open new opportunities for this deadly disease. PMID:26217585

  19. GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer.

    PubMed

    Labrie, Fernand

    2014-08-01

    The discovery of medical castration with GnRH agonists in 1979 rapidly replaced surgical castration and high doses of estrogens for the treatment of prostate cancer. Soon afterwards, it was discovered that androgens were made locally in the prostate from the inactive precursor DHEA of adrenal origin, a mechanism called intracrinology. Taking into account these novel facts, combined androgen blockade (CAB) using a pure antiandrogen combined with castration in order to block the two sources of androgens was first published in 1982. CAB was the first treatment shown in randomized and placebo-controlled trials to prolong life in prostate cancer, even at the metastatic stage. Most importantly, the results recently obtained with the novel pure antiandrogen enzalutamide as well as with abiraterone, an inhibitor of 17α-hydroxylase in castration-resistant prostate cancer, has revitalized the CAB concept. The effects of CAB observed on survival of heavily pretreated patients further demonstrates the importance of the androgens made locally in the prostate and are a strong motivation to apply CAB to efficiently block all sources of androgens earlier at start of treatment and, even better, before metastasis occurs. The future of research in this field thus seems to be centered on the development of more potent blockers of androgens formation and action in order to obtain better results at the metastatic stage and, for the localized stage, reduce the duration of treatment required to achieve complete apoptosis and control of prostate cancer proliferation before it reaches the metastatic or noncurable stage. PMID:24825748

  20. Multifunctional Superparamagnetic Iron Oxide Nanoparticles for Combined Chemotherapy and Hyperthermia Cancer Treatment

    PubMed Central

    Quinto, Christopher A.; Mohindra, Priya; Tong, Sheng

    2015-01-01

    Superparamagnetic iron oxide nanoparticles (SPIOs) have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43°C, enough to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy. PMID:26154916

  1. Anticoagulation in combination with antiangiogenesis and chemotherapy for cancer patients: evidence and hypothesis

    PubMed Central

    Wang, Ji; Zhu, Chengchu

    2016-01-01

    Hypercoagulable state and disorganized angiogenesis are two conspicuous characteristics during tumor progression. There are a considerable number of clinical trials focusing on the effects of anticoagulant and antiangiogenic drugs on the survival of cancer patients. Favorable outcomes have been observed. Excessive blood coagulation not only causes cancer-associated thrombosis, which is a common complication and is the second leading cause of death in patients, but also decreases intratumoral perfusion rates and drug delivery by reducing the effective cross-sectional area of blood vessels. Meanwhile, structural and functional abnormalities of the tumor microvasculature also compromise convective drug transport and create a hypoxic and acidic microenvironment. Vascular normalization strategy can temporarily recover the abnormal state of tumor vasculature by improving blood density, dilation, and leakiness, resulting in enhanced penetration of chemotherapies and oxygen within a short time window. In this article, we first review the evidence to support the opinion that anticoagulant and antiangiogenic therapy can improve cancer survival through several underlying mechanisms. Next, we speculate on the feasibility and value of the combined strategy and discuss whether such a combination has a synergistic antineoplastic effect in cancer patients by way of increasing blood vessel perfusion and drug distribution. PMID:27536135

  2. Association between obesity and local control of advanced rectal cancer after combined surgery and radiotherapy

    PubMed Central

    Choi, Yunseon; Lee, Yun-Han; Park, Sung Kwang; Cho, Heunglae; Ahn, Ki Jung

    2016-01-01

    Purpose: The association between metabolism and cancer has been recently emphasized. This study aimed to find the prognostic significance of obesity in advanced stage rectal cancer patients treated with surgery and radiotherapy (RT). Materials and Methods: We retrospectively reviewed the medical records of 111 patients who were treated with combined surgery and RT for clinical stage 2–3 (T3 or N+) rectal cancer between 2008 and 2014. The prognostic significance of obesity (body mass index [BMI] ≥25 kg/m2) in local control was evaluated. Results: The median follow-up was 31.2 months (range, 4.1 to 85.7 months). Twenty-five patients (22.5%) were classified as obese. Treatment failure occurred in 33 patients (29.7%), including local failures in 13 patients (11.7%), regional lymph node failures in 5, and distant metastases in 24. The 3-year local control, recurrence-free survival, and overall survival rates were 88.7%, 73.6%, and 87.7%, respectively. Obesity (n = 25) significantly reduced the local control rate (p = 0.045; 3-year local control, 76.2%), especially in women (n = 37, p = 0.021). Segregation of local control was best achieved by BMI of 25.6 kg/m2 as a cutoff value. Conclusion: Obese rectal cancer patients showed poor local control after combined surgery and RT. More effective local treatment strategies for obese patients are warranted. PMID:27306771

  3. Anticoagulation in combination with antiangiogenesis and chemotherapy for cancer patients: evidence and hypothesis.

    PubMed

    Wang, Ji; Zhu, Chengchu

    2016-01-01

    Hypercoagulable state and disorganized angiogenesis are two conspicuous characteristics during tumor progression. There are a considerable number of clinical trials focusing on the effects of anticoagulant and antiangiogenic drugs on the survival of cancer patients. Favorable outcomes have been observed. Excessive blood coagulation not only causes cancer-associated thrombosis, which is a common complication and is the second leading cause of death in patients, but also decreases intratumoral perfusion rates and drug delivery by reducing the effective cross-sectional area of blood vessels. Meanwhile, structural and functional abnormalities of the tumor microvasculature also compromise convective drug transport and create a hypoxic and acidic microenvironment. Vascular normalization strategy can temporarily recover the abnormal state of tumor vasculature by improving blood density, dilation, and leakiness, resulting in enhanced penetration of chemotherapies and oxygen within a short time window. In this article, we first review the evidence to support the opinion that anticoagulant and antiangiogenic therapy can improve cancer survival through several underlying mechanisms. Next, we speculate on the feasibility and value of the combined strategy and discuss whether such a combination has a synergistic antineoplastic effect in cancer patients by way of increasing blood vessel perfusion and drug distribution. PMID:27536135

  4. Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer.

    PubMed

    Kumar, Rajeev; Verma, Vikas; Jain, Ashish; Jain, Rajeev K; Maikhuri, Jagdamba P; Gupta, Gopal

    2011-08-01

    Combination of dietary phytoestrogens with diverse molecular mechanisms may enhance their anticancer efficacy at physiological concentrations, as evidenced in epidemiological studies. A select combination of three dietary phytoestrogens containing 8.33 μM each of genistein (G), quercetin (Q) and biochanin A (B) was found to be more potent in inhibiting the growth of androgen-responsive prostate cancer cells (LNCaP) as well as DU-145 and PC-3 prostate cancer cells in vitro than either 25 μM of G, B or Q or 12.5+12.5 μM of G+Q, Q+B or G+B. Subsequent mechanistic studies in PC-3 cells indicated that the action of phytoestrogens was mediated both through estrogen receptor (ER)-dependent and ER-independent pathways as potent estrogen antagonist ICI-182780 (ICI, 5 μM) could not completely mask the synergistic anticancer effects, which were sustained appreciably in presence of ICI. G+Q+B combination was significantly more effective than individual compounds or their double combinations in increasing ER-β, bax (mRNA expression); phospho-JNK, bax (protein levels); and in decreasing bcl-2, cyclin E, c-myc (mRNA expression); phospho-AKT, phospho-ERK, bcl-2, proliferating cell nuclear antigen (protein levels) in PC-3 cells. Phytoestrogens also synergistically stimulated caspase-3 activity. Our findings suggest that selectively combining anticancer phytoestrogens could significantly increase the efficacy of individual components resulting in improved efficacy at physiologically achievable concentrations. The combination mechanism of multiple anticancer phytochemicals may be indicative of the potential of some vegetarian diet components to elicit chemopreventive effects against prostate cancer at their physiologically achievable concentrations, in vivo. PMID:21062672

  5. Meta-analysis of New Genome-wide Association Studies of Colorectal Cancer Risk

    PubMed Central

    Peters, Ulrike; Hutter, Carolyn M.; Hsu, Li; Schumacher, Fredrick R.; Conti, David V.; Carlson, Christopher S.; Edlund, Christopher K.; Haile, Robert W.; Gallinger, Steven; Zanke, Brent W.; Lemire, Mathieu; Rangrej, Jagadish; Vijayaraghavan, Raakhee; Chan, Andrew T.; Hazra, Aditi; Hunter, David J.; Ma, Jing; Fuchs, Charles S.; Giovannucci, Edward L.; Kraft, Peter; Liu, Yan; Chen, Lin; Jiao, Shuo; Makar, Karen W.; Taverna, Darin; Gruber, Stephen B.; Rennert, Gad; Moreno, Victor; Ulrich, Cornelia M.; Woods, Michael O.; Green, Roger C.; Parfrey, Patrick S.; Prentice, Ross L.; Kooperberg, Charles; Jackson, Rebecca D.; LaCroix, Andrea Z.; Caan, Bette J.; Hayes, Richard B.; Berndt, Sonja I.; Chanock, Stephen J.; Schoen, Robert E.; Chang-Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; Frank, Bernd; Bézieau, Stéphane; Küry, Sébastien; Slattery, Martha L.; Hopper, John L.; Jenkins, Mark A.; Le Marchand, Loic; Lindor, Noralane M.; Newcomb, Polly A.; Seminara, Daniela; Hudson, Thomas J.; Duggan, David J.; Potter, John D.; Casey, Graham

    2011-01-01

    Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow-up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for genome-wide association studies (GWAS) of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using 10 independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured 10 SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p-value range: 0.02 to 1.8 × 10−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p<0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p-value 0.03; combined p-value 7.3 × 10−5). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant

  6. Preclinical Activity of the Rational Combination of Selumetinib (AZD6244) in Combination with Vorinostat in KRAS-Mutant Colorectal Cancer Models

    PubMed Central

    Morelli, M. Pia; Tentler, John J.; Kulikowski, Gillian N.; Tan, Aik-Choon; Bradshaw-Pierce, Erica L.; Pitts, Todd M.; Brown, Amy M.; Nallapareddy, Sujatha; Arcaroli, John J.; Serkova, Natalie J.; Hidalgo, Manuel; Ciardiello, Fortunato; Eckhardt, S. Gail

    2013-01-01

    Purpose Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%,supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor. Experimental Design Transcriptional profiling and gene set enrichment analysis (baseline and post-treatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts. Results In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G1, and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups. Conclusion These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative

  7. Combination of internal radiation therapy and hyperthermia to treat liver cancer

    SciTech Connect

    Grady, E.D.; McLaren, J.; Auda, S.P.; McGinley, P.H.

    1983-09-01

    Sixteen patients were treated for liver cancer (primary and metastatic) by a combination of internal radiation therapy with intra-arterial yttrium 90 microspheres and regional hyperthermia with electromagnetic radiation. Four patients have their liver disease apparently controlled; two had a partial regression of more than 50%; and two had a partial regression of less than 50%. The complications consisted of one case of radiation hepatitis and one of peptic ulcer.

  8. Update on capecitabine alone and in combination regimens in colorectal cancer patients.

    PubMed

    Silvestris, N; Maiello, E; De Vita, F; Cinieri, S; Santini, D; Russo, A; Tommasi, S; Azzariti, A; Numico, G; Pisconti, S; Petriella, D; Lorusso, V; Millaku, A; Colucci, G

    2010-11-01

    Capecitabine is an orally administered fluoropyrimidine carbamate which has been developed as a prodrug of 5-FU with the goal to improve its tolerability and intratumoral drug concentration. The review aims to provide an evidence-based update of clinical trials investigating the clinical efficacy, adverse-event profile, dosage and administration of this drug, alone or in combination with conventional chemotherapeutics and/or new target-oriented drugs, in the management of colorectal cancer patients. PMID:21129610

  9. Complications of combined radical hysterectomy-postoperative radiation therapy in women with early stage cervical cancer

    SciTech Connect

    Barter, J.F.; Soong, S.J.; Shingleton, H.M.; Hatch, K.D.; Orr, J.W. Jr.

    1989-03-01

    Fifty patients with cervical cancer were treated with radical hysterectomy and lymphadenectomy followed by postoperative radiation therapy for high risk factors (nodal metastases, lymphvascular space invasion, close or involved margins) at the University of Alabama at Birmingham Medical Center from 1969 to 1984. Fifteen (30%) of the patients treated had serious complications, 8 (16%) requiring an operation, and 1 (2%) dying as a result of treatment-related problems. This combined modality approach is associated with significant complications.

  10. Combining genomic and network characteristics for extended capability in predicting synergistic drugs for cancer

    PubMed Central

    Sun, Yi; Sheng, Zhen; Ma, Chao; Tang, Kailin; Zhu, Ruixin; Wu, Zhuanbin; Shen, Ruling; Feng, Jun; Wu, Dingfeng; Huang, Danyi; Huang, Dandan; Fei, Jian; Liu, Qi; Cao, Zhiwei

    2015-01-01

    The identification of synergistic chemotherapeutic agents from a large pool of candidates is highly challenging. Here, we present a Ranking-system of Anti-Cancer Synergy (RACS) that combines features of targeting networks and transcriptomic profiles, and validate it on three types of cancer. Using data on human β-cell lymphoma from the Dialogue for Reverse Engineering Assessments and Methods consortium we show a probability concordance of 0.78 compared with 0.61 obtained with the previous best algorithm. We confirm 63.6% of our breast cancer predictions through experiment and literature, including four strong synergistic pairs. Further in vivo screening in a zebrafish MCF7 xenograft model confirms one prediction with strong synergy and low toxicity. Validation using A549 lung cancer cells shows similar results. Thus, RACS can significantly improve drug synergy prediction and markedly reduce the experimental prescreening of existing drugs for repurposing to cancer treatment, although the molecular mechanism underlying particular interactions remains unknown. PMID:26412466

  11. FOLFIRI and regorafenib combination therapy with dose escalation of irinotecan as fourth-line treatment for patients with metastatic colon cancer according to UGT1A1 genotyping.

    PubMed

    Lu, Chien-Yu; Yeh, Yung-Sung; Huang, Ching-Wen; Ma, Cheng-Jen; Yu, Fang-Jung; Wang, Jaw-Yuan

    2014-01-01

    Here we report a case of metastatic colon cancer treated with 5-fluorouracil, leucovorin, and escalated doses of irinotecan (FOLFIRI) combined with regorafenib in the fourth-line setting after uridine diphosphate glucuronosyltransferase (UGT)1A1 genotyping analysis. A 66-year-old male was initially diagnosed with Union Internationale Contre le Cancer stage III descending colon cancer and underwent curative surgery. He received postoperative adjuvant chemotherapy; however, liver metastasis developed and a partial hepatectomy was performed thereafter. Unfortunately, pulmonary metastases and recurrent liver tumors were found despite a series of systemic treatments with multiple combinations of cytotoxic and biologic agents. Recently, a novel multikinase inhibitor, regorafenib, was approved for the treatment of metastatic colorectal cancer refractory to other therapeutic modalities. As further treatment, we combined regorafenib with FOLFIRI, which included dose escalations of irinotecan, after UGT1A1 genotyping analysis. The therapeutic results were promising, with the improvement in liver and pulmonary metastases being classified as stable disease and partial response, respectively. Moreover, the progression-free survival was over 6 months. FOLFIRI, with dose escalation of irinotecan according to UGT1A1 genotyping plus regorafenib appears to be a promising salvage therapy for patients with refractory metastatic colorectal cancer. PMID:25473295

  12. Nanotechnology-based combination therapy improves treatment response in cancer models

    NASA Astrophysics Data System (ADS)

    Rai, Prakash; Chang, Sung K.; Mai, Zhiming; Neuman, Daniel; Hasan, Tayyaba

    2009-06-01

    Pancreatic cancer (PanCa) has a poor prognosis with a 5-year survival rate of only 5%. Photodynamic therapy (PDT) has shown promising results in treating PanCa. Mechanism-based combinations with PDT have enhanced treatment outcome. Agents tested with PDT include Avastin, an antibody against vascular endothelial growth factor (VEGF) which is approved for treating various cancers. Simultaneous delivery of drugs in nano-constructs could improve the treatment response of mechanism based combination therapies. Here, we investigate the effect of neutralizing VEGF using nanotechnology for the delivery of Avastin in combination with PDT. For this we used a construct called "nanocells" in which the photosensitizer was trapped inside polymer nanoparticles and these, with Avastin, were then encapsulated inside liposomes. In vitro, nanocells containing Avastin (NCA) significantly enhanced cytotoxicity in PanCa cells. NCA based PDT also significantly improved treatment response in mice that were orthotopically implanted with PanCa. Avastin delivered extracellularly in combination with PDT did not show any improvement. Here we propose a new paradigm for Avastin-based therapy by combining intracellular delivery of the antibody and PDT using nanotechnology for treating PanCa.

  13. Polydopamine Nanoparticles as a Versatile Molecular Loading Platform to Enable Imaging-guided Cancer Combination Therapy

    PubMed Central

    Dong, Ziliang; Gong, Hua; Gao, Min; Zhu, Wenwen; Sun, Xiaoqi; Feng, Liangzhu; Fu, Tingting; Li, Yonggang; Liu, Zhuang

    2016-01-01

    Cancer combination therapy to treat tumors with different therapeutic approaches can efficiently improve treatment efficacy and reduce side effects. Herein, we develop a theranostic nano-platform based on polydopamine (PDA) nanoparticles, which then are exploited as a versatile carrier to allow simultaneous loading of indocyanine green (ICG), doxorubicin (DOX) and manganese ions (PDA-ICG-PEG/DOX(Mn)), to enable imaging-guided chemo & photothermal cancer therapy. In this system, ICG acts as a photothermal agent, which shows red-shifted near-infrared (NIR) absorbance and enhanced photostability compared with free ICG. DOX, a model chemotherapy drug, is then loaded onto the surface of PDA-ICG-PEG with high efficiency. With Mn2+ ions intrinsically chelated, PDA-ICG-PEG/DOX(Mn) is able to offer contrast under T1-weighted magnetic resonance (MR) imaging. In a mouse tumor model, the MR imaging-guided combined chemo- & photothermal therapy achieves a remarkable synergistic therapeutic effect compared with the respective single treatment modality. This work demonstrates that PDA nanoparticles could serve as a versatile molecular loading platform for MR imaging guided combined chemo- & photothermal therapy with minimal side effects, showing great potential for cancer theranostics. PMID:27217836

  14. Summary of combined treatment under endoscope on 70 esophagus cancer inpatients

    NASA Astrophysics Data System (ADS)

    Wang, Cheng; Nong, Meilong; Li, Laisheng; Jia, Fang; Hao, Runchun

    1993-03-01

    We announce with satisfaction that combined treatment on 70 inpatients who suffered esophageal cancer in its middle or late course is perfectly successful. The combined methods include phototherapy, microwave therapy, and anticarcinogen local injection. The results are as follows: CR 3 cases, holds 4.3% of the total inpatients; PR 36 cases, 51.4%; MR 24 cases, 34.3%; NR 7 cases, 10%; the total effective rate 90%. Splendid results of treatment on enlarging the canal, improving dysphagia, and releasing obstruction have been obtained. The dysphagic grade increased from 66 to 148, the grade of esophagostenosis from 64 to 147, and the obstruction releasing rate is 69 out of 70 (that is 98.6%). The histological observation after treatment shows that 59/62 inpatients being reported as having cancer cells appear to have retrogression accompanied with a few or large quantities of necrotic cancer cells, and 3 inpatients were changed to negative reaction. No obvious poisoning or side effects arose. The combined treatment is more advantageous on those of old age or the physically weak and those who cannot stand for an operation, radiotherapy, or normal chemotherapy.

  15. Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells

    PubMed Central

    Tsai, Cheng-Chia; Chuang, Tang-Wei; Chen, Li-Jen; Niu, Ho-Shan; Chung, Kun-Ming; Cheng, Juei-Tang; Lin, Kao-Chang

    2015-01-01

    AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer (COLO 205) cells. METHODS: MTT assays were performed to quantify cell viability. Western blot assays were applied to identify the expression of signaling proteins. RESULTS: The combined treatment of COLO 205 cells with metformin and silibinin decreased cell survival at a dose insufficient to influence the non-malignant cells [Human colonic epithelial cells (HCoEpiC)]. Silibinin and metformin increased phosphatase and tensin homolog and 5’-adenosine monophosphate-activated protein kinase expression in COLO 205 cells and inhibited the phosphorylation of mammol/Lalian target of rapamycin. This combined treatment resulted in an increase in the expression of activated caspase 3 and apoptosis inducing factor, indicating apoptosis. CONCLUSION: The combined treatment of human colorectal cancer cells with silibinin and metformin may induce apoptosis at a dose that does not affect HCoEpiC. This finding reveals a potential therapeutic strategy for the treatment of colorectal cancer. PMID:25892866

  16. Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer

    PubMed Central

    Falchook, Gerald S.; Naing, Aung; Wheler, Jennifer J.; Tsimberidou, Apostolia M.; Zinner, Ralph; Hong, David S.; Fu, Siqing; Piha-Paul, Sarina A.; Janku, Filip; Hess, Kenneth R.; Bastida, Christel; Kurzrock, Razelle

    2014-01-01

    Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD>6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer. PMID:25594061

  17. Berberine in combination with cisplatin suppresses breast cancer cell growth through induction of DNA breaks and caspase-3-dependent apoptosis.

    PubMed

    Zhao, Yuwan; Jing, Zuolei; Li, Yan; Mao, Weifeng

    2016-07-01

    Berberine (BBR) is an isoquinoline alkaloid extracted from medicinal plants such as Hydrastis canadensis, Berberis aristata and Coptis chinensis. BBR displays a number of beneficial roles in the treatment of various types of cancers, yet the precise mechanisms of its action remain unclear. Cisplatin is an effective cancer chemotherapeutic agent and functions by generating DNA damage, promoting DNA damage-induced cell cycle arrest and apoptosis; however, its efficacy is challenged by the resistance of tumor cells in clinical application. The aim of the present study was to investigate the effects of BBR in combination with cisplatin on human breast cancer cells. MTT assay showed that BBR inhibited breast cancer MCF-7 cell growth with a 50% inhibitory concentration (IC50) value of 52.178±1.593 µM and the IC50 value of cisplatin was 49.541±1.618 µM, while in combination with 26 µM BBR, the IC50 value of cisplatin was 5.759±0.76 µM. BBR sensitized the MCF-7 cells to cisplatin in a time- and dose-dependent manner. After treatment of BBR and cisplatin, the cellular pro-apoptotic capase-3 and cleaved capspase-3 and caspase-9 were upregulated and the anti-apoptotic Bcl-2 was downregulated. Importantly, BBR restrained the expression of cellular PCNA, and immunofluoresence analysis of γH2AX showed that BBR increased the DNA damages induced by cisplatin. Taken together, the results demonstrated that BBR sensitized MCF-7 cells to cisplatin through induction of DNA breaks and caspase-3-dependent apoptosis. PMID:27177238

  18. Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

    PubMed Central

    2015-01-01

    Background While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease. Results We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations. PMID:26356760

  19. An Evidence-Based Combining Classifier for Brain Signal Analysis

    PubMed Central

    Kheradpisheh, Saeed Reza; Nowzari-Dalini, Abbas; Ebrahimpour, Reza; Ganjtabesh, Mohammad

    2014-01-01

    Nowadays, brain signals are employed in various scientific and practical fields such as Medical Science, Cognitive Science, Neuroscience, and Brain Computer Interfaces. Hence, the need for robust signal analysis methods with adequate accuracy and generalizability is inevitable. The brain signal analysis is faced with complex challenges including small sample size, high dimensionality and noisy signals. Moreover, because of the non-stationarity of brain signals and the impacts of mental states on brain function, the brain signals are associated with an inherent uncertainty. In this paper, an evidence-based combining classifiers method is proposed for brain signal analysis. This method exploits the power of combining classifiers for solving complex problems and the ability of evidence theory to model as well as to reduce the existing uncertainty. The proposed method models the uncertainty in the labels of training samples in each feature space by assigning soft and crisp labels to them. Then, some classifiers are employed to approximate the belief function corresponding to each feature space. By combining the evidence raised from each classifier through the evidence theory, more confident decisions about testing samples can be made. The obtained results by the proposed method compared to some other evidence-based and fixed rule combining methods on artificial and real datasets exhibit the ability of the proposed method in dealing with complex and uncertain classification problems. PMID:24392125

  20. Selecting supplier combination based on fuzzy multicriteria analysis

    NASA Astrophysics Data System (ADS)

    Han, Zhi-Qiu; Luo, Xin-Xing; Chen, Xiao-Hong; Yang, Wu-E.

    2015-07-01

    Existing multicriteria analysis (MCA) methods are probably ineffective in selecting a supplier combination. Thus, an MCA-based fuzzy 0-1 programming method is introduced. The programming relates to a simple MCA matrix that is used to select a single supplier. By solving the programming, the most feasible combination of suppliers is selected. Importantly, this result differs from selecting suppliers one by one according to a single-selection order, which is used to rank sole suppliers in existing MCA methods. An example highlights such difference and illustrates the proposed method.

  1. Clinical features and outcomes of patients with lung cancer as well as combined pulmonary fibrosis and emphysema

    PubMed Central

    Otsuka, Hajime; Sugino, Keishi; Hata, Yoshinobu; Makino, Takashi; Koezuka, Satoshi; Isobe, Kazutoshi; Tochigi, Naobumi; Shibuya, Kazutoshi; Homma, Sakae; Iyoda, Akira

    2016-01-01

    The syndrome of combined pulmonary fibrosis and emphysema (CPFE) has been characterized by severely impaired gas exchange and poor survival. However, the clinical features of patients with lung cancer plus CPFE have remained elusive. The present study performed a retrospective analysis to examine the clinical characteristics and outcome of surgically resected patients with lung cancer plus CPFE. Among 831 patients with primary lung cancer who underwent surgical resection, 23 patients (2.8%) were diagnosed with CPFE and 9 patients (1.1%) with solely idiopathic pulmonary fibrosis (IPF). Thirty-five patients were stratified as the solely emphysema group with adjustment of the pathological stage. The clinicopathological characteristics of patients in the CPFE group and their outcomes were evaluated and compared with those with the solely IPF or solely emphysema groups. Within the CPFE group, no significant differences in survival between patients with post-operative acute exacerbation (AE; n=3) and those without AE (n=20) were noted; however, in the solely IPF group, patients with post-operative AE (n=4) had a significantly shorter survival than those without AE (n=5; P=0.022). The 5-year survival rate of patients in the CPFE, solely IPF and solely emphysema groups was 22, 22 and 58%, respectively. Furthermore, the CPFE and solely IPF groups showed a significantly shorter survival than the solely emphysema group (P=0.001 and 0.011, respectively). In conclusion, surgically resected lung cancer patients with CPFE had poor survival, which was, in contrast to that of lung cancer patients with solely IPF, not affected by AE. PMID:27602222

  2. Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer

    PubMed Central

    Foster, Fiona M; Owens, Thomas W; Tanianis-Hughes, Jolanta; Clarke, Robert B; Brennan, Keith; Bundred, Nigel J; Streuli, Charles H

    2009-01-01

    Introduction Inhibitor of apoptosis (IAPs) proteins are a family of proteins that can block apoptosis in normal cells and have been suggested to cause resistance to apoptosis in cancer. Overexpression of oncogenic receptor tyrosine kinases is common in breast cancer; in particular 20% of all cases show elevated Her2. Despite clinical success with the use of targeted therapies, such as Trastuzumab, only up to 35% of Her2-positive patients initially respond. We reasoned that IAP-mediated apoptosis resistance might contribute to this insensitivity to receptor tyrosine kinase therapy, in particular ErbB antagonists. Here we examine the levels of IAPs in breast cancer and evaluate whether targeting IAPs can enhance apoptosis in response to growth factor receptor antagonists and TRAIL. Methods IAP levels were examined in a breast cancer cell line panel and in patient samples. IAPs were inhibited using siRNA or cell permeable mimetics of endogenous inhibitors. Cells were then exposed to TRAIL, Trastuzumab, Lapatinib, or Gefitinib for 48 hours. Examining nuclear morphology and staining for cleaved caspase 3 was used to score apoptosis. Proliferation was examined by Ki67 staining. Results Four members of the IAP family, Survivin, XIAP, cIAP1 and cIAP2, were all expressed to varying extents in breast cancer cell lines or tumours. MDAMB468, BT474 and BT20 cells all expressed XIAP to varying extents. Depleting the cells of XIAP overcame the intrinsic resistance of BT20 and MDAMB468 cells to TRAIL. Moreover, siRNA-based depletion of XIAP or use of a Smac mimetic to target multiple IAPs increased apoptosis in response to the ErbB antagonists, Trastuzumab, Lapatinib or Gefitinib in Her2-overexpressing BT474 cells, or Gefitinib in EGFR-overexpressing MDAMB468 cells. Conclusions The novel findings of this study are that multiple IAPs are concomitantly expressed in breast cancers, and that, in combination with clinically relevant Her2 treatments, IAP antagonists promote apoptosis

  3. Bevacizumab and Combination Chemotherapy Before Surgery in Treating Patients With Locally Advanced Esophageal or Stomach Cancer

    ClinicalTrials.gov

    2016-03-01

    Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Squamous Cell Carcinoma of the Esophagus; Stage IA Esophageal Cancer; Stage IA Gastric Cancer; Stage IB Esophageal Cancer; Stage IB Gastric Cancer; Stage IIA Esophageal Cancer; Stage IIA Gastric Cancer; Stage IIB Esophageal Cancer; Stage IIB Gastric Cancer; Stage IIIA Esophageal Cancer; Stage IIIA Gastric Cancer; Stage IIIB Esophageal Cancer; Stage IIIB Gastric Cancer; Stage IIIC Esophageal Cancer; Stage IIIC Gastric Cancer

  4. Bortezomib and etoposide combinations exert synergistic effects on the human prostate cancer cell line PC-3

    PubMed Central

    ARAS, BEKIR; YERLIKAYA, AZMI

    2016-01-01

    Novel treatment modalities are urgently required for androgen-independent prostate cancer. In order to develop an alternative treatment for prostate cancer, the cytotoxic effects of the 26S proteasome inhibitor bortezomib, either alone or in combination with the two commonly used chemotherapeutic agents irinotecan and etoposide, on the human prostate cancer cell line PC-3 were evaluated in the present study. The PC-3 cell line was maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum and treated with various doses of bortezomib, irinotecan, etoposide or their combinations. The growth inhibitory and cytotoxic effects were determined by water-soluble tetrazolium (WST)-1 assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or iCELLigence system. The combination index values were determined by the Chou-Talalay method. The half maximal inhibitory concentration (IC50) value of bortezomib on the PC-3 cell line was determined to be 53.4 nM by WST-1 assay, whereas the IC50 values of irinotecan and etoposide were determined to be 2.1 and 26.5 µM, respectively. These results suggest that the 26S proteasome inhibitor bortezomib is more potent, compared with irinotecan and etoposide, in the androgen-insensitive and tumor protein p53-null cell line PC-3. The combined effects of bortezomib+irinotecan and bortezomib+etoposide were also tested on PC-3 cells. The effect of bortezomib+irinotecan combination was not significantly different than that produced by either monotherapy, according to the results of iCELLigence system and MTT assay. However, 40 nM bortezomib+5 µM etoposide or 40 nM bortezomib+20 µM etoposide combinations were observed to be more effective than each drug tested alone. The results of the current study suggest that bortezomib and etoposide combination may be additionally evaluated in clinical trials for the treatment of hormone-refractory prostate cancer. PMID:27123085

  5. Combination Chemotherapy Plus Amifostine in Treating Patients With Metastatic or Unresectable Cancer

    ClinicalTrials.gov

    2009-02-06

    Bladder Cancer; Brain and Central Nervous System Tumors; Carcinoma of Unknown Primary; Extragonadal Germ Cell Tumor; Head and Neck Cancer; Kidney Cancer; Lung Cancer; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  6. CRCDA—Comprehensive resources for cancer NGS data analysis

    PubMed Central

    Thangam, Manonanthini; Gopal, Ramesh Kumar

    2015-01-01

    Next generation sequencing (NGS) innovations put a compelling landmark in life science and changed the direction of research in clinical oncology with its productivity to diagnose and treat cancer. The aim of our portal comprehensive resources for cancer NGS data analysis (CRCDA) is to provide a collection of different NGS tools and pipelines under diverse classes with cancer pathways and databases and furthermore, literature information from PubMed. The literature data was constrained to 18 most common cancer types such as breast cancer, colon cancer and other cancers that exhibit in worldwide population. NGS-cancer tools for the convenience have been categorized into cancer genomics, cancer transcriptomics, cancer epigenomics, quality control and visualization. Pipelines for variant detection, quality control and data analysis were listed to provide out-of-the box solution for NGS data analysis, which may help researchers to overcome challenges in selecting and configuring individual tools for analysing exome, whole genome and transcriptome data. An extensive search page was developed that can be queried by using (i) type of data [literature, gene data and sequence read archive (SRA) data] and (ii) type of cancer (selected based on global incidence and accessibility of data). For each category of analysis, variety of tools are available and the biggest challenge is in searching and using the right tool for the right application. The objective of the work is collecting tools in each category available at various places and arranging the tools and other data in a simple and user-friendly manner for biologists and oncologists to find information easier. To the best of our knowledge, we have collected and presented a comprehensive package of most of the resources available in cancer for NGS data analysis. Given these factors, we believe that this website will be an useful resource to the NGS research community working on cancer. Database URL: http

  7. CRCDA--Comprehensive resources for cancer NGS data analysis.

    PubMed

    Thangam, Manonanthini; Gopal, Ramesh Kumar

    2015-01-01

    Next generation sequencing (NGS) innovations put a compelling landmark in life science and changed the direction of research in clinical oncology with its productivity to diagnose and treat cancer. The aim of our portal comprehensive resources for cancer NGS data analysis (CRCDA) is to provide a collection of different NGS tools and pipelines under diverse classes with cancer pathways and databases and furthermore, literature information from PubMed. The literature data was constrained to 18 most common cancer types such as breast cancer, colon cancer and other cancers that exhibit in worldwide population. NGS-cancer tools for the convenience have been categorized into cancer genomics, cancer transcriptomics, cancer epigenomics, quality control and visualization. Pipelines for variant detection, quality control and data analysis were listed to provide out-of-the box solution for NGS data analysis, which may help researchers to overcome challenges in selecting and configuring individual tools for analysing exome, whole genome and transcriptome data. An extensive search page was developed that can be queried by using (i) type of data [literature, gene data and sequence read archive (SRA) data] and (ii) type of cancer (selected based on global incidence and accessibility of data). For each category of analysis, variety of tools are available and the biggest challenge is in searching and using the right tool for the right application. The objective of the work is collecting tools in each category available at various places and arranging the tools and other data in a simple and user-friendly manner for biologists and oncologists to find information easier. To the best of our knowledge, we have collected and presented a comprehensive package of most of the resources available in cancer for NGS data analysis. Given these factors, we believe that this website will be an useful resource to the NGS research community working on cancer. Database URL: http

  8. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial

    PubMed Central

    Warde, Padraig; Mason, Malcolm; Ding, Keyue; Kirkbride, Peter; Brundage, Michael; Cowan, Richard; Gospodarowicz, Mary; Sanders, Karen; Kostashuk, Edmund; Swanson, Greg; Barber, Jim; Hiltz, Andrea; Parmar, Mahesh KB; Sathya, Jinka; Anderson, John; Hayter, Charles; Hetherington, John; Sydes, Matthew R; Parulekar, Wendy

    2011-01-01

    Summary Background Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. Methods Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65–69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. Results Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4–8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0·77, 95% CI 0·61–0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). Interpretation The benefits of combined

  9. Hedyotis diffusa Combined with Scutellaria barbata Are the Core Treatment of Chinese Herbal Medicine Used for Breast Cancer Patients: A Population-Based Study

    PubMed Central

    Yeh, Yuan-Chieh; Chen, Hsing-Yu; Yang, Sien-Hung; Lin, Yi-Hsien; Chiu, Jen-Hwey; Lin, Yi-Hsuan; Chen, Jiun-Liang

    2014-01-01

    Traditional Chinese medicine (TCM), which is the most common type of complementary and alternative medicine (CAM) used in Taiwan, is increasingly used to treat patients with breast cancer. However, large-scale studies on the patterns of TCM prescriptions for breast cancer are still lacking. The aim of this study was to determine the core treatment of TCM prescriptions used for breast cancer recorded in the Taiwan National Health Insurance Research Database. TCM visits made for breast cancer in 2008 were identified using ICD-9 codes. The prescriptions obtained at these TCM visits were evaluated using association rule mining to evaluate the combinations of Chinese herbal medicine (CHM) used to treat breast cancer patients. A total of 37,176 prescriptions were made for 4,436 outpatients with breast cancer. Association rule mining and network analysis identified Hedyotis diffusa plus Scutellaria barbata as the most common duplex medicinal (10.9%) used for the core treatment of breast cancer. Jia-Wei-Xiao-Yao-San (19.6%) and Hedyotis diffusa (41.9%) were the most commonly prescribed herbal formula (HF) and single herb (SH), respectively. Only 35% of the commonly used CHM had been studied for efficacy. More clinical trials are needed to evaluate the efficacy and safety of these CHM used to treat breast cancer. PMID:24734104

  10. Hedyotis diffusa Combined with Scutellaria barbata Are the Core Treatment of Chinese Herbal Medicine Used for Breast Cancer Patients: A Population-Based Study.

    PubMed

    Yeh, Yuan-Chieh; Chen, Hsing-Yu; Yang, Sien-Hung; Lin, Yi-Hsien; Chiu, Jen-Hwey; Lin, Yi-Hsuan; Chen, Jiun-Liang

    2014-01-01

    Traditional Chinese medicine (TCM), which is the most common type of complementary and alternative medicine (CAM) used in Taiwan, is increasingly used to treat patients with breast cancer. However, large-scale studies on the patterns of TCM prescriptions for breast cancer are still lacking. The aim of this study was to determine the core treatment of TCM prescriptions used for breast cancer recorded in the Taiwan National Health Insurance Research Database. TCM visits made for breast cancer in 2008 were identified using ICD-9 codes. The prescriptions obtained at these TCM visits were evaluated using association rule mining to evaluate the combinations of Chinese herbal medicine (CHM) used to treat breast cancer patients. A total of 37,176 prescriptions were made for 4,436 outpatients with breast cancer. Association rule mining and network analysis identified Hedyotis diffusa plus Scutellaria barbata as the most common duplex medicinal (10.9%) used for the core treatment of breast cancer. Jia-Wei-Xiao-Yao-San (19.6%) and Hedyotis diffusa (41.9%) were the most commonly prescribed herbal formula (HF) and single herb (SH), respectively. Only 35% of the commonly used CHM had been studied for efficacy. More clinical trials are needed to evaluate the efficacy and safety of these CHM used to treat breast cancer. PMID:24734104

  11. Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination.

    PubMed

    Bhattacharya, Arup; Li, Yun; Shi, Yi; Zhang, Yuesheng

    2013-11-01

    Allyl isothiocyanate (AITC) occurs in cruciferous vegetables that are commonly consumed by humans and has been shown to inhibit urinary bladder cancer growth and progression in previous preclinical studies. However, AITC does not significantly modulate cyclooxygenase-2 (Cox-2), whose oncogenic activity has been well documented in bladder cancer and other cancers. Celecoxib is a selective Cox-2 inhibitor and has been widely used for treatment of several diseases. Celecoxib has also been evaluated in bladder cancer patients, but its efficacy against bladder cancer as a single agent remains unclear. In a syngeneic rat model of orthotopic bladder cancer, treatment of the animals with the combination of AITC and celecoxib at low dose levels (AITC at 1 mg/kg and celecoxib at 10 mg/kg) led to increased or perhaps synergistic inhibition of bladder cancer growth and muscle invasion, compared with each agent used alone. The combination regime was also more effective than each single agent in inhibiting microvessel formation and stimulating microvessel maturation in the tumor tissues. The anticancer efficacy of the combination regime was associated with depletion of prostaglandin E2, a key downstream signaling molecule of Cox-2, caspase activation and downregulation of vascular endothelial growth factor in the tumor tissues. These data show that AITC and celecoxib complement each other for inhibition of bladder cancer and provide a novel combination approach for potential use for prevention or treatment of human bladder cancer. PMID:23946495

  12. Differential Network Analysis in Human Cancer Research

    PubMed Central

    Gill, Ryan; Datta, Somnath; Datta, Susmita

    2016-01-01

    A complex disease like cancer is hardly caused by one gene or one protein singly. It is usually caused by the perturbation of the network formed by several genes or proteins. In the last decade several research teams have attempted to construct interaction maps of genes and proteins either experimentally or reverse engineer interaction maps using computational techniques. These networks were usually created under a certain condition such as an environmental condition, a particular disease, or a specific tissue type. Lately, however, there has been greater emphasis on finding the differential structure of the existing network topology under a novel condition or disease status to elucidate the perturbation in a biological system. In this review/tutorial article we briefly mention some of the research done in this area; we mainly illustrate the computational/statistical methods developed by our team in recent years for differential network analysis using publicly available gene expression data collected from a well known cancer study. This data includes a group of patients with acute lymphoblastic leukemia and a group with acute myeloid leukemia. In particular, we describe the statistical tests to detect the change in the network topology based on connectivity scores which measure the association or interaction between pairs of genes. The tests under various scores are applied to this data set to perform a differential network analysis on gene expression for human leukemia. We believe that, in the future, differential network analysis will be a standard way to view the changes in gene expression and protein expression data globally and these types of tests could be useful in analyzing the complex differential signatures. PMID:23530503

  13. Paclitaxel combined with capecitabine as first-line chemotherapy for advanced or recurrent gastric cancer.

    PubMed

    Yuan, Meiqin; Yang, Yunshan; Lv, Wangxia; Song, Zhengbo; Zhong, Haijun

    2014-07-01

    Chemotherapy is of crucial importance in advanced gastric cancer (AGC) patients, in order to obtain palliation of symptoms and improve survival. To date, no standard chemotherapy regimen has been established for AGC. The purpose of the present study was to evaluate the efficacy and toxicity of the combination regimen of paclitaxel and capecitabine (PX) as first-line chemotherapy in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated with PX as first-line chemotherapy between January 2001 and December 2012 at the Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. In total, 36 patients were enrolled, with a median age of 53.5 years and a Karnofsky performance status (KPS) score of ≥80. A median of 4 PX cycles were administered (range, 2-8 cycles). The median progression-free survival time was 3.7 months [95% confidence interval (CI), 2.9-4.5 months) and the median overall survival time was 12.0 months (95% CI, 9.8-14.1 months). From the 36 patients evaluated, one (2.8%) achieved a complete response, seven (19.4%) achieved a partial response, 24 (66.7%) exhibited stable disease and four (11.1%) exhibited progressive disease. The objective response rate was 22.2% (8/36), and the disease control rate was 88.9% (32/36). All 36 patients were assessed for treatment toxicity. Grade 3 or 4 adverse events included neutropenia (2.8% of patients), hand-foot syndrome (2.8%) and vomiting (2.8%). No neutropenic fever or treatment-related mortalities were observed. PX combination chemotherapy may be a valuable first-line therapy for advanced or recurrent gastric cancer. PMID:24959275

  14. Dangerous Combinations: Ingestible CAM Supplement Use During Chemotherapy in Patients with Ovarian Cancer

    PubMed Central

    Sweet, Erin; Lowe, Kimberly A.; Standish, Leanna J.; Drescher, Charles W.; Goff, Barbara A.

    2013-01-01

    Abstract Objective Some ingestible complementary and alternative medicine (CAM) supplements, including herbal remedies, teas, and vitamins, have biological activities that make them likely to interact poorly with conventional chemotherapeutic treatments. This study surveyed women with ovarian cancer to document the extent to which women use ingestible CAM supplements and conventional chemotherapeutic treatments that are believed to be of potential concern when used together. Methods A total of 219 patients with ovarian cancer who received care from 1 of 2 participating conventional oncology practices were surveyed about CAM use during and after ovarian cancer treatment. Results A total of 200 women reported having chemotherapy to treat their ovarian cancer. Of those, 79 (40%) reported using 1 or more CAM supplements that could be cause for concern when taken with 1 or more of the chemotherapy medications they were receiving. Many patients took multiple supplements of potential concern. Of these women, 42% (n=33) consulted with a conventional provider and 24% (n=19) consulted with a CAM provider about the contraindicated supplements they used. Conclusion Although it is not clear that any of these contraindicated combinations of CAM and conventional therapy actually caused adverse outcomes, increased toxicities, or reduced the effectiveness of primary therapies, all these effects are possible given the substances being used in combination. Research is needed to understand the real risk associated with CAM and conventional polypharmacy. If risks associated with CAM use prove substantial, then improved systems to assure that all women get advice regarding supplement use during ovarian cancer treatment will be needed. PMID:23445210

  15. Combination chemotherapy with docetaxel and carboplatin for elderly patients with endometrial cancer

    PubMed Central

    YOSHIDA, HIROYUKI; IMAI, YUICHI; FUJIWARA, KEIICHI

    2016-01-01

    Approximately half of all endometrial cancer cases are diagnosed in patients aged >65 years. The objective of this study was to compare the tolerability and effectiveness of combination chemotherapy with docetaxel and carboplatin between endometrial cancer patients older and younger than 65 years of age. Chemotherapy-naive patients with endometrial cancer were enrolled in this retrospective study between April, 2008 and March, 2015. The patients received docetaxel (60 mg/m2) and carboplatin (area under the curve of 6 mg/ml/min) on day 1 of a 3-week cycle. The tolerability and effectiveness of this regimen were analyzed. A total of 41 patients with endometrial cancer were enrolled in this study, of whom 26 (63%) were aged <65 years and 15 (37%) were aged ≥65 years. There were no significant differences with regard to Eastern Cooperative Oncology Group performance status score and disease stage between the two groups. Patients aged >65 years were significantly more likely to have serous or clear-cell histology and high-grade tumors compared with the younger group (P=0.014 and 0.012, respectively). Although the number of chemotherapy cycles, cycle delays and treatment interruptions were comparable between older and younger patients, there was a trend toward more dose reductions in the older group (P=0.12). The incidence of hematological toxicities did not differ significantly between the two groups. The incidence of grade 3/4 diarrhea was significantly higher in the older group (P=0.014) and hypersensitivity was significantly more frequent in the younger group (P=0.035). Patients aged ≥65 years had equivalent response rates, progression-free survival and overall survival compared with those aged <65 years. These results suggest that combination chemotherapy with docetaxel and carboplatin was tolerable and effective for the treatment of elderly chemotherapy-naive patients with endometrial cancer. PMID:27123279

  16. Combination of 12-O-tetradecanoylphorbol-13-acetate with diethyldithiocarbamate markedly inhibits pancreatic cancer cell growth in 3D culture and in immunodeficient mice

    PubMed Central

    HUANG, HUARONG; CAO, KAJIA; MALIK, SAQUIB; ZHANG, QIUYAN; LI, DONGLI; CHANG, RICHARD; WANG, HUAQIAN; LIN, WEIPING; VAN DOREN, JEREMIAH; ZHANG, KUN; DU, ZHIYUN; ZHENG, XI

    2015-01-01

    The aim of the present study was to determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and diethyldithiocarbamate (DDTC) alone or in combination on human pancreatic cancer cells cultured in vitro and grown as xenograft tumors in nude mice. Pancreatic cancer cells were treated with either DDTC or TPA alone, or in combination and the number of viable cells was then determined by trypan blue ecxlusion assay and the number of apoptotic cells was determined by morphological assessment by staining the cells with propidium idiode and examining them under a fluorescence microscope. Treatment with DDTC or TPA alone inhibited the growth and promoted the apoptosis of pancreatic cancer cells in a concentration-dependent manner. These effects were more prominent following treatment with TPA in combination with DDTC than following treatment with either agent alone in PANC-1 cells in monolayer cultures and in 3 dimensional (3D) cultures. The potent effects of the combination treatment on PANC-1 cells were associated with the inhibition of nuclear factor-κB (NF-κB) activation and the decreased expression of Bcl-2 induced by DDTC, as shown by NF-κB-dependent reporter gene expression assay and western blot analysis. Furthermore, treatment of nude mice with DDTC + TPA strongly inhibited the growth of PANC-1 xenograft tumors. The results of the present study indicate that the administration of TPA and DDTC in combination may be an effective strategy for inhibiting the growth of pancreatic cancer. PMID:25847449

  17. Concomitant Statin Use Has a Favorable Effect on Gemcitabine-Erlotinib Combination Chemotherapy for Advanced Pancreatic Cancer

    PubMed Central

    Moon, Do Chang; Lee, Hee Seung; Lee, Yong Il; Chung, Moon Jae; Park, Jeong Youp; Park, Seung Woo; Song, Si Young; Chung, Jae Bock

    2016-01-01

    Purpose Erlotinib-gemcitabine combined chemotherapy is considered as the standard treatment for unresectable pancreatic cancer. This study aimed to determine the clinical factors associated with response to this treatment. Materials and Methods This retrospective study included 180 patients with unresectable pancreatic cancer who received ≥2 cycles of gemcitabine-erlotinib combination therapy as first-line palliative chemotherapy between 2006 and 2014. "Long-term response" was defined as tumor stabilization after >6 chemotherapy cycles. Results The median progression-free survival (PFS) and overall survival (OS) were 3.9 and 8.1 months, respectively. On univariate analysis, liver metastasis (p=0.023) was negatively correlated with long-term response. Locally advanced stage (p=0.017), a history of statin treatment (p=0.01), and carcinoembryonic antigen levels <4.5 (p=0.029) had a favorable effect on long-term response. On multivariate analysis, a history of statin treatment was the only independent favorable factor for long-term response (p=0.017). Prognostic factors for OS and PFS were significantly correlated with liver metastasis (p=0.031 and 0.013, respectively). A history of statin treatment was also significantly associated with OS after adjusting for all potential confounders (hazard ratio, 0.48; 95% confidence interval, 0.26–0.92; p=0.026). Conclusion These results suggest that statins have a favorable effect on "long-term response" to gemcitabine-erlotinib chemotherapy in unresectable pancreatic cancer patients. Statins may have a chemoadjuvant role in stabilizing long-term tumor growth. PMID:27401642

  18. Modulating cancer multidrug resistance by sertraline in combination with a nanomedicine.

    PubMed

    Drinberg, Velthe; Bitcover, Rivka; Rajchenbach, Wolf; Peer, Dan

    2014-11-28

    Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacle in cancer treatment. The ATP Binding Cassettes (ABC) transporter super family that act as extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins have prominent roles in cancer MDR. One of the most efficient strategies to modulate this active drug efflux from the cells is to physically block the pump proteins and thus change the balance between drug influx and efflux toward an accumulation of drug inside the cell, which eventually cumulates into cell death. MDR modulators (also known as chemosensitizers) were found among drugs approved for non-cancer indications. Yet, toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Previous reports have shown that drugs belonging to the selective serotonin reuptake inhibitors (SSRI) family, which are clinically used as antidepressants, can act as effective chemosensitizers both in vitro and in vivo in tumor bearing mouse models. Here, we set out to explore whether sertraline (Zoloft®), a molecule belonging to the SSRI family, can be used as an MDR modulator. Combining sertraline with another FDA approved drug, Doxil® (pegylated liposomal doxorubicin), is expected to enhance the effect of chemotherapy while potentially reducing adverse effects. Our findings reveal that sertraline acts as a pump modulator in cellular models of MDR. In addition, in an aggressive and highly resistant human ovarian xenograft mouse model the use of sertraline in combination with Doxil® generated substantial reduction in tumor progression, with extension of the median survival of tumor-bearing mice. Taken together, our results show that sertraline could act as a clinically relevant cancer MDR inhibitor. Moreover, combining two FDA approved drugs, DOXIL®, which favor the influx of chemotherapy inside the malignant cell with sertraline, which blocks the

  19. Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome

    PubMed Central

    Nebgen, Denise R.; Lu, Karen H.; Rimes, Sue; Keeler, Elizabeth; Broaddus, Russell; Munsell, Mark F.; Lynch, Patrick M.

    2015-01-01

    Objective Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. Methods We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1–2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. Results Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. Conclusions Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1–2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer. PMID:25149916

  20. Intravesical radiofrequency-induced hyperthermia combined with chemotherapy for non-muscle-invasive bladder cancer.

    PubMed

    van Valenberg, Hans; Colombo, Renzo; Witjes, Fred

    2016-06-01

    Although many treatment modalities and schedules for non-muscle-invasive bladder cancer (NMIBC) exist, all yet prove to have limitations. Therefore the search for new forms of therapy continues. One of these forms consists of combining intravesical chemotherapy, typically mitomycin C (MMC), with hyperthermia achieved by a microwave-applicator. We aimed to review the current status of intravesical radiofrequency (RF) induced chemohyperthermia (CHT) for NMIBC with regard to efficacy, adverse-events (AEs) and its future perspective. A search for RF-induced CHT in MEDLINE, Embase, Cochrane and ClinicalTrials.gov databases was performed. Relevant conference abstracts were searched for manually. If applicable, experts on the area were consulted. Papers were selected based on abstract and title. A table of newly published clinical trials since 2011 was constructed. No meta-analysis could be performed based on these new papers. Efficacy proved to be better for RF-induced CHT compared to both MMC alone and bacillus Calmette-Guérin (BCG) instillations, with the latter being based on just one abstract of a randomised controlled trial. The AE rate in CHT is higher compared to MMC instillation, but is similar compared to BCG, albeit different in the type of AE. In almost all studies no severe AEs are reported. Although heterogeneity in methodology exists, RF-induced CHT seems promising. However, alternative methods of applying hyperthermia are starting to present their first results, imposing as effective options too. Intravesical RF-induced CHT may become an alternative for BCG instillation, and possibly for cystectomy, although further level 1 evidence is required for both reliable and reproducible data on efficacy and adverse events. PMID:26905963

  1. Trend Analysis of Cancer Mortality and Incidence in Panama, Using Joinpoint Regression Analysis

    PubMed Central

    Politis, Michael; Higuera, Gladys; Chang, Lissette Raquel; Gomez, Beatriz; Bares, Juan; Motta, Jorge

    2015-01-01

    Abstract Cancer is one of the leading causes of death worldwide and its incidence is expected to increase in the future. In Panama, cancer is also one of the leading causes of death. In 1964, a nationwide cancer registry was started and it was restructured and improved in 2012. The aim of this study is to utilize Joinpoint regression analysis to study the trends of the incidence and mortality of cancer in Panama in the last decade. Cancer mortality was estimated from the Panamanian National Institute of Census and Statistics Registry for the period 2001 to 2011. Cancer incidence was estimated from the Panamanian National Cancer Registry for the period 2000 to 2009. The Joinpoint Regression Analysis program, version 4.0.4, was used to calculate trends by age-adjusted incidence and mortality rates for selected cancers. Overall, the trend of age-adjusted cancer mortality in Panama has declined over the last 10 years (−1.12% per year). The cancers for which there was a significant increase in the trend of mortality were female breast cancer and ovarian cancer; while the highest increases in incidence were shown for breast cancer, liver cancer, and prostate cancer. Significant decrease in the trend of mortality was evidenced for the following: prostate cancer, lung and bronchus cancer, and cervical cancer; with respect to incidence, only oral and pharynx cancer in both sexes had a significant decrease. Some cancers showed no significant trends in incidence or mortality. This study reveals contrasting trends in cancer incidence and mortality in Panama in the last decade. Although Panama is considered an upper middle income nation, this study demonstrates that some cancer mortality trends, like the ones seen in cervical and lung cancer, behave similarly to the ones seen in high income countries. In contrast, other types, like breast cancer, follow a pattern seen in countries undergoing a transition to a developed economy with its associated lifestyle, nutrition, and

  2. Trend Analysis of Cancer Mortality and Incidence in Panama, Using Joinpoint Regression Analysis

    PubMed Central

    Politis, Michael; Higuera, Gladys; Chang, Lissette Raquel; Gomez, Beatriz; Bares, Juan; Motta, Jorge

    2015-01-01

    Abstract Cancer is one of the leading causes of death worldwide and its incidence is expected to increase in the future. In Panama, cancer is also one of the leading causes of death. In 1964, a nationwide cancer registry was started and it was restructured and improved in 2012. The aim of this study is to utilize Joinpoint regression analysis to study the trends of the incidence and mortality of cancer in Panama in the last decade. Cancer mortality was estimated from the Panamanian National Institute of Census and Statistics Registry for the period 2001 to 2011. Cancer incidence was estimated from the Panamanian National Cancer Registry for the period 2000 to 2009. The Joinpoint Regression Analysis program, version 4.0.4, was used to calculate trends by age-adjusted incidence and mortality rates for selected cancers. Overall, the trend of age-adjusted cancer mortality in Panama has declined over the last 10 years (−1.12% per year). The cancers for which there was a significant increase in the trend of mortality were female breast cancer and ovarian cancer; while the highest increases in incidence were shown for breast cancer, liver cancer, and prostate cancer. Significant decrease in the trend of mortality was evidenced for the following: prostate cancer, lung and bronchus cancer, and cervical cancer; with respect to incidence, only oral and pharynx cancer in both sexes had a significant decrease. Some cancers showed no significant trends in incidence or mortality. This study reveals contrasting trends in cancer incidence and mortality in Panama in the last decade. Although Panama is considered an upper middle income nation, this study demonstrates that some cancer mortality trends, like the ones seen in cervical and lung cancer, behave similarly to the ones seen in high income countries. In contrast, other types, like breast cancer, follow a pattern seen in countries undergoing a transition to a developed economy with its associated lifestyle, nutrition, and

  3. Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer.

    PubMed

    Hughes, Paul E; Caenepeel, Sean; Wu, Lawren C

    2016-07-01

    Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer. PMID:27216414

  4. Anticancer activity of NOB1-targeted shRNA combination with TRAIL in epithelial ovarian cancer cells

    PubMed Central

    Lin, Yang; Xu, Tianmin; Teng, Hong; Cui, Manhua

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of ovarian cancer. However, the effectiveness of the treatment remains limited due to the inherent or acquired resistance of tumor cells to TRAIL. Our previously study demonstrated that downregulation of NOB1 (NIN1/RPN12 binding protein 1 homolog) expression by a lentiviral short hairpin RNA (shRNA) delivery system (Lv/sh-NOB1) suppressed ovarian cancer growth. Here, Lv/sh-NOB1 and TRAIL were combined and tested the effects of this combination on ovarian cancer cells to identify more effective therapeutics against ovarian cancer by several in vitro experiments. Tumor growth ability in SKVO3 xenograft nude mice was also determined to define this combination treatment effect in tumorigenesis in vivo. In vitro assay showed that Lv/sh-NOB1 in combination with TRAIL treatment in ovarian cancer cell synergistically suppressed the proliferation and colony formation, as well as induced cell apoptosis and increased the activity of caspase-3, -8 and -9. In vivo assay showed that Lv/sh-NOB1 combination with TRAIL synergistically suppressed tumor growth of nude mice model. Importantly, we found that downregulation of NOB1 could upregulate DR5 expression and active MAPK pathway, which might contribute to increase sensitivity TRAIL to ovarian cancer cells. These findings suggested that Lv/sh-NOB1 combination with TRAIL treatment may be a potential treatment approach for ovarian cancer. PMID:26617713

  5. Hyaluronic acid-functionalized polymeric nanoparticles for colon cancer-targeted combination chemotherapy

    NASA Astrophysics Data System (ADS)

    Xiao, Bo; Han, Moon Kwon; Viennois, Emilie; Wang, Lixin; Zhang, Mingzhen; Si, Xiaoying; Merlin, Didier

    2015-10-01

    Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments demonstrated that the introduction of HA to the NP surface endowed NPs with colon cancer-targeting capability and markedly increased cellular uptake efficiency compared with chitosan-coated NPs. Importantly, the combined delivery of CPT and CUR in one HA-functionalized NP exerted strong synergistic effects. HA-CPT/CUR-NP (1 : 1) showed the highest antitumor activity among the three HA-CPT/CUR-NPs, resulting in an extremely low combination index. Collectively, our findings indicate that this HA-CPT/CUR-NP can be exploited as an efficient formulation for colon cancer-targeted combination chemotherapy.Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments

  6. Combining small molecules for cell reprogramming through an interatomic analysis.

    PubMed

    Feltes, Bruno César; Bonatto, Diego

    2013-11-01

    The knowledge available about the application and generation of induced pluripotent stem cells (iPSC) has grown since their discovery, and new techniques to enhance the reprogramming process have been described. Among the new approaches to induce iPSC that have gained great attention is the use of small molecules for reprogramming. The application of small molecules, unlike genetic manipulation, provides for control of the reprogramming process through the shifting of concentrations and the combination of different molecules. However, different researchers have reported the use of "reprogramming cocktails" with variable results and drug combinations. Thus, the proper combination of small molecules for successful and enhanced reprogramming is a matter for discussion. However, testing all potential drug combinations in different cell lineages is very costly and time-consuming. Therefore, in this article, we discuss the use of already employed molecules for iPSC generation, followed by the application of systems chemo-biology tools to create different data sets of protein-protein (PPI) and chemical-protein (CPI) interaction networks based on the knowledge of already used and new reprogramming cocktail combinations. We further analyzed the biological processes associated with PPI-CPI networks and provided new potential protein targets to be inhibited or expressed for stem cell reprogramming. In addition, we applied a new interference analysis to prospective targets that could negatively affect the classical pluripotency-associated factors (SOX2, NANOG, KLF4 and OCT4) and thus potentially improve reprogramming protocols. PMID:24056910

  7. Cardiac arrhythmia and ischaemic events after combination chemotherapy for testicular cancer.

    PubMed

    Villani, F; Misrachi, D; Galimberti, M

    1994-11-01

    The aim of the present investigation was to evaluate the type and the incidence of cardiac arrhythmias and ischaemic events in patients suffering from testicular cancer and submitted to combination chemotherapy with cisplatin, bleomycin and vinblastine (PVB) or etoposide (PEB). Forty-seven patients took part in the study; 23 were treated with PVB and 24 with PEB. Holter monitoring was performed in each patient before chemotherapy and on the 1st, 2nd and 5th day of the first cycle of drug administration. The results showed that combination chemotherapy with PVB or PEB was accompanied by the appearance of, or an increase in, the incidence of supraventricular ectopic beats. No significant difference was found between the two groups. No significant conduction disturbances were recorded. These results show that combination chemotherapy with PVB or PEB, at least during the first cycle, has no significant ventricular arrhythmogenic or ischaemic potency in young people with no history of cardiac disease. PMID:7530660

  8. Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer

    PubMed Central

    Lucena, Silvia Rocío; Salazar, Nerea; Gracia-Cazaña, Tamara; Zamarrón, Alicia; González, Salvador; Juarranz, Ángeles; Gilaberte, Yolanda

    2015-01-01

    Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer. PMID:26516853

  9. Multifunctional Fe2O3@PPy-PEG nanocomposite for combination cancer therapy with MR imaging

    NASA Astrophysics Data System (ADS)

    Zhou, Jun; Li, Jinghua; Ding, Xingwei; Liu, Junjie; Luo, Zhong; Liu, Yun; Ran, Qichun; Cai, Kaiyong

    2015-10-01

    In recent years, magnetic hyperthermia nanoparticles have drawn great attention for cancer therapy because they have no limitation of tissue penetration during the therapy process. In this study, cubic nanoporous Fe2O3 nanoparticles derived from cubic Prussian blue nanoparticles were used as magnetic cores to generate heat by alternating the current magnetic field (AMF) for killing cancer cells. In addition, polypyrrole (PPy) was coated on the surfaces of the cubic Fe2O3 nanoparticles to load doxorubicin hydrochloride (DOX). The PEG component was then physically adsorbed onto the surfaces of the nanoparticles, resulting in a Fe2O3@PPy-DOX-PEG nanocomposite. The nanocomposite was triggered by acid stimulus and AMF to release DOX, resulting in a remarkable combination therapeutic effect via chemotherapy and magnetic hyperthermia. Furthermore, the nanocomposite could realize magnetic resonance imaging (MRI) due to the magnetic core structure. The study provides an alternative for the development of new nanocomposites for combination cancer therapy with MR imaging in vivo.

  10. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism

    PubMed Central

    Donadelli, M; Dando, I; Zaniboni, T; Costanzo, C; Dalla Pozza, E; Scupoli, M T; Scarpa, A; Zappavigna, S; Marra, M; Abbruzzese, A; Bifulco, M; Caraglia, M; Palmieri, M

    2011-01-01

    Gemcitabine (GEM, 2′,2′-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl--cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells. PMID:21525939

  11. A Combined Shotgun and Targeted Mass Spectrometry Strategy for Breast Cancer Biomarker Discovery.

    PubMed

    Sjöström, Martin; Ossola, Reto; Breslin, Thomas; Rinner, Oliver; Malmström, Lars; Schmidt, Alexander; Aebersold, Ruedi; Malmström, Johan; Niméus, Emma

    2015-07-01

    It is of highest importance to find proteins responsible for breast cancer dissemination, for use as biomarkers or treatment targets. We established and performed a combined nontargeted LC-MS/MS and a targeted LC-SRM workflow for discovery and validation of protein biomarkers. Eighty breast tumors, stratified for estrogen receptor status and development of distant recurrence (DR ± ), were collected. After enrichment of N-glycosylated peptides, label-free LC-MS/MS was performed on each individual tumor in triplicate. In total, 1515 glycopeptides from 778 proteins were identified and used to create a map of the breast cancer N-glycosylated proteome. Based on this specific proteome map, we constructed a 92-plex targeted label-free LC-SRM panel. These proteins were quantified across samples by LC-SRM, resulting in 10 proteins consistently differentially regulated between DR+/DR- tumors. Five proteins were further validated in a separate cohort as prognostic biomarkers at the gene expression level. We also compared the LC-SRM results to clinically reported HER2 status, demonstrating its clinical accuracy. In conclusion, we demonstrate a combined mass spectrometry strategy, at large scale on clinical samples, leading to the identification and validation of five proteins as potential biomarkers for breast cancer recurrence. All MS data are available via ProteomeXchange and PASSEL with identifiers PXD001685 and PASS00643. PMID:25944384

  12. Superparamagnetic iron oxide nanocargoes for combined cancer thermotherapy and MRI applications.

    PubMed

    Thorat, Nanasaheb D; Lemine, O M; Bohara, Raghvendra A; Omri, Karim; El Mir, L; Tofail, Syed A M

    2016-08-01

    Nanoparticle-based cancer diagnosis-therapy integrative systems (cancer theranostics) represent an emerging approach in oncology. To address this issue in the present work iron oxide (γ-Fe2O3-maghemite) nanoparticles (IONPs) were encapsulated within the matrix of (bis(p-sulfonatophenyl)phenylphosphine)-methoxypolyethylene glycol-thiol (mPEG) polymer vesicles using a two-step process for active chemotherapeutic cargo loading in cancer theranostics. This formation method gives simple access to highly reactive surface groups present on IONPs together with good control over the vesicle size (50-100 nm). The simultaneous loading of a chemotherapeutic drug cargo (doxorubicin) and its in vitro release in cancer cells was achieved. The feasibility of controlled drug release under different pH conditions was demonstrated in the case of encapsulated doxorubicin molecules, showing the viability of the concept of stimulated drug delivery for magneto-chemotherapy. These polymer-magnetic nanocargoes (PMNCs) exhibit enhanced contrast properties that open potential applications for magnetic resonance imaging. These self-assembled magnetic polymersomes can be used as efficient multifunctional nanocarriers for combined therapy and imaging. PMID:27427175

  13. Combinations of FUT2 gene polymorphisms and environmental factors are associated with oral cancer risk.

    PubMed

    Su, Kuo-Jung; Ho, Chuan-Chen; Lin, Chiao-Wen; Chen, Mu-Kuan; Su, Shih-Chi; Yu, Yung-Luen; Yang, Shun-Fa

    2016-05-01

    In humans, fucosyltransferase-2 (FUT2) plays an important role in α1,2- linkage of fucose and participates in complex cellular processes such as fertilization, embryogenesis, and immune responses. However, little information is available concerning the FUT2 expression in tumorigenesis. The aim of this work was to investigate the combined effect of FUT2 gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinic pathological characteristics of oral cancer. Four SNPs of the FUT2 gene (rs281377, rs1047781, rs601338, and rs602662) from 1200 non-cancer controls and 700 oral squamous cell carcinoma (OSCC) patients were analyzed by real-time polymerase chain reaction (PCR). The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of OSCC, and the impact of these SNPs on the susceptibility and clinic pathological characteristics of OSCC. After adjusting for other covariant, we observed that betel quid chewing among 1255 smokers who carrying at least one C genotype (TC and CC) at rs281377 and least one T genotype (TA and TT) at rs1047781 were exhibited synergistic effects of environmental factors (betel quid and cigarette use) on the susceptibility of oral cancer. Taken together, our results support gene-environment interactions of FUT2 polymorphisms with smoking and betel quid chewing habits possibly altering oral cancer susceptibility. Furthermore, to our knowledge, this is the first study of association between FUT2 gene variants and OSCC risk. PMID:26646561

  14. Cytotoxic Effect of Erythroxylum suberosum Combined with Radiotherapy in Head and Neck Cancer Cell Lines.

    PubMed

    Macedo, Taysa B C; Elias, Silvia T; Torres, Hianne M; Yamamoto-Silva, Fernanda Paula; Silveira, Dâmaris; Magalhães, Pérola O; Lofrano-Porto, Adriana; Guerra, Eliete N S; Silva, Maria Alves G

    2016-01-01

    The mouth and oropharynx cancer is the 6th most common type of cancer in the world. The treatment may involve surgery, chemotherapy and radiotherapy. More than 50% of drugs against cancer were isolated from natural sources, such as Catharanthus roseus and epipodophyllotoxin, isolated from Podophyllum. The biggest challenge is to maximize the control of the disease, while minimizing morbidity and toxicity to the surrounding normal tissues. The Erythroxylum suberosum is a common plant in the Brazilian Cerrado biome and is popularly known as "cabelo-de-negro". The objective of this study was to evaluate the cytotoxic activity of Erythroxylum suberosum plant extracts of the Brazilian Cerrado biome associated with radiotherapy in human cell lines of oral and hypopharynx carcinomas. Cells were treated with aqueous, ethanolic and hexanic extracts of Erythroxylum suberosum and irradiated at 4 Gy, 6 Gy and 8 Gy. Cytotoxicity was evaluated by MTT assay and the absorbance was measured at 570 nm in a Beckman Counter reader. Cisplatin, standard chemotherapy, was used as positive control. The use of Erythroxylum suberosum extracts showed a possible radiosensitizing effect in vitro for head and neck cancer. The cytotoxicity effect in the cell lines was not selective and it is very similar to the effect of standard chemotherapy. The aqueous extract of Erythroxylum suberosum, combined with radiotherapy was the most cytotoxic extract to oral and hypopharynx carcinomas. PMID:27007356

  15. An overview of the effective combination therapies for the treatment of breast cancer.

    PubMed

    Núñez, Cristina; Capelo, José Luis; Igrejas, Gilberto; Alfonso, Amparo; Botana, Luis M; Lodeiro, Carlos

    2016-08-01

    Breast cancer (BC) is generally classified based on the receptors overexpressed on the cell nucleus, which include hormone receptors such as progesterone (PR) and estrogen (ER), and HER2. Triple-negative breast cancer (TNBC) is a type of cancer that lacks any of these three types of receptor proteins (ER/PR/HER2). Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. Generally, drug resistance has a genetic basis that is caused by an abnormal gene expression, nevertheless, there are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints. The use of "combination therapy" is recognized as an efficient solution to treat human diseases, in particular, breast cancer. In this review, we give examples of different nanocarriers used to co-deliver multiple therapeutics (chemotherapeutic agent and nucleic acid) to drug-resistant tumor cells, and lastly, we give our recommendations for the future directions for the co-delivery treatments. PMID:27162073

  16. Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer.

    PubMed

    Thapa, Raj Kumar; Choi, Ju Yeon; Gupta, Biki; Ramasamy, Thiruganesh; Poudel, Bijay Kumar; Ku, Sae Kwang; Youn, Yu Seok; Choi, Han Gon; Yong, Chul Soon; Kim, Jong Oh

    2016-08-16

    Cancer remains a leading cause of death. A combination of anticancer agents can effectively kill cancer through multiple pathways; however, improvements to their delivery are needed. Hence, docetaxel and cisplatin-loaded liquid crystalline nanoparticles with folic acid were prepared for effective and targeted anticancer therapy. Notably, hydroxypropyl-β-cyclodextrin/cisplatin complexes in 0.9% NaCl solution were used for the prevention of possible aquation of cisplatin, which would otherwise lead to severe adverse effects. The optimized nanoparticles exhibited small particle size, high drug loading capacity (>90%), and controlled drug release profiles. In vitro cell cytotoxicity assays demonstrated that the optimized nanoparticles were taken up by folate receptor-expressing cells to a greater extent than non-folate expressing cells, which is attributable to folate-specific endocytosis of the optimized nanoparticles. Enhanced expression of apoptotic markers (Bax, p21, and cleaved caspase-3) along with enhanced anti-migration effects in MDA-MB-231 cells following treatment suggests that the optimized nanoparticles provide an effective treatment for metastatic breast cancer. These results were further supported by in vivo findings obtained for a MDA-MB-231 tumor xenograft model. Altogether, the optimized nanoparticles may potentially be developed as an effective treatment modality for folate-targeted metastatic breast cancer treatment. PMID:27412822

  17. Combinations of platinums and selected phytochemicals as a means of overcoming resistance in ovarian cancer.

    PubMed

    Huq, Fazlul; Yu, Jun Q; Beale, Philip; Chan, Charles; Arzuman, Lalia; Nessa, Meher U; Mazumder, Mohammed E H

    2014-01-01

    Cancer sufferers are often found to use herbal products along with targeted therapy although not much information (whether beneficial or harmful) is available about the effects of such combinations. In this study, we investigated synergism from the combination of platinum drugs and a number of tumour-active phytochemicals including curcumin, epigallocatechin-3-gallate, thymoquinone, genistein, resveratrol, betulinic acid and ursolic acid in three human ovarian cancer cell lines A2780, A2780(cisR) and A2780(ZD0473R), as a function of concentration and the sequence of administration. Both the dose-effect curves and combination indices show that the binary combinations of platinum drugs with the phytochemicals exert concentration- and sequence-dependent synergism in the cell lines. Generally the degree of synergism is found to be greater in sequenced administration such as 0/2 h, 2/0 h, 0/4 h and 4/0 h than the bolus. The variation in the nature of the combined drug action from being highly synergistic to antagonistic with the change in sequence of administration clearly indicates that the action of one drug modulates that of the other (towards the induction or inhibition of apoptosis). We have also used sequenced combinations of platinum drugs and bortezomib (a proteasome inhibitor that prevents cisplatin-induced proteasomal degration of copper transporter CTR1) to enhance cellular platinum accumulation and the level of platinum-DNA binding especially in the resistant human ovarian tumour models. Proteomic studies to identify the key proteins associated with platinum resistance are ongoing. We have identified 59 proteins associated with platinum resistance in ovarian tumor models. PMID:24403514

  18. Cancer risk estimates from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy.

    PubMed

    Schneider, Uwe; Walsh, Linda

    2008-04-01

    Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors who were exposed to gamma-rays and neutrons. Since, for radiation protection purposes, the dose span of main interest is between 0 and 1 Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses above 1 Gy are becoming more important for radiotherapy patients and for long-term manned missions in space research. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation-induced solid cancer. The analysis of the A-bomb survivor's data was extended by including two extra high-dose categories (4-6 Sv and 6-13 Sv) and by an attempted combination with cancer data on patients receiving radiotherapy for Hodgkin's disease. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear, a linear-exponential and a plateau-dose-response relationship. Best agreement was found for the plateau model with a dose-varying RBE. It can be concluded that for doses above 1 Gy there is a tendency for a nonlinear dose-response curve. In addition, there is evidence of a neutron RBE greater than 10 for the A-bomb survivor data. Many problems and uncertainties are involved in combing these two datasets. However, since very little is currently known about the shape of dose-response relationships for radiation-induced cancer in the radiotherapy dose range, this approach could be regarded as a first attempt to acquire more information on this area. The work presented here also provides the first direct evidence that the bending over of the solid cancer excess risk dose response curve for the A-bomb survivors, generally observed above 2 Gy

  19. Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells.

    PubMed

    Degirmenci, Mustafa; Erdogan, Atike Pinar; Bulut, Gulcan; Atmaca, Harika; Uzunoglu, Selim; Karaca, Burcak; Karabulut, Bulent; Uslu, Ruchan

    2016-04-01

    Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU-145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU-145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation. PMID:26531719

  20. Diagnostic value of dynamic and morphologic breast MRI analysis in the diagnosis of breast cancer

    PubMed Central

    Stusińska, Małgorzata; Szabo-Moskal, Jadwiga; Bobek-Billewicz, Barbara

    2014-01-01

    Summary Background Mammography is the most widely used method of breast imaging. However, its low sensitivity poses a problem. Breast MRI is one of so the called “complementary” breast imaging methods. The purpose of this study was to improve the specificity of breast MRI by combining 2 methods: dynamic and morphologic analysis of enhancing lesions. Material/Methods 222 women aged 19–76 years, who underwent breast MRI examination between November 2002 and April 2004 at the Radiology Department of Oncology Center in Bydgoszcz, were included in this study. Results The pathological examination revealed cancer in 55 women (25%). No cancer was found in 167 women (75%), 56 of which were verified pathologically, 111 by cytology and/or during follow-up (at least 24 months). Results of breast MRI were positive in 80 women (36%), in 54 of which cancer was found during pathological examination, 26 breast MRI results were false positive. Sensitivity and specificity of breast MRI for dynamic analysis were 87% and 72%, respectively; in case of morphologic analysis 98% and 74%, respectively. The combined dynamic and morphologic analysis achieved high (84%) specificity without loss of sensitivity (98%). The difference in specificity between the evaluated methods was statistically significant (p<0.05). Conclusions The combined dynamic and morphologic breast MRI analysis is a useful method for the diagnosis of breast cancer. PMID:24847391

  1. Effect of interleukin-2 treatment combined with magnetic fluid hyperthermia on Lewis lung cancer-bearing mice

    PubMed Central

    HU, RUNLEI; MA, SHENGLIN; KE, XIANFU; JIANG, HONG; WEI, DONGSHAN; WANG, WEI

    2016-01-01

    The present study aimed to investigate the therapeutic effect of interleukin-2 (IL-2) treatment combined with magnetic fluid hyperthermia (MFH) on Lewis lung cancer-bearing mice. Magnetic fluids were prepared in vitro and directly injected into the tumors in the mice, which were subjected to an alternating magnetic field. The temperature in the tumor reached 43°C and was maintained by controlling the strength of magnetic field for 30 min. Twenty-four hours later, IL-2 was injected directly into the tumors. Mice were divided into four groups: Group I (control), II (MFH), III (IL-2) and IV (IL-2+MFH). The tumor grew gradually in groups II and IV (both P<0.05) compared to the control group. Histological analysis showed that the tumor cells underwent apoptosis and necrosis. Immunohistochemistry results demonstrated that heat-shock protein 70 and cluster of differentiation (CD) 8-positive and CD4-positive T cells were strongly expressed following hypothermia. Therefore, the present study provided evidence that IL-2 treatment combined with MFH improves the therapeutic effect on lung cancer-bearing mice. PMID:26870335

  2. 5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells

    SciTech Connect

    Lan, Keng-Hsueh; Shih, Yi-Sheng; Chang, Cheng Allen; Yen, Sang-Hue; Lan, Keng-Li

    2012-11-16

    Highlights: Black-Right-Pointing-Pointer EGFR-expressing epithelial cancers account for significant portion of cancer deaths. Black-Right-Pointing-Pointer EGF-EGFR signaling pathway is validated as an important anticancer drug target. Black-Right-Pointing-Pointer EGF and Fcy fusion protein (Fcy-hEGF) can bind to EGFR and convert 5-FC to 5-FU. Black-Right-Pointing-Pointer Fcy-hEGF combined with 5-FC preferentially inhibits EGFR-expressing cells viability. -- Abstract: Human epithelial cancers account for approximately 50% of all cancer deaths. This type of cancer is characterized by excessive activation and expression of the epidermal growth factor receptor (EGFR). The EGFR pathway is critical for cancer cell proliferation, survival, metastasis and angiogenesis. The EGF-EGFR signaling pathway has been validated as an important anticancer drug target. Increasing numbers of targeted therapies against this pathway have been either approved or are currently under development. Here, we adopted a prodrug system that uses 5-fluorocytosine (5-FC) and human EGF (hEGF) fused with yeast cytosine deaminase (Fcy) to target EGFR-overexpressing cancer cells and to convert 5-FC to a significantly more toxic chemotherapeutic, 5-fluorouracil (5-FU). We cloned and purified the Fcy-hEGF fusion protein from Pichia pastoris yeast. This fusion protein specifically binds to EGFR with a similar affinity as hEGF, approximately 10 nM. Fcy-hEGF binds tightly to A431 and MDA-MB-468 cells, which overexpress EGFR, but it binds with a lower affinity to MDA-MB-231 and MCF-7, which express lower levels of EGFR. Similarly, the viability of EGFR-expressing cells was suppressed by Fcy-hEGF in the presence of increasing concentrations of 5-FC, and the IC{sub 50} values for A431 and MDA-MB-468 were approximately 10-fold lower than those of MDA-MB-231 and MCF-7. This novel prodrug system, Fcy-hEGF/5-FC, might represent a promising addition to the available class of inhibitors that specifically target EGFR

  3. Epigallocatechin Gallate and Sulforaphane Combination Treatment Induce Apoptosis in Paclitaxel-Resistant Ovarian Cancer Cells through hTERT and Bcl-2 Down-regulation

    PubMed Central

    Chen, Huaping; Landen, Charles N; Li, Yuanyuan; Alvarez, Ronald D; Tollefsbol, Trygve O

    2013-01-01

    The cellular development of resistance to chemotherapy contributes to the high mortality noted in patients affected by ovarian cancer. Novel compounds that specifically target cellular drug resistance in ovarian cancer are therefore highly desired. Previous epidemiological studies indicate that consumption of green tea and cruciferous vegetables is inversely associated with occurrence of ovarian cancer. Therefore revealing the effects and mechanisms of major components of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) on ovarian cancer cells will provide necessary knowledge for developing potential novel treatments for the disease. In this study, EGCG or SFN was used to treat both paclitaxel-sensitive (SKOV3-ip1) and -resistant (SKOV3TR-ip2) ovarian cancer cell lines alone or in combination. We found that SFN inhibits cell viability of both ovarian cancer cell lines time- and dose-dependently and that EGCG potentiates the inhibiting effect of SFN on ovarian cancer cells. Cell cycle analysis indicates SFN can arrest ovarian cancer cells in G2/M phase, while EGCG and SFN co-treatment can arrest cells in both G2/M and S phase. Combined EGCG and SFN treatment increases apoptosis significantly in paclitaxel-resistant SKOV3TR-ip2 cells after 6 days of treatment, while reducing the expression of hTERT, the main regulatory subunit of telomerase. Western blotting also indicates that SFN can down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types. Cleaved poly(ADP-ribose) polymerase (PARP) becomes up-regulated by 6 days of treatment with SFN and this is more pronounced for combination treatment indicating induction of apoptosis. Furthermore, phosphorylated H2AX is up-regulated after 6 days of treatment with SFN alone, and EGCG can potentiate this effect, suggesting that DNA damage is a potential cellular mechanism contributing to the inhibiting effect of EGCG and SFN combination treatment. Taken

  4. Cervical cancer and the global health agenda: Insights from multiple policy-analysis frameworks

    PubMed Central

    Parkhurst, Justin O.; Vulimiri, Madhulika

    2013-01-01

    Cervical cancer is the second leading cause of cancer deaths for women globally, with an estimated 88% of deaths occurring in the developing world. Available technologies have dramatically reduced mortality in high-income settings, yet cervical cancer receives considerably little attention on the global health policy landscape. The authors applied four policy-analysis frameworks to literature on global cervical cancer to explore the question of why cervical cancer may not be receiving the international attention it may otherwise warrant. Each framework explores the process of agenda setting and discerns factors that either facilitate or hinder policy change in cases where there is both a clear problem and a potential effective solution. In combination, these frameworks highlight a number of crucial elements that may be needed to raise the profile of cervical cancer on global health agendas, including improving local (national or sub-national) information on the condition; increasing mobilisation of affected civil society groups; framing cervical cancer debates in ways that build upon its classification as a non-communicable disease (NCD) and an issue of women's rights; linking cervical cancer screening to well-funded services such as those for HIV treatment in some countries; and identifying key global policy windows of opportunity to promote the cervical cancer agenda, including emerging NCD global health discussions and post-2015 reviews of the Millennium Development Goals. PMID:24236409

  5. Predicting MicroRNA Biomarkers for Cancer Using Phylogenetic Tree and Microarray Analysis.

    PubMed

    Wang, Hsiuying

    2016-01-01

    MicroRNAs (miRNAs) are shown to be involved in the initiation and progression of cancers in the literature, and the expression of miRNAs is used as an important cancer prognostic tool. The aim of this study is to predict high-confidence miRNA biomarkers for cancer. We adopt a method that combines miRNA phylogenetic structure and miRNA microarray data analysis to discover high-confidence miRNA biomarkers for colon, prostate, pancreatic, lung, breast, bladder and kidney cancers. There are 53 miRNAs selected through this method that either have potential to involve a single cancer's development or to involve several cancers' development. These miRNAs can be used as high-confidence miRNA biomarkers of these seven investigated cancers for further experiment validation. miR-17, miR-20, miR-106a, miR-106b, miR-92, miR-25, miR-16, miR-195 and miR-143 are selected to involve a single cancer's development in these seven cancers. They have the potential to be useful miRNA biomarkers when the result can be confirmed by experiments. PMID:27213352

  6. A naringenin–tamoxifen combination impairs cell proliferation and survival of MCF-7 breast cancer cells

    SciTech Connect

    Hatkevich, Talia; Ramos, Joseph; Santos-Sanchez, Idalys; Patel, Yashomati M.

    2014-10-01

    Since over 60% of breast cancers are estrogen receptor positive (ER+), many therapies have targeted the ER. The ER is activated by both estrogen binding and phosphorylation. While anti-estrogen therapies, such as tamoxifen (Tam) have been successful they do not target the growth factor promoting phosphorylation of the ER. Other proliferation pathways such as the phosphatidylinositol-3 kinase, (PI3K) and the mitogen-activated protein kinase (MAPK) pathways are activated in breast cancer cells and are associated with poor prognosis. Thus targeting multiple cellular proliferation and survival pathways at the onset of treatment is critical for the development of more effective therapies. The grapefruit flavanone naringenin (Nar) is an inhibitor of both the PI3K and MAPK pathways. Previous studies examining either Nar or Tam used charcoal-stripped serum which removed estrogen as well as other factors. We wanted to use serum containing medium in order to retain all the potential inducers of cell proliferation so as not to exclude any targets of Nar. Here we show that a Nar–Tam combination is more effective than either Tam alone or Nar alone in MCF-7 breast cancer cells. We demonstrate that a Nar–Tam combination impaired cellular proliferation and viability to a greater extent than either component alone in MCF-7 cells. Furthermore, the use of a Nar–Tam combination requires lower concentrations of both compounds to achieve the same effects on proliferation and viability. Nar may function by inhibiting both PI3K and MAPK pathways as well as localizing ERα to the cytoplasm in MCF-7 cells. Our results demonstrate that a Nar–Tam combination induces apoptosis and impairs proliferation signaling to a greater extent than either compound alone. These studies provide critical information for understanding the molecular mechanisms involved in cell proliferation and apoptosis in breast cancer cells. - Highlights: • Nar–Tam impairs cell viability more effectively than

  7. An intraoperative probe combining positron detection and OCT imaging for ovarian cancer detection and characterization

    NASA Astrophysics Data System (ADS)

    Yang, Yi; Wang, Tianheng; Biswal, Nrusingh; Kumavor, Patrick; Wang, Xiaohong; Karimeddini, Mozafareddin; Vento, John; Sanders, Melinda; Brewer, Molly; Zhu, Quing

    2012-01-01

    In this paper, we report an intraoperative approach by combining optical coherence tomography (OCT) and position detection to detect and characterize ovarian cancers. A total of 18 ovaries were studied ex vivo. Based on histopathology result, they were classified into normal and malignant groups, respectively. On average positron count rate of 8.0-fold higher was found between malignant and normal ovaries. OCT imaging of ovaries revealed many detailed morphologic features that could be potentially valuable for detecting early malignant changes in ovarian tissue. Optical scattering coefficients of these ovaries were estimated from OCT A-lines. Normal ovarian tissue showed higher scattering coefficient than that of malignant ovarian tissue. Using a threshold of 2.00 mm-1 for all ovaries, a sensitivity of 100% and a specificity of 100% were achieved. This initial data shows our intraoperative probe based on OCT and positron detection has a great potential for ovarian cancer detection and characterization.

  8. On probabilistic certification of combined cancer therapies using strongly uncertain models.

    PubMed

    Alamir, Mazen

    2015-11-01

    This paper proposes a general framework for probabilistic certification of cancer therapies. The certification is defined in terms of two key issues which are the tumor contraction and the lower admissible bound on the circulating lymphocytes which is viewed as indicator of the patient health. The certification is viewed as the ability to guarantee with a predefined high probability the success of the therapy over a finite horizon despite of the unavoidable high uncertainties affecting the dynamic model that is used to compute the optimal scheduling of drugs injection. The certification paradigm can be viewed as a tool for tuning the treatment parameters and protocols as well as for getting a rational use of limited or expensive drugs. The proposed framework is illustrated using the specific problem of combined immunotherapy/chemotherapy of cancer. PMID:26300070

  9. Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

    PubMed Central

    Castel, Pau; Toska, Eneda; Zumsteg, Zachary S; Carmona, F Javier; Elkabets, Moshe; Bosch, Ana; Scaltriti, Maurizio

    2014-01-01

    The PI3K/AKT/mTOR signaling is important for cell proliferation, survival, and metabolism. Hyperactivation of this pathway is one of the most common signaling abnormalities observed in cancer and a substantial effort has recently been made to develop molecules targeting this signaling cascade. However, it is becoming evident that PI3K inhibitors used as single agents do not elicit dramatic or durable responses. Given the numerous mechanisms mediating intrinsic and acquired resistance to these agents, hypothesis-based combinatorial strategies are probably needed to fully exploit their antitumor activity. In the first part of this review, we briefly dissect the PI3K/AKT/mTOR axis and list the most advanced compounds targeting different nodes of this cascade. The second part focuses on what we believe to be the most promising rationale-based therapeutic combinations with PI3K/AKT/mTOR inhibitors in solid tumors, with special emphasis on breast cancer. PMID:27308344

  10. Biosensing platform combining label-free and labelled analysis using Bloch surface waves

    NASA Astrophysics Data System (ADS)

    Danz, Norbert; Sinibaldi, Alberto; Munzert, Peter; Anopchenko, Aleksei; Förster, Erik; Schmieder, Stefan; Chandrawati, Rona; Rizzo, Riccardo; Heller, Rene; Sonntag, Frank; Mascioletti, Alessandro; Rana, Subinoy; Schubert, Thomas; Stevens, Molly M.; Michelotti, Francesco

    2015-05-01

    Bloch surface waves (BSW) propagating at the boundary of truncated photonic crystals (1D-PC) have emerged as an attractive approach for label-free sensing in plasmon-like sensor configurations. Due to the very low losses in such dielectric thin film stacks, BSW feature very low angular resonance widths compared to the surface plasmon resonance (SPR) case. Besides label-free operation, the large field enhancement and the absence of quenching allow utilizing BSW coupled fluorescence detection to additionally sense the presence of fluorescent labels. This approach can be adapted to the case of angularly resolved resonance detection, thus giving rise to a combined label-free / labelled biosensor platform. It features a parallel analysis of multiple spots arranged as a one-dimensional array inside a microfluidic channel of a disposable chip. Application of such a combined biosensing approach to the detection of the Angiopoietin-2 cancer biomarker in buffer solutions is reported.

  11. Combined cardiotocographic and ST event analysis: A review.

    PubMed

    Amer-Wahlin, Isis; Kwee, Anneke

    2016-01-01

    ST-analysis of the fetal electrocardiogram (ECG) (STAN(®)) combined with cardiotocography (CTG) for intrapartum fetal monitoring has been developed following many years of animal research. Changes in the ST-segment of the fetal ECG correlated with fetal hypoxia occurring during labor. In 1993 the first randomized controlled trial (RCT), comparing CTG with CTG + ST-analysis was published. STAN(®) was introduced for daily practice in 2000. To date, six RCTs have been performed, out of which five have been published. Furthermore, there are six published meta-analyses. The meta-analyses showed that CTG + ST-analysis reduced the risks of vaginal operative delivery by about 10% and fetal blood sampling by 40%. There are conflicting results regarding the effect on metabolic acidosis, much because of controveries about which RCTs should be included in a meta-analysis, and because of differences in methodology, execution and quality of the meta-analyses. Several cohort studies have been published, some showing significant decrease of metabolic acidosis after the introduction of ST-analysis. In this review, we discuss not only the scientific evidence from the RCTs and meta-analyses, but also the limitations of these studies. In conclusion, ST-analysis is effective in reducing operative vaginal deliveries and fetal blood sampling but the effect on neonatal metabolic acidosis is still under debate. Further research is needed to determine the place of ST-analysis in the labor ward for daily practice. PMID:26206514

  12. Application of a GRNN oracle to the intelligent combination of several breast cancer benign/malignant predictive paradigms

    NASA Astrophysics Data System (ADS)

    Land, Walker H., Jr.; Masters, Timothy D.; Lo, Joseph Y.

    2000-06-01

    The General Regression Neural Network (GRNN) is well known to be an extremely effective prediction model in a wide variety of problems. It has been recently established that in many prediction problems, the results obtained by intelligently combining the outputs of several different prediction models are generally superior to the results obtained by using any one of the models. An overseer model that combines predictions from other independently trained prediction models is often called an oracle. This paper describes how the GRNN is modified to serve as a powerful oracle for combining decisions from four different breast cancer benign/malignant prediction models using mammogram data. Specifically, the GRNN oracle combines decisions from an evolutionary programming derived neural network, a probabilistic neural network, a fully- interconnected three-layer, feed-forward, error backpropagation network, and a linear discriminant analysis model. In all experiments conducted, the oracle consistently provided superior benign/malignant classification discrimination as measured by the receiver operator characteristic curve Az index values.

  13. Antiproliferative effects of anastrozole on MCF-7 human breast cancer cells in vitro are significantly enhanced by combined treatment with testosterone undecanoate.

    PubMed

    Chen, Rong; Cui, Junwei; Wang, Qinqin; Li, Peng; Liu, Xiaoling; Hu, Hui; Wei, Wei

    2015-07-01

    The present study aimed to assess the effects of aromatase inhibitor anastrozole and testosterone undecanoate, separately and in combination, on proliferation and apoptosis in MCF-7 human breast cancer cells cultured in vitro. The effects of various concentrations of these drugs on the proliferation of MCF-7 cells were evaluated by CCK8 assay, the levels of cell apoptosis were evaluated by flow cytometry with Annexin-V/propidium iodide staining and androgen receptor (AR) protein expression was determined by western blot analysis. The results of the CCK8 assay indicated that greater antiproliferative activity was detected in the MCF-7 cells in the combined treatment groups, compared with those treated with anastrozole or testosterone undecanoate alone. Flow cytometric analysis of apoptosis revealed that treatment with a combination of the two drugs generated a higher percentage of apoptotic cells, particularly when the two drugs were applied for 48 h, compared with single drug treatment. Western blot analysis revealed a significant decrease in AR protein expression in the combined treatment groups compared with MCF7 cells treated with single drugs. The results of the present study provided evidence supporting the potential of a combination of anastrozole and testosterone undecanoate as a novel therapeutic strategy for the treatment of breast cancer. Furthermore, it was demonstrated that the antiproliferative effects of anastrozole were significantly enhanced by combined treatment with testosterone undecanoate via the AR signaling pathway. PMID:25738971

  14. [Which patients with ovarian cancer shows the combination of trabectedin with pegylated liposomal doxorubicin].

    PubMed

    Khokhlova, S V; Cherkasova, M V; Orel, N F; Limareva, S V; Bazaeva, I Ia; Gorbunova, V A

    2013-01-01

    Given the high rate of recurrence of ovarian cancer, the search for new therapeutic strategies are topical issue. According to various studies the effectiveness of drug treatment relapse depends on the platinum-free interval, increasing in proportion to its duration. If therapy is platinum-resistant recurrent ovarian cancer is a standard approach, the treatment of platinum-sensitive recurrent algorithm is not fully defined. Comparison of platinum and non-platinum combinations revealed the advantage of combined platinum- treatment for patients with platinum-free interval of more than 6 months without an increase in life expectancy. Non-platinum combination of trabected in with pegylated liposomal doxorubicin has shown comparable efficacy with an advantage in overall survival in patients with platinum-free interval of 6-12 months. A platinum-free interval prolongation by the use of non-platinum mode increases the efficiency of subsequent platinum-based therapy, increasing the life expectancy of patients. Currently under study molecular markers and prognostic factors allowing to define a group of patients who have the greatest benefit from the use trabectedin with pegylated liposomal doxorubicin as second-line chemotherapy. PMID:24640740

  15. A Reactive 1O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-07-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen (1O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of 1O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this 1O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency.

  16. Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

  17. A Reactive (1)O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer.

    PubMed

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-01-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen ((1)O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of (1)O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this (1)O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency. PMID:27443831

  18. A Reactive 1O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer

    PubMed Central

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-01-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen (1O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of 1O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this 1O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency. PMID:27443831

  19. [A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy].

    PubMed

    Sugie, Tomoharu; Nagai, Toshihiro; Ohgaki, Kazuhisa

    2008-04-01

    A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer. PMID:18408445

  20. Evaluation of Acute Locoregional Toxicity in Patients With Breast Cancer Treated With Adjuvant Radiotherapy in Combination With Bevacizumab

    SciTech Connect

    Goyal, Sharad

    2011-02-01

    Purpose: Preclinical studies have shown that bevacizumab combined with radiotherapy (RT) induces a radiosensitizing effect. Published reports regarding the safety of combination therapy involving bevacizumab and RT are lacking. The purpose of this study was to analyze acute locoregional toxicity in patients with breast cancer receiving concurrent bevacizumab plus RT. Methods and Materials: After institutional review board approval was obtained, patients with breast cancer who received bevacizumab were identified; these patients were then cross-referenced with patients receiving RT. Toxicity was scored by the Common Terminology Criteria for Adverse Events. Patients were matched 1:1 with those who did not receive bevacizumab. Statistical analysis was performed to analyze toxicity between the two groups. Results: Fourteen patients were identified to have received bevacizumab plus RT. All patients receivedbevacizumab during RT without delay or treatment breaks; there were no RT treatment breaks in all patients. No patient receiving bevacizumab plus RT experienced {>=}Grade 3 toxicity; 3 matched control patients experienced a Grade 3 skin reaction. There was no difference in fatigue, radiation fibrosis, pneumonitis, or lymphedema between the two groups. Five patients (35%) developed reduction in ejection fraction; 2 with right-sided and 3 with left-sided treatment. Patients with left-sided treatment experienced a persistent reduction in ejection fraction compared with those receiving right-sided treatment. Conclusion: Concurrent bevacizumab and RT did not increase acute locoregional toxicity in comparison with matched control patients who did not receive RT alone. The addition of concurrent RT when treating the intact breast, chest wall, and associated nodal regions in breast cancer seems to be safe and well tolerated.

  1. Use of the Charlson Combined Comorbidity Index To Predict Postradiotherapy Quality of Life for Prostate Cancer Patients

    SciTech Connect

    Wahlgren, Thomas; Levitt, Seymour; Kowalski, Jan; Nilsson, Sten; Brandberg, Yvonne

    2011-11-15

    Purpose: To determine the impact of pretreatment comorbidity on late health-related quality of life (HRQoL) scores after patients have undergone combined radiotherapy for prostate cancer, including high-dose rate brachytherapy boost and hormonal deprivation therapy. Methods and Materials: Results from the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire survey of 158 patients 5 years or more after completion of therapy were used from consecutively accrued subjects treated with curative radiotherapy at our institution, with no signs of disease at the time of questionnaire completion. HRQoL scores were compared with the Charlson combined comorbidity index (CCI), using analysis of covariance and multivariate regression models together with pretreatment factors including tumor stage, tumor grade, pretreatment prostate-specific antigen level, neoadjuvant hormonal treatment, diabetes status, cardiovascular status, and age and Charlson score as separate variables or the composite CCI. Results: An inverse correlation between the two HRQoL domains, long-term global health (QL) and physical function (PF) scores, and the CCI score was observed, indicating an impact of comorbidity in these function areas. Selected pretreatment factors poorly explained the variation in functional HRQoL in the multivariate models; however, a statistically significant impact was found for the CCI (with QL and PF scores) and the presence of diabetes (with QL and emotional function). Cognitive function and social function were not statistically significantly predicted by any of the pretreatment factors. Conclusions: The CCI proved to be valid in this context, but it seems useful mainly in predicting long-term QL and PF scores. Of the other variables investigated, diabetes had more impact than cardiovascular morbidity on HRQoL outcomes in prostate cancer.

  2. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

    PubMed

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I; Conti, David V; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N; Le Marchand, Loic; Hoover, Robert N; Machiela, Mitchell J; Yeager, Merideth; Burdette, Laurie; Chung, Charles C; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L J; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C; Key, Tim J; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G; Nielsen, Sune F; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M; Diver, W Ryan; Stevens, Victoria L; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E; Strom, Sara S; Pettaway, Curtis; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B; Partin, Alan W; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L; Ma, Jing; Stampfer, Meir; Penney, Kathryn L; Mucci, Lorelei; John, Esther M; Ingles, Sue A; Kittles, Rick A; Murphy, Adam B; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M; Blot, William; Signorello, Lisa B; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S; Rybicki, Benjamin A; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Zheng, S Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S; Casey, Graham; Gillanders, Elizabeth M; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C; Coetzee, Gerhard A; Li, Qiyuan; Freedman, Matthew L; Hunter, David J; Muir, Kenneth; Gronberg, Henrik; Neal, David E; Southey, Melissa; Giles, Graham G; Severi, Gianluca; Cook, Michael B; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J; Henderson, Brian E; Easton, Douglas F; Eeles, Rosalind A; Haiman, Christopher A

    2014-10-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease. PMID:25217961

  3. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

    PubMed Central

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I.; Conti, David V.; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J.; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O.; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C.; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N.; Le Marchand, Loic; Hoover, Robert N.; Machiela, Mitchell J.; Yeager, Merideth; Burdette, Laurie; Chung, Charles C.; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L.J.; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A.; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C.; Key, Tim J.; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G.; Nielsen, Sune F.; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N.; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L.; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M.; Diver, W. Ryan; Stevens, Victoria L.; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E.; Strom, Sara S.; Pettaway, Curtis; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B.; Partin, Alan W.; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L.; Ma, Jing; Stampfer, Meir; Penney, Kathryn L.; Mucci, Lorelei; John, Esther M.; Ingles, Sue A.; Kittles, Rick A.; Murphy, Adam B.; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M.; Blot, William; Signorello, Lisa B.; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S.; Rybicki, Benjamin A.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A; Zheng, S. Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S.; Casey, Graham; Gillanders, Elizabeth M.; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C.; Coetzee, Gerhard A.; Li, Qiyuan; Freedman, Matthew L.; Hunter, David J.; Muir, Kenneth; Gronberg, Henrik; Neal, David E.; Southey, Melissa; Giles, Graham G.; Severi, Gianluca; Cook, Michael B.; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J.; Henderson, Brian E.; Easton, Douglas F.; Eeles, Rosalind A.; Haiman, Christopher A.

    2014-01-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease. PMID:25217961

  4. Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer

    PubMed Central

    Sanchez, C; Chan, R; Bajgain, P; Rambally, S; Palapattu, G; Mims, M; Rooney, CM; Leen, AM; Brenner, MK; Vera, JF

    2013-01-01

    BACKGROUND Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by substantial side effects. Adoptive immunotherapy represents an attractive alternative to conventional treatments as a means to control tumor growth. METHODS To selectively target the tumor-expressed form of Muc1 we constructed a retroviral vector encoding a chimeric antigen receptor (CAR) directed against the aberrantly-expressed extracellular portion of Muc1 called the ‘variable number of tandem repeats’. RESULTS We now demonstrate that T cells can be genetically engineered to express a CAR targeting the tumor-associated antigen Muc1. CAR-Muc1 T cells were able to selectively kill Muc1-expressing human prostate cancer cells. However, we noted that heterogeneous expression of the Muc1 antigen on tumor cells facilitated immune escape and the outgrowth of target-antigen loss variants of the tumor. Given the importance of androgen ablation therapy in the management of metastatic prostate cancer, we therefore also tested the value of combining conventional (anti-androgen) and experimental (CAR-Muc1 T cells) approaches. We show that CAR-Muc1 T cells were not adversely impacted by anti-androgen therapy and subsequently demonstrate the feasibility of combining the approaches to produce additive anti-tumor effects in vitro. CONCLUSIONS Adoptive transfer of CAR-Muc1 T cells alone or in combination with other luteinizing hormone-releasing hormone analogs or antagonists should be tested in human clinical trials. PMID:23295316

  5. CpG Oligodeoxynucleotide1826 combined with radioresistant cancer cell vaccine confers significant antitumor effects.

    PubMed

    Zhuang, X B; Xing, N; Zhang, Q; Yuan, S J; Chen, W; Qiao, T K

    2015-01-01

    Immunotherapy is a hot issue in cancer research over the years and tumor cell vaccine is one of the increasing number of studies. Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. CpG Oligodeoxynucleotides (CpG ODNs), synthetic oligonucleotides containing a cytosine-phosphate-guanine(CpG) motif, was shown to enhance immune responses to a wide variety of antigens. In this study, we generated the radioresistant Lewis lung cancer cell by repeated X-ray radiation and inactivated it as a whole tumor cell vaccine to enhance the immunogenicity of tumor cell vaccine. Mice were subcutaneously immunized with this inactivated vaccine combined with CpG ODN1826 and then inoculated with autologous Lewis lung cancer (LLC) to estimate the antitumor efficacy. The results showed that the radioresistant tumor cell vaccine combined with CpG ODN1826 could significantly inhibit tumor growth, increased survival of the mice and with 20% of the mice surviving tumor free in vivo compared with the unimmunized mice bearing LLC tumor. A significant increase of apoptosis was also observed in the tumor prophylactically immunized with vaccine of inactivated radioresistant tumor cell plus CpG ODN1826. The potent antitumor effect correlated with higher secretion levels of tumor necrosis factor-alpha(TNF-α) and lower levels of interleukin-10(IL-10) concentration in serum. Furthermore, the results suggested that the antitumor mechanism was probably depended on the decreased level of programmed death ligand-1(PD-L1) which plays an important role in the negative regulation of immune response by the inhibition of tumor antigen-specific T cell activation. These findings clearly demonstrated that the radioresistant tumor cell vaccine combined with CpG ODN1826 as an appropriate adjuvant could induce effective antitumor immunity in vivo. PMID:26458317

  6. Trastuzumab and Combination Chemotherapy in Treating Patients With Locally Recurrent or Metastatic Urinary Tract Cancer

    ClinicalTrials.gov

    2013-01-11

    Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Squamous Cell Carcinoma of the Bladder; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder

  7. Everolimus and Combination Chemotherapy in Treating Patients With Metastatic Stomach or Esophageal Cancer

    ClinicalTrials.gov

    2016-07-27

    Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer

  8. Systematic pan-cancer analysis of tumour purity

    PubMed Central

    Aran, Dvir; Sirota, Marina; Butte, Atul J.

    2015-01-01

    The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, but also fibroblasts and cells that comprise supporting blood vessels. These non-cancerous components of the tumour may play an important role in cancer biology. They also have a strong influence on the genomic analysis of tumour samples, and may alter the biological interpretation of results. Here we present a systematic analysis using different measurement modalities of tumour purity in >10,000 samples across 21 cancer types from the Cancer Genome Atlas. Patients are stratified according to clinical features in an attempt to detect clinical differences driven by purity levels. We demonstrate the confounding effect of tumour purity on correlating and clustering tumours with transcriptomics data. Finally, using a differential expression method that accounts for tumour purity, we find an immunotherapy gene signature in several cancer types that is not detected by traditional differential expression analyses. PMID:26634437

  9. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer

    PubMed Central

    Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

    2013-01-01

    Introduction: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. Methods: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Results: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m−2 on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1–147.3 weeks). Common treatment-emergent adverse events (all grades/grade ⩾3) included diarrhoea (92%/29% none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9–81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan–Meier median progression-free survival was 57

  10. Tolerability of Combined Modality Therapy for Rectal Cancer in Elderly Patients Aged 75 Years and Older

    SciTech Connect

    Margalit, Danielle N.; Mamon, Harvey J.; Ryan, David P.; Blaszkowsky, Lawrence S.; Clark, Jeffrey; Willett, Christopher G.; Hong, Theodore S.

    2011-12-01

    Purpose: To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older. Methods and Materials: We reviewed the records of consecutively treated patients with rectal cancer aged 75 years and older treated with combined modality therapy at Massachusetts General Hospital and Brigham and Women's Hospital from 2002 to 2007. The primary endpoint was the rate of treatment deviation, defined as a treatment break, dose reduction, early discontinuation of therapy, or hospitalization during combined modality therapy. Patient comorbidity was rated using the validated Adult Comorbidity Evaluation 27 Test (ACE-27) comorbidity index. Fisher's exact test and the Mantel-Haenszel trend test were used to identify predictors of treatment tolerability. Results: Thirty-six eligible patients had a median age of 79.0 years (range, 75-87 years); 53% (19/36) had no or mild comorbidity and 47% (17/36) had moderate or severe comorbidity. In all, 58% of patients (21/36) were treated with preoperative chemoradiotherapy (CRT) and 33% (12/36) with postoperative CRT. Although 92% patients (33/36) completed the planned radiotherapy (RT) dose, 25% (9/36) required an RT-treatment break, 11% (4/36) were hospitalized, and 33% (12/36) had a dose reduction, break, or discontinuation of concurrent chemotherapy. In all, 39% of patients (14/36) completed {>=}4 months of adjuvant chemotherapy, and 17% (6/36) completed therapy without a treatment deviation. More patients with no to mild comorbidity completed treatment than did patients with moderate to severe comorbidity (21% vs. 12%, p = 0.66). The rate of deviation did not differ between patients who had preoperative or postoperative CRT (19% vs. 17%, p = 1.0). Conclusions: The majority of elderly patients with rectal cancer in this series required early termination of treatment, treatment interruptions, or dose reductions. These data suggest that further intensification of

  11. 125I particle implantation combined with chemoradiotherapy to treat advanced pancreatic cancer

    PubMed Central

    Guo, J-M; Jiang, H-T; Di, X-Y; Zhu, Y

    2014-01-01

    Objective: To evaluate the therapy effects of 125I implantation combined with chemoradiotherapy on pancreatic cancer patients. Methods: 30 patients with Stage III or IV pancreatic cancer were equally divided into two groups (control and treatment group). The patients in the treatment group (nine males, six females) received chemotherapy in the first week and 125I implantation in the third week, followed by combined chemoradiotherapy in the fifth week. The patients in the control group (10 males, 5 females) received the same treatment except 125I implantation. The therapy in the control group and treatment group was repeated every 4 weeks. Results: The median conformal radiotherapy dose in the treatment group (30.62 Gy) was significantly lower than that in the control group (47.86 Gy). The total radiation dose was 88.71 ± 27.39 Gy, and the surface activity was 0.6 mCi in the treatment group. After treatment, the average tumour size decreased both in the treatment group [9.17 cm2, 95% confidence interval (CI): 5.60–12.74, p < 0.001] and in the control group (4.54 cm2, 95% CI: 2.74–6.35, p < 0.001). The median survival time in the treatment group was 14 months (95% CI: 12.215–14.785) and in the control group was 12 months (95% CI: 10.884–13.116). There was no statistical significance in survival rates between the two groups (χ2 = 0.908, p = 0.341). Conclusion: 125I implanted into tumour combined with chemoradiotherapy has higher local control rate of advanced pancreatic cancer than chemoradiotherapy. Advances in knowledge: We combined chemoradiotherapy with 125I implantation to treat advanced pancreatic cancer and obtained a higher local control rate and better quality of life than when using chemoradiatherapy alone. PMID:24625042

  12. [The influence of the combined treatment on the energy metabolism in patients with the uterine cancer].

    PubMed

    Antipova, S V

    2000-12-01

    The experience of management of the patients with cancer of the uterus body was summarized to improve the results of combined (surgical and radiation) treatment. The essential initial disorders of the power supply metabolism, keeping worsening after the operation, were revealed. The conduction of the immune correction therapy in complex of preoperative preparation with individual selection of the immune preparations using the tests in vitro had promoted the postoperative period course improvement, the frequency of complications reduction, the stabilization and tendency for the power supply metabolism restoration after the operation and further during the radiation therapy conduction. PMID:11247494

  13. [Jinlong capsule combined with chemoradiotherapy for NSCLC: a Meta-analysis].

    PubMed

    Lu, Qiang; Luo, Jing-bin; Feng, Yi-fan; She, Qin; Shi, Zhong-feng

    2015-11-01

    The purpose of this study was to evaluate the effect and safety of Jinlong capsule combined with chemotherapy or radio-therapy for non-small cell lung cancer (NSCLS) using Meta-analysis. PubMed, Embase, CNKI and Wanfang databases were all searched without language restriction, and searching time was from January 1990 to July 2015. All eligible published studies were included in this study for quality assessment and data extraction. All the data were analyzed using Revman 5.3. A total of ten studies including 736 subjects (370 in Jinlong capsule plus chemoradiotherapy and 366 in chemoradiotherapy only) were finally included in this Meta-analysis. The result of Meta analysis showed that compared with pure chemoradiotherapy group, Jinlong capsule combined with chemoradiotherapy for NSCLC could improve the patients' curative effect (OR = 1.77, 95% CI: 1.29-2.43, P < 0.05), clinical benefit rate (OR = 1.89, 95% CI: 1.22-2.91, P < 0.05), life quality improvement rate (OR = 2. 56, 95% CI: 1.61-4.05, P < 0.05), and decrease leucopenia incidence rate (OR = 0.35, 95% CI: 0. 22-0.56, P < 0.05) and gastrointestinal reaction rate (OR = 0.67, 95% CI: 0.40-1.11, P < 0.05). The pooled results showed that Jinlong capsule combined with chemoradiotherapy for NSCLC could improve the curative effect and life quality, and decrease the adverse reaction of patients. PMID:27097429

  14. Peripheral platelet/lymphocyte ratio predicts lymph node metastasis and acts as a superior prognostic factor for cervical cancer when combined with neutrophil

    PubMed Central

    Chen, Liang; Zhang, Fang; Sheng, Xiu-gui; Zhang, Shi-qian; Chen, Yue-ting; Liu, Bo-wen

    2016-01-01

    Abstract Inflammation-based indicators such as neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), and platelet/lymphocyte ratio (PLR) have been reported to possess significant predictive value for several types of cancer. We investigated the predictive value of these 3 biomarkers on lymph node metastasis (LNM) and clinical outcome in patients with stage Ib1–IIa cervical cancer undergoing radical surgery. A total of 407 patients with FIGO stage Ib1–IIa cervical cancer, who underwent radical surgery between January 2006 and December 2009 at the Department of Gynecological and Oncology of Shandong Cancer Hospital Affiliated to Shandong University were recruited. Binary logistic regression analysis was performed to determine the relationship between PLR, NLR, dNLR, and LNM. Multivariate Cox regression analysis was performed to determine the association between the 3 indices and recurrence-free survival (RFS) and overall survival (OS). Optimal cut-off values for the 3 indices were determined by applying receiver operating curve (ROC) analysis. Univariate and binary logistic regression analyses both indicate that PLR was significantly associated with increased LNM (P < 0.05). In the multivariate survival analysis, increased preoperative PLR and NLR were significantly associated with reduced RFS (P = 0.001 and P = 0.002, respectively), whereas a combination of both PLR and NLR revealed a more significant association with reduced RFS (P < 0.001). Furthermore, increased preoperative PLR and NLR were significantly associated with reduced OS (P = 0.007 and P = 0.009, respectively), whereas the combined use of PLR and NLR revealed a more significant association with reduced OS (P = 0.003). PLR is an independent risk factor for increased LNM and clinical outcome in patients with stage Ib1–IIa cervical cancer. A combination of PLR and NLR may enable better risk stratification for predicting survival. PMID:27512849

  15. Celecoxib-erlotinib combination delays growth and inhibits angiogenesis in EGFR-mutated lung cancer

    PubMed Central

    Li, Yi Xiao; Wang, Jia Le; Gao, Meng; Tang, Hao; Gui, Rong; Fu, Yun Feng

    2016-01-01

    Combination treatment for non-small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose celecoxib-erlotinib combination in NSCLC in vitro and in vivo. In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination celecoxib-erlotinib treatment led to synergistic cell death, but there was minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased vascular endothelial growth factor A (VEGFA) levels and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through the modulation of of the PI3K/AKT and ERK/Raf1-1 pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen. PMID:27508092

  16. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    PubMed Central

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  17. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer.

    PubMed

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles' charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  18. Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

    PubMed Central

    YAN, BINGBING; YIN, FUQIANG; WANG, QI; ZHANG, WEI; LI, LI

    2016-01-01

    The main obstacle to the successful treatment of ovarian cancer is the development of drug resistance to combined chemotherapy. Among all the factors associated with drug resistance, DNA methylation apparently plays a critical role. In this study, we performed an integrative analysis of the 26 DNA-methylated genes associated with drug resistance in ovarian cancer, and the genes were further evaluated by comprehensive bioinformatics analysis including gene/protein interaction, biological process enrichment and annotation. The results from the protein interaction analyses revealed that at least 20 of these 26 methylated genes are present in the protein interaction network, indicating that they interact with each other, have a correlation in function, and may participate as a whole in the regulation of ovarian cancer drug resistance. There is a direct interaction between the phosphatase and tensin homolog (PTEN) gene and at least half of the other genes, indicating that PTEN may possess core regulatory functions among these genes. Biological process enrichment and annotation demonstrated that most of these methylated genes were significantly associated with apoptosis, which is possibly an essential way for these genes to be involved in the regulation of multidrug resistance in ovarian cancer. In addition, a comprehensive analysis of clinical factors revealed that the methylation level of genes that are associated with the regulation of drug resistance in ovarian cancer was significantly correlated with the prognosis of ovarian cancer. Overall, this study preliminarily explains the potential correlation between the genes with DNA methylation and drug resistance in ovarian cancer. This finding has significance for our understanding of the regulation of resistant ovarian cancer by methylated genes, the treatment of ovarian cancer, and improvement of the prognosis of ovarian cancer. PMID:27347118

  19. Toward a Comprehensive Genomic Analysis of Cancer - TCGA

    Cancer.gov

    The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) convened a "Toward a Comprehensive Genomic Analysis of Cancer" workshop in Washington, D.C. This workshop brought together physicians, basic scientists and other members of the U.S. and international cancer communities to assist in outlining the most effective strategies for the development of a successful project. Information about this workshop is reported in the Executive Summary.

  20. A Combined Metabolomic and Proteomic Analysis of Gestational Diabetes Mellitus

    PubMed Central

    Hajduk, Joanna; Klupczynska, Agnieszka; Dereziński, Paweł; Matysiak, Jan; Kokot, Piotr; Nowak, Dorota M.; Gajęcka, Marzena; Nowak-Markwitz, Ewa; Kokot, Zenon J.

    2015-01-01

    The aim of this pilot study was to apply a novel combined metabolomic and proteomic approach in analysis of gestational diabetes mellitus. The investigation was performed with plasma samples derived from pregnant women with diagnosed gestational diabetes mellitus (n = 18) and a matched control group (n = 13). The mass spectrometry-based analyses allowed to determine 42 free amino acids and low molecular-weight peptide profiles. Different expressions of several peptides and altered amino acid profiles were observed in the analyzed groups. The combination of proteomic and metabolomic data allowed obtaining the model with a high discriminatory power, where amino acids ethanolamine, l-citrulline, l-asparagine, and peptide ions with m/z 1488.59; 4111.89 and 2913.15 had the highest contribution to the model. The sensitivity (94.44%) and specificity (84.62%), as well as the total group membership classification value (90.32%) calculated from the post hoc classification matrix of a joint model were the highest when compared with a single analysis of either amino acid levels or peptide ion intensities. The obtained results indicated a high potential of integration of proteomic and metabolomics analysis regardless the sample size. This promising approach together with clinical evaluation of the subjects can also be used in the study of other diseases. PMID:26694367

  1. Combined cancer therapy with hyaluronan-decorated fullerene-silica multifunctional nanoparticles to target cancer stem-like cells.

    PubMed

    Wang, Hai; Agarwal, Pranay; Zhao, Shuting; Yu, Jianhua; Lu, Xiongbin; He, Xiaoming

    2016-08-01

    Cancer stem-like cells (CSCs) are resistant to chemotherapy and highly tumorigenic, which contributes to tumor occurrence and post-treatment relapse. We developed a novel C60 fullerene-silica nanoparticle system surface-decorated with hyaluronan (HA) to target the variant CD44 overexpressed on breast CSCs. Furthermore, doxorubicin hydrochloride (DOX) and indocyanine green (ICG) can be encapsulated in the nanoparticles with ultrahigh encapsulation efficiency (>90%) and loading content (e.g., 48.5% at a drug-to-nanoparticle feeding ratio of 1:1, compared to the commonly used drug-to-nanoparticle feeding ratio of 1:20 with a drug loading content of less than 5%). As a result, the DOX and ICG-laden nanoparticles can be used as a single nanoplatform to achieve combined chemo, photodynamic, and photothermal therapy under near infrared laser irradiation for effective destruction of the breast CSCs both in vitro and in vivo, with no evident systemic toxicity. Moreover, we found the nanoparticles with a higher drug loading content (e.g., 48.5 versus 4.6%) also have significantly higher antitumor efficacy, given the same total drug dose. These results demonstrate the great potential of the multifunctional hybrid nanoparticle system for augmenting cancer therapy by eliminating the CSCs. PMID:27162075

  2. Phase I-II Study of Fluorouracil in Combination With Phenylbutyrate in Advanced Colorectal Cancer

    ClinicalTrials.gov

    2013-01-31

    Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  3. The bivariate combined model for spatial data analysis.

    PubMed

    Neyens, Thomas; Lawson, Andrew B; Kirby, Russell S; Faes, Christel

    2016-08-15

    To describe the spatial distribution of diseases, a number of methods have been proposed to model relative risks within areas. Most models use Bayesian hierarchical methods, in which one models both spatially structured and unstructured extra-Poisson variance present in the data. For modelling a single disease, the conditional autoregressive (CAR) convolution model has been very popular. More recently, a combined model was proposed that 'combines' ideas from the CAR convolution model and the well-known Poisson-gamma model. The combined model was shown to be a good alternative to the CAR convolution model when there was a large amount of uncorrelated extra-variance in the data. Less solutions exist for modelling two diseases simultaneously or modelling a disease in two sub-populations simultaneously. Furthermore, existing models are typically based on the CAR convolution model. In this paper, a bivariate version of the combined model is proposed in which the unstructured heterogeneity term is split up into terms that are shared and terms that are specific to the disease or subpopulation, while spatial dependency is introduced via a univariate or multivariate Markov random field. The proposed method is illustrated by analysis of disease data in Georgia (USA) and Limburg (Belgium) and in a simulation study. We conclude that the bivariate combined model constitutes an interesting model when two diseases are possibly correlated. As the choice of the preferred model differs between data sets, we suggest to use the new and existing modelling approaches together and to choose the best model via goodness-of-fit statistics. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26928309

  4. Cancer risk estimates for gamma-rays with regard to organ-specific doses. Part I: All solid cancers combined.

    PubMed

    Walsh, Linda; Rühm, Werner; Kellerer, Albrecht M

    2004-09-01

    A previous analysis of the solid cancer mortality data for 1950-1990 from the Japanese life-span study of the A-bomb survivors has assessed the solid cancer risk coefficients for gamma-rays in terms of the low dose risk coefficient ERR/Gy, i.e. the initial slope of the ERR vs. dose relation, and also in terms of the more precisely estimated intermediate dose risk coefficient, ERR(D1)/D1, for a reference dose, D1, which was chosen to be 1 Gy. The computations were performed for tentatively assumed values 20-50 of the neutron RBE against the reference dose and in terms of organ-averaged doses, rather than the traditionally applied colon doses. The resulting risk estimate for a dose of 1 Gy was about half as large as the most recent UNSCEAR estimate. The present assessment repeats the earlier analysis with two major extensions. It parallels computations based on organ-average doses with computations based on organ-specific doses and it updates the previous results by using the cancer mortality data for 1950-1997 which have recently been made available. With an assumed neutron RBE of 35, the resulting intermediate dose estimate of the lifetime attributable risk (LAR) for solid cancer mortality for a working population (ages 25-65 years) is 0.059/Gy with the attained-age model, and 0.044/Gy with the age-at-exposure model. For a population of all ages, 0.055/Gy is obtained with the attained-age model and 0.073/Gy with the age-at-exposure model. These values are up to about 20% higher than those obtained in the previous analysis with the 1950-1990 data. However, considerably more curvature in the dose-effect relation is now supported by the computations. A dose and dose-rate reduction factor DDREF=2 is now much more in line with the data than before. With this factor the LAR for a working population is--averaged over the age-at-exposure and the age-attained model--equal to 0.026/Gy. This is only half as large as the current ICRP estimate which is also based on the

  5. Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy

    PubMed Central

    Sultana, A; Tudur Smith, C; Cunningham, D; Starling, N; Tait, D; Neoptolemos, J P; Ghaneh, P

    2007-01-01

    There is no consensus on the management of locally advanced pancreatic cancer, with either chemotherapy or combined modality approaches being employed (Maheshwari and Moser, 2005). No published meta-analysis (Fung et al, 2003; Banu et al, 2005; Liang, 2005; Bria et al, 2006; Milella et al, 2006) has included randomised controlled trials employing radiation therapy. The aim of this systematic review was to compare the following: (i) chemoradiation followed by chemotherapy (combined modality therapy) vs best supportive care (ii) radiotherapy vs chemoradiation (iii) radiotherapy vs combined modality therapy (iv) chemotherapy vs combined modality therapy (v) 5FU-based combined modality treatment vs another-agent-based combined modality therapy. Relevant randomised controlled trials were identified by searching databases, trial registers and conference proceedings. The primary end point was overall survival and secondary end points were progression-free survival/time-to-progression, response rate and adverse events. Survival data were summarised using hazard ratio (HR) and response-rate/adverse-event data with relative risk. Eleven trials involving 794 patients met the inclusion criteria. Length of survival with chemoradiation was increased compared with radiotherapy alone (two trials, 168 patients, HR 0.69; 95% confidence interval (CI) 0.51–0.94), but chemoradiation followed by chemotherapy did not lead to a survival advantage over chemotherapy alone (two trials, 134 patients, HR 0.79; CI 0.32–1.95). Meta-analyses could not be performed for the other comparisons. A survival benefit was demonstrated for chemoradiation over radiotherapy alone. Chemoradiation followed by chemotherapy did not demonstrate any survival advantage over chemotherapy alone, but important clinical differences cannot be ruled out due to the wide CI. PMID:17406358

  6. Carotenoid intake and head and neck cancer: a pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

    PubMed

    Leoncini, Emanuele; Edefonti, Valeria; Hashibe, Mia; Parpinel, Maria; Cadoni, Gabriella; Ferraroni, Monica; Serraino, Diego; Matsuo, Keitaro; Olshan, Andrew F; Zevallos, Jose P; Winn, Deborah M; Moysich, Kirsten; Zhang, Zuo-Feng; Morgenstern, Hal; Levi, Fabio; Kelsey, Karl; McClean, Michael; Bosetti, Cristina; Schantz, Stimson; Yu, Guo-Pei; Boffetta, Paolo; Lee, Yuan-Chin Amy; Chuang, Shu-Chun; Decarli, Adriano; La Vecchia, Carlo; Boccia, Stefania

    2016-04-01

    Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case-control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39 % (95 % CI 29-47 %) for oral/pharyngeal cancer and 39 % (95 % CI 24-50 %) for laryngeal cancer. Intakes of β-carotene equivalents, β-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18 % reduction in the rate of oral and pharyngeal cancer (95 % CI 6-29 %) and 17 % reduction in the rate of laryngeal cancer (95 % CI 0-32 %). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p < 0.05). The odds ratio for the combined effect of low carotenoid intake and high alcohol or tobacco consumption versus high carotenoid intake and low alcohol or tobacco consumption ranged from 7 (95 % CI 5-9) to 33 (95 % CI 23-49). A diet rich in carotenoids may protect against HNC. Persons with both low carotenoid intake and high tobacco or alcohol are at substantially higher risk of HNC. PMID:25930054

  7. Prognostic value of caveolin-1 in genitourinary cancer: a meta-analysis

    PubMed Central

    Liu, Jia-Ming; Cheng, Si-Hang; Liu, Xiao-Xiao; Xia, Chao; Wang, Wei-Wen; Ma, Xue-Lei

    2015-01-01

    We aimed to obtain the most comprehensive picture to date of the prognostic value of caveolin-1 (Cav-1) in genitourinary carcinoma by meta-analyzing all eligible studies in PubMed and EMBASE. Data on patient clinical characteristics, cancer-specific survival (CSS) and recurrence-free survival (RFS) were extracted. The meta-analysis included 6 articles on prostate cancer, 5 on renal cancer, 1 on bladder cancer and 1 on transition cell carcinoma of the upper urinary tract. Two studies examining the association of ELISA-measured Cav-1 levels in serum with RFS in 621 patients with prostate cancer gave a combined hazard ratio (HR) of 1.25 (95% CI 0.36 to 4.36). The other 4 studies on prostate cancer examined the association of immunohistochemically determined Cav-1 levels in cancerous tissue with RFS and gave a combined HR of 1.83 (95% CI 1.36 to 2.47). Three studies on renal cancer examining the association of Cav-1 levels with CSS gave a multivariate HR of 1.98 (95% CI 1.35 to 2.90). The single studies on bladder carcinoma and upper urinary tract carcinoma gave, respectively, a multivariate HR of 2.28 (95% CI 1.09 to 4.74) for the relationship of Cav-1 levels to DFS, and a multivariate HR of 5.08 (95% CI 1.799 to 14.342) for the relationship of Cav-1 levels to CSS. This meta-analysis of available evidence suggests that elevated Cav-1 levels in serum can predict poor survival in patients with genitourinary cancer, which may help identify high-risk patients earlier and guide clinical decision-making. PMID:26884999

  8. Association between cadmium exposure and renal cancer risk: a meta-analysis of observational studies

    PubMed Central

    Song, Ju kun; Luo, Hong; Yin, Xin hai; Huang, Guang lei; Luo, Si yang; Lin, Du ren; Yuan, Dong Bo; Zhang, Wei; Zhu, Jian guo

    2015-01-01

    Cadmium (Cd) is a widespread environmental pollutant and has been a recognized carcinogen for several decades. Many observational studies reported Cd exposure might be one cause of renal cancer. However, these findings are inconsistent. We conducted a meta-analysis to evaluate the relationship between cadmium exposure and renal cancer risk. A comprehensive PubMed and Embase search was conducted to retrieve observational studies meeting our meta-analysis criteria. A combined odds ratio (OR) and corresponding 95% confidence interval (CI) were applied to assess the association between Cd exposure and renal cancer risk. The meta-analysis showed that a high Cd exposure significantly increased renal cancer 1.47 times (OR = 1.47; 95% CI = 1.27 to 1.71, for highest versus lowest category of cadmium categories). The significant association remained consistent when stratified by geographic region and gender, however mixed results were produced when stratified by sample size, study design, NOS score, adjustment for covariates, effects measure, and exposure type. Our results indicated that a high Cd exposure was associated with increased renal cancer risk and the association was higher for occupational exposure compared with non-occupational exposure. This meta-analysis suggests that a high Cd exposure may be a risk factor for renal cancer in occupational population. PMID:26656678

  9. Combination of the PI3K inhibitor ZSTK474 with a PSMA-targeted immunotoxin accelerates apoptosis and regression of prostate cancer.

    PubMed

    Baiz, Daniele; Hassan, Sazzad; Choi, Young A; Flores, Anabel; Karpova, Yelena; Yancey, Dana; Pullikuth, Ashok; Sui, Guangchao; Sadelain, Michel; Debinski, Waldemar; Kulik, George

    2013-10-01

    The phosphoinositide 3-kinase (PI3K) pathway is activated in most advanced prostate cancers, yet so far treatments with PI3K inhibitors have been at best tumorostatic in preclinical cancer models and do not show significant antitumor efficacy in clinical trials. Results from tissue culture experiments in prostate cancer cells suggest that PI3K inhibitors should be combined with other cytotoxic agents; however, the general toxicity of such combinations prevents translating these experimental data into preclinical and clinical models. We investigated the emerging concept of tumor-targeted synthetic lethality in prostate cancer cells by using the pan-PI3K inhibitor ZSTK474 and the immunotoxin J591PE, a protein chimera between the single-chain variable fragment of the monoclonal antibody J591 against the prostate-specific membrane antigen (PSMA) and the truncated form of the Pseudomonas aeruginosa exotoxin A (PE38QQR). The combination of ZSTK474 and J591PE increased apoptosis within 6 hours and cell death (monitored at 24-48 hours) in the PSMA-expressing cells LNCaP, C4-2, and C4-2Luc but not in control cells that do not express PSMA (PC3 and BT549 cells). Mechanistic analysis suggested that induction of apoptosis requires Bcl-2-associated death promoter (BAD) dephosphorylation and decreased expression of myeloid leukemia cell differentiation protein 1 (MCL-1). A single injection of ZSTK474 and J591PE into engrafted prostate cancer C4-2Luc cells led to consistent and stable reduction of luminescence within 6 days. These results suggest that the combination of a PI3K inhibitor and a PSMA-targeted protein synthesis inhibitor toxin represents a promising novel strategy for advanced prostate cancer therapy that should be further investigated. PMID:24204196

  10. A Monte Carlo method for combined segregation and linkage analysis.

    PubMed Central

    Guo, S W; Thompson, E A

    1992-01-01

    We introduce a Monte Carlo approach to combined segregation and linkage analysis of a quantitative trait observed in an extended pedigree. In conjunction with the Monte Carlo method of likelihood-ratio evaluation proposed by Thompson and Guo, the method provides for estimation and hypothesis testing. The greatest attraction of this approach is its ability to handle complex genetic models and large pedigrees. Two examples illustrate the practicality of the method. One is of simulated data on a large pedigree; the other is a reanalysis of published data previously analyzed by other methods. PMID:1415253

  11. Treatment dilemmas of cetuximab combined with chemotherapy for metastatic colorectal cancer

    PubMed Central

    Wen, Feng; Li, Qiu

    2016-01-01

    Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC. PMID:27340349

  12. Mechanistic exploration of a bi-directional PDT-based combination in pancreatic cancer (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Huang, Huang-Chiao; Mallidi, Srivalleesha; Liu, Joyce; Chiang, Chun-Te; Mai, Zhiming; Goldschmidt, Ruth; Rizvi, Imran; Ebrahim-Zadeh, Neema; Hasan, Tayyaba

    2016-03-01

    It is increasingly evident that the most effective cancer treatments will involve interactive regimens that target multiple non-overlapping pathways, preferably such that each component enhances the others to improve outcomes while minimizing systemic toxicities. Toward this goal, we developed a combination of photodynamic therapy and irinotecan, which mechanistically cooperate with each other, beyond their individual tumor destruction pathways, to cause synergistic reduction in orthotopic pancreatic tumor burden. A three-way mechanistic basis of the observed the synergism will be discussed: (i) PDT downregulates drug efflux transporters to increase intracellular irinotecan levels. (ii) Irinotecan reduces the expression of hypoxia-induced marker, which is upregulated by PDT. (iii) PDT downregulates irinotecan-induced survivin expression to amplify the apoptotic and anti-proliferative effects. The clinical translation potential of the combination will also be highlighted.

  13. Treatment dilemmas of cetuximab combined with chemotherapy for metastatic colorectal cancer.

    PubMed

    Wen, Feng; Li, Qiu

    2016-06-21

    Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC. PMID:27340349

  14. Combined ultrasound and photoacoustic imaging of pancreatic cancer using nanocage contrast agents

    NASA Astrophysics Data System (ADS)

    Homan, Kimberly; Shah, Jignesh; Gomez, Sobeyda; Gensler, Heidi; Karpiouk, Andrei; Brannon-Peppas, L.; Emelianov, Stanislav

    2009-02-01

    A new metallodielectric nanoparticle consisting of a silica core and silver outer cage was developed for the purpose of enhancing photoacoustic imaging contrast in pancreatic tissue. These nanocages were injected into an ex vivo porcine pancreas and imaged using a combined photoacoustic and ultrasound (PAUS) assembly. This custom-designed PAUS assembly delivered 800 nm light through a fiber optical light delivery system integrated with 128 element linear array transducer operating at 7.5 MHz center frequency. Imaging results prove that the nanocage contrast agents have the ability to enhance photoacoustic imaging contrast. Furthermore, the value of the combined PAUS imaging modality was demonstrated as the location of nanocages against background native tissue was evident. Future applications of these nanocage contrast agents could include targeting them to pancreatic cancer for enhancement of photoacoustic imaging for diagnosis and therapy.

  15. Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets

    PubMed Central

    McConnell, Jeanette R.; McAlpine, Shelli R.

    2013-01-01

    The heat shock proteins are essential players in the development of cancer and they are prime therapeutic targets. Targeting multiple hsps in dual therapies decreases the likelihood of drug resistance compared to utilizing mono-therapies. Further, employing an hsp inhibitor in combination with another therapy has proven clinically successful. Examples of efficacious strategies include the inhibition of hsp27, which prevents protein aggregation, controlling hsp40’s role as an ATPase modulator, and inhibiting hsp70 from acting as a molecular chaperone. While hsp40 therapies are just in the beginning stages, hsp27 and hsp70 therapies have been successfully used in dual inhibition treatments with hsp90 inhibitors and in combinational therapy with antineoplastic drugs. Both dual and combinatorial therapies show encouraging results when used in treating chemotherapeutically resistant diseases. PMID:23453837

  16. Salvage chemotherapy for ovarian cancer recurrence: weekly cisplatin in combination with epirubicin or etoposide.

    PubMed

    Zanaboni, F; Scarfone, G; Presti, M; Maggi, R; Borello, C; Bolis, G

    1991-10-01

    From December 1986 to April 1990, 40 consecutive ovarian cancer patients who relapsed after response to cisplatin-based chemotherapy regimens were treated with seven courses of weekly cisplatin, in combination with epirubicin or etoposide. The overall response rate obtained with the intensive schedule was 60% and the complete response rate was 25%; median duration of response was 7 months and median survival time, 13.5 months. Responsive cases seem to have longer survival; a prognostic factor for response to salvage treatment and longer survival is the disease-free interval after the first-line chemotherapy. Weekly cisplatin as intensive treatment was very well tolerated and showed acceptable toxicity in both the combination protocols with epirubicin or etoposide. PMID:1959783

  17. Analysis of MicroRNAs in Sputum to Improve Computed Tomography for Lung Cancer Diagnosis

    PubMed Central

    Shen, Jun; Liao, Jipei; Guarnera, Maria A.; Fang, HongBin; Cai, Ling; Stass, Sanford A.; Jiang, Feng

    2016-01-01

    Introduction Computed tomography (CT) plays a central role in lung cancer diagnosis. However, CT has relatively low specificity, presenting a challenge in clinical settings. We previously identified 12 microRNAs (miRNAs) whose expressions in tumor tissues were associated with lung cancer. Methods Using quantitative reverse transcriptase polymerase chain reaction, we aimed to identify miRNA biomarkers in sputum that could complement CT for diagnosis of lung cancer. Results In a training set consisting of 66 lung cancer patients and 68 cancer-free smokers, 10 of the 12 miRNAs were differentially expressed between the cases and controls (p ≤ 0.01). From the miRNAs, a logistic regression model was built on the basis of miR-31 and miR-210, both of which had the best prediction for lung cancer, producing an area under receiver operating characteristic curve of 0.83. Combined use of the two miRNAs yielded 65.2% sensitivity and 89.7% specificity, CT had 93.9% sensitivity and 83.8% specificity for lung cancer diagnosis. Notably, combined analysis of the miRNA biomarkers and CT produced a higher specificity than does CT used alone (91.2% versus 83.8%; p < 0.05). The diagnostic performance of the biomarkers was confirmed in a testing set comprising 64 lung cancer patients and 73 cancer-free smokers. Conclusion The sputum miRNA biomarkers might be useful in improving CT for diagnosis of lung cancer, but further independent validation on an external and prospective cohort of patients is required. PMID:24305007

  18. Combination of Antiestrogens and Omega-3 Fatty Acids for Breast Cancer Prevention

    PubMed Central

    Manni, Andrea; El-Bayoumy, Karam; Skibinski, Christine G.; Thompson, Henry J.; Santucci-Pereira, Julia; Bidinotto, Lucas Tadeu; Russo, Jose

    2015-01-01

    The molecular and biological heterogeneity of human breast cancer emphasizes the importance of a multitargeted approach for effective chemoprevention. Targeting the estrogen receptor pathway alone with the antiestrogens, Tamoxifen and Raloxifene reduces the incidence of estrogen receptor positive tumors but is ineffective against the development of hormone independent cancers. Our preclinical data indicate that the administration of omega-3 fatty acids potentiates the antitumor effects of Tamoxifen by inhibiting multiple proliferative and antiapoptotic pathways, several of which interact with estrogen receptor signaling. The complementarity in the mechanism of antitumor action of Tamoxifen and omega-3 fatty acids is well supported by our signaling, genomic, and proteomic studies. Furthermore, administration of omega-3 fatty acids allows the use of lower and, hence, likely less toxic doses of Tamoxifen. If these findings are supported in the clinical setting, the combination of omega-3 fatty acids and anteistrogens may emerge as a promising, effective, and safe chemopreventive strategy to be tested in a large multi-institutional trial using breast cancer incidence as the primary endpoint. PMID:26339626

  19. Organ preservation in invasive bladder cancer: Brachytherapy, an alternative to cystectomy and combined modality treatment?

    SciTech Connect

    Pos, Floris

    2005-03-01

    Purpose: To evaluate our long-term results of bladder preservation with brachytherapy in the treatment of bladder cancer. Methods and materials: Between 1987 and 2000, 108 patients with T1-G3 and T2-T3a stages of bladder cancer were treated with a transurethral resection (TUR) and a course of external beam radiotherapy (30 Gy in 15 fractions) followed by brachytherapy (40 Gy). All tumors were solitary lesions with a diameter {<=}5 cm. Median follow-up was 54 months (range, 1-178 months). Results: The 5-year and 10-year overall survival rates were 62% and 50%, respectively. The 5-year and 10-year disease-specific survival rates were 73% and 67%, respectively. The actuarial local control rate was 73% at 5 and 73% at 10 years, respectively. The 5-year and 10-year disease-specific survival rates for patients with a preserved bladder were 68% and 59%, respectively. Of all long-term surviving patients, 90% preserved their native bladders. The treatment was well tolerated. Acute toxicity was mild. Two patients experienced serious late toxicity: 1 patient developed a persisting vesicocutaneous fistula and the other a stricture of the urethra and ureters. Conclusion: For patients with solitary, organ confined invasive bladder cancer {<=}5 cm, bladder preservation with brachytherapy is an excellent alternative to radical cystectomy and combined modality treatment.

  20. Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer.

    PubMed

    Elgogary, Amira; Xu, Qingguo; Poore, Brad; Alt, Jesse; Zimmermann, Sarah C; Zhao, Liang; Fu, Jie; Chen, Baiwei; Xia, Shiyu; Liu, Yanfei; Neisser, Marc; Nguyen, Christopher; Lee, Ramon; Park, Joshua K; Reyes, Juvenal; Hartung, Thomas; Rojas, Camilo; Rais, Rana; Tsukamoto, Takashi; Semenza, Gregg L; Hanes, Justin; Slusher, Barbara S; Le, Anne

    2016-09-01

    Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer. PMID:27559084

  1. Combined Effect of Opioids and Corticosteroids for Alleviating Dyspnea in Terminal Cancer Patients: A Retrospective Review.

    PubMed

    Maeda, Tsuyoshi; Hayakawa, Toru

    2016-06-01

    Dyspnea is a prognostic factor that affects the quality of life of terminal cancer patients, and many reports have described opioid treatment for dyspnea alleviation. Here, we retrospectively evaluated differences in the effects of various opioids administered concomitantly with corticosteroids on dyspnea in 20 terminal-stage cancer patients (13 men, 7 women; mean age [range]: 71 [49-94] years) who received opioids concomitantly with corticosteroids. Effectiveness was assessed throughout administration using the Support Team Assessment Schedule, Japanese version (STAS-J), particularly the subscale indicating how strongly a patient is affected by symptoms. The effectiveness of combined opioid and corticosteroid therapy against dyspnea and the opioid dose comprised the primary and secondary foci, respectively. Among concomitantly treated patients, STAS-J scores at initiation (mean ± SD: 3.1 ± 0.24) and lowest recorded STAS-J scores (1.4 ± 0.22) differed significantly (P = .0034) among those receiving morphine, but not among those receiving oxycodone (P = .068) or fentanyl (P = .18). Concomitant opioid and corticosteroid treatment was associated with a ≥2-point STAS-J score improvement in 14/20 patients (effectiveness: 70%). The opioid dose did not significantly affect dyspnea alleviation. We conclude that concomitant opioid and corticosteroid treatment can effectively alleviate dyspnea in terminal cancer patients. PMID:27093633

  2. Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells.

    PubMed

    Minami, Daisuke; Takigawa, Nagio; Takeda, Hiromasa; Takata, Minoru; Ochi, Nobuaki; Ichihara, Eiki; Hisamoto, Akiko; Hotta, Katsuyuki; Tanimoto, Mitsune; Kiura, Katsuyuki

    2013-02-01

    PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650(PTEN+)) and knocked down PTEN expression in the PC-9 cells (PC-9(PTEN-)) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9(PTEN-) cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650(PTEN+) and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair. PMID:23239809

  3. Gemcitabine-Based Combination Chemotherapy Followed by Radiation With Capecitabine as Adjuvant Therapy for Resected Pancreas Cancer

    SciTech Connect

    Desai, Sameer; Ben-Josef, Edgar; Griffith, Kent A.; Simeone, Diane; Greenson, Joel K.; Francis, Isaac R.; Hampton, Janet; Colletti, Lisa; Chang, Alfred E.; Lawrence, Theodore S.; Zalupski, Mark M.

    2009-12-01

    Purpose: To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. Patients and Methods: We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m{sup 2} intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m{sup 2} intravenously on Days 1 and 8 or capecitabine 1500 mg/m{sup 2} orally in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m{sup 2} orally in divided doses) day 1 to treatment completion. Results: Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. Conclusions: A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.

  4. Analysis of intratumor heterogeneity unravels lung cancer evolution.

    PubMed

    de Bruin, Elza C; McGranahan, Nicholas; Swanton, Charles

    2015-01-01

    Lung cancer is a disease with dismal outcome. We recently reported a detailed intratumor heterogeneity analysis in 7 non-small cell lung cancer samples, revealing spatially separated driver events as well as the temporal dynamics of mutational processes and demonstrating an important role for APOBEC-mediated heterogeneity later in disease evolution. PMID:27308463

  5. Analysis of intratumor heterogeneity unravels lung cancer evolution

    PubMed Central

    de Bruin, Elza C; McGranahan, Nicholas; Swanton, Charles

    2015-01-01

    Lung cancer is a disease with dismal outcome. We recently reported a detailed intratumor heterogeneity analysis in 7 non-small cell lung cancer samples, revealing spatially separated driver events as well as the temporal dynamics of mutational processes and demonstrating an important role for APOBEC-mediated heterogeneity later in disease evolution. PMID:27308463

  6. Human papillomavirus and breast cancer in Iran: a meta- analysis

    PubMed Central

    Haghshenas, Mohammad Reza; Mousavi, Tahoora; Moosazadeh, Mahmood; Afshari, Mahdi

    2016-01-01

    Objective(s): This study aims to investigate the relationship between human papillomavirus (HPV) and breast cancer using meta- analysis. Materials and Methods: Relevant studies were identified reviewing the national and international databases. We also increased the search sensitivity by investigating the references as well as interview with research centers and experts. Finally, quality assessment and implementation of inclusion/exclusion criteria determined the eligible articles for meta-analysis. Based on the heterogeneity observed among the results of the primary studies, random effects model was used to estimate the pooled prevalence of HPV infection and also pooled odds ratio between HPV and developing breast cancer using Stata SE V. 11 software. Results: This meta- analysis included 11 primary studies investigating the HPV infection prevalence among 1539 Iranian women. Pooled prevalence (95% confidence interval) of HPV infection among Iranian women with breast cancer was estimated as of 23.6% (6.7- 40.5), while, the odds ratio (95% confidence interval) between HPV infection and developing breast cancer was estimated as of 5.7% (0.7- 46.8). Conclusion: This meta- analysis showed a high prevalence of HPV infection among women with breast cancer. We also found that the odds of developing breast cancer among women with breast cancer was more than that of women without breast cancer. PMID:27114791

  7. β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis.

    PubMed

    Childers, W Kurtis; Hollenbeak, Christopher S; Cheriyath, Pramil

    2015-12-01

    The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the β-adrenergic receptor (β-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the β-AR. Retrospective cohort studies on the clinical outcomes of β-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving β-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of β-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of β-blockers significantly reduced risk of breast cancer death among women with breast cancer. PMID:26516037

  8. Thermal-economic analysis of organic Rankine combined cycle cogeneration

    NASA Astrophysics Data System (ADS)

    Porter, R. W.

    1982-12-01

    An evaluation of organic rankine cycles (ORC) as combined with topping incorporating gas turbines or diesel engines, and with subsequent waste heat utilization is presented. It is found that the potential benefit of the proposed organic Rankine combined cycle cogeneration of useful heat and electricity is more flexible in meeting demands for the two products, by varying the mode of operation of the system. A thermal-economic analysis is developed and illustrated with cost and performance data for commercially available equipment, and with general economic parameters reflecting current regulations and market conditions. The performance of the ORC and of the entire combined cycle is described. Equations to evaluate the various thermodynamic and economic parameter, and the resultant case flows are presented. Criteria are developed to assess the addition of an ORC to a cogeneration system without ORC is viable based on rate of return on incremental investment. It is indicated that the proposed system is potentially viable, however, it is not viable under conditions prevailing in Chicago for the selected case studies.

  9. A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer.

    PubMed Central

    Siddiqui, N.; Boddy, A. V.; Thomas, H. D.; Bailey, N. P.; Robson, L.; Lind, M. J.; Calvert, A. H.

    1997-01-01

    The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel, combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction. Twelve chemonaive patients with ovarian cancer were treated with paclitaxel followed by a 30-min infusion of carboplatin. Paclitaxel dose was escalated from 150 mg m-2 to 225 mg m-2 in cohorts of three patients. Carboplatin dose was based on renal function. Pharmacokinetic studies were performed in nine patients (at least two at each dose level). A total of 66 courses were evaluable for assessment. Grade 3 or 4 neutropenia was seen in 70% of the courses, however hospitalization was not required. Grade 3 or 4 thrombocytopenia occurred in 24% of the courses. Alopecia, myalgia and peripheral neuropathy were common but rarely severe. The pharmacokinetics of paclitaxel was non-linear and did not appear to be influenced by co-administration of carboplatin. The AUC of carboplatin was 7.0 +/- 1.4 mg ml-1 min, indicating that there was no pharmacokinetic interaction. The combination of carboplatin and paclitaxel may be administered as first-line treatment for advanced ovarian cancer. Although myelosuppression is the dose-limiting toxicity of the component drugs, the severity of thrombocytopenia was less than anticipated. The results of this study, with only a small number of patients, need to be confirmed in future investigations. PMID:9010040

  10. Treatment of cancer using pulsed electric field in combination with chemotherapeutic agents or genes.

    PubMed

    Nishi, T; Dev, S B; Yoshizato, K; Kuratsu, J; Ushio, Y

    1997-03-01

    Electroporation is a standard laboratory technique originally developed for in vitro transfer of molecules into cells. It involves application of electrical pulses ranging from micro- to milliseconds that create transient pores in the cell membrane allowing intracellular access of exogenous molecules. This technique has been successfully applied to regress tumors in animal models by combining electroporation with chemotherapeutic agents--a process known as electrochemotherapy (ECT) which substantially enhance cytotoxicity of some antineoplastic agents. Recently ECT has moved into clinical arena and patients with cutaneous tumors and head and neck cancers have been treated very effectively with ECT. Parallel to ECT, a technique has also been developed which makes it possible to inject plasmid DNA and combine it with in vivo electroporation--electro--genetherapy (EGT)--to deliver in a highly efficient manner both marker and functional genes into target tissue and achieve gene expression. Thus, in vivo electroporation is contributing to the development of a new strategy for cancer treatment with both drugs and genes. PMID:9234068

  11. Novel agents and new combination treatments on phase I studies on solid tumors and pancreatic cancer.

    PubMed

    Strimpakos, Alexios S; Syrigos, Kostas N; Saif, Muhammad W

    2012-07-01

    Pancreatic cancer is a relatively rare malignancy with a very aggressive natural course, not restrained by the existing current treatments. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of few phase I clinical studies on solid tumors and pancreatic cancer were presented. In particular, in the field of immunotherapy, a pilot phase I study tested for first time a carcinoembryonic antigen (CEA)-based vaccine (Abstract #2561) on patients with pancreatic adenocarcinoma and another one the optimal dose and efficacy of trabedersen, an inhibitor of tissue growth factor-beta 2 (TGF-β2) aiming to enhance antitumor immune responses (Abstract #4034). Other phase I studies explored the pharmacokinetic and pharmacodynamic properties of an oral gemcitabine pro-drug (LY2334737; Abstract #2554), or of the combination of gemcitabine with sirolimus (Abstract #3096) or the combination of gemcitabine with an inhibitor of mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase (ERK) (MEK 1/2; Abstract #4034). PMID:22797386

  12. Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations

    PubMed Central

    Pin, Fabrizio; Busquets, Silvia; Toledo, Miriam; Camperi, Andrea; Lopez-Soriano, Francisco J.; Costelli, Paola; Argilés, Josep M.; Penna, Fabio

    2015-01-01

    Cancer cachexia is a syndrome characterized by loss of skeletal muscle mass, inflammation, anorexia and anemia, contributing to patient fatigue and reduced quality of life. In addition to nutritional approaches, exercise training (EX) has been proposed as a suitable tool to manage cachexia. In the present work the effect of mild exercise training, coupled to erythropoietin (EPO) administration to prevent anemia, has been tested in tumor-bearing mice. In the C26 hosts, acute exercise does not prevent and even worsens muscle wasting. Such pattern is prevented by EPO co-administration or by the adoption of a chronic exercise protocol. EX and EPO co-treatment spares oxidative myofibers from atrophy and counteracts the oxidative to glycolytic shift, inducing PGC-1α. LLC hosts are responsive to exercise and their treatment with the EX-EPO combination prevents the loss of muscle strength and the onset of mitochondrial ultrastructural alterations, while increases muscle oxidative capacity and intracellular ATP content, likely depending on PGC-1α induction and mitophagy promotion. Consistently, muscle-specific PGC-1α overexpression prevents LLC-induced muscle atrophy and Atrogin-1 hyperexpression. Overall, the present data suggest that low intensisty exercise can be an effective tool to be included in combined therapeutic approaches against cancer cachexia, provided that anemia is coincidently treated in order to enhance the beneficial action of exercise. PMID:26636649

  13. "Smart" nickel oxide based core-shell nanoparticles for combined chemo and photodynamic cancer therapy.

    PubMed

    Bano, Shazia; Nazir, Samina; Munir, Saeeda; AlAjmi, Mohamed Fahad; Afzal, Muhammad; Mazhar, Kehkashan

    2016-01-01

    We report "smart" nickel oxide nanoparticles (NOPs) as multimodal cancer therapy agent. Water-dispersible and light-sensitive NiO core was synthesized with folic acid (FA) connected bovine serum albumin (BSA) shell on entrapped doxorubicin (DOX). The entrapped drug from NOP-DOX@BSA-FA was released in a sustained way (64 hours, pH=5.5, dark conditions) while a robust release was found under red light exposure (in 1/2 hour under λmax=655 nm, 50 mW/cm(2), at pH=5.5). The cell viability, thiobarbituric acid reactive substances and diphenylisobenzofuran assays conducted under light and dark conditions revealed a high photodynamic therapy potential of our construct. Furthermore, we found that the combined effect of DOX and NOPs from NOP-DOX@BSA-FA resulted in cell death approximately eightfold high compared to free DOX. We propose that NOP-DOX@BSA-FA is a potential photodynamic therapy agent and a collective drug delivery system for the systemic administration of cancer chemotherapeutics resulting in combination therapy. PMID:27471383

  14. Iron and cancer risk--a systematic review and meta-analysis of the epidemiological evidence.

    PubMed

    Fonseca-Nunes, Ana; Jakszyn, Paula; Agudo, Antonio

    2014-01-01

    Iron has been suggested as a risk factor for different types of cancers mainly due to its prooxidant activity, which can lead to oxidative DNA damage. Furthermore, subjects with hemochromatosis or iron overload have been shown to have a higher risk of developing liver cancer. We have systematically reviewed 59 epidemiologic studies, published between 1995 and 2012, reporting information on total iron, dietary iron, heme iron, and biomarkers of iron status and cancer risk. Furthermore we conducted meta-analysis for colorectal [relative risk (RR), 1.08; 95% confidence interval (CI), 1.00-1.17], colon (RR = 1.12; 95% CI, 1.03-1.22), breast (RR = 1.03; 95% CI, 0.97-1.09), and lung cancer (RR = 1.12; 95% CI, 0.98-1.29), for an increase of 1 mg/day of heme iron intake. Globally, on the basis of the systematic review and the meta-analysis results, a higher intake of heme iron has shown a tendency toward a positive association with cancer risk. Evidence regarding high levels of biomarkers of iron stores (mostly with serum ferritin) suggests a negative effect toward cancer risk. More prospective studies combining research on dietary iron intake, iron biomarkers, genetic susceptibility, and other relevant factors need to be conducted to clarify these findings and better understand the role of iron in cancer development. PMID:24243555

  15. Combined effects of lapatinib and bortezomib in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and activity of bortezomib against lapatinib-resistant breast cancer cells.

    PubMed

    Ma, Chuandong; Niu, Xiuqing; Luo, Jianmin; Shao, Zhimin; Shen, Kunwei

    2010-10-01

    Lapatinib and bortezomib are highly active against breast cancer cells. Breast cancer patients who initially respond to lapatinib may eventually manifest acquired resistance to this treatment. Thus, the identification of novel agents that may prevent or delay the development of acquired resistance to lapatinib is critical. In the current study, we show that the combination of lapatinib and bortezomib results in a synergistic growth inhibition in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and that the combination enhances apoptosis of SK-BR-3 cells. Importantly, we found that the combination of lapatinib plus bortezomib more effectively blocked activation of the HER2 pathway in SK-BR-3 cells, compared with monotherapy. In addition, we established a model of acquired resistance to lapatinib by chronically challenging SK-BR-3 breast cancer cells with increasing concentrations of lapatinib. Here, we showed that bortezomib notably induced apoptosis of lapatinib-resistant SK-BR-3 pools and further inhibited HER2 signaling in the resistant cells. Taken together, the current data indicate a synergistic interaction between lapatinib and bortezomib in HER2-overexpressing breast cancer cells and provide the rationale for the clinical evaluation of these two noncross-resistant targeted therapies. The combination of lapatinib and bortezomib may be a potentially novel approach to prevent or delay the onset of acquired resistance to lapatinib in HER2-overxpressing/estrogen receptor (ER)-negative breast cancers. PMID:20701607

  16. Spatiotemporally synchronized cancer combination therapy using photo-activated nanoparticle drug delivery systems (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hasan, Tayyaba

    2016-03-01

    This talk will introduce a new nanotechnology platform for cancer combination therapy that utilizes near infrared light activation not only for photodynamic damage but also as an extrinsic mechanism to initiate release of complimentary drugs to suppress dynamic bursts in molecular signaling networks that promote tumor cell survival and treatment escape. The goal is to achieve co-delivery with concomitant activity of photodynamic, molecular inhibitor and chemotherapeutic agents, selectively within the tumor. This approach overcomes challenges in achieving synergistic interactions using sequential drug delivery. Conventional drug delivery is compromised by the differential pharmacokinetics of individual agents and potentially antagonistic effects—such as vascular shutdown by one agent that limits delivery of the second. Here, photodynamic damage—which efficiently kills drug-resistant cells via damage of common proteins involved in drug-resistance (such as anti-apoptosis factors and drug-efflux transporters)—is synchronized spatially and temporally with the photo-initiated release of complimentary agents—to enable full interaction amongst the individual therapies. This spatiotemporal synchronization offers new prospects for exploiting time-sensitive synergistic interactions. Specific implementations of these concepts will be presented in preclinical models of cancer. Strategies to enable molecular-targeting of cancer cells via site-specific attachment of targeting moieties to the outer lipid shell of these nanovehicles will also be discussed. If successful in humans, this new paradigm for synchronized, tumor-focused combination therapy will ultimately supersede the present use of chronic drug injection by increasing efficacy per cycle whilst reducing systemic exposure to toxic drugs.

  17. Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer.

    PubMed

    Mancini, Maicol; Gaborit, Nadège; Lindzen, Moshit; Salame, Tomer Meir; Dall'Ora, Massimiliano; Sevilla-Sharon, Michal; Abdul-Hai, Ali; Downward, Julian; Yarden, Yosef

    2015-06-01

    Despite initial responses to targeted kinase inhibitors, lung cancer patients presenting with primary epidermal growth factor receptor (EGFR) mutations acquire resistance, often due to a second-site mutation (T790M). However, clinical trials found no survival benefits in patients treated with a monoclonal antibody (mAb) to EGFR that should block activation of the mutated receptor and thus bypass resistance to molecules that target the catalytic or ATP-binding site. Using cell lines with the T790M mutation, we discovered that prolonged exposure to mAbs against only the EGFR triggered network rewiring by (i) stimulating the extracellular signal-regulated kinase (ERK) pathway; (ii) inducing the transcription of HER2 (human epidermal growth factor receptor 2) and HER3, which encode other members of the EGFR family, and the gene encoding HGF, which is the ligand for the receptor tyrosine kinase MET; and (iii) stimulating the interaction between MET and HER3, which promoted MET activity. Supplementing the EGFR-specific mAb with those targeting HER2 and HER3 suppressed these compensatory feedback loops in cultured lung cancer cells. The triple mAb combination targeting all three receptors prevented the activation of ERK, accelerated the degradation of the receptors, inhibited the proliferation of tumor cells but not of normal cells, and markedly reduced the growth of tumors in mice xenografted with cells that were resistant to combined treatment with erlotinib and the single function-blocking EGFR mAb. These findings uncovered feedback loops that enable resistance to treatment paradigms that use a single antibody and indicate a new strategy for the treatment of lung cancer patients. PMID:26038598

  18. A Phase II Trial of a Combination Herbal Supplement for Men with Biochemically Recurrent Prostate Cancer

    PubMed Central

    Dorff, Tanya B.; Groshen, Susan; Tsao-Wei, Denice D.; Xiong, Shigang; Gross, Mitchell E.; Vogelzang, Nicholas; Quinn, David I.; Pinski, Jacek K.

    2014-01-01

    Background Men with biochemical recurrence (BCR) of prostate cancer are typically observed or treated with androgen deprivation therapy. Non-hormonal, non-toxic treatments to slow the rise of PSA are desirable. We studied a combination herbal supplement, Prostate Health Cocktail (PHC), in prostate cancer cell lines and in a population of men with BCR. Methods PC3, LAPC3, and LNCaP cells were incubated with increasing concentrations of PHC suspension. Men previously treated for prostate cancer with surgery, radiation, or both with rising PSA but no radiographic metastases were treated with 3 capsules of PHC daily; the primary endpoint was 50% PSA decline. Circulating tumor cells (CTCs) were identified using parylene membrane filters. Results PHC showed a strong dose-dependent anti-proliferative effect in androgen-sensitive and independent cell lines in vitro and suppression of androgen receptor expression. 40 eligible patients were enrolled in the clinical trial. Median baseline PSA was 2.8 ng/mL (1.1-84.1) and 15 men (38%) had a PSA decline on study (1%-55% reduction) ; 25 (62%) had rising PSA on study. The median duration of PSA stability was 6.4 months. Two patients had grade 2/3 transaminitis; the only other grade 2 toxicities were hyperglycemia, hypercalcemia and flatulence. There were no significant changes in testosterone or dihydrotestosterone. CTCs were identified in 19 men (47%). Conclusion Although the primary endpoint was not met, Prostate Health Cocktail was well tolerated and was associated with PSA declines and stabilization in a significant number of patients. This is the first report of detecting CTCs in men with BCR prostate cancer. Randomized studies are needed to better define the effect of PHC in men with BCR. PMID:25245366

  19. Analysis methodology and recent results of the IGS network combination

    NASA Astrophysics Data System (ADS)

    Ferland, R.; Kouba, J.; Hutchison, D.

    2000-11-01

    A working group of the International GPS Service (IGS) was created to look after Reference Frame (RF) issues and contribute to the densification and improvement of the International Terrestrial Reference Frame (ITRF). One important objective of the Reference Frame Working Group is to generate consistent IGS station coordinates and velocities, Earth Rotation Parameters (ERP) and geocenter estimates along with the appropriate covariance information. These parameters have a direct impact on other IGS products such as the estimation of GPS satellite ephemerides, as well as satellite and station clocks. The information required is available weekly from the Analysis Centers (AC) (cod, emr, esa, gfz, jpl, ngs, sio) and from the Global Network Associate Analysis Centers (GNAAC) (JPL, mit, ncl) using a "Software Independent Exchange Format" (SINEX). The AC are also contributing daily ERPs as part of their weekly submission. The procedure in place simultaneously combines the weekly station coordinates, geocenter and daily ERP estimates. A cumulative solution containing station coordinates and velocity is also updated with each weekly combination. This provides a convenient way to closely monitor the quality of the estimated station coordinates and to have an up to date cumulative solution available at all times. To provide some necessary redundancy, the weekly station coordinates solution is compared against the GNAAC solutions. Each of the 3 GNAAC uses its own software, allowing independent verification of the combination process. The RMS of the coordinate differences in the north, east and up components between the AC/GNAAC and the ITRF97 Reference Frame Stations are 4-10 mm, 5-20 mm and 6-25 mm. The station velocities within continental plates are compared to the NNR-NUVEL1A plate motion model (DeMets et al., 1994). The north, east and up velocity RMS are 2 mm/y, 3 mm/y and 8 mm/y. Note that NNR-NUVEL1A assumes a zero vertical velocity.

  20. Immunotherapy regimens for combination with photodynamic therapy aimed at eradication of solid cancers

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen

    2000-06-01

    Due to inflammatory/immune responses elicited by photodynamic therapy (PDT), this modality is particularly suitable in combination with various forms of immunotherapy for an improved therapeutic gain. A wide variety of approaches that may be applicable in this context include those focusing on amplifying the activity of particular immune cell types (neutrophils, macrophages, dendritic cells, natural killer cells, helper or cytotoxic T lymphocytes). Another type of approach is to focus on a specific phase of immune response development, which comprises the activation of non-specific inflammatory immune effectors, immune recognition, immune memory, immune rejection, or blocking of immune suppression. These different strategies call for a variety of immunotherapeutic protocols to be employed in combination with PDT. These include treatments such as: (1) non-specific immunoactivators (e.g. bacterial vaccines), (2) specific immune agents (cytokines, or other activating factors), (3) adoptive immunotherapy treatments (transfer of dendritic cells, tumor-sensitized T lymphocytes or natural killer cells), or (4) their combinations. Techniques of gene therapy employed in some of these protocols offer novel opportunities for securing a potent and persistent immune activity. Using PDT and immunotherapy represents an attractive combination for cancer therapy that is capable of eradicating both localized and disseminated malignant lesions.

  1. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment

    PubMed Central

    Lee, Gyeong Jin; Kang, Joo-Hee

    2014-01-01

    Objective. Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy. PMID:24860812

  2. Docetaxel in combination with irinotecan (CPT-11) in platinum-resistant paclitaxel-pretreated ovarian cancer.

    P