Landmann, Alessandra; Farrugia, Daniel J; Zhu, Li; Diego, Emilia J; Johnson, Ronald R; Soran, Atilla; Dabbs, David J; Clark, Beth Z; Puhalla, Shannon L; Jankowitz, Rachel C; Brufsky, Adam M; Ahrendt, Gretchen M; McAuliffe, Priscilla F; Bhargava, Rohit
2018-05-08
Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)-negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. Human epidermal growth factor receptor 2-positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. The pCR rate of low ER+ tumors was similar to the pCR rate of ER- tumors (37% and 26% for low ER and ER- respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER- and low ER+ cases compared with moderate and high ER+ cases. Low ER+ breast cancers are biologically similar to ER- tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy.
Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma
International Nuclear Information System (INIS)
Ma, Ji; Zhang, Jian; Liu, Wenchao; Guo, Yan; Chen, Suning; Zhong, Cuiping; Xue, Yan; Zhang, Yuan; Lai, Xiaofeng; Wei, Yifang; Yu, Shentong
2014-01-01
Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy. The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay. When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo. The present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer
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Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng
2015-01-01
Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice.
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Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng, E-mail: zhouqs@suda.edu.cn
2015-10-15
Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice.
Serum soluble ST2 is associated with ER-positive breast cancer
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Lu, Da-peng; Zhou, Xiang-yu; Yao, Lu-tian; Liu, Cai-gang; Ma, Wei; Jin, Feng; Wu, Yun-fei
2014-01-01
ST2, a member of the interleukin (IL)-1receptor family, regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions. However, the role of ST2 signaling in tumor growth and metastasis of breast cancers has not been investigated. This study investigated the possible role of soluble ST2 (sST2) in breast cancer. The serum levels of IL-33, sST2, and vascular endothelial growth factor (VEGF) in 150 breast cancer patients and 90 healthy women were measured by enzyme-linked immunosorbent assay. Estrogen receptor(ER), progesterone receptor, human epithelial receptor (HER)-2, and cell cycle regulated protein Ki-67 were measured. Clinical stage, tumor size, lymph node metastasis, and histological type were also recorded. The serum levels of sST2, IL-33, and VEGF were significantly higher in breast cancer patients than in the control group (P < 0.05, each). Serum sST2 levels in ER-positive breast cancer patients were significantly associated with age, histological type, clinical stage, tumor size, and Ki-67 status (P < 0.05, each). Moreover, the serum levels of IL-33 and sST2 in breast cancers significantly correlated with VEGF levels (IL-33: r = 0.375, P < 0.0001; sST2: r = 0.164, P = 0.045). Serum levels of sST2, IL-33, and VEGF decreased after modified radical mastectomy in ER-positive breast cancers. Serum levels of IL-33, sST2, and VEGF and clinicopathological factors were not significantly correlated with disease-free survival and overall survival of ER-positive breast cancer women during follow-up. Serum sST2 levels in ER-positive breast cancer patients are significantly associated with factors that indicate poor prognosis
Giuliano, Mario; Hu, Huizhong; Wang, Yen-Chao; Fu, Xiaoyong; Nardone, Agostina; Herrera, Sabrina; Mao, Sufeng; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Hilsenbeck, Susan G.; De Angelis, Carmine; Wang, Nicholas J.; Heiser, Laura M.; Gray, Joe W.; Lopez-Tarruella, Sara; Pavlick, Anne C.; Trivedi, Meghana V.; Chamness, Gary C.; Chang, Jenny C.; Osborne, C. Kent; Rimawi, Mothaffar F.; Schiff, Rachel
2015-01-01
Purpose To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. Experimental design Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies, and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 post treatment), were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and western blot. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. Results Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy, compared with untreated tumors, in both preclinical models (UACC812: ER p=0.0014; Bcl2 p<0.001. MCF7/HER2-18: ER p=0.0007; Bcl2 p=0.0306). In the neoadjuvant clinical study, lapatinib treatment for two weeks was associated with parallel upregulation of ER and Bcl2 (Spearman’s coefficient: 0.70; p=0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER re-expression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (p=0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (p<0.0001). Conclusion HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. PMID:26015514
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Glynn, Sharon A; Ambs, Stefan; Prueitt, Robyn L; Ridnour, Lisa A; Boersma, Brenda J; Dorsey, Tiffany M; Wink, David A; Goodman, Julie E; Yfantis, Harris G; Lee, Dong H
2010-01-01
Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype
Ma, W; Zhang, T-F; Lu, P; Lu, S H
2014-01-01
Breast cancer is categorized into two broad groups: estrogen receptor positive (ER+) and ER negative (ER-) groups. Previous study proposed that under trastuzumab-based neoadjuvant chemotherapy, tumor initiating cell (TIC) featured ER- tumors response better than ER+ tumors. Exploration of the molecular difference of these two groups may help developing new therapeutic strategies, especially for ER- patients. With gene expression profile from the Gene Expression Omnibus (GEO) database, we performed partial least squares (PLS) based analysis, which is more sensitive than common variance/regression analysis. We acquired 512 differentially expressed genes. Four pathways were found to be enriched with differentially expressed genes, involving immune system, metabolism and genetic information processing process. Network analysis identified five hub genes with degrees higher than 10, including APP, ESR1, SMAD3, HDAC2, and PRKAA1. Our findings provide new understanding for the molecular difference between TIC featured ER- and ER+ breast tumors with the hope offer supports for therapeutic studies.
ER, p53 and MIB-1 are significantly associated with malignant phyllodes tumor.
Munawer, Nurhayati H; Md Zin, Reena; Md Ali, Siti-Aishah; Muhammad, Rohaizak; Ali, Jasmi; Das, Srijit
2012-01-01
Fibroadenomas (FA) are common while phyllodes tumors (PT) are rare and both tumors are composed of epithelial and stromal components. We evaluated the expression status of ER, Bc12, p53, and MIB-1 protein in these tumors. One hundred and ninety-three tumors comprising of 117 FAs and 76 PTs were examined using immunohistochemistry on tissue microarray. The mean age of patients with FA was 28.5 years while the mean ages of patients with benign, borderline and malignant PTs were 41.7, 48.6 and 42.1 years, respectively. Also all types of PTs were large (>Scm). ER showed a strong nuclear staining in the epithelial component of all tumors while ER/3 immunoreactivity was detected in both the epithelial and stromal components ofF A and PT. ER/β (pcomponent were associated with tumor size. p53 expression was significantly associated with both the epithelial and stromal components of malignant PTs (pcomponent (p=0.000). In addition, MIB-1 was also found to be associated with ER and ER/3 in the stromal component (p=0.000). The expression of p53 with tumor size and histological grade in PT may increase the risk for malignancy.
Risk of mortality of node-negative, ER/PR/HER2 breast cancer subtypes in T1, T2, and T3 tumors.
Parise, Carol A; Caggiano, Vincent
2017-10-01
The purpose of this study was to assess differences in breast cancer-specific mortality within tumors of the same size when breast cancer was defined using the three tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We identified 104,499 cases of node-negative primary female invasive breast cancer from the California Cancer Registry. Tumor size was categorized as T1a, T1b, T1c, T2, and T3. Breast cancer was defined using ER, PR, and HER2. Kaplan-Meier Survival analysis was conducted and Cox Regression was used to compute the adjusted risk of mortality for the ER+/PR+/HER2+, ER-/PR-/HER2- (TNBC), and ER-/PR-/HER2+ (HER2-overexpressing) subtypes when compared with the ER+/PR+/HER2-. Separate models were computed for each tumor size. Unadjusted survival analysis showed that for all tumor sizes, the ER+/PR+ subtypes regardless of HER status have better breast cancer-specific survival than ER-/PR- subtypes. Subtype was not an important factor for risk of mortality for T1a tumors. The ER+/PR+/HER2+ subtype was only a risk for mortality in T1b tumors that were unadjusted for treatment. For all other tumor sizes, the ER+/PR+/HER2+ had the same mortality as the ER+/PR+/HER2- subtype regardless of adjustment for treatment. The HER2-overexpressing subtype had a higher risk of mortality than the ER+/PR+/HER2- subtype except for T1b tumors that were adjusted for treatment. For all tumor sizes, the TNBC had higher hazard ratios than all other subtypes. T1a tumors have the same risk of mortality regardless of ER/PR/HER2 subtype, and ER and PR negativity plays a stronger role in survival than HER2 positivity for tumors of all size.
Directory of Open Access Journals (Sweden)
Thomas eSimmen
2014-10-01
Full Text Available Endoplasmic reticulum (ER chaperones and oxidoreductases are abundant enzymes that mediate the production of fully folded secretory and transmembrane proteins. Resisting the Golgi and plasma membrane-directed bulk flow, ER chaperones and oxidoreductases enter retrograde trafficking whenever they are pulled outside of the ER. However, solid tumors are characterized by the increased production of reactive oxygen species (ROS, combined with reduced blood flow that leads to low oxygen supply and ER stress. Under these conditions, hypoxia and the unfolded protein response (UPR upregulate ER chaperones and oxidoreductases. When this occurs, ER oxidoreductases and chaperones become important regulators of tumor growth. However, under these conditions, these proteins not only promote the production of proteins, but also alter the properties of the plasma membrane and hence modulate tumor immune recognition. For instance, high levels of calreticulin serve as an eat-me signal on the surface of tumor cells. Conversely, both intracellular and surface BiP/GRP78 promotes tumor growth. Other ER folding assistants able to modulate the properties of tumor tissue include protein disulfide isomerase (PDI, Ero1α and GRP94. Understanding the roles and mechanisms of ER chaperones in regulating tumor cell functions and immunorecognition will lead to important insight for the development of novel cancer therapies.
Mamounas, Eleftherios P; Liu, Qing; Paik, Soonmyung; Baehner, Frederick L; Tang, Gong; Jeong, Jong-Hyeon; Kim, S Rim; Butler, Steven M; Jamshidian, Farid; Cherbavaz, Diana B; Sing, Amy P; Shak, Steven; Julian, Thomas B; Lembersky, Barry C; Wickerham, D Lawrence; Costantino, Joseph P; Wolmark, Norman
2017-01-01
The 21-gene recurrence score (RS) predicts risk of locoregional recurrence (LRR) in node-negative, estrogen receptor (ER)-positive breast cancer. We evaluated the association between RS and LRR in node-positive, ER-positive patients treated with adjuvant chemotherapy plus tamoxifen in National Surgical Adjuvant Breast and Bowel Project B-28. B-28 compared doxorubicin/cyclophosphamide (AC X 4) with AC X 4 followed by paclitaxel X 4. Tamoxifen was given to patients age 50 years or older and those younger than age 50 years with ER-positive and/or progesterone receptor-positive tumors. Lumpectomy patients received breast radiotherapy. Mastectomy patients received no radiotherapy. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Cumulative incidence functions and subdistribution hazard regression models were used for LRR to account for competing risks including distant recurrence, second primary cancers, and death from other causes. Median follow-up was 11.2 years. All statistical tests were one-sided. There were 80 LRRs (7.5%) as first events (68% local/32% regional). RS was low: 36.2%; intermediate: 34.2%; and high: 29.6%. RS was a statistically significant predictor of LRR in univariate analyses (10-year cumulative incidence of LRR = 3.3%, 7.2%, and 12.2% for low, intermediate, and high RS, respectively, P < .001). In multivariable regression analysis, RS remained an independent predictor of LRR (hazard ratio [HR] = 2.59, 95% confidence interval [CI] = 1.28 to 5.26, for a 50-point difference, P = .008) along with pathologic nodal status (HR = 1.91, 95% CI = 1.20 to 3.03, for four or more vs one to three positive nodes, P = .006) and tumor size (HR = 1.28, 95% CI = 1.05 to 1.55, for a 1 cm difference, P = .02). RS statistically significantly predicts risk of LRR in node-positive, ER-positive breast cancer patients after adjuvant chemotherapy plus tamoxifen. These findings can help in the selection of
Torres, Cristian Gabriel; Pino, Ana María; Sierralta, Walter Daniel
2009-06-01
The effects of estradiol (E2) and of an AFP-derived cyclized peptide (cP) on the proliferation of primary cultures of cancer cells isolated from spontaneous canine mammary tumors were studied. The cellular response to E2 and cP was related to the expression of estradiol receptor (isoforms alpha and beta). In ER-positive cells, 2 nM estradiol increased cell proliferation and the phosphorylation of ERK1/2; 2 microg/ml cP inhibited all these effects. Estradiol also increased HER2 immunoreactivity in ER-positive cells, an effect that was reverted to its basal values by cP. Estradiol stimulated in these cells the release of MMP2 and MMP9 and the shedding of HB-EGF, effects that the cP did not affect. ER-negative cells were refractory to estradiol or cP. All canine mammary tumor cells in culture responded to treatments analogously to human mammary cancer cells. Our results support the proposal of cP as a new, potentially effective therapeutic agent for the management of mammary cancer.
Genome-wide association studies identify four ER negative-specific breast cancer risk loci
Garcia-Closas, Montserrat; Couch, Fergus J.; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K.; Brook, Mark N.; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather S.; Le Marchand, Loic; Buring, Julie E.; Eccles, Diana; Miron, Penelope; Fasching, Peter A.; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K.; Nevanlinna, Heli; Giles, Graham G.; Cox, Angela; Hopper, John L.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J.; Schoof, Nils; Bojesen, Stig E.; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L.; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J.; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S.; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H.; Radice, Paolo; teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C.; Park, Daniel J.; Hammet, Fleur; Stone, Jennifer; Veer, Laura J. Van't; Rutgers, Emiel J.; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G.; Ekici, Arif B.; Beckmann, Matthias W.; dos Santos Silva, Isabel; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N.; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Balleine, Rosemary; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O.; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E.; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Coetzee, Gerhard A.; Feng, Ye; Henderson, Brian E.; Schumacher, Fredrick; Bogdanova, Natalia V.; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A. E. M.; Seynaeve, Caroline M.; Kriege, Mieke; Hooning, Maartje J.; van den Ouweland, Ans M. W.; van Deurzen, Carolien H. M.; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P.; Cross, Simon S.; Reed, Malcolm W. R.; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B.; Bandera, Elisa V.; John, Esther M.; Chen, Gary K.; Hu, Jennifer J.; Rodriguez-Gil, Jorge L.; Bernstein, Leslie; Press, Michael F.; Ziegler, Regina G.; Millikan, Robert M.; Deming-Halverson, Sandra L.; Nyante, Sarah; Ingles, Sue A.; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K.; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G.; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G.; Montgomery, Grant W.; Slamon, Dennis J.; Rauh, Claudia; Lux, Michael P.; Jud, Sebastian M.; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H.; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N.; Chen, Constance; Beck, Andy; Hankinson, Susan E.; Berg, Christine D.; Hoover, Robert N.; Lissowska, Jolanta; Figueroa, Jonine D.; Chasman, Daniel I.; Gaudet, Mia M.; Diver, W. Ryan; Willett, Walter C.; Hunter, David J.; Simard, Jacques; Benitez, Javier; Dunning, Alison M.; Sherman, Mark E.; Chenevix-Trench, Georgia; Chanock, Stephen J.; Hall, Per; Pharoah, Paul D. P.; Vachon, Celine; Easton, Douglas F.; Haiman, Christopher A.; Kraft, Peter
2013-01-01
Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including
ER, p53 and MIB-1 are significantly associated with malignant phyllodes tumor
Directory of Open Access Journals (Sweden)
Nurhayati H Munawer
2012-12-01
Full Text Available Background: Phyllodes tumors (PT are rare. We evaluated the expression status of ER, Bcl2, p53, and MIB-1 protein in these tumors. Methods: One hundred and ninety-three tumors were examined using immunohistochemistry on tissue microarray. Results: ERβ (p <0.001, and p53 (p=0.006 in the stromal component were associated with tumor size. p53 expression was significantly associated with both epithelial and stromal components of malignant PTs (p<0.05. In PT, the decreased expressions of p53 and MIB-1 were significantly different with positive Bcl2 protein expression in epithelial component (p=0.000. Besides, MIB-1 was also found to be associated with ERα and ERβ in stromal component (p=0.000. Conclusion: The expression of p53 with tumor size and histological grade in PTs may increase risk for malignancy.
Genome-wide association studies identify four ER negative-specific breast cancer risk loci.
Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather S; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van't; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Dos Santos Silva, Isabel; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; van den Ouweland, Ans M W; van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-Gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter
2013-04-01
Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
The role of the AR/ER ratio in ER-positive breast cancer patients.
Rangel, Nelson; Rondon-Lagos, Milena; Annaratone, Laura; Osella-Abate, Simona; Metovic, Jasna; Mano, Maria Piera; Bertero, Luca; Cassoni, Paola; Sapino, Anna; Castellano, Isabella
2018-03-01
The significance of androgen receptor (AR) in breast cancer (BC) management is not fully defined, and it is still ambiguous how the level of AR expression influences oestrogen receptor-positive (ER+) tumours. The aim of the present study was to analyse the prognostic impact of AR/ER ratio, evaluated by immunohistochemistry (IHC), correlating this value with clinical, pathological and molecular characteristics. We retrospectively selected a cohort of 402 ER+BC patients. On each tumour, IHC analyses for AR, ER, PgR, HER2 and Ki67 were performed and AR+ cases were used to calculate the AR/ER value. A cut-off of ≥2 was selected using receiver-operating characteristic (ROC) curve analyses. RNA from 19 cases with AR/ER≥2 was extracted and used for Prosigna-PAM50 assays. Tumours with AR/ER≥2 (6%) showed more frequent metastatic lymph nodes, larger size, higher histological grade and lower PgR levels than cases with AR/ERAR/ER≥2 had worse disease-free interval (DFI) and disease-specific survival (DSS) (hazard ratios (HR) = 4.96 for DFI and HR = 8.69 for DSS, both P ≤ 0.004). According to the Prosigna-PAM50 assay, 63% (12/19) of these cases resulted in intermediate or high risk of recurrence categories. Additionally, although all samples were positive for ER assessed by IHC, the molecular test assigned 47.4% (9/19) of BCs to intrinsic non-luminal subtypes. In conclusion, the AR/ER ratio ≥2 identifies a subgroup of patients with aggressive biological features and may represent an additional independent marker of worse BC prognosis. Moreover, the Prosigna-PAM50 results indicate that a significant number of cases with AR/ER≥2 could be non-luminal tumours. © 2018 Society for Endocrinology.
Fan, Ming; Cheng, Hu; Zhang, Peng; Gao, Xin; Zhang, Juan; Shao, Guoliang; Li, Lihua
2017-01-01
Breast tumor heterogeneity is related to risk factors that lead to worse prognosis, yet such heterogeneity has not been well studied.To predict the Ki-67 status of estrogen receptor (ER)-positive breast cancer patients via analysis of tumor
Mouse models of estrogen receptor-positive breast cancer
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Shakur Mohibi
2011-01-01
Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.
International Nuclear Information System (INIS)
Parise, C. A.; Caggiano, V.
2014-01-01
ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1-3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification.
Directory of Open Access Journals (Sweden)
Carol A. Parise
2014-01-01
Full Text Available Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1–3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification.
Genome-wide association studies identify four ER negative–specific breast cancer risk loci
Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van’t; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Silva, Isabel dos Santos; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; Van den Ouweland, Ans M W; Van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter
2013-01-01
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. PMID:23535733
Risi, Emanuela; Grilli, Andrea; Migliaccio, Ilenia; Biagioni, Chiara; McCartney, Amelia; Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo; Vitale, Stefania; Biganzoli, Laura; Bicciato, Silvio; Di Leo, Angelo; Malorni, Luca
2018-07-01
HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.
Steroid metabolism and steroid receptors in dimethylbenz(a)anthracene-induced rat mammary tumors
International Nuclear Information System (INIS)
Eechaute, W.; de Thibault de Boesinghe, L.; Lacroix, E.
1983-01-01
Mammary tumors were induced in rats by treatment with dimethylbenz(a)anthracene. Cytosol receptors for 17 beta-estradiol and progesterone were estimated by means of sucrose density gradient centrifugation, and the metabolism of [ 14 C]progesterone, [ 14 C]testosterone, and 17 beta-[ 14 C]estradiol by minced tumor tissue was studied. The estradiol receptor (ER) and progesterone receptor (PR) levels of the tumors varied considerably from less than 5 to 48 fmol/mg protein for ER and to 243 fmol/mg protein for PR. Considering a receptor level lower than 5 fmol/mg protein to be negative, four groups of tumors were found: ER-negative and PR-negative; ER-positive and PR-negative; ER-negative and PR-positive; ER-positive and PR-positive. In dimethylbenz(a)anthracene-induced tumor tissue, high 5 alpha-reductase and 20 alpha-hydroxysteroid dehydrogenase activities and somewhat lower 3 alpha-hydroxysteroid dehydrogenase and 6 alpha-hydroxylase activities were found. No aromatization was detectable. Steroids, especially estradiol, were also metabolized in a high degree to unextractable metabolites. It was concluded that steroid metabolism of dimethylbenz(a)anthracene-induced rat mammary tumors was not related to the ER and/or PR concentration of tumor tissue
Directory of Open Access Journals (Sweden)
Ibrahim Tekedereli
2013-01-01
Full Text Available Bcl-2 is overexpressed in about a half of human cancers and 50–70% of breast cancer patients, thereby conferring resistance to conventional therapies and making it an excellent therapeutic target. Small interfering RNA (siRNA offers novel and powerful tools for specific gene silencing and molecularly targeted therapy. Here, we show that therapeutic silencing of Bcl-2 by systemically administered nanoliposomal (NL-Bcl-2 siRNA (0.15 mg siRNA/kg, intravenous twice a week leads to significant antitumor activity and suppression of growth in both estrogen receptor-negative (ER(− MDA-MB-231 and ER-positive (+ MCF7 breast tumors in orthotopic xenograft models (P < 0.05. A single intravenous injection of NL-Bcl-2-siRNA provided robust and persistent silencing of the target gene expression in xenograft tumors. NL-Bcl-2-siRNA treatment significantly increased the efficacy of chemotherapy when combined with doxorubicin in both MDA-MB-231 and MCF-7 animal models (P < 0.05. NL-Bcl-2-siRNA treatment-induced apoptosis and autophagic cell death, and inhibited cyclin D1, HIF1α and Src/Fak signaling in tumors. In conclusion, our data provide the first evidence that in vivo therapeutic targeting Bcl-2 by systemically administered nanoliposomal-siRNA significantly inhibits growth of both ER(− and ER(+ breast tumors and enhances the efficacy of chemotherapy, suggesting that therapeutic silencing of Bcl-2 by siRNA is a viable approach in breast cancers.
Directory of Open Access Journals (Sweden)
Anna Babayan
Full Text Available BACKGROUND: Endocrine treatment is the most preferable systemic treatment in metastatic breast cancer patients that have had an estrogen receptor (ER positive primary tumor or metastatic lesions, however, approximately 20% of these patients do not benefit from the therapy and demonstrate further metastatic progress. One reason for failure of endocrine therapy might be the heterogeneity of ER expression in tumor cells spreading from the primary tumor to distant sites which is reflected in detectable circulating tumor cells (CTCs. METHODS: A sensitive and specific staining protocol for ER, keratin 8/18/19, CD45 was established. Peripheral blood from 35 metastatic breast cancer patients with ER-positive primary tumors was tested for the presence of CTCs. Keratin 8/18/19 and DAPI positive but CD45 negative cells were classified as CTCs and evaluated for ER staining. Subsequently, eight individual CTCs from four index patients (2 CTCs per patient were isolated and underwent whole genome amplification and ESR1 gene mutation analysis. RESULTS: CTCs were detected in blood of 16 from 35 analyzed patients (46%, with a median of 3 CTCs/7.5 ml. In total, ER-negative CTCs were detected in 11/16 (69% of the CTC positive cases, including blood samples with only ER-negative CTCs (19% and samples with both ER-positive and ER-negative CTCs (50%. No correlation was found between the intensity and/or percentage of ER staining in the primary tumor with the number and ER status of CTCs of the same patient. ESR1 gene mutations were not found. CONCLUSION: CTCs frequently lack ER expression in metastatic breast cancer patients with ER-positive primary tumors and show a considerable intra-patient heterogeneity, which may reflect a mechanism to escape endocrine therapy. Provided single cell analysis did not support a role of ESR1 mutations in this process.
Babayan, Anna; Hannemann, Juliane; Spötter, Julia; Müller, Volkmar
2013-01-01
Background Endocrine treatment is the most preferable systemic treatment in metastatic breast cancer patients that have had an estrogen receptor (ER) positive primary tumor or metastatic lesions, however, approximately 20% of these patients do not benefit from the therapy and demonstrate further metastatic progress. One reason for failure of endocrine therapy might be the heterogeneity of ER expression in tumor cells spreading from the primary tumor to distant sites which is reflected in detectable circulating tumor cells (CTCs). Methods A sensitive and specific staining protocol for ER, keratin 8/18/19, CD45 was established. Peripheral blood from 35 metastatic breast cancer patients with ER-positive primary tumors was tested for the presence of CTCs. Keratin 8/18/19 and DAPI positive but CD45 negative cells were classified as CTCs and evaluated for ER staining. Subsequently, eight individual CTCs from four index patients (2 CTCs per patient) were isolated and underwent whole genome amplification and ESR1 gene mutation analysis. Results CTCs were detected in blood of 16 from 35 analyzed patients (46%), with a median of 3 CTCs/7.5 ml. In total, ER-negative CTCs were detected in 11/16 (69%) of the CTC positive cases, including blood samples with only ER-negative CTCs (19%) and samples with both ER-positive and ER-negative CTCs (50%). No correlation was found between the intensity and/or percentage of ER staining in the primary tumor with the number and ER status of CTCs of the same patient. ESR1 gene mutations were not found. Conclusion CTCs frequently lack ER expression in metastatic breast cancer patients with ER-positive primary tumors and show a considerable intra-patient heterogeneity, which may reflect a mechanism to escape endocrine therapy. Provided single cell analysis did not support a role of ESR1 mutations in this process. PMID:24058649
DEFF Research Database (Denmark)
Larsen, Mathilde Skaarup; Bjerre, Karsten; Lykkesfeldt, Anne Elisabeth
2012-01-01
) in endocrine treated breast cancer in terms of co-expression and association with disease-free survival (DFS) in 1062 patients with ER-positive tumors. Furthermore, HER2 amplification was evaluated. We found positive associations between the phosphorylated receptors. pHER1 and pHER3 were co-expressed with one......The four human epidermal growth factor receptors (HER1-4) are involved in growth stimulation and may play a role in endocrine resistance. The receptors form dimers, leading to activation by mutual phosphorylation. Our purpose was to explore the role of the activated receptors (pHER1, pHER2, pHER3...
Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio
2017-01-01
Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that
International Nuclear Information System (INIS)
Leygue, Etienne; Dotzlaw, Helmut; Watson, Peter H; Murphy, Leigh C
2000-01-01
Using semiquantitative reverse transcription-polymerase chain reaction assays, we investigated the expression of variant messenger RNAs relative to wild-type estrogen receptor (ER)-α messenger RNA in normal breast tissues and their adjacent matched breast tumor tissues. Higher ER variant truncated after sequences encoding exon 2 of the wild-type ER-α (ERC4) messenger RNA and a lower exon 3 deleted ER-α variant (ERD3) messenger RNA relative expression in the tumor compartment were observed in the ER-positive/PR-positive and the ER-positive subsets, respectively. A significantly higher relative expression of exon 5 deleted ER-α varient (ERD5) messenger RNA was observed in tumor components overall. These data demonstrate that changes in the relative expression of ER-α variant messenger RNAs occur between adjacent normal and neoplastic breast tissues. We suggest that these changes might be involved in the mechanisms that underlie breast tumorigenesis. Estrogen receptor (ER)-α and ER-β are believed to mediate the action of estradiol in target tissues. Several ER-α and ER-β variant messenger RNAs have been identified in both normal and neoplastic human tissues. Most of these variants contain a deletion of one or more exons of the wild-type (WT) ER messenger RNAs. The putative proteins that are encoded by these variant messenger RNAs would therefore be missing some functional domains of the WT receptors, and might interfere with WT-ER signaling pathways. The detection of ER-α variants in both normal and neoplastic human breast tissues raised the question of their possible role in breast tumorigenesis. We have previously reported an increased relative expression of exon 5 deleted ER-α variant (ERD5) messenger RNA and of another ER-α variant truncated of all sequences following the exon 2 of the WT ER-α (ERC4) messenger RNA in breast tumor samples versus independent normal breast tissues. In contrast, a decreased relative expression of exon 3 deleted ER
Pirouzpanah, Saeed; Taleban, Forough-Azam; Mehdipour, Parvin; Sabour, Siamak; Atri, Morteza
2018-02-14
The option of endocrine therapy in breast cancer remains conventionally promising. We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, PPR- conditions (Cramer's V= 0.44, PPR (77.1%, PPR expressions (55.6%, PPR- (64.4%, PPR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer.
Wong, Hilda; Lau, Silvia; Cheung, Polly; Wong, Ting Ting; Parker, Andrew; Yau, Thomas; Epstein, Richard J
2014-11-10
Although invasive lobular carcinoma (ILC) of the breast differs from invasive ductal carcinoma (IDC) in numerous respects - including its genetics, clinical phenotype, metastatic pattern, and chemosensitivity - most experts continue to manage ILC and IDC identically in the adjuvant setting. Here we address this discrepancy by comparing early-stage ILC and IDC in two breast cancer patient cohorts of differing nationality and ethnicity. The clinicopathologic features of 2029 consecutive breast cancer patients diagnosed in Hong Kong (HK) and Australia (AUS) were compared. Interrelationships between tumor histology and other clinicopathologic variables, including ER/PR and Ki67, were analysed. Two hundred thirty-nine patients were identified with ILC (11.8%) and 1790 patients with IDC. AUS patients were older (p patients. As expected, ILC tumors were lower in grade and proliferative rate, and more often ER-positive and HER2-negative, than IDC (p 0.7). Moreover, whereas IDC tumors exhibited a strongly negative relationship between ER/PR and Ki67 status (p 0.6). These data imply that the primary adhesion defect in ILC underlies a secondary stromal-epithelial disconnect between hormonal signaling and tumor growth, suggesting in turn that this peritumoral feedback defect could reduce both the antimetastatic (adjuvant) and tumorilytic (palliative) efficacy of cytotoxic therapies for such tumors. Hence, we caution against assuming similar adjuvant chemotherapeutic survival benefits for ILC and IDC tumors with similar ER and Ki67, whether based on immunohistochemical or gene expression assays.
Directory of Open Access Journals (Sweden)
Fatma Ashour
2018-06-01
Full Text Available Background and Objectives: Breast cancer (BC is classified according to estrogen receptor (ER status into ER+ and ER− tumors. ER+ tumors have a worse response to chemotherapy compared to ER− tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER+ tumors. Recently it was shown that Cancer Stem Cells (CSCs play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER+ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB. Methods: CSCs were isolated by anoikis resistance assay from MCF7 (ER+ and MDA-MB-231 (ER− cell lines. Isolated CSCs were treated with doxorubicin (DOX and the mRNA expression levels of BCL-2, TP53, BAX and NFKB were investigated by quantitative real time PCR (qPCR with and without treatment. Results: BCL-2, BAX and NF-ΚB showed decreased expression in MCF7 bulk cancer cells after DOX treatment whereas only BCL-2 and BAX showed decreased expression in MDA-MB-231 bulk cancer cells. Interestingly TP53 was the only gene showed a considerable increase in its expression in CSCs of the ER+ MCF7 cell line compared to bulk cancer cells. Moreover, TP53 was the only gene showing exceptionally higher level of expression in MCF7-CSCs compared to MDA-MB-231-CSCs. Conclusion: Our results suggest that CSCs in the ER+ cells escape the effect of DOX treatment by the elevation of p53 expression. Keywords: Breast cancer, Cancer Stem Cells, Drug resistance, Estrogen receptors
Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.
Shen, Tiansheng; Brandwein-Gensler, Margaret; Hameed, Omar; Siegal, Gene P; Wei, Shi
2015-11-01
Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P < .0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P = .0002) or ER-/PR+ (P = .0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P = .001) and disease-specific survival (P = .005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine. Copyright © 2015 Elsevier Inc. All rights reserved.
DEFF Research Database (Denmark)
Anderson, William F; Rosenberg, Philip S; Petito, Lucia
2013-01-01
-period-cohort models to estimate age-specific EAPCs, cohort rate ratios and projections for future time periods (2011-2018). In Denmark, the overall rate of ER-positive cancers rose between 1993 and 2010 by 3.0% per year (95% CI: 2.8-3.3% per year), whereas the overall rate of ER-negative cancers fell by 2.1% per year...... (95% CI: -2.5 to -1.6% per year). The ER-positive rate increased fastest among postmenopausal women and the ER-negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER-positive tumors and lower risk of ER-negative tumors......Long-term breast cancer trends in incidence in the United States (US) show rising estrogen receptor (ER)-positive rates and falling ER-negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries...
Lee, Su Hyun; Ha, Seunggyun; An, Hyun Joon; Lee, Jae Sung; Han, Wonshik; Im, Seock-Ah; Ryu, Han Suk; Kim, Won Hwa; Chang, Jung Min; Cho, Nariya; Moon, Woo Kyung; Cheon, Gi Jeong
2016-08-01
Oncotype DX, a 21-gene expression assay, provides a recurrence score (RS) which predicts prognosis and the benefit from adjuvant chemotherapy in patients with early-stage, estrogen receptor-positive (ER-positive), and human epidermal growth factor receptor 2-negative (HER2-negative) invasive breast cancer. However, Oncotype DX tests are expensive and not readily available in all institutions. The purpose of this study was to investigate whether metabolic parameters on (18)F-FDG PET/CT are associated with the Oncotype DX RS and whether (18)F-FDG PET/CT can be used to predict the Oncotype DX RS. The study group comprised 38 women with stage I/II, ER-positive/HER2-negative invasive breast cancer who underwent pretreatment (18)F-FDG PET/CT and Oncotype DX testing. On PET/CT, maximum (SUVmax) and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis were measured. Partial volume-corrected SUVmax (PVC-SUVmax) determined using the recovery coefficient method was also evaluated. Oncotype DX RS (0 - 100) was categorized as low (negative breast cancer.
LENUS (Irish Health Repository)
Brennan, Donal J
2011-01-31
Abstract Introduction We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive\\/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as
DEFF Research Database (Denmark)
Jensen, Jeanette Dupont; Knoop, Ann; Ewertz, Marianne
2011-01-01
with the primary tumors with respect to ER, HER2, and TOP2A. In the prospective tissue-collection study, 81 patients had biopsy from a suspected relapse. Additional archived paired material was included, leaving a total of 119 patients with paired primary tumor, synchronous axillary nodes (available in 52 patients......At recurrence of breast cancer, the therapeutic target is the metastases. However, it is current practice to base the choice of systemic treatment on the biomarker profile of the primary tumor. In the present study, confirmatory biopsies were obtained from suspected metastatic lesions and compared......) and asyncronous metastases available for analysis. ER, HER2, and TOP2A expression of primary tumors, axillary nodes and metastases were re-analysed and determined centrally by immunohistochemistry, chromogenic in situ hybridization, and fluorescence in situ hybridization. Of the 81 patients with a biopsy from...
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Hui eHan
2013-10-01
Full Text Available Mortality from liver cancer in humans is increasingly attributable to heavy or long-term alcohol consumption. The mechanisms by which alcohol exerts its carcinogenic effect are not well understood. In this study, the role of alcohol-induced endoplasmic reticulum (ER stress response in liver cancer development was investigated using an animal model with a liver knockout of the chaperone BiP and under constitutive hepatic ER stress. Long-term alcohol and high fat diet (HFD feeding resulted in higher levels of serum alanine aminotransferase (ALT, impaired ER stress response, and higher incidence of liver tumor in older (aged 16 months knockout females than in either middle-aged (6 months knockouts or older (aged 16 months wild type females. In the older knockout females, stronger effects of the alcohol on methylation of CpG islands at promoter regions of genes involved in the ER associated degradation (ERAD were also detected. Altered expression of ERAD factors including derlin 3, Creld2 (cysteine-rich with EGF-like domains 2, Herpud1 (ubiquitin-like domain member, Wfs1 (wolfram syndrome gene, and Yod1 (deubiquinating enzyme 1 was co-present with decreased proteasome activities, increased estrogen receptor alpha variant (ERa36, and enhanced phosphorylations of ERK1/2 (extracellular signal-regulated protein kinases 1 and 2 and STAT3 (the signal transducers and activators of transcription in the older knockout female fed alcohol. Our results suggest that long-term alcohol consumption and ageing may promote liver tumorigenesis in females through interfering with DNA methylation and expression of genes involved in the ER associated degradation.
Fan, Ming
2017-12-08
Breast tumor heterogeneity is related to risk factors that lead to worse prognosis, yet such heterogeneity has not been well studied.To predict the Ki-67 status of estrogen receptor (ER)-positive breast cancer patients via analysis of tumor heterogeneity with subgroup identification based on patterns of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Retrospective study.Seventy-seven breast cancer patients with ER-positive breast cancer were investigated, of whom 51 had low Ki-67 expression.T1 -weighted 3.0T DCE-MR images.Each tumor was partitioned into multiple subregions using three methods based on patterns of dynamic enhancement: 1) time to peak (TTP), 2) peak enhancement rate (PER), and 3) kinetic pattern clustering (KPC). In each tumor subregion, 18 texture features were computed.Univariate and multivariate logistic regression analyses were performed using a leave-one-out-based cross-validation (LOOCV) method. The partitioning results were compared with the same feature extraction methods across the whole tumor.In the univariate analysis, the best-performing feature was the texture statistic of sum variance in the tumor subregion with early TTP for differentiating between patients with high and low Ki-67 expression (area under the receiver operating characteristic curves, AUC = 0.748). Multivariate analysis showed that features from the tumor subregion associated with early TTP yielded the highest performance (AUC = 0.807) among the subregions for predicting the Ki-67 status. Among all regions, the tumor area with high PER at a precontrast MR image achieved the highest performance (AUC = 0.722), while the subregion that exhibited the highest overall enhancement rate based on KPC had an AUC of 0.731. These three models based on intratumoral texture analysis significantly (P < 0.01) outperformed the model using features from the whole tumor (AUC = 0.59).Texture analysis of intratumoral heterogeneity has the potential to serve as a valuable
Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes.
Cobleigh, Melody A; Tabesh, Bita; Bitterman, Pincas; Baker, Joffre; Cronin, Maureen; Liu, Mei-Lan; Borchik, Russell; Mosquera, Juan-Miguel; Walker, Michael G; Shak, Steven
2005-12-15
This study, along with two others, was done to develop the 21-gene Recurrence Score assay (Oncotype DX) that was validated in a subsequent independent study and is used to aid decision making about chemotherapy in estrogen receptor (ER)-positive, node-negative breast cancer patients. Patients with >or=10 nodes diagnosed from 1979 to 1999 were identified. RNA was extracted from paraffin blocks, and expression of 203 candidate genes was quantified using reverse transcription-PCR (RT-PCR). Seventy-eight patients were studied. As of August 2002, 77% of patients had distant recurrence or breast cancer death. Univariate Cox analysis of clinical and immunohistochemistry variables indicated that HER2/immunohistochemistry, number of involved nodes, progesterone receptor (PR)/immunohistochemistry (% cells), and ER/immunohistochemistry (% cells) were significantly associated with distant recurrence-free survival (DRFS). Univariate Cox analysis identified 22 genes associated with DRFS. Higher expression correlated with shorter DRFS for the HER2 adaptor GRB7 and the macrophage marker CD68. Higher expression correlated with longer DRFS for tumor protein p53-binding protein 2 (TP53BP2) and the ER axis genes PR and Bcl2. Multivariate methods, including stepwise variable selection and bootstrap resampling of the Cox proportional hazards regression model, identified several genes, including TP53BP2 and Bcl2, as significant predictors of DRFS. Tumor gene expression profiles of archival tissues, some more than 20 years old, provide significant information about risk of distant recurrence even among patients with 10 or more nodes.
International Nuclear Information System (INIS)
Truong, Pauline T.; Olivotto, Ivo A.; Kader, Hosam A.; Panades, Miguel; Speers, Caroline H.; Berthelet, Eric
2005-01-01
Purpose: To define the individual factors and combinations of factors associated with increased risk of locoregional recurrence (LRR) that may justify postmastectomy radiotherapy (PMRT) in patients with T1-T2 breast cancer and one to three positive nodes. Methods and Materials: The study cohort comprised 821 women referred to the British Columbia Cancer Agency between 1989 and 1997 with pathologic T1-T2 breast cancer and one to three positive nodes treated with mastectomy without adjuvant RT. The 10-year Kaplan-Meier estimates of isolated LRR and LRR with or without simultaneous distant recurrence (LRR ± SDR) were analyzed according to age, histologic findings, tumor location, size, and grade, lymphovascular invasion status, estrogen receptor (ER) status, margin status, number of positive nodes, number of nodes removed, percentage of positive nodes, and systemic therapy use. Multivariate analyses were performed using Cox proportional hazards modeling. A risk classification model was developed using combinations of the statistically significant factors identified on multivariate analysis. Results: The median follow-up was 7.7 years. Systemic therapy was used in 94% of patients. Overall, the 10-year Kaplan-Meier isolated LRR and LRR ± SDR rate was 12.7% and 15.9%, respectively. Without PMRT, a 10-year LRR risk of >20% was identified in women with one to three positive nodes plus at least one of the following factors: age 25% of nodes positive (all p 25% of nodes positive, medial tumor location, and ER-negative status were statistically significant predictors of isolated LRR and LRR ± SDR. In the classification model, the first split was according to age ( 25% of nodes positive was associated with a risk of LRR ± SDR of 58.0% compared with 23.8% for those with ≤25% of nodes positive (p = 0.01). Of 698 women >45 years, the presence of >25% of nodes positive also conferred a greater LRR ± SDR risk (26.7%) compared with women with ≤25% of nodes positive (10
BP1 Homeoprotein Enhances Metastatic Potential in ER-negative Breast Cancer
Fu, Yebo; Lian, Yi; Kim, Kyung Soon; Zhang, Lei; Hindle, A. Katharine; Brody, Fred; Siegel, Robert S.; McCaffrey, Timothy A.; Fu, Sidney W.
2010-01-01
Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. It was reported that BP1, a homeobox isoform of DLX4, is overexpressed in 80% of breast cancer patients and in 100% of estrogen receptor negative (ER-) tumors. The prevalence of BP1 positive cells and the intensity of BP1 immunoreactivity increased with the extent of ductal proliferation and tumorigenesis. These findings imply that BP1 may play an important role in ER- breast cancer. We sought to determine the effects and mechanisms of BP1 on cell proliferation and metastasis using ER- Hs578T cells as a model. Cells were transfected with either pcDNA3.2 plasmid containing BP1 gene, or pcDNA3.2 vector, then selected and cloned. Overexpression of BP1 increased cell proliferation rate by 2-5 fold (p=2.0. Of those genes, 49 were up-regulated and 22 were down-regulated. Significant pathways were identified involving cell proliferation and metastasis. These data demonstrated that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in ER- Hs578T cells. Further analysis with more ER- cell lines and patient samples is warranted to establish BP1 as a therapeutic target for ER- breast cancer. PMID:20842225
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Arindam Banerjee
Full Text Available The neurotrophic factor ARTEMIN (ARTN has been reported to possess a role in mammary carcinoma progression and metastasis. Herein, we report that ARTN modulates endothelial cell behaviour and promotes angiogenesis in ER-mammary carcinoma (ER-MC. Human microvascular endothelial cells (HMEC-1 do not express ARTN but respond to exogenously added, and paracrine ARTN secreted by ER-MC cells. ARTN promoted endothelial cell proliferation, migration, invasion and 3D matrigel tube formation. Angiogenic behaviour promoted by ARTN secreted by ER-MC cells was mediated by AKT with resultant increased TWIST1 and subsequently VEGF-A expression. In a patient cohort of ER-MC, ARTN positively correlated with VEGF-A expression as measured by Spearman's rank correlation analysis. In xenograft experiments, ER-MC cells with forced expression of ARTN produced tumors with increased VEGF-A expression and increased microvessel density (CD31 and CD34 compared to tumors formed by control cells. Functional inhibition of ARTN by siRNA decreased the angiogenic effects of ER-MC cells. Bevacizumab (a humanized monoclonal anti-VEGF-A antibody partially inhibited the ARTN mediated angiogenic effects of ER-MC cells and combined inhibition of ARTN and VEGF-A by the same resulted in further significant decrease in the angiogenic effects of ER-MC cells. Thus, ARTN stimulates de novo tumor angiogenesis mediated in part by VEGF-A. ARTN therefore co-ordinately regulates multiple aspects of tumor growth and metastasis.
West, Diana C.; Pan, Deng; Tonsing-Carter, Eva Y.; Hernandez, Kyle M.; Pierce, Charles F.; Styke, Sarah C.; Bowie, Kathleen R.; Garcia, Tzintzuni I.; Kocherginsky, Masha; Conzen, Suzanne D.
2016-01-01
In estrogen receptor (ER)-negative breast cancer (BC), high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a meta-analysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapse-free survival (RFS) (independently of progesterone receptor (PR) expression). To understand the mechanism by which GR expression is associated with a better ER+ BC outcome, the global effect of GR-mediated transcriptional activation in ER+ BC cells was studied. Analysis of GR chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in ER+/GR+ MCF-7 cells revealed that upon co-activation of GR and ER, GR chromatin association became enriched at proximal promoter regions. Furthermore, following ER activation, increased GR chromatin association was observed at ER, FOXO, and AP1 response elements. In addition, ER associated with GR response elements, suggesting that ER and GR interact in a complex. Co-activation of GR and ER resulted in increased expression (relative to ER activation alone) of transcripts that encode proteins promoting cellular differentiation (e.g. KDM4B, VDR) and inhibiting the Wnt-signaling pathway (IGFBP4). Finally, expression of these individual pro-differentiation genes was associated with significantly improved RFS in ER+ BC patients. Together, these data suggest that the co-expression and subsequent activity of tumor cell GR and ER contribute to the less aggressive natural history of early-stage BC by coordinating the altered expression of genes favoring differentiation. Implications The interaction between estrogen and glucocorticoid receptor activity highlights the importance of context-dependent nuclear receptor function in cancer. PMID:27141101
International Nuclear Information System (INIS)
Zhao, Xi; Rødland, Einar Andreas; Sørlie, Therese; Vollan, Hans Kristian Moen; Russnes, Hege G; Kristensen, Vessela N; Lingjærde, Ole Christian; Børresen-Dale, Anne-Lise
2014-01-01
The aim was to assess and compare prognostic power of nine breast cancer gene signatures (Intrinsic, PAM50, 70-gene, 76-gene, Genomic-Grade-Index, 21-gene-Recurrence-Score, EndoPredict, Wound-Response and Hypoxia) in relation to ER status and follow-up time. A gene expression dataset from 947 breast tumors was used to evaluate the signatures for prediction of Distant Metastasis Free Survival (DMFS). A total of 912 patients had available DMFS status. The recently published METABRIC cohort was used as an additional validation set. Survival predictions were fairly concordant across most signatures. Prognostic power declined with follow-up time. During the first 5 years of followup, all signatures except for Hypoxia were predictive for DMFS in ER-positive disease, and 76-gene, Hypoxia and Wound-Response were prognostic in ER-negative disease. After 5 years, the signatures had little prognostic power. Gene signatures provide significant prognostic information beyond tumor size, node status and histological grade. Generally, these signatures performed better for ER-positive disease, indicating that risk within each ER stratum is driven by distinct underlying biology. Most of the signatures were strong risk predictors for DMFS during the first 5 years of follow-up. Combining gene signatures with histological grade or tumor size, could improve the prognostic power, perhaps also of long-term survival
Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ER-α status.
Harrison, Hannah; Rogerson, Lynsey; Gregson, Hannah J; Brennan, Keith R; Clarke, Robert B; Landberg, Göran
2013-02-15
Tumor hypoxia is often linked to decreased survival in patients with breast cancer and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia-induced angiogenesis. Antiangiogenic therapies show some therapeutic potential with increased disease-free survival, but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and four cell lines. There was a HIF-1α-dependent CSC increase in ER-α-positive cancers following hypoxic exposure, which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-α-negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-α expression and CSC. The same ER-α-dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-α-positive and negative breast cancer subtypes respond differently to hypoxia and, as a consequence, antiangiogenic therapies will not be suitable for both subgroups.
ER and PR expression and survival after endometrial cancer.
Smith, Deborah; Stewart, Colin J R; Clarke, Edward M; Lose, Felicity; Davies, Claire; Armes, Jane; Obermair, Andreas; Brennan, Donal; Webb, Penelope M; Nagle, Christina M; Spurdle, Amanda B
2018-02-01
To measure association between endometrial carcinoma ER and PR status and endometrial cancer (EC) survival, accounting for inter-observer variation. The intensity and proportion of tumor cell expression of ER and PR in ECs were assessed independently and semi-quantitatively by two pathologists using digital images of duplicate tumor tissue microarrays (TMAs). Cases with inconsistent initial assessment were reviewed and final scoring agreed. The association between overall and EC-specific survival and hormone receptor expression (intensity, proportion and combined) was assessed using Cox regression analysis. The C-index was used to evaluate model discrimination with addition of ER and PR status. Tumor ER and PR analysis was possible in 659 TMAs from 255 patients, and in 459 TMAs from 243 patients, respectively. Initial ER and PR scoring was consistent in 82% and 80% of cases, respectively. In multivariate analyses decreased ER and PR expression was associated with increased tumor-related mortality. Associations reached statistical significance for ER proportion score (P=0.05), ER intensity score (P=0.003), and PR combined score (P=0.04). Decreased expression of combined ER/PR expression was associated with poorer EC-specific survival than decreased expression of either hormone receptor alone (P=0.005). However, hormone receptor status did not significantly improve mortality prediction in individual cases. ER and PR expression combined, using cut-points that capture variation in scoring and across cores, is significantly associated with EC-specific survival in analyses adjusting for known prognostic factors. However, at the individual level, ER and PR expression does not improve mortality prediction. Copyright © 2017 Elsevier Inc. All rights reserved.
Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L; Costantino, Joseph P; Baehner, Frederick L; Baker, Joffre; Cronin, Maureen T; Watson, Drew; Shak, Steven; Bohn, Olga L; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L; Vogel, Victor G; McCaskill-Stevens, Worta; Ford, Leslie G; Geyer, Charles E; Wickerham, D Lawrence; Wolmark, Norman; Paik, Soonmyung
2011-11-01
Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.
Huang, Weisun; Nie, Weiwei; Zhang, Wenwen; Wang, Yanru; Zhu, Aiyu; Guan, Xiaoxiang
2016-01-01
The ER signaling pathway plays a critical role in breast cancer. ER signaling pathway-related proteins, such as TRX, AR, and cyclin D1, may have an important function in breast cancer. However, the ways that they influence breast cancer development and progression are still unclear. A total of 101 Chinese female patients diagnosed with invasive ductal breast adenocarcinoma were retrospectively enrolled in the study. The expression levels of TRX, AR, and cyclin D1 were detected by immunohistochemistry and analyzed via correlation with clinicopathological characteristics and the expression status of ER, PR, and HER2. The expression status of TRX, AR, and cyclin D1 was not associated with the patient's age, menopausal status, tumor size, or histological differentiation (P>0.05), but was positively correlated with ER and PR (PTRX-positive patients were also HER2-positive (P=0.003). Of AR- or cyclin D1-positive patients, most had relatively earlier I-II tumor stage (P=0.005 and P=0.047, respectively) and no metastatic lymph node involvement (P=0.008 and P=0.005, respectively). TRX was found to be positively correlated with ER and PR expression, whereas it was negatively correlated with HER2 expression. In addition, we found that the positive expression of AR and cyclin D1 was correlated with lower TNM stage and fewer metastatic lymph nodes, and it was more common in ER-positive breast cancer than in the basal-like subtype. This may indicate that AR and cyclin D1 are good predictive and prognostic factors and closely interact with ER signaling pathway. Further studies will be necessary to investigate the response and clinical outcomes of treatment targeting TRX, AR, and cyclin D1.
Haricharan, Svasti; Bainbridge, Matthew N; Scheet, Paul; Brown, Powel H
2014-07-01
Breast cancer is one of the most commonly diagnosed cancers in women. While there are several effective therapies for breast cancer and important single gene prognostic/predictive markers, more than 40,000 women die from this disease every year. The increasing availability of large-scale genomic datasets provides opportunities for identifying factors that influence breast cancer survival in smaller, well-defined subsets. The purpose of this study was to investigate the genomic landscape of various breast cancer subtypes and its potential associations with clinical outcomes. We used statistical analysis of sequence data generated by the Cancer Genome Atlas initiative including somatic mutation load (SML) analysis, Kaplan-Meier survival curves, gene mutational frequency, and mutational enrichment evaluation to study the genomic landscape of breast cancer. We show that ER(+), but not ER(-), tumors with high SML associate with poor overall survival (HR = 2.02). Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes. While it is known that somatic mutations in specific genes affect breast cancer survival, this study is the first to identify that SML may constitute an important global signature for a subset of ER(+) tumors prone to high mortality. Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival. Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.
Wang, Lijun; Wang, Ying; Du, Huaqing; Jiang, Yao; Tang, Zhichao; Liu, Hongyi; Xiang, Hua; Xiao, Hong
2015-12-01
ER520, a derivative of indenoisoquinoline, is a patented compound. This study was designed to screen its biological properties and to evaluate its antineoplastic and antiangiogenic effect. Western blot was employed to monitor the ERα and ERβ protein expression in human breast cancer MCF-7 cells and endometrial carcinoma Ishikawa cells. MTT assay was employed to determine cell proliferation. Cell adhesion, scratch and Transwell assay were utilized to estimate the ability of cellular adhesion, migration and invasion. ELISA kit was applied to detect the VEGF products in culture medium. In addition, the inhibitory effect of ER520 on the vessel-like construction of HUVEC cells and the angiogenesis of chicken embryos was investigated. The efficiency of ER520 on tumor growth in nude mice was also assessed. ER520 inhibited the expression of ERα in MCF-7 and Ishikawa cells, while it increased ERβ protein level. ER520 also suppressed the proliferation of MCF-7 and Ishikawa cells. Due to its remarkably negative role in cell adhesion, migration and invasion, ER520 showed a potential ability of inhibiting tumor metastasis. Meanwhile, ER520 reduced the VEGF secretion of MCF-7 and Ishikawa cells, prevented the formation of VEGF-stimulated tubular structure and the cell migration of HUVEC cells, and inhibited the angiogenesis of chicken chorioallantoic membrane. Animal experiment also demonstrated that ER520 could frustrate the in vivo tumor growth and the inhibitory ratio was 48.5 % compared with control group. Our findings indicate that ER520 possesses the competence to be a candidate against breast cancer and angiogenesis.
The integrative epigenomic-transcriptomic landscape of ER positive breast cancer.
Gao, Yang; Jones, Allison; Fasching, Peter A; Ruebner, Matthias; Beckmann, Matthias W; Widschwendter, Martin; Teschendorff, Andrew E
2015-01-01
While recent integrative analyses of copy number and gene expression data in breast cancer have revealed a complex molecular landscape with multiple subtypes and many oncogenic/tumour suppressor driver events, much less is known about the role of DNA methylation in shaping breast cancer taxonomy and defining driver events. Here, we applied a powerful integrative network algorithm to matched DNA methylation and RNA-Seq data for 724 estrogen receptor (ER)-positive (ER+) breast cancers and 111 normal adjacent tissue specimens from The Cancer Genome Atlas (TCGA) project, in order to identify putative epigenetic driver events and to explore the resulting molecular taxonomy. This revealed the existence of nine functionally deregulated epigenetic hotspots encompassing a total of 146 genes, which we were able to validate in independent data sets encompassing over 1000 ER+ breast cancers. Integrative clustering of the matched messenger RNA (mRNA) and DNA methylation data over these genes resulted in only two clusters, which correlated very strongly with the luminal-A and luminal B subtypes. Overall, luminal-A and luminal-B breast cancers shared the same epigenetically deregulated hotspots but with luminal-B cancers exhibiting increased aberrant DNA methylation patterns relative to normal tissue. We show that increased levels of DNA methylation and mRNA expression deviation from the normal state define a marker of poor prognosis. Our data further implicates epigenetic silencing of WNT signalling antagonists and bone morphogenetic proteins (BMP) as key events underlying both luminal subtypes but specially of luminal-B breast cancer. Finally, we show that DNA methylation changes within the identified epigenetic interactome hotspots do not exhibit mutually exclusive patterns within the same cancer sample, instead exhibiting coordinated changes within the sample. Our results indicate that the integrative DNA methylation and transcriptomic landscape of ER+ breast cancer is
Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L.; Costantino, Joseph P.; Baehner, Frederick L.; Baker, Joffre; Cronin, Maureen T.; Watson, Drew; Shak, Steven; Bohn, Olga L.; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L.; Vogel, Victor G.; McCaskill-Stevens, Worta; Ford, Leslie G.; Geyer, Charles E.; Wickerham, D. Lawrence; Wolmark, Norman; Paik, Soonmyung
2011-01-01
Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors. PMID:21947828
Directory of Open Access Journals (Sweden)
Hélène Bonsang-Kitzis
Full Text Available Avoiding axillary lymph node dissection (ALND for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB could decrease morbidity with minimal clinical significance.The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN prediction nomogram for ER+ HER2- breast cancer patients.We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients' characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results.A 0.3 threshold discriminate the type of sentinel node (SN metastases: 98.8% of patients with pN0(i+ and 91.6% of patients with pN1(mic had a MSKCC score under 0.3 (false negative rate = 6.4%. If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients.We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+ or pN1(mic ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3.
Directory of Open Access Journals (Sweden)
Chatterjee S
2015-12-01
Full Text Available Sanjoy Chatterjee,1 Animesh Saha,1 Indu Arun,2 Sonali Susmita Nayak,2 Subir Sinha,3 Sanjit Agrawal,4 Mayur Parihar,5 Rosina Ahmed4 1Department of Radiation Oncology, 2Department of Pathology, 3Department of Medical Statistics, 4Department of Breast Surgery, 5Department of Molecular Pathology, Tata Medical Center, Kolkata, West Bengal, India Background: Following neoadjuvant chemotherapy (NACT for breast cancer, changes in estrogen receptor (ER, progesterone receptor (PR, HER2 status, and Ki-67 index (IHC4 status and its correlation with pathological complete response (pCR or relapse-free survival (RFS rates could lead to better understanding of tumor management. Patients and methods: Pre- and post-NACT IHC4 status and its changes were analyzed in 156 patients with breast cancer. Associations between pCR, RFS rates to IHC4 status pre- and post-NACT were investigated. Results: pCR was found in 25.3% patients. Both ER and PR positive tumors had the lowest (14.3% pCR compared to ER and PR negative (29% or either ER-/PR-positive (38.6% tumors. PR positivity was significantly associated with less likelihood of pCR (15% versus 34%. The pCR rate was low for luminal A subtype (13.68% compared to 24.36%, 26.31%, and 33.33% for luminal B, HER2-enriched, and triple-negative subtypes, respectively. There was significant reduction in ER expression and Ki-67 index post-NACT. RFS of patients in whom the hormonal status changed from positive to negative was better compared to those of patients in whom the hormonal status changed from negative to positive. Conclusion: Although changes in IHC4 occurred post-NACT, pre-NACT hazard ratio status prognosticated RFS better. pCR and RFS rates were lower in PR-positive tumors. Keywords: neoadjuvant chemotherapy, IHC4 status changes, survival
Mitigating Errors in External Respiratory Surrogate-Based Models of Tumor Position
Energy Technology Data Exchange (ETDEWEB)
Malinowski, Kathleen T. [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States); McAvoy, Thomas J. [Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States); Department of Chemical and Biomolecular Engineering and Institute of Systems Research, University of Maryland, College Park, MD (United States); George, Rohini [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Dieterich, Sonja [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); D' Souza, Warren D., E-mail: wdsou001@umaryland.edu [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States)
2012-04-01
Purpose: To investigate the effect of tumor site, measurement precision, tumor-surrogate correlation, training data selection, model design, and interpatient and interfraction variations on the accuracy of external marker-based models of tumor position. Methods and Materials: Cyberknife Synchrony system log files comprising synchronously acquired positions of external markers and the tumor from 167 treatment fractions were analyzed. The accuracy of Synchrony, ordinary-least-squares regression, and partial-least-squares regression models for predicting the tumor position from the external markers was evaluated. The quantity and timing of the data used to build the predictive model were varied. The effects of tumor-surrogate correlation and the precision in both the tumor and the external surrogate position measurements were explored by adding noise to the data. Results: The tumor position prediction errors increased during the duration of a fraction. Increasing the training data quantities did not always lead to more accurate models. Adding uncorrelated noise to the external marker-based inputs degraded the tumor-surrogate correlation models by 16% for partial-least-squares and 57% for ordinary-least-squares. External marker and tumor position measurement errors led to tumor position prediction changes 0.3-3.6 times the magnitude of the measurement errors, varying widely with model algorithm. The tumor position prediction errors were significantly associated with the patient index but not with the fraction index or tumor site. Partial-least-squares was as accurate as Synchrony and more accurate than ordinary-least-squares. Conclusions: The accuracy of surrogate-based inferential models of tumor position was affected by all the investigated factors, except for the tumor site and fraction index.
International Nuclear Information System (INIS)
Baumann, Jan; Wong, Jason; Sun, Yan; Conklin, Douglas S.
2016-01-01
HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and
International Nuclear Information System (INIS)
Kakite, Suguru; Dyvorne, Hadrien A.; Lee, Karen M.; Jajamovich, Guido H.; Knight-Greenfield, Ashley; Taouli, Bachir
2015-01-01
To correlate intra voxel incoherent motion (IVIM) diffusion parameters of liver parenchyma and hepatocellular carcinoma (HCC) with degree of liver/tumor enhancement and necrosis; and to assess the diagnostic performance of diffusion parameters vs. enhancement ratios (ER) for prediction of complete tumor necrosis. In this IRB approved HIPAA compliant study, we included 46 patients with HCC who underwent IVIM diffusion-weighted (DW) MRI in addition to routine sequences at 3.0 T. True diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (PF) and apparent diffusion coefficient (ADC) were quantified in tumors and liver parenchyma. Tumor ER were calculated using contrast-enhanced imaging, and degree of tumor necrosis was assessed using post-contrast image subtraction. IVIM parameters and ER were compared between HCC and background liver and between necrotic and viable tumor components. ROC analysis for prediction of complete tumor necrosis was performed. 79 HCCs were assessed (mean size 2.5 cm). D, PF and ADC were significantly higher in HCC vs. liver (p < 0.0001). There were weak significant negative/positive correlations between D/PF and ER, and significant correlations between D/PF/ADC and tumor necrosis (for D, r 0.452, p < 0.001). Among diffusion parameters, D had the highest area under the curve (AUC 0.811) for predicting complete tumor necrosis. ER outperformed diffusion parameters for prediction of complete tumor necrosis (AUC > 0.95, p < 0.002). D has a reasonable diagnostic performance for predicting complete tumor necrosis, however lower than that of contrast-enhanced imaging
International Nuclear Information System (INIS)
Ritte, Rebecca; Grote, Verena; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Berrino, Franco; Mattiello, Amalia; Tumino, Rosario; Tikk, Kaja; Sacerdote, Carlotta; Quirós, José Ramón; Buckland, Genevieve; Molina-Montes, Esther; Chirlaque, María-Dolores; Ardanaz, Eva; Amiano, Pilar; Bueno-de-Mesquita, H Bas; Gils, Carla H van; Peeters, Petra HM; Lukanova, Annekatrin; Wareham, Nick; Khaw, Kay-Tee; Key, Timothy J; Travis, Ruth C; Weiderpass, Elisabete; Dumeaux, Vanessa; Lund, Eliv; Sund, Malin; Andersson, Anne; Romieu, Isabelle; Tjønneland, Anne; Rinaldi, Sabina; Vineis, Paulo; Merritt, Melissa A; Riboli, Elio; Kaaks, Rudolf; Olsen, Anja; Overvad, Kim; Dossus, Laure; Fournier, Agnès; Clavel-Chapelon, Françoise
2013-01-01
The association of reproductive factors with hormone receptor (HR)-negative breast tumors remains uncertain. Within the EPIC cohort, Cox proportional hazards models were used to describe the relationships of reproductive factors (menarcheal age, time between menarche and first pregnancy, parity, number of children, age at first and last pregnancies, time since last full-term childbirth, breastfeeding, age at menopause, ever having an abortion and use of oral contraceptives [OC]) with risk of ER-PR- (n = 998) and ER+PR+ (n = 3,567) breast tumors. A later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors (≥35 vs. ≤19 years HR: 1.47 [95% CI 1.15-1.88] p trend < 0.001 for ER+PR+ tumors; ≥35 vs. ≤19 years HR: 0.93 [95% CI 0.53-1.65] p trend = 0.96 for ER-PR- tumors; P het = 0.03). The risk associations of menarcheal age, and time period between menarche and first full-term childbirth with ER-PR-tumors were in the similar direction with risk of ER+PR+ tumors (p het = 0.50), although weaker in magnitude and statistically only borderline significant. Other parity related factors such as ever a full-term birth, number of births, age- and time since last birth were associated only with ER+PR+ malignancies, however no statistical heterogeneity between breast cancer subtypes was observed. Breastfeeding and OC use were generally not associated with breast cancer subtype risk. Our study provides possible evidence that age at menarche, and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although the associations with HR-negative breast cancer were only borderline significant
Energy Technology Data Exchange (ETDEWEB)
Lin, Frank I. [National Cancer Institute, NIH, Cancer Imaging Program, Bethesda, MD (United States); National Cancer Institute, Molecular Imaging Program, Bethesda, MD (United States); Gonzalez, E.M.; Kurdziel, K.A.; Ton, A.; Turkbey, B.; Choyke, P.L.; Lindenberg, M.L. [National Cancer Institute, Molecular Imaging Program, Bethesda, MD (United States); Kummar, S.; Do, K.; Collins, J.M.; Doroshow, J.H. [National Cancer Institute, Division of Cancer Treatment and Diagnosis and Center for Cancer Research, Bethesda, MD (United States); Shih, J. [National Cancer Institute, NIH, Biometric Research Program, Bethesda, MD (United States); Adler, S. [Leidos Biomedical Research, Inc., Clinical Research Directorate/Clinical Monitoring Research Program, Frederick, MD (United States); Jacobs, P.M. [National Cancer Institute, NIH, Cancer Imaging Program, Bethesda, MD (United States); Bhattacharyya, S. [Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD (United States); Chen, A.P. [National Cancer Institute, Early Clinical Trials Development Program, DCTD, Bethesda, MD (United States)
2017-03-15
Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. {sup 18}F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes {sup 18}F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with {sup 18}F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with {sup 18}F-FES 1-5 days post administration of Z-endoxifen. Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy. (orig.)
International Nuclear Information System (INIS)
Sarfstein, Rive; Belfiore, Antonino; Werner, Haim
2010-01-01
The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells
Energy Technology Data Exchange (ETDEWEB)
Sarfstein, Rive [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Belfiore, Antonino [Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, Catanzaro 88100 (Italy); Werner, Haim, E-mail: hwerner@post.tau.ac.il [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)
2010-03-25
The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells.
International Nuclear Information System (INIS)
Cizeron-Clairac, Geraldine; Lallemand, François; Vacher, Sophie; Lidereau, Rosette; Bieche, Ivan; Callens, Celine
2015-01-01
MicroRNAs (miRNAs) show differential expression across breast cancer subtypes and have both oncogenic and tumor-suppressive roles. Numerous microarray studies reported different expression patterns of miRNAs in breast cancers and found clinical interest for several miRNAs but often with contradictory results. Aim of this study is to identify miRNAs that are differentially expressed in estrogen receptor positive (ER + ) and negative (ER − ) breast primary tumors to better understand the molecular basis for the phenotypic differences between these two sub-types of carcinomas and to find potential clinically relevant miRNAs. We used the robust and reproductive tool of quantitative RT-PCR in a large cohort of well-annotated 153 breast cancers with long-term follow-up to identify miRNAs specifically differentially expressed between ER + and ER − breast cancers. Cytotoxicity tests and transfection experiments were then used to examine the role and the regulation mechanisms of selected miRNAs. We identified a robust collection of 20 miRNAs significantly deregulated in ER + compared to ER − breast cancers : 12 up-regulated and eight down-regulated miRNAs. MiR-190b retained our attention as it was the miRNA the most strongly over-expressed in ER + compared to ER − with a fold change upper to 23. It was also significantly up-regulated in ER + /Normal breast tissue and down-regulated in ER − /Normal breast tissue. Functional experiments showed that miR-190b expression is not directly regulated by estradiol and that miR-190b does not affect breast cancer cell lines proliferation. Expression level of miR-190b impacts metastasis-free and event-free survival independently of ER status. This study reveals miR-190b as the highest up-regulated miRNA in hormone-dependent breast cancers. Due to its specificity and high expression level, miR-190b could therefore represent a new biomarker in hormone-dependent breast cancers but its exact role carcinogenesis remains to
Mitigating Errors in External Respiratory Surrogate-Based Models of Tumor Position
International Nuclear Information System (INIS)
Malinowski, Kathleen T.; McAvoy, Thomas J.; George, Rohini; Dieterich, Sonja; D'Souza, Warren D.
2012-01-01
Purpose: To investigate the effect of tumor site, measurement precision, tumor–surrogate correlation, training data selection, model design, and interpatient and interfraction variations on the accuracy of external marker-based models of tumor position. Methods and Materials: Cyberknife Synchrony system log files comprising synchronously acquired positions of external markers and the tumor from 167 treatment fractions were analyzed. The accuracy of Synchrony, ordinary-least-squares regression, and partial-least-squares regression models for predicting the tumor position from the external markers was evaluated. The quantity and timing of the data used to build the predictive model were varied. The effects of tumor–surrogate correlation and the precision in both the tumor and the external surrogate position measurements were explored by adding noise to the data. Results: The tumor position prediction errors increased during the duration of a fraction. Increasing the training data quantities did not always lead to more accurate models. Adding uncorrelated noise to the external marker-based inputs degraded the tumor–surrogate correlation models by 16% for partial-least-squares and 57% for ordinary-least-squares. External marker and tumor position measurement errors led to tumor position prediction changes 0.3–3.6 times the magnitude of the measurement errors, varying widely with model algorithm. The tumor position prediction errors were significantly associated with the patient index but not with the fraction index or tumor site. Partial-least-squares was as accurate as Synchrony and more accurate than ordinary-least-squares. Conclusions: The accuracy of surrogate-based inferential models of tumor position was affected by all the investigated factors, except for the tumor site and fraction index.
Energy Technology Data Exchange (ETDEWEB)
Kim, Jin You; Lee, Suck Hong; Kim, Suk [Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Department of Radiology, Seo-gu, Busan (Korea, Republic of); Kang, Taewoo [Pusan National University Hospital, Busan Cancer Center, Busan (Korea, Republic of); Bae, Young Tae [Pusan National University Hospital, Department of Surgery, Busan (Korea, Republic of)
2015-04-01
To evaluate the association between tumour FDG uptake on preoperative PET/CT and axillary lymph node metastasis (ALNM) according to breast cancer subtype. The records of 671 patients with invasive breast cancer who underwent {sup 18} F-FDG PET/CT and surgery were reviewed. Using immunohistochemistry, tumours were divided into three subtypes: oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive, and triple-negative. Tumour FDG uptake, expressed as maximum standardized uptake value (SUV{sub max}), and clinicopathological variables were analysed. ALNM was present in 187 of 461 ER-positive/HER2-negative, 54 of 97 HER2-positive, and 38 of 113 triple-negative tumours. On multivariate analysis, high tumour SUV{sub max} (≥4.25) (P < 0.001), large tumour size (>2 cm) (P = 0.003) and presence of lymphovascular invasion (P < 0.001) were independent variables associated with ALNM. On subset analyses, tumour SUV{sub max} maintained independent significance for predicting ALNM in ER-positive/HER2-negative (adjusted odds ratio: 3.277, P < 0.001) and HER2-positive tumours (adjusted odds ratio: 14.637, P = 0.004). No association was found for triple-negative tumours (P = 0.161). Tumour SUV{sub max} may be an independent prognostic factor for ALNM in patients with invasive breast cancer, especially in ER-positive/HER2-negative and HER2-positive subtypes, but not in those with triple-negative subtype. (orig.)
DEFF Research Database (Denmark)
Larsen, Mathilde S; Bjerre, Karsten; Giobbie-Hurder, Anita
2012-01-01
Estrogen receptor (ER) status is not an optimal marker for response to adjuvant endocrine therapy since approximately 30% of patients with ER-positive tumors eventually relapse. Bcl-2 is regulated by ER and may thus be considered as an indicator of ER activity and a candidate supplementary marker...
National Research Council Canada - National Science Library
Pentecost, Brian
2002-01-01
Positive Estrogen Receptor alpha (ER) status correlates with a reduced incidence of breast cancer recurrence in the first years after resection of tumors, and predicts a favorable response to adjuvant anti-estrogens...
BP1 Homeoprotein Enhances Metastatic Potential in Er-Negative Breast Cancer
Directory of Open Access Journals (Sweden)
Yebo Fu, Yi Lian, Kyung Soon Kim, Lei Zhang, A. Katharine Hindle, Fred Brody, Robert S. Siegel, Timothy A. McCaffrey, Sidney W. Fu
2010-01-01
Full Text Available Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. It was reported that BP1, a homeobox isoform of DLX4, is overexpressed in 80% of breast cancer patients and in 100% of estrogen receptor negative (ER- tumors. The prevalence of BP1 positive cells and the intensity of BP1 immunoreactivity increased with the extent of ductal proliferation and tumorigenesis. These findings imply that BP1 may play an important role in ER- breast cancer. I sought to determine the effects and mechanisms of BP1 on cell proliferation and metastasis using ER- Hs578T cells as a model. Cells were transfected with either pcDNA3.2 plasmid containing BP1 gene, or pcDNA3.2 vector, then selected and cloned. Overexpression of BP1 increased cell proliferation rate by 2-5 fold (p<0.005, and enhanced the in vitro invasive activity by 25-65 fold (p<0.001. Microarray experiments were performed to identify differentially expressed genes when BP1 is overexpressed. The gene expression profile of the transfected cell lines were compared, resulting in 71 differentially expressed genes with a fold-change of >=2.0. Of those genes, 49 were up-regulated and 22 were down-regulated. Significant pathways were identified involving cell proliferation and metastasis. These data demonstrated that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in ER- Hs578T cells. Further analysis with more ER- cell lines and patient samples is warranted to establish BP1 as a therapeutic target.
Peevey, Joseph F; Seagle, Brandon-Luke L; Maniar, Kruti P; Kim, J Julie
2017-06-27
Obesity is a prominent risk factor for endometrial cancer (EC) and can impede on surgical and hormonal treatments. Markers of EC, estrogen receptor (ER), progesterone receptor (PR), phospho(Ser473)-AKT (pAKT) and 14-3-3 sigma (14-3-3σ) were measured in EC tissues in both the tumor and stroma and grouped by body mass index (BMI). Immunohistochemical scoring of 82 cases of Type 1 and Type II EC tissues revealed a significantly increased tumor expression of ER, PR and 14-3-3σ in women with Type I (BMI PR and 14-3-3σ in the tumor epithelium was significantly higher in Type I than Type II. In particular, Type I EC exhibited significantly increased levels of only PR from patients with BMI > 40 compared to BMI PR, PIK3CA, PTEN and SFN (gene for 14-3-3σ) confirmed increased PR expression in EC of obese women. In conclusion, ER, PR and 14-3-3σ are differentially regulated in Type I compared to Type II EC while PR is dysregulated in obese women with Type I EC. These findings have potential implications for efficacy of progestin treatment in obese women.
Acid-induced autophagy protects human lung cancer cells from apoptosis by activating ER stress.
Xie, Wen-Yue; Zhou, Xiang-Dong; Li, Qi; Chen, Ling-Xiu; Ran, Dan-Hua
2015-12-10
An acidic tumor microenvironment exists widely in solid tumors. However, the detailed mechanism of cell survival under acidic stress remains unclear. The aim of this study is to clarify whether acid-induced autophagy exists and to determine the function and mechanism of autophagy in lung cancer cells. We have found that acute low pH stimulated autophagy by increasing LC3-positive punctate vesicles, increasing LC3 II expression levels and reducing p62 protein levels. Additionally, autophagy was inhibited by the addition of Baf or knockdown of Beclin 1, and cell apoptosis was increased markedly. In mouse tumors, the expression of cleaved caspase3 and p62 was enhanced by oral treatment with sodium bicarbonate, which can raise the intratumoral pH. Furthermore, the protein levels of ER stress markers, including p-PERK, p-eIF2α, CHOP, XBP-1s and GRP78, were also increased in response to acidic pH. The antioxidant NAC, which reduces ROS accumulation, alleviated acid-mediated ER stress and autophagy, and knocking down GRP78 reduced autophagy activation under acidic conditions, which suggests that autophagy was induced by acidic pH through ER stress. Taken together, these results indicate that the acidic microenvironment in non-small cell lung cancer cells promotes autophagy by increasing ROS-ER stress, which serves as a survival adaption in this setting. Copyright © 2015 Elsevier Inc. All rights reserved.
DEFF Research Database (Denmark)
Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel
2011-01-01
BRCA1 carriers, SNP rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele HR for ER-positive=1.35, 95%CI:1.17-1.56 vs HR=0.91, 95%CI:0.85-0.98 for ER-negative, P-heterogeneity=6.5e-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER...... in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumor. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumor......, to assess the associations of twelve loci with breast cancer tumor characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for eleven loci in both BRCA1 and BRCA2 carriers. Among...
Raphael, Jacques; Gandhi, Sonal; Li, Nim; Lu, Fang-I; Trudeau, Maureen
2017-07-01
Estrogen receptor (ER) negative (-) breast cancer (BC) patients have better tumor response rates than ER-positive (+) patients after neoadjuvant chemotherapy (NCT). We conducted a retrospective review using the institutional database "Biomatrix" to assess the value of quantitative ER status in predicting tumor response at surgery and to identify potential predictors of survival outcomes. Univariate followed by multivariable regression analyses were conducted to assess the association between quantitative ER and tumor response assessed as tumor size reduction and pathologic complete response (pCR). Predictors of recurrence-free survival (RFS) were identified using a cox proportional hazards model (CPH). A log-rank test was used to compare RFS between groups if a significant predictor was identified. 304 patients were included with a median follow-up of 43.3 months (Q1-Q3 28.7-61.1) and a mean age of 49.7 years (SD 10.9). Quantitative ER was inversely associated with tumor size reduction and pCR (OR 0.99, 95% CI 0.99-1.00, p = 0.027 and 0.98 95% CI 0.97-0.99, p Quantitative ER status is inversely associated with tumor response in BC patients treated with NCT. A cut-off of 60 and 80% predicts best the association with tumor size reduction and pCR, respectively. Therefore, patients with an ER status higher than the cut-off might benefit from a neoadjuvant endocrine therapy approach. Patients with pCR had better survival outcomes independently of their tumor phenotype. Further prospective studies are needed to validate the clinical utility of quantitative ER as a predictive marker of tumor response.
Biodistribution and breast tumor uptake of 16α-[18F]-fluoro-17β-estradiol in rat
International Nuclear Information System (INIS)
Sasaki, Masayuki; Fukumura, Toshimitsu; Kuwabara, Yasuo; Yoshida, Tsuyoshi; Nakagawa, Makoto; Ichiya, Yuichi; Masuda, Kouji
2000-01-01
To evaluate the usefulness of 16α-[ 18 F]-fluoro-17β-estradiol (FES) for the assessment of estrogen receptor (ER), we examined the tissue distribution and kinetics of FES in immature female Sprague-Dawley rats and then examined FES uptake in rat breast tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA). The FES uptake by the uterus, an ER-rich tissue, was highly selective and it was 3.34±0.79%ID/g at 60 minutes and 1.57±0.57%ID/g at 120 minutes after injection. The FES uptakes in ER-negative tissues were 0.12±0.05%ID/g or less and 0.05±0.03%ID/g or less, respectively. Coadministration of unlabeled β-estradiol showed marked depression of uterine FES uptake. The FES uptake by rat breast tumors was 0.14±0.06%ID/g at 60 min and 0.12±0.09%ID/g at 120 min. The FES uptake by rat breast tumors correlated with the ER concentration (r=0.45, p<0.05). In conclusion, these results suggest that the FES uptake by tissue is mainly ER mediated and FES is thus useful for detecting ER positive breast tumors. (author)
International Nuclear Information System (INIS)
Hunjan, Sandeep; Starkschall, George; Prado, Karl; Dong Lei; Balter, Peter
2010-01-01
Purpose: For thoracic tumors, if four-dimensional computed tomography (4DCT) is unavailable, the internal margin can be estimated by use of breath-hold (BH) CT scans acquired at end inspiration (EI) and end expiration (EE). By use of external surrogates for tumor position, BH accuracy is estimated by minimizing the difference between respiratory extrema BH and mean equivalent-phase free breathing (FB) positions. We tested the assumption that an external surrogate for BH accuracy correlates with internal tumor positional accuracy during BH CT. Methods and Materials: In 16 lung cancer patients, 4DCT images, as well as BH CT images at EI and EE, were acquired. Absolute differences between BH and mean equivalent-phase (FB) positions were calculated for both external fiducials and gross tumor volume (GTV) centroids as metrics of external and internal BH accuracy, respectively, and the results were correlated. Results: At EI, the absolute difference between mean FB and BH fiducial displacement correlated poorly with the absolute difference between FB and BH GTV centroid positions on CT images (R 2 = 0.11). Similarly, at EE, the absolute difference between mean FB and BH fiducial displacements correlated poorly with the absolute difference between FB and BH GTV centroid positions on CT images (R 2 = 0.18). Conclusions: External surrogates for tumor position are not an accurate metric of BH accuracy for lung cancer patients. This implies that care should be taken when using such an approach because an incorrect internal margin could be generated.
Sarink, Danja; Schock, Helena; Johnson, Theron; Overvad, Kim; Holm, Marianne; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; His, Mathilde; Kvaskoff, Marina; Boeing, Heiner; Lagiou, Pagona; Papatesta, Eleni-Maria; Trichopoulou, Antonia; Palli, Domenico; Pala, Valeria; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Bueno-de-Mesquita, H B As; van Gils, Carla H; Peeters, Petra H; Weiderpass, Elisabete; Agudo, Antonio; Sánchez, Maria-José; Chirlaque, Maria-Dolores; Ardanaz, Eva; Amiano, Pilar; Khaw, Kay Tee; Travis, Ruth; Dossus, Laure; Gunter, Mark; Rinaldi, Sabina; Merritt, Melissa; Riboli, Elio; Kaaks, Rudolf; Fortner, Renée T
2017-09-01
Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n = 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status ( P het = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01-1.63); P trend = 0.20], but not ER- disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER-PR- disease [5th vs. 1st quintile RR = 0.60 (0.31-1.14); P trend = 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk. Cancer Prev Res; 10(9); 525-34. ©2017 AACR . ©2017 American Association for Cancer Research.
Immunohistochemical detection of estrogen receptors in canine mammary tumors
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Elena Atanaskova Petrov
2016-03-01
Full Text Available Mammary tumors are among the most common neoplasms in intact female dogs.They have a complex morphology, usually affecting middle age and older bitches. Almost 50% of the mammary tumors in dogs are malignant neoplasms. Prognosis is based on several factors: stage, age, tumor size, metastasis, histopathology, ovariectomy status and hormone-receptor activity. Immunohistochemical (IHC measurement has become increasingly an important diagnostic and prognostic parameter, with the development of monoclonal antibodies against nuclear estrogen and progestin receptors. The aim of this study was to detect the presence of ER receptors in malignant canine mammary tumors and to identify their association with the clinical course of the tumor. Mammary tumor samples have been obtained by mastectomy from dogs presented at our clinic. Detailed clinical examination, CBC and basic serum biochemical profile were performed in all patients. Surgery was the only treatment. Histopathological examination and immunohistochemical detection of estrogen α receptors (ERα was performed on 8 formalin-fixed, paraffin-embedded tissue samples, using the PT LINK immunoperoxidase technique. Histopathological examination of the mammary tumor samples (n=11 revealed tubular adenocarcinoma (n=6,54.5% and ductal adenocarcinoma (n=3, 27.3%, one patient with benign adenoma and one with mastitis. Patients with positive ER tumors are alive, without remission, while 3 of the patients that were ER negative died due to lung metastases. According to our results, it can be concluded that the appearance and development of canine mammary tumors is highly connected with ovarian steroid hormones and that immunostaining of the tumors may be used as a good prognostic parameter in these patients.
International Nuclear Information System (INIS)
Feng, Mary; Balter, James M.; Normolle, Daniel; Adusumilli, Saroja; Cao Yue; Chenevert, Thomas L.; Ben-Josef, Edgar
2009-01-01
Purpose: Our current understanding of intrafraction pancreatic tumor motion due to respiration is limited. In this study, we characterized pancreatic tumor motion and evaluated the application of several radiotherapy motion management strategies. Methods and Materials: Seventeen patients with unresectable pancreatic cancer were enrolled in a prospective internal review board-approved study and imaged during shallow free-breathing using cine MRI on a 3T scanner. Tumor borders were agreed on by a radiation oncologist and an abdominal MRI radiologist. Tumor motion and correlation with the potential surrogates of the diaphragm and abdominal wall were assessed. These data were also used to evaluate planning target volume margin construction, respiratory gating, and four-dimensional treatment planning for pancreatic tumors. Results: Tumor borders moved much more than expected. To provide 99% geometric coverage, margins of 20 mm inferiorly, 10 mm anteriorly, 7 mm superiorly, and 4 mm posteriorly are required. Tumor position correlated poorly with diaphragm and abdominal wall position, with patient-level Pearson correlation coefficients of -0.18-0.43. Sensitivity and specificity of gating with these surrogates was also poor, at 53%-68%, with overall error of 35%-38%, suggesting that the tumor may be underdosed and normal tissues overdosed. Conclusions: Motion of pancreatic tumor borders is highly variable between patients and larger than expected. There is substantial deformation with breathing, and tumor border position does not correlate well with abdominal wall or diaphragmatic position. Current motion management strategies may not account fully for tumor motion and should be used with caution.
Gulbahce, H Evin; Blair, Cindy K; Sweeney, Carol; Salama, Mohamed E
2017-09-01
Estrogen exposure is important in the pathogenesis of breast cancer and is a contributing risk factor. In this study we quantified estrogen receptor (ER) alpha expression in normal breast epithelium (NBR) in women with breast cancer and correlated it with breast cancer subtypes. Tissue microarrays were constructed from 204 breast cancer patients for whom normal breast tissue away from tumor was available. Slides stained with ER were scanned and expression in normal terminal duct lobular epithelium was quantitated using computer-assisted image analysis. ER expression in normal terminal duct lobular epithelium of postmenopausal women with breast cancer was significantly associated with estrogen and triple (estrogen, progesterone receptors, and HER2) negative phenotypes. Also increased age at diagnosis was significantly associated with ER expression in NBR. ER positivity in normal epithelium did not vary by tumor size, lymph node status, tumor grade, or stage. On the basis of quantitative image analysis, we confirm that ER expression in NBR increases with age in women with breast cancer, and report for the first time, a significant association between ER expression in NBR with ER-negative and triple-negative cancers in postmenopausal women.
Energy Technology Data Exchange (ETDEWEB)
Ulaner, Gary A.; Castillo, Raychel [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Wills, Jonathan [Memorial Sloan Kettering Cancer Center, Department of Information Systems, New York, NY (United States); Goenen, Mithat; Goldman, Debra A. [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States)
2017-08-15
This study assesses {sup 18}F-FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer. In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent {sup 18}F-FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.{sup 18}F-FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI). A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9-20%). {sup 18}F-FDG-PET/CT revealed distant metastases in 14% (95% CI: 9-20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9-24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with {sup 18}F-FDG-PET/CT at the time of initial diagnosis. (orig.)
Cheung, Victoria; Segal, Devorah; Gardner, Sharon L; Zagzag, David; Wisoff, Jeffrey H; Allen, Jeffrey C; Karajannis, Matthias A
2016-09-01
Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6 months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.
Wu, Huizhe; Wang, Hui; Guan, Shu; Zhang, Jing; Chen, Qiuchen; Wang, Xiaodong; Ma, Ke; Zhao, Pengfei; Zhao, Haishan; Yao, Weifan; Jin, Feng; Xiao, Qinghuan; Wei, Minjie
2017-10-17
The calcium-activated chloride channel Ano1 (TMEM16A) is overexpressed in many tumors. However, conflicting data exist regarding the role of Ano1 in cell proliferation. Here, we performed immunohistochemistry to investigate the expression of Ano1 and Ki67 in 403 patients with breast cancer, and analyzed the association between the expression of Ano1 and Ki67 in breast cancer subtypes categorized according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Ano1 expression was negatively correlated with Ki67 expression. Ano1 overexpression more frequently occurred in ER-positive or HER2-negative patients with the low expression of Ki67. Ano1 overexpression was associated with longer overall survival (OS) in breast cancer with the low expression of Ki67, especially in ER-positive, PR-positive, and HER2-negative breast cancer. Multivariate Cox regression analysis showed that Ano1 overexpression was a prognostic factor for longer overall survival in ER-positive, PR-positive, or HER2-negative patients with the low expression of Ki67. Furthermore, Ano1 promoted cell proliferation in ER-positive, PR-positive, and HER2-negative MCF7 cells, but inhibited cell proliferation in ER-negative, PR-negative, and HER2-negative MDA-MB-435S cells. Our findings suggest that Ano1 may differentially regulate cell proliferation in a subtype of breast cancer defined by ER, PR, and HER2. Combined expression of Ano1 and Ki67 may be used for predicting clinical outcomes of breast cancer patients with different subtypes of ER, PR, and HER2.
Ritte, Rebecca; Lukanova, Annekatrin; Tjønneland, Anne; Olsen, Anja; Overvad, Kim; Mesrine, Sylvie; Fagherazzi, Guy; Dossus, Laure; Teucher, Birgit; Steindorf, Karen; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Grioni, Sara; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Quirós, José Ramón; Buckland, Genevieve; Molina-Montes, Esther; Chirlaque, María-Dolores; Ardanaz, Eva; Amiano, Pilar; Bueno-de-Mesquita, Bas; van Duijnhoven, Franzel; van Gils, Carla H; Peeters, Petra Hm; Wareham, Nick; Khaw, Kay-Tee; Key, Timothy J; Travis, Ruth C; Krum-Hansen, Sanda; Gram, Inger Torhild; Lund, Eiliv; Sund, Malin; Andersson, Anne; Romieu, Isabelle; Rinaldi, Sabina; McCormack, Valerie; Riboli, Elio; Kaaks, Rudolf
2013-06-01
Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.08-1.20]) had a stronger risk association than leg length (1.05[1.00-1.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (≤13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and -negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women. Copyright © 2012 UICC.
Evaluating the potential bioactivity of a novel compound ER1626.
Wang, Lijun; Zeng, Yanyan; Wang, Tianling; Liu, Hongyi; Xiao, Hong; Xiang, Hua
2014-01-01
ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626. MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and chicken embryos. The expression of estrogen receptor protein was investigated with western-blot analysis. ER1626 down-regulated the expression of estrogen receptor α protein and up-regulated β protein in MCF-7 and Ishikawa cells. The value of IC50 of ER1626 on MCF-7 and Ishikawa cells were respectively 8.52 and 3.08 µmol/L. Meanwhile, ER1626 decreased VEGF secretion of MCF-7 and Ishikawa cells, disturbed the formation of VEGF-stimulated tubular structure in HUVEC cells, and inhibited the angiogenesis on the chicken chorioallantoic membrane. Scratch assay revealed that ER1626 suppressed the migration of MCF-7, Ishikawa and HUVEC cells. In addition to induction tumor cell apoptosis, ER1626 arrested cell cycle in G1/G0 phase in MCF-7 cells and G2/M phase in Ishikawa cells. In conclusion, our results demonstrated that ER1626 has favorable bioactivities to be a potential candidate against breast cancer and angiogenesis.
Evaluating the potential bioactivity of a novel compound ER1626.
Directory of Open Access Journals (Sweden)
Lijun Wang
Full Text Available ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626.MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and chicken embryos. The expression of estrogen receptor protein was investigated with western-blot analysis.ER1626 down-regulated the expression of estrogen receptor α protein and up-regulated β protein in MCF-7 and Ishikawa cells. The value of IC50 of ER1626 on MCF-7 and Ishikawa cells were respectively 8.52 and 3.08 µmol/L. Meanwhile, ER1626 decreased VEGF secretion of MCF-7 and Ishikawa cells, disturbed the formation of VEGF-stimulated tubular structure in HUVEC cells, and inhibited the angiogenesis on the chicken chorioallantoic membrane. Scratch assay revealed that ER1626 suppressed the migration of MCF-7, Ishikawa and HUVEC cells. In addition to induction tumor cell apoptosis, ER1626 arrested cell cycle in G1/G0 phase in MCF-7 cells and G2/M phase in Ishikawa cells.In conclusion, our results demonstrated that ER1626 has favorable bioactivities to be a potential candidate against breast cancer and angiogenesis.
Tumor scintigraphy using 123I-labelled estradiol in breast cancer - receptor scintigraphy
International Nuclear Information System (INIS)
Scheidhauer, K.; Mueller, S.; Smolarz, K.; Braeutigam, P.; Briele, B.
1991-01-01
16-α- 123 I-Iodestradiol-17β ( 123 I-E 2 ) as a receptor-specific radiopharmacon was used for scintigraphic tumor detection in 62 patients suspected of breast cancer. The studies were performed as a multicenter trial to validate the method and to overcome methodical problems. A fast tracer elimination from the blood pool into the liver was seen, followed by biliary excretion allowing early imaging of the thorax due to low background activity but resulting in difficult imaging conditions of the abdomen. In 42 patients (30 carcinomas, 12 benign lesions) are overall sensitivity was 66%. Some patients with breast cancer showed focal or diffuse uptake in the area of primary lymph drainage without any clinical correlation. There was only one false-positive result in a receptor-negative primary carcinoma. The sensitivity of 123 I-E 2 in the detection of primary breast cancer or metastases and recurrences is low compared to mammography and other methods. Differentiation of malignant and benign tissue is difficult as both may have a positive ER status, in. Nevertheless, 123 I-E 2 scintigraphy is an in vivo imaging technique for the detection of breast cancer depending on the ER status and provides information about tumor localisation. It may become a specific method for the non-invasive diagnosis of the ER status and may be helpful in follow-up studies. As a receptor-specific agent 123 I-E 2 may give answers to questions of tumor heterogeneity and changes of the ER status during therapy. (orig./MG) [de
Zhang, Xuehong; Eliassen, A Heather; Tamimi, Rulla M; Hazra, Aditi; Beck, Andrew H; Brown, Myles; Collins, Laura C; Rosner, Bernard; Hankinson, Susan E
2015-06-01
Obesity and physical activity have been hypothesized to affect breast cancer risk partly via the androgen signaling pathway. We conducted the first study to evaluate these associations by tumor androgen receptor (AR) status. Height, weight, and physical activity were assessed using questionnaires in the Nurses' Health Study. AR, estrogen receptor (ER), and progesterone receptor (PR) status were determined using immunohistochemistry on tumor tissue and medical/pathology reports. A total of 1,701 AR(+) and 497 AR(-) cases were documented during 26 years of follow-up of 103,577 women. After adjusting for ER/PR status and other risk factors, the relative risks (RR) and 95% confidence intervals (95% CI) for every 5 kg/m(2) increase in body mass index (BMI) were 1.07 (1.01-1.13) for AR(+) and 1.16 (1.05-1.29) for AR(-) tumors (P-heterogeneity = 0.17). The RRs (95% CIs) per 5 hours of brisk walking/week were 0.87 (0.73-1.04) for AR(+) and 0.67 (0.45-0.99) for AR(-) tumors (P-heterogeneity = 0.22). Further, BMI, but not physical activity, associations differed significantly across ER/PR/AR subtypes (P-heterogeneity = 0.04 and 0.63, respectively). The RRs (95% CIs) for 5 kg/m(2) increase in BMI were 1.23 (1.04-1.45) for ER(+)PR(+)AR(-), 1.19 (1.01-1.39) for ER(-)PR(-)AR(-), 1.15 (1.08-1.23) for ER(+)PR(+)AR(+), and 0.88 (0.75-1.03) for ER(+)PR(-)AR(+) tumors. Higher BMI was associated with an increased risk of both AR(+) and AR(-) breast tumors in postmenopausal women, whereas physical activity, including brisk walking, was associated with a reduced risk of both subtypes. In addition, a significant positive association was observed between higher BMI and ER(-)PR(-)AR(-) tumors. The similar associations observed by AR status suggest that mechanisms other than androgen signaling underlie these two breast cancer risk factors. ©2015 American Association for Cancer Research.
Directory of Open Access Journals (Sweden)
Tashima Rumiko
2011-10-01
Full Text Available Abstract Background In breast cancer, ER/PgR, HER2, and Ki-67 are important biological markers for predicting prognosis and making effective treatment decisions. In addition, changes in markers due to relapse are also clinically experienced; however, the frequency and clinical significance are still not fully understood. Thus, changes in markers and their correlations with prognosis were investigated. Patients and Methods Out of the patients with relapse from 1997 to March 2011, there were 97 consecutive patients from whom the lesion was resected and evaluated by immunostaining. The biopsy sites were chest wall, lymph node, ipsilateral breast tumor recurrence, lungs, bones, ovaries and brain. The markers sought were ER, PgR, HER2, p53 and Ki-67. Results The hormone receptor positive rate from the primary tumor to recurrence decreased from 63.9% to 57.7% and from 56.7% to 43.3% for ER and PgR, respectively. Changes in the positive/negative evaluation were seen at the rate of 10.3% and 25.8% for ER and PgR, respectively. The Ki-67 index increased significantly from a mean of 29.1% at primary tumor to 36.3% at relapse. When divided into 2 groups ( Conclusion Estrogen receptor and PgR decreased while Ki-67 increased due to relapse; however, the rate of change was high for PgR and Ki-67. Change in the subtypes was seen in 25%. In addition, PgR at relapse and Ki-67 at primary tumor were significant factors for post-relapse prognosis while PgR becoming negative was a poor prognostic factor. These findings are important for making effective treatment decisions.
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Man, Yan-gao; Vinh, Tuyethoa N; Strauss, Brian L; Tai, Lisa; Barner, Ross; Vang, Russell; Saenger, Jeffrey S; Shekitka, Kris M; Bratthauer, Gary L; Wheeler, Darren T; Liang, Chang Y
2003-01-01
Our previous studies detected focal disruptions in myoepithelial cell layers of several ducts with carcinoma in situ. The cell cluster overlying each of the myoepithelial disruptions showed a marked reduction in or a total loss of immunoreactivity for the estrogen receptor (ER). This is in contrast to the adjacent cells within the same duct, which were strongly immunoreactive for the ER. The current study attempts to confirm and expand previous observations on a larger scale. Paraffin sections from 220 patients with ER-positive intraductal breast tumors were double immunostained with the same protocol previously used. Cross-sections of ducts lined by ≥ 40 epithelial cells were examined for myoepithelial cell layer disruptions and for ER expression. In five selected cases, ER-negative cells overlying the disrupted myoepithelial cell layer and adjacent ER-positive cells within the same duct were separately microdissected and assessed for loss of heterozygosity and microsatellite instability. Of the 220 cases with 5698 duct cross-sections examined, 94 showed disrupted myoepithelial cell layers with 405 focal disruptions. Of the 94 cases, 79 (84%) contained only ER-negative cell clusters, nine (9.6%) contained both ER-negative and ER-positive cell clusters, and six (6.4%) contained only ER-positive cell clusters overlying disrupted myoepithelial cell layers. Of the 405 disruptions, 350 (86.4%) were overlain by ER-negative cell clusters and 55 (13.6%) were overlain by ER-positive cell clusters (P < 0.01). Microdissected ER-negative and ER-positive cells within the same duct from all five selected cases displayed a different frequency or pattern of loss of heterozygosity and/or microsatellite instability at 10 of the 15 DNA markers. Cells overlying focally disrupted myoepithelial layers and their adjacent counterparts within the same duct displayed different immunohistochemical and molecular features. These features potentially represent an early sign of the formation
Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.
Tse, Lap Ah; Li, Mengjie; Chan, Wing-cheong; Kwok, Chi-hei; Leung, Siu-lan; Wu, Cherry; Yu, Ignatius Tak-sun; Yu, Wai-cho; Lao, Xiangqian; Wang, Xiaorong; Wong, Carmen Ka-man; Lee, Priscilla Ming-yi; Wang, Feng; Yang, Xiaohong Rose
2015-01-01
The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+) type. Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings) were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age) and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated. Altogether 52 (6.96%) breast cancer cases and 23 (2.95%) controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR) of 2.41 (95%CI: 1.45-4.02). An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28), with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79) than an affected sister (OR = 2.06, 95%CI: 1.07-3.97), while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives. This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.
Regan, Meredith M; Pagani, Olivia; Francis, Prudence A; Fleming, Gini F; Walley, Barbara A; Kammler, Roswitha; Dell'Orto, Patrizia; Russo, Leila; Szőke, János; Doimi, Franco; Villani, Laura; Pizzolitto, Stefano; Öhlschlegel, Christian; Sessa, Fausto; Peg Cámara, Vicente; Rodríguez Peralto, José Luis; MacGrogan, Gaëtan; Colleoni, Marco; Goldhirsch, Aron; Price, Karen N; Coates, Alan S; Gelber, Richard D; Viale, Giuseppe
2015-11-01
The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.
Li, Min Hua; Hou, Chuan Ling; Wang, Cheng; Sun, Ai Jing
2016-04-01
To compare the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) in the primary site and the metastatic lesion of lymph nodes in invasive breast cancer for investigating whether the expression of these biomarkers in the primary site could act as a surrogate to the lymphatic metastatic lesion in the same patient. In lymphatic metastatic lesion and corresponding primary lesion of 107 cases of invasive breast cancer, ER and PR statuses were assessed by immunohistochemistry (IHC). HER-2 expression level was evaluated by IHC and/or fluorescence in situ hybridization (FISH). In the primary lesions, 43.9% were ER positive; 46.7% were PR positive; 34.6% were HER-2 positive. In corresponding lymphatic metastatic lesions, the HER-2 status was concordant in 90 patients; 9 patients were diagnosed positive in metastatic lesion while negative in primary lesion; 8 patients were negative in metastatic lesion while positive in primary site (agreement, 84.1%; κ=0.647). A change in ER status was observed in 24 cases: 17 cases positive in metastatic site while negative in primary site; 7 cases negative in metastatic site while positive in primary site (agreement, 77.6%; κ=0.534). PR status discordance between the primary lesion and the metastatic regional lymph nodes was reported in 19 cases (agreement, 82.2%; κ=0.640). This study revealed that there was only a moderate concordance of ER, PR and HER-2 status between primary tumors and metastatic lymph nodes. These results indicate that it was inappropriate to predict the status of ER, PR and HER-2 in metastatic lymph nodes based on the results of evaluation of that in primary lesions. Copyright © 2015 Elsevier GmbH. All rights reserved.
Akiyama, Y.; Heyde, K.; Arima, A.; Yoshinaga, N.
1986-05-01
Extending the interacting boson model by incorporating besides s and d, also the g-boson, we can describe the population of positive parity states of 168Er in the 166Er(t,P) 168Er reaction rather well. In particular, the excitation of I,Kπi = 4,3 +1; 2,2 +2; 0,0 +3 and 0,0 +4 states is much improved over the sd-IBM approach.
Luo, Lan; Xu, Lina; Tang, Liang
2017-12-12
Endometrial carcinoma (EC) is a common malignant tumor in gynecology. Its incidence and development are closely associated with the levels of estrogenic and progesterone hormone. Extracellular signal-regulated kinase (ERK) signaling pathway abnormity is associated with a variety of tumors. This study detected estrogen receptor (ER), progesterone receptor (PR), ERK1, and ERK2 expression in EC and analyzed their correlations. A total of 40 EC patients in our hospital were selected as test group, while another 40 healthy volunteers were enrolled as control group. ER, PR, ERK1, and ERK2 expression in EC tissue, para-carcinoma tissue, and normal endometrial tissue were detected by immunohistochemistry and Western blot. The positive rate of ER, PR, ERK1, and ERK2 in the test group was 50%, 40%, 60%, and 65%, respectively, which were significantly higher than those in the control (PPR, ERK1, and ERK2 protein expressions in EC cell were significantly higher than those in the control (PPR (PPR, which were correlated with higher levels of ERK1 and ERK2, suggesting they might be involved in the pathogenesis of EC.
Calcium Homeostasis and ER Stress in Control of Autophagy in Cancer Cells
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Elżbieta Kania
2015-01-01
Full Text Available Autophagy is a basic catabolic process, serving as an internal engine during responses to various cellular stresses. As regards cancer, autophagy may play a tumor suppressive role by preserving cellular integrity during tumor development and by possible contribution to cell death. However, autophagy may also exert oncogenic effects by promoting tumor cell survival and preventing cell death, for example, upon anticancer treatment. The major factors influencing autophagy are Ca2+ homeostasis perturbation and starvation. Several Ca2+ channels like voltage-gated T- and L-type channels, IP3 receptors, or CRAC are involved in autophagy regulation. Glucose transporters, mainly from GLUT family, which are often upregulated in cancer, are also prominent targets for autophagy induction. Signals from both Ca2+ perturbations and glucose transport blockage might be integrated at UPR and ER stress activation. Molecular pathways such as IRE 1-JNK-Bcl-2, PERK-eIF2α-ATF4, or ATF6-XBP 1-ATG are related to autophagy induced through ER stress. Moreover ER molecular chaperones such as GRP78/BiP and transcription factors like CHOP participate in regulation of ER stress-mediated autophagy. Autophagy modulation might be promising in anticancer therapies; however, it is a context-dependent matter whether inhibition or activation of autophagy leads to tumor cell death.
Evaluating the Potential Bioactivity of a Novel Compound ER1626
Wang, Lijun; Zeng, Yanyan; Wang, Tianling; Liu, Hongyi; Xiao, Hong; Xiang, Hua
2014-01-01
Background ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626. Method MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and ...
Prognostic and functional role of subtype-specific tumor-stroma interaction in breast cancer.
Merlino, Giuseppe; Miodini, Patrizia; Callari, Maurizio; D'Aiuto, Francesca; Cappelletti, Vera; Daidone, Maria Grazia
2017-10-01
None of the clinically relevant gene expression signatures available for breast cancer were specifically developed to capture the influence of the microenvironment on tumor cells. Here, we attempted to build subtype-specific signatures derived from an in vitro model reproducing tumor cell modifications after interaction with activated or normal stromal cells. Gene expression signatures derived from HER2+, luminal, and basal breast cancer cell lines (treated by normal fibroblasts or cancer-associated fibroblasts conditioned media) were evaluated in clinical tumors by in silico analysis on published gene expression profiles (GEPs). Patients were classified as microenvironment-positive (μENV+ve), that is, with tumors showing molecular profiles suggesting activation by the stroma, or microenvironment-negative (μENV-ve) based on correlation of their tumors' GEP with the respective subtype-specific signature. Patients with estrogen receptor alpha (ER)+/HER2-/μENV+ve tumors were characterized by 2.5-fold higher risk of developing distant metastases (HR = 2.546; 95% CI: 1.751-3.701, P = 9.84E-07), while μENV status did not affect, or only suggested the risk of distant metastases, in women with HER2+ (HR = 1.541; 95% CI: 0.788-3.012, P = 0.206) or ER-/HER2- tumors (HR = 1.894; 95% CI: 0.938-3.824; P = 0.0747), respectively. In ER+/HER2- tumors, the μENV status remained significantly associated with metastatic progression (HR = 2.098; CI: 1.214-3.624; P = 0.00791) in multivariable analysis including size, age, and Genomic Grade Index. Validity of our in vitro model was also supported by in vitro biological endpoints such as cell growth (MTT assay) and migration/invasion (Transwell assay). In vitro-derived gene signatures tracing the bidirectional interaction with cancer activated fibroblasts are subtype-specific and add independent prognostic information to classical prognostic variables in women with ER+/HER2- tumors. © 2017 The Authors. Published
Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.
Directory of Open Access Journals (Sweden)
Lap Ah Tse
Full Text Available The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+ type.Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated.Altogether 52 (6.96% breast cancer cases and 23 (2.95% controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR of 2.41 (95%CI: 1.45-4.02. An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28, with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79 than an affected sister (OR = 2.06, 95%CI: 1.07-3.97, while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives.This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.
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Sperduto, Paul W., E-mail: psperduto@mropa.com [University of Minnesota Gamma Knife, Minneapolis Radiation Oncology, Minneapolis, MN (United States); Kased, Norbert [Department of Radiation Oncology, University of California-San Francisco, San Francisco, CA (United States); Roberge, David [Radiation Oncology, McGill University Health Center, Montreal, QC (Canada); Xu Zhiyuan [Department of Neurosurgery, Cleveland Clinic, Cleveland, OH (United States); Shanley, Ryan [Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); Luo, Xianghua [Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN (United States); Sneed, Penny K. [Department of Radiation Oncology, University of California-San Francisco, San Francisco, CA (United States); Chao, Samuel T. [Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH (United States); Weil, Robert J. [Department of Neurosurgery, Cleveland Clinic, Cleveland, OH (United States); Suh, John [Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH (United States); Bhatt, Amit [Department of Human Oncology, University of Wisconsin, Madison, WI (United States); Jensen, Ashley W.; Brown, Paul D. [Department of Radiation Oncology, Mayo Clinic, Rochester, MN (United States); Shih, Helen A. [Massachusetts General Hospital, Department of Radiation Oncology, Harvard Medical School, Boston, MA (United States); Kirkpatrick, John [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Gaspar, Laurie E. [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO (United States); Fiveash, John B. [Radiation Oncology, University of Alabama Medical Center at Birmingham, Birmingham, AL (United States); and others
2012-04-01
Purpose: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. Methods and Materials: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. Results: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. Conclusions: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.
Suitability of markerless EPID tracking for tumor position verification in gated radiotherapy
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Serpa, Marco; Baier, Kurt; Guckenberger, Matthias; Cremers, Florian; Meyer, Juergen
2014-01-01
Purpose: To maximize the benefits of respiratory gated radiotherapy (RGRT) of lung tumors real-time verification of the tumor position is required. This work investigates the feasibility of markerless tracking of lung tumors during beam-on time in electronic portal imaging device (EPID) images of the MV therapeutic beam. Methods: EPID movies were acquired at ∼2 fps for seven lung cancer patients with tumor peak-to-peak motion ranges between 7.8 and 17.9 mm (mean: 13.7 mm) undergoing stereotactic body radiotherapy. The external breathing motion of the abdomen was synchronously measured. Both datasets were retrospectively analyzed inPortalTrack, an in-house developed tracking software. The authors define a three-step procedure to run the simulations: (1) gating window definition, (2) gated-beam delivery simulation, and (3) tumor tracking. First, an amplitude threshold level was set on the external signal, defining the onset of beam-on/-off signals. This information was then mapped onto a sequence of EPID images to generate stamps of beam-on/-hold periods throughout the EPID movies in PortalTrack, by obscuring the frames corresponding to beam-off times. Last, tumor motion in the superior-inferior direction was determined on portal images by the tracking algorithm during beam-on time. The residual motion inside the gating window as well as target coverage (TC) and the marginal target displacement (MTD) were used as measures to quantify tumor position variability. Results: Tumor position monitoring and estimation from beam's-eye-view images during RGRT was possible in 67% of the analyzed beams. For a reference gating window of 5 mm, deviations ranging from 2% to 86% (35% on average) were recorded between the reference and measured residual motion. TC (range: 62%–93%; mean: 77%) losses were correlated with false positives incidence rates resulting mostly from intra-/inter-beam baseline drifts, as well as sudden cycle-to-cycle fluctuations in exhale positions. Both
Levine, A Joan; Phipps, Amanda I; Baron, John A; Buchanan, Daniel D; Ahnen, Dennis J; Cohen, Stacey A; Lindor, Noralane M; Newcomb, Polly A; Rosty, Christophe; Haile, Robert W; Laird, Peter W; Weisenberger, Daniel J
2016-01-01
The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31-0.82). These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. MLH1 DNA methylation status should be taken into account in etiologic studies. ©2015 American Association for Cancer Research.
Levine, A. Joan; Phipps, Amanda I.; Baron, John A.; Buchanan, Daniel D.; Ahnen, Dennis J.; Cohen, Stacey A.; Lindor, Noralane M.; Newcomb, Polly A.; Rosty, Christophe; Haile, Robert W.; Laird, Peter W.; Weisenberger, Daniel J.
2015-01-01
Background The CpG Island Methylator Phenotype (CIMP) is a major molecular pathway in colorectal cancer (CRC). Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. Methods We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations and family CRC history with MLH1 methylation status in a large population-based sample of CIMP-positive CRCs defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Results Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR=0.50; 95% Confidence Interval (0.31, 0.82)). Conclusions These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. Impact MLH1 DNA methylation status should be taken into account in etiologic studies. PMID:26512054
Discrimination of p53 immunohistochemistry-positive tumors by its staining pattern in gastric cancer
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Ando, Koji; Oki, Eiji; Saeki, Hiroshi; Yan, Zhao; Tsuda, Yasuo; Hidaka, Gen; Kasagi, Yuta; Otsu, Hajime; Kawano, Hiroyuki; Kitao, Hiroyuki; Morita, Masaru; Maehara, Yoshihiko
2015-01-01
Immunohistochemistry staining of p53 is a cheap and simple method to detect aberrant function of p53. However, there are some discrepancies between the result of immunohistochemistry staining and mutation analysis. This study attempted to find a new definition of p53 staining by its staining pattern. Immunohistochemistry staining of p53 and TP53 gene mutation analysis were performed in 148 gastric cancer patients. Also SNP-CGH array analysis was conducted to four cases. Positive staining of p53 was observed in 88 (59.5%) tumors. Tumors with positive p53 staining showed malignant features compared to negative tumors. Mutation of TP53 gene was observed in 29 (19.6%) tumors with higher age and differentiated type. In positive p53 tumors, two types could be distinguished; aberrant type and scattered type. With comparison to TP53 gene mutation analysis, all the scattered type had wild-type TP53 gene (P = 0.0003). SNP-CGH array showed that scattered-type tumors had no change in the structure of chromosome 17. P53-scattered-type staining tumors may reflect a functionally active nonmutated TP53 gene. In interpretation of p53 immunohistochemistry staining, distinguishing p53-positive tumors by their staining pattern may be important in gastric cancer
Saito, Tetsuo; Matsuyama, Tomohiko; Toya, Ryo; Fukugawa, Yoshiyuki; Toyofuku, Takamasa; Semba, Akiko; Oya, Natsuo
2014-01-01
We evaluated the effects of respiratory gating on treatment accuracy in lung cancer patients undergoing lung stereotactic body radiotherapy by using electronic portal imaging device (EPID) images. Our study population consisted of 30 lung cancer patients treated with stereotactic body radiotherapy (48 Gy/4 fractions/4 to 9 days). Of these, 14 were treated with- (group A) and 16 without gating (group B); typically the patients whose tumors showed three-dimensional respiratory motion ≧5 mm were selected for gating. Tumor respiratory motion was estimated using four-dimensional computed tomography images acquired during treatment simulation. Tumor position variability during all treatment sessions was assessed by measuring the standard deviation (SD) and range of tumor displacement on EPID images. The two groups were compared for tumor respiratory motion and position variability using the Mann-Whitney U test. The median three-dimensional tumor motion during simulation was greater in group A than group B (9 mm, range 3-30 mm vs. 2 mm, range 0-4 mm; psimulation, tumor position variability in the EPID images was low and comparable to patients treated without gating. This demonstrates the benefit of respiratory gating.
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Spoelstra, Femke; Soernsen de Koste, John R. van; Vincent, Andrew; Cuijpers, Johan P.; Slotman, Ben J.; Senan, Suresh
2009-01-01
Purpose: Both carina and diaphragm positions have been used as surrogates during respiratory-gated radiotherapy. We studied the correlation of both surrogates with three-dimensional (3D) tumor position. Methods and Materials: A total of 59 repeat artifact-free four-dimensional (4D) computed tomography (CT) scans, acquired during uncoached breathing, were identified in 23 patients with Stage I lung cancer. Repeat scans were co-registered to the initial 4D CT scan, and tumor, carina, and ipsilateral diaphragm were manually contoured in all phases of each 4D CT data set. Correlation between positions of carina and diaphragm with 3D tumor position was studied by use of log-likelihood ratio statistics. Models to predict 3D tumor position from internal surrogates at end inspiration (EI) and end expiration (EE) were developed, and model accuracy was tested by calculating SDs of differences between predicted and actual tumor positions. Results: Motion of both the carina and diaphragm significantly correlated with tumor motion, but log-likelihood ratios indicated that the carina was more predictive for tumor position. When craniocaudal tumor position was predicted by use of craniocaudal carina positions, the SDs of the differences between the predicted and observed positions were 2.2 mm and 2.4 mm at EI and EE, respectively. The corresponding SDs derived with the diaphragm positions were 3.7 mm and 3.9 mm at EI and EE, respectively. Prediction errors in the other directions were comparable. Prediction accuracy was similar at EI and EE. Conclusions: The carina is a better surrogate of 3D tumor position than diaphragm position. Because residual prediction errors were observed in this analysis, additional studies will be performed using audio-coached scans.
Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei
2017-05-02
Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.
Directory of Open Access Journals (Sweden)
Inam Jasim Lafta
2017-12-01
Full Text Available FLI1 is a member of ETS family of transcription factors that regulate a variety of normal biologic activities including cell proliferation, differentiation, and apoptosis. The expression of FLI1 and its correlation with well-known breast cancer prognostic markers (ER, PR and HER2 was determined in primary breast tumors as well as four breast cancer lines including: MCF-7, T47D, MDA-MB-231 and MDA-MB-468 using RT-qPCR with either 18S rRNA or ACTB (β-actin for normalization of data. FLI1 mRNA level was decreased in the breast cancer cell lines under study compared to the normal breast tissue; however, Jurkat cells, which were used as a positive control, showed overexpression compared to the normal breast. Regarding primary breast carcinomas, FLI1 is significantly under expressed in all of the stages of breast cancer upon using 18S as an internal control. This FLI1 expression was correlated with ER, PR and HER2 status. In conclusion FLI1 can be exploited as a preliminary marker that can predict the status of ER, PR and HER2 in primary breast tumors.
Detecting somatostatin receptor in breast tumor tissue and its clinical significance
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Zhang Yongjian; Yu Xian; Lin Wei; Ding Xuan; Huang Shizhang; Lu Guangming
2002-01-01
The authors observe the difference of somatostatin receptor (SSR) between benign and malignant breast tumor and the relation between SSR and estrogen receptor (ER) or progesterone receptor (PR) in breast tumor tissue, and to predict the clinical value of detecting breast tumor by SSR receptor imaging. These tissues excised from operation in breast tumor were divided into 4 groups: breast malignant tumor group (BMTG) and its control group (C1G), breast benign tumor group (BBTG) and its control group (C2G). SSR was detected by radioligand binding assay (RBA) and ER, PR by LsAB method in these groups. Results is: (1) The SSR express quantity is 108.6 +- 67.3 fmol/mg pr, 37.2 +- 9.6 fmol/mg pr, 43.4 +- 12.6 fmol/mg pr 33.9 +- 10.2 fmol/mg pr respectively in BMTG, C1G, BBTG, C2G. The SSR of BMTG is the most among these groups, the difference is obvious, P 0.05); (2) The correlation coefficient of SSR and ER is 0.859, SSR and PR is 0.750. Most breast tumor tissues express high density SSR, the authors suppose that malignant tumor can been distinguished from benign tumor preliminarily by SSR receptor imaging. There is a good correlation between SSR and ER, PR, detecting SSR may predict the quality of tumor and the prognosis of the patient
Xu, Chen; Liu, Yalan; Ge, Xiaowen; Jiang, Dongxian; Zhang, Ying; Ji, Yuan; Hou, Jun; Huang, Jie; Su, Jieakesu; Zeng, Haiying; Qin, Jing; Hou, Yingyong
2017-05-26
HER2 assessment in biopsy specimens of gastric cancer (GC) is challenging because of the intratumoral heterogeneity. False negative results may be get because of limited biopsy material. The aim of this study is to explore how tumor-containing fragment number and biopsy specimen number affect HER2 immunohistochemistry (IHC) positive rate. Eight hundred and ninety biopsy specimens and 459 paired resected specimens were collected. IHC staining of HER2 was performed. HER2 IHC positive (scored 3+) rate was compared based on tumor-containing fragment number, biopsy specimen number, average size and tumor tissue proportion of tumor-containing fragments. The positive predictability of biopsy specimens to resected specimens was analyzed based on tumor fragment number. HER2 IHC positive rates were 2.0, 3.5, 7.0, 13.2, 17.1, and 15.9% when tumor fragment numbers were 1, 2, 3, 4, 5 and 6 respectively. The rate rose with the increase of tumor fragment number (P = 0.004). ROC curve analysis showed that biopsy specimens exhibited positive predictability when tumor fragment number reached 3, but showed better performance when the number was ≥4 (P fragment number reached 4, no statistic differences were reached in either HER2 IHC positive rate or positive predictability with further increase of the number (P > 0.05). HER2 IHC positive rate was not associated with biopsy number (P = 0.127), average size of tumor fragments (P = 0.397), and tumor tissue proportion of tumor fragments (P = 0.825) directly. The number of tumor-containing fragments influences HER2 IHC positive (scored 3+) rate. Greater than or equal to 4 (≥4) tumor fragments give better results in the positive rate as well as positive predictability. We recommend the number of tumor containing fragments be described in the HER2 IHC pathology reports for clinical reference in endoscopic biopsy specimens of GC.
Energy Technology Data Exchange (ETDEWEB)
Akiyama, Y.; Heyde, K.; Arima, A.; Yoshinaga, N.
1986-05-29
Extending the interacting boson model by incorporating besides s and d, also the g-boson, we can describe the population of positive parity states of /sup 168/Er in the /sup 166/Er(t,P)/sup 168/Er reaction rather well. In particular, the excitation of I,Ksub(i)sup(..pi..) = 4,3/sub 1//sup +/; 2,2/sub 2//sup +/; 0,0/sub 3//sup +/ and 0,0/sub 4//sup +/ states is much improved over the sd-IBM appraoch.
Loo, Claudette E; Rigter, Lisanne S; Pengel, Kenneth E; Wesseling, Jelle; Rodenhuis, Sjoerd; Peeters, Marie-Jeanne T F D Vrancken; Sikorska, Karolina; Gilhuijs, Kenneth G A
2016-01-01
BACKGROUND: Pathological complete remission (pCR) of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We
Impact of Audio-Coaching on the Position of Lung Tumors
International Nuclear Information System (INIS)
Haasbeek, Cornelis J.A.; Spoelstra, Femke; Lagerwaard, Frank J.; Soernsen de Koste, John R. van; Cuijpers, Johan P.; Slotman, Ben J.; Senan, Suresh
2008-01-01
Purpose: Respiration-induced organ motion is a major source of positional, or geometric, uncertainty in thoracic radiotherapy. Interventions to mitigate the impact of motion include audio-coached respiration-gated radiotherapy (RGRT). To assess the impact of coaching on average tumor position during gating, we analyzed four-dimensional computed tomography (4DCT) scans performed both with and without audio-coaching. Methods and Materials: Our RGRT protocol requires that an audio-coached 4DCT scan is performed when the initial free-breathing 4DCT indicates a potential benefit with gating. We retrospectively analyzed 22 such paired scans in patients with well-circumscribed tumors. Changes in lung volume and position of internal target volumes (ITV) generated in three consecutive respiratory phases at both end-inspiration and end-expiration were analyzed. Results: Audio-coaching increased end-inspiration lung volumes by a mean of 10.2% (range, -13% to +43%) when compared with free breathing (p = 0.001). The mean three-dimensional displacement of the center of ITV was 3.6 mm (SD, 2.5; range, 0.3-9.6mm), mainly caused by displacement in the craniocaudal direction. Displacement of ITV caused by coaching was more than 5 mm in 5 patients, all of whom were in the subgroup of 9 patients showing total tumor motion of 10 mm or more during both coached and uncoached breathing. Comparable ITV displacements were observed at end-expiration phases of the 4DCT. Conclusions: Differences in ITV position exceeding 5 mm between coached and uncoached 4DCT scans were detected in up to 56% of mobile tumors. Both end-inspiration and end-expiration RGRT were susceptible to displacements. This indicates that the method of audio-coaching should remain unchanged throughout the course of treatment
Directory of Open Access Journals (Sweden)
Zahraa I. Khamis
2011-01-01
Full Text Available Research efforts were focused on genetic alterations in epithelial cancer cells. Epithelial-stromal interactions play a crucial role in cancer initiation, progression, invasion, angiogenesis, and metastasis; however, the active role of stroma in human breast tumorigenesis in relation to estrogen receptor (ER status of epithelial cells has not been explored. Using proteomics and biochemical approaches, we identified two stromal proteins in ER-positive and ER-negative human breast cancer tissues that may affect malignant transformation in breast cancer. Two putative biomarkers, T-cell receptor alpha (TCR-α and zinc finger and BRCA1-interacting protein with a KRAB domain (ZBRK1, were detected in leukocytes of ER-positive and endothelial cells of ER-negative tissues, respectively. Our data suggest an immunosuppressive role of leukocytes in invasive breast tumors, propose a multifunctional nature of ZBRK1 in estrogen receptor regulation and angiogenesis, and demonstrate the aggressiveness of ER-negative human breast carcinomas. This research project may identify new stromal drug targets for the treatment of breast cancer patients.
Rausch, Matthew P; Sertil, Aparna Ranganathan
2015-03-01
The recent clinical success of immunotherapy in the treatment of certain types of cancer has demonstrated the powerful ability of the immune system to control tumor growth, leading to significantly improved patient survival. However, despite these promising results current immunotherapeutic strategies are still limited and have not yet achieved broad acceptance outside the context of metastatic melanoma. The limitations of current immunotherapeutic approaches can be attributed in part to suppressive mechanisms present in the tumor microenvironment that hamper the generation of robust antitumor immune responses thus allowing tumor cells to escape immune-mediated destruction. The endoplasmic reticulum (ER) stress response has recently emerged as a potent regulator of tumor immunity. The ER stress response is an adaptive mechanism that allows tumor cells to survive in the harsh growth conditions inherent to the tumor milieu such as low oxygen (hypoxia), low pH and low levels of glucose. Activation of ER stress can also alter the cancer cell response to therapies. In addition, the ER stress response promotes tumor immune evasion by inducing the production of protumorigenic inflammatory cytokines and impairing tumor antigen presentation. However, the ER stress response can boost antitumor immunity in some situations by enhancing the processing and presentation of tumor antigens and by inducing the release of immunogenic factors from stressed tumor cells. Here, we discuss the dualistic role of the ER stress response in the modulation of tumor immunity and highlight how strategies to either induce or block ER stress can be employed to improve the clinical efficacy of tumor immunotherapy.
Molecular profiles of progesterone receptor loss in human breast tumors
Creighton, Chad J.; Kent Osborne, C.; van de Vijver, Marc J.; Foekens, John A.; Klijn, Jan G.; Horlings, Hugo M.; Nuyten, Dimitry; Wang, Yixin; Zhang, Yi; Chamness, Gary C.; Hilsenbeck, Susan G.; Lee, Adrian V.; Schiff, Rachel
2009-01-01
Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR- compared to ER+/PR+ tumors. Methods To better understand the underlying
R.L. Milne (Roger); E.L. Goode (Ellen); M. García-Closas (Montserrat); F.J. Couch (Fergus); G. Severi (Gianluca); R. Hein (Rebecca); Z. Fredericksen (Zachary); N. Malats (Núria); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); J. Benítez (Javier); T. Dörk (Thilo); P. Schürmann (Peter); J.H. Karstens (Johann); P. Hillemanns (Peter); A. Cox (Angela); I.W. Brock (Ian); K.S. Elliot (Katherine); S.S. Cross (Simon); S. Seal (Sheila); C. Turnbull (Clare); A. Renwick (Anthony); N. Rahman (Nazneen); C-Y. Shen (Chen-Yang); J-C. Yu (Jyh-Cherng); C.-S. Huang (Chiun-Sheng); M.-F. Hou (Ming-Feng); B.G. Nordestgaard (Børge); S.E. Bojesen (Stig); C. Lanng (Charlotte); G.G. Alnæs (Grethe); V. Kristensen (Vessela); A.-L. Børrensen-Dale (Anne-Lise); J.L. Hopper (John); G.S. Dite (Gillian); C. Apicella (Carmel); M.C. Southey (Melissa); D. Lambrechts (Diether); B.T. Yesilyurt (Betül); O.A.M. Floris; K. Leunen; S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); G.G. Giles (Graham); L. Baglietto (Laura); E.M. John (Esther); A. Miron (Alexander); S.J. Chanock (Stephen); J. Lissowska (Jolanta); M.E. Sherman (Mark); J.D. Figueroa (Jonine); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); I.V. Zalutsky (Iosif); Y.I. Rogov (Yuri); P.A. Fasching (Peter); T. Bayer (T.); A.B. Ekici (Arif); M.W. Beckmann (Matthias); H. Brenner (Hermann); H. Müller (Heike); V. Arndt (Volker); C. Stegmaier (Christa); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A.M. Mulligan (Anna Marie); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); A. Meindl (Alfons); J. Heil (Joerg); C.R. Bartram (Claus); R.K. Schmutzler (Rita); G. Thomas (Gilles); R.N. Hoover (Robert); O. Fletcher (Olivia); L.J. Gibson (Lorna); I. dos Santos Silva (Isabel); J. Peto (Julian); S. Nickels (Stefan); D. Flesch-Janys (Dieter); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.J. van 't Veer (Laura); R.A.E.M. Tollenaar (Rob); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); K.A. Pooley (Karen); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); B. Burwinkel (Barbara); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); D. Kang (Daehee); K-Y. Yoo (Keun-Young); D-Y. Noh (Dong-Young); S.-H. Ahn (Sei-Hyun); D. Hunter (David); S.E. Hankinson (Susan); P. Kraft (Peter); S. Lindstrom (Stephen); X. Chen (Xiaoqing); J. Beesley (Jonathan); U. Hamann (Ute); V. Harth (Volker); C. Justenhoven (Christina); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); R.A. Oldenburg (Rogier); M.M.A. Tilanus-Linthorst (Madeleine); E.K. Khusnutdinova (Elza); M. Bermisheva (Marina); D. Prokofieva (Darya); A. Farahtdinova (Albina); J.E. Olson (Janet); X. Wang (Xing); M.K. Humphreys (Manjeet); Q. Wang (Qing); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas)
2011-01-01
textabstractBackground: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer
DEFF Research Database (Denmark)
Baselga, José; Morales, Serafin M.; Awada, Ahmad
2017-01-01
Purpose: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). Methods: This randomized...
Er frygten for Kina vores eneste håb?
DEFF Research Database (Denmark)
Mehlsen, Camilla
2011-01-01
Man siger, at håbet er lysegrønt, men i det 21. århundrede er håbet rødt som riget i midten. Mens optimismen vinder frem i Asien med Kina som bannerfører, er Vesten ramt af frygt, og det forplanter sig negativt til uddannelsessystemet. Er positive følelser hemmeligheden bag, at asiatiske lande st...... stormer frem i internationale undersøgelser som PISA?...
Mammographic density and risk of breast cancer by tumor characteristics: a case-control study.
Krishnan, Kavitha; Baglietto, Laura; Stone, Jennifer; McLean, Catriona; Southey, Melissa C; English, Dallas R; Giles, Graham G; Hopper, John L
2017-12-16
In a previous paper, we had assumed that the risk of screen-detected breast cancer mostly reflects inherent risk, and the risk of whether a breast cancer is interval versus screen-detected mostly reflects risk of masking. We found that inherent risk was predicted by body mass index (BMI) and dense area (DA) or percent dense area (PDA), but not by non-dense area (NDA). Masking, however, was best predicted by PDA but not BMI. In this study, we aimed to investigate if these associations vary by tumor characteristics and mode of detection. We conducted a case-control study nested within the Melbourne Collaborative Cohort Study of 244 screen-detected cases matched to 700 controls and 148 interval cases matched to 446 controls. DA, NDA and PDA were measured using the Cumulus software. Tumor characteristics included size, grade, lymph node involvement, and ER, PR, and HER2 status. Conditional and unconditional logistic regression were applied as appropriate to estimate the Odds per Adjusted Standard Deviation (OPERA) adjusted for age and BMI, allowing the association with BMI to be a function of age at diagnosis. For screen-detected cancer, both DA and PDA were associated to an increased risk of tumors of large size (OPERA ~ 1.6) and positive lymph node involvement (OPERA ~ 1.8); no association was observed for BMI and NDA. For risk of interval versus screen-detected breast cancer, the association with risk for any of the three mammographic measures did not vary by tumor characteristics; an association was observed for BMI for positive lymph nodes (OPERA ~ 0.6). No associations were observed for tumor grade and ER, PR and HER2 status of tumor. Both DA and PDA were predictors of inherent risk of larger breast tumors and positive nodal status, whereas for each of the three mammographic density measures the association with risk of masking did not vary by tumor characteristics. This might raise the hypothesis that the risk of breast tumours with poorer prognosis
International Nuclear Information System (INIS)
Liu, Zhiguo; Wang, Yi; Sun, Yusheng; Ren, Luqing; Huang, Yi; Cai, Yuepiao; Weng, Qiaoyou; Shen, Xueqian; Li, Xiaokun; Liang, Guang
2013-01-01
Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC
Rab7a modulates ER stress and ER morphology.
Mateus, Duarte; Marini, Elettra Sara; Progida, Cinzia; Bakke, Oddmund
2018-05-01
The Endoplasmic Reticulum (ER) is a membranous organelle with diverse structural and functional domains. Peripheral ER includes interconnected tubules, and dense tubular arrays called "ER matrices" together with bona fide flat cisternae. Transitions between these states are regulated by membrane-associated proteins and cytosolic factors. Recently, the small GTPases Rab10 and Rab18 were reported to control ER shape by regulating ER dynamics and fusion. Here, we present evidence that another Rab protein, Rab7a, modulates the ER morphology by controlling the ER homeostasis and ER stress. Indeed, inhibition of Rab7a expression by siRNA or expression of the dominant negative mutant Rab7aT22 N, leads to enlargement of sheet-like ER structures and spreading towards the cell periphery. Notably, such alterations are ascribable neither to a direct modulation of the ER shaping proteins Reticulon-4b and CLIMP63, nor to interactions with Protrudin, a Rab7a-binding protein known to affect the ER organization. Conversely, depletion of Rab7a leads to basal ER stress, in turn causing ER membrane expansion. Both ER enlargement and basal ER stress are reverted in rescue experiments by Rab7a re-expression, as well as by the ER chemical chaperone tauroursodeoxycholic acid (TUDCA). Collectively, these findings reveal a new role of Rab7a in ER homeostasis, and indicate that genetic and pharmacological ER stress manipulation may restore ER morphology in Rab7a silenced cells. Copyright © 2018 Elsevier B.V. All rights reserved.
Ono, Tomohiro; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Ono, Yuka; Ishigaki, Takashi; Hiraoka, Masahiro
2017-09-01
To estimate the lung tumor position from multiple anatomical features on four-dimensional computed tomography (4D-CT) data sets using single regression analysis (SRA) and multiple regression analysis (MRA) approach and evaluate an impact of the approach on internal target volume (ITV) for stereotactic body radiotherapy (SBRT) of the lung. Eleven consecutive lung cancer patients (12 cases) underwent 4D-CT scanning. The three-dimensional (3D) lung tumor motion exceeded 5 mm. The 3D tumor position and anatomical features, including lung volume, diaphragm, abdominal wall, and chest wall positions, were measured on 4D-CT images. The tumor position was estimated by SRA using each anatomical feature and MRA using all anatomical features. The difference between the actual and estimated tumor positions was defined as the root-mean-square error (RMSE). A standard partial regression coefficient for the MRA was evaluated. The 3D lung tumor position showed a high correlation with the lung volume (R = 0.92 ± 0.10). Additionally, ITVs derived from SRA and MRA approaches were compared with ITV derived from contouring gross tumor volumes on all 10 phases of the 4D-CT (conventional ITV). The RMSE of the SRA was within 3.7 mm in all directions. Also, the RMSE of the MRA was within 1.6 mm in all directions. The standard partial regression coefficient for the lung volume was the largest and had the most influence on the estimated tumor position. Compared with conventional ITV, average percentage decrease of ITV were 31.9% and 38.3% using SRA and MRA approaches, respectively. The estimation accuracy of lung tumor position was improved by the MRA approach, which provided smaller ITV than conventional ITV. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.
MR pancreatography (MRP) for mucin-producing pancreatic tumors
International Nuclear Information System (INIS)
Usuki, Noriaki; Nishimoto, Masaoki; Shima, Tomoko; Hirokawa, Keiko; Tashiro, Takahiko; Saiwai, Shigeo; Miyamoto, Takeshi; Okabe, Sumihiro
1997-01-01
MR pancreatography was performed in 11 patients with mucin-producing pancreatic tumor (main duct type: four and branch duct type: seven) using HASTE with a body phased array coil on a 1.5-T unit. The results of MR pancreatography were compared with imaging of endoscopic retrograde pancreatography (ERP). In all cases, MR pancreatography demonstrated all dilated pancreatic ducts and cysts. ERP did not completely demonstrate dilated ducts and cysts because of mucinous materials. Conspicuity of an intraductal tumor was more excellent by ER pancreatography than MR pancreatography. Therefore MR pancreatography and ER pancreatography are complementary methods in diagnosis for mucin-producing pancreatic tumors. (author)
Molina, Rafael; Augé, Jose M; Escudero, Jose M; Filella, Xavier; Zanon, Gabriel; Pahisa, Jaume; Farrus, Blanca; Muñoz, Montserrat; Velasco, Martin
2010-06-01
Tumor markers were studied in the sera of 883 untreated patients with primary breast cancer diagnosed between 1989 and 2007. Abnormal human epidermal growth factor receptor 2 (HER-2)/neu levels (>15 ng/mL) were found in 9.5%, carcinoembryonic antigen (CEA) in 15.9%, and cancer antigen (CA) 15.3 in 19.7% of the patients. One or more tumor markers were abnormal in 305 (34.5%) of the 883 studied patients. Significantly higher serum HER-2/neu levels were found in patients with tissue overexpression of this oncoprotein (p CEA, CA 15.3, and HER-2/neu (only in those patients with tissue overexpression) serum levels were related with tumor stage (tumor size and nodal involvement) and steroid receptors (higher values in estrogen receptor-negative (ER-) tumors). Univariate analysis showed that HER-2/neu serum levels were prognostic factors in disease-free survival (DFS) and overall survival (OS) only in patients with tissue overexpression. Multivariate analysis in 834 patients show that nodal involvement, tumor size, ER, CEA, and adjuvant treatment were independent prognostic factors in DFS and OS. When only patients with HER-2/neu overexpression in tissue were studied, tumor size, nodal involvement, and tumor markers (one or another positive) were independent prognostic factors for both DFS and OS. HER-2/neu serum levels were also an independent prognostic factor, with CEA, ER, and nodes in 106 patients treated with neoadjuvant treatment. In summary, serum HER-2/neu, CEA, and CA 15.3 are useful tools in the prognostic evaluation of patients with primary breast cancer.
Prat, Aleix; Cheang, Maggie Chon U.; Martín, Miguel; Parker, Joel S.; Carrasco, Eva; Caballero, Rosalía; Tyldesley, Scott; Gelmon, Karen; Bernard, Philip S.; Nielsen, Torsten O.; Perou, Charles M.
2013-01-01
Purpose Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. Patients and Methods Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) –positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. Results Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) –positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. Conclusion Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A
Tension pneumoventricle after excision of third ventricular tumor in sitting position
Directory of Open Access Journals (Sweden)
Nidhi Gupta
2011-01-01
Full Text Available Occurrence of tension pneumoventricle (symptomatic intraventricular air can result in rapid clinical deterioration in an otherwise stable patient. It is a rare clinical entity, mentioned in relation to cerebrospinal fluid (CSF diversion procedures, during the late postoperative period. We present a patient with posterior third ventricular tumor who underwent excision by midline suboccipital craniotomy in sitting position. Neurological status of the patient deteriorated rapidly in the immediate postoperative period owing to development of tension pneumoventricle. The condition improved after twist-drill burr-hole evacuation of air under water-seal. Pre-existing gross hydrocephalus, exploration of third ventricle in sitting position, and residual tumor in third ventricle were possibly the factors responsible for this complication.
[(99)Tc(m)N-NOET dual-phase SPECT in differential diagnosis of benign and malignant lung tumors].
Liu, Haiyan; Li, Sijin; Yang, Suyun; Wu, Zhifang
2014-01-01
To investigate the value of (99)Tc(m)N-NOET dual-phase SPECT in differential diagnosis of benign and malignant lung tumors. CT scan, early (20 to 30 min) and delayed (2 h) imaging of NOET SPECT were performed on 61 patients suspected of lung lesions before operation. The results were compared with the pathological findings. All cases were not treated with radiotherapy, chemotherapy or surgery before checks. Moreover, all patients had pathological diagnosis. To determine the value in differential diagnosis of tumors by analyzing the tumor uptake and excretion of (99)Tc(m)N-NOET, and the results were compared with that of CT. The value of early T/N ratio (ER) in the malignant (G1) and benign (G2) groups was 1.25 ± 0.15 and 1.09 ± 0.11 (P 0.05). The ER, DR and RI of NOET SPECT in the malignant patients were not significantly correlated with TNM staging, pathological types, tumor diameter, cavity in the lung tumor mass, history of smoking, tumor size and patient gender (P > 0.05). The sensitivity of NOET dual-phase SPECT and CT in the differential diagnosis of benign and malignant lung tumors was 94.1% vs. 90.2%, specificity was 70.0% vs. 80.0% , positive predictive value (PPV) was 94.1% vs. 95.8%, negative predictive value (NPV) was 70.0% vs. 61.5 %, and accuracy was 90.2%. vs. 88.5% (P > 0.05 for all). (99)Tc(m)N- NOET dual-phase SPECT could be used in differential diagnosis of benign and malignant lung tumors, with no significant differences compared with the efficacy of CT imaging. The semiquantitative indexes (ER, DR and RI) of NOET SPECT can also be used in differential diagnosis of benign and malignant lung tumors, and are not significantly correlated with TNM staging, pathological types, tumor diameter, cavity of the lung tumor mass, history of smoking, tumor size and patient gender.
A CLINICAL STUDY ON CARCINOMA BREAST IN RELATION TO ER AND PR STATUS
Directory of Open Access Journals (Sweden)
Ramanaiah
2015-09-01
Full Text Available INTRODUCTION : Breast carcinoma is the most common malignant tumor and the leading cause of death in women worldwide 1 . It accounts for 15 % of all cancer deaths 2 . According to the World Health Organisation (WHO, approximately 70% of breast cancers occur in women with none of the known risk factors. Only about 5% of breast cancers are inherited. Various protocols are in use for the assessment of prognosis, and also to assist further management of these cases. Of various parameters, expression of hormonereceptors Estrogen receptor (ER and Progesterone receptor (PR ar e significant AIMS AND OBJECTIVES : To study the occurrence of ER and PR status in breast cancer patients attending S.V.R.R.G.G. Hospital. To correlate the expression of prognostic factors like age at presentation menarche, menopause, parity, tumor size, number of lymph nodes, metastasis histology, grading with ER and PR status. MATERIALS AND METHODS : This clinic opathological study of carcinoma breast was carried out in patients admitted to SVRRGG Hospital, Tirupati during the period from September 2011 to August 2013 after obtaining approval from scientific committee and ethical committee .Forty cases of breast carcinoma were taken into study. The clinical study done by interviewing, detailed examination and subjecting to relevant investigations and surgeries depending upon the stage of the disease. Excised specimen is sent for Histopathological examination in 10% formaline Reports of light microscopy (Hematoxilin and Eosin and immunohistochemistry on tumor histology including MBR (Modified Bloom Richardson grading and Estrogen and Progesterone status is analysed. CONCLUSION: In conclusion, ER and PR status correlates well with histopathological grading and other clinico - pathological parameters. Higher grade is associated with ER PR negativity. Hence. Immunohistochemical assessment of ER and PR status should be incorporated as a routine investigation. This along with
Tumor-associated macrophages: Oblivious confederates in invasive mammary carcinoma
Directory of Open Access Journals (Sweden)
Imtiaz Ahmed
2017-01-01
Full Text Available Background: The infiltrating margins of carcinomas are associated with presence of inflammatory cell infiltrate which are an integral part of the tumor microenvironment. Amongst the inflammatory cells, Tumor Associated Macrophages (TAMs play a key role in the tumorigenesis. This study elucidates the density of TAMs in invasive mammary carcinomas and attempts to establish aa association with the following pathological variables: tumor size, histological grade, nodal status, hormonal expression status and Her2Neu overexpression. Materials and Methods: 90 diagnosed archival cases of invasive mammary carcinomas at a tertiary care centre were included. Density of TAMs was assessed by using CD68 which is a pan-macrophage marker by immunohistochemistry on the archival tissue blocks. The density TAMs (CD68 positive cells was dichotomised into high (>50 CD68 positive cells/ HPF and low (<5050 CD68 positive cells/ HPF and compared with the above mentioned pathological variables using appropriate statistical tests. Results: The density of TAMs was significantly higher around the infiltrating edge of the carcinoma in comparison to the adjoining normal terminal duct lobular units. The density of TAMs was more in the infiltrating edge of the tumor than within the tumor nodule/nests. A higher TAM density showed a significant association in tumors having large tumor size, higher histological grade, nodal metastasis, absence of ER and PR expression and Her2Neu overexpression (p value <0.05. Conclusion: TAMs play an important role in tumor progression in invasive mammary carcinomas. This is as a result of the multiple roles enacted by TAMs in the various stages of tumor development starting from tumor growth, invasion, angiogenesis and metastases. Targeted therapy against TAMs has great potential in the being important components of future treatment strategies against breast carcinomas.
Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.
Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu
2018-04-01
Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen
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Edneia A. S. Ramos
Full Text Available Summary Introduction: Breast cancer is the most cause of death, and approximately 90% of these deaths are due to metastases. Matrix metalloproteinase-2 (MMP-2 gelatinase activity is able to degrade a major constituent of the tumor microenvironment, type IV collagen. Two well-established proteins used as markers in clinical practice for breast cancer are the receptors for estrogen (ER and progesterone (PR. Although the presence of these receptors has been associated with a better prognosis, loss of these proteins can occur during tumor progression, with subsequent resistance to hormone therapy. Objective: To study the correlation among MMP-2, ER, and PR, as well as the establishment of the metastatic process in primary breast tumors. Method: Breast cancer samples (n=44 were analyzed by immunohistochemistry for MMP-2, ER, and PR. Results: We observed that 90% of patients who had metastases and died showed positive staining for MMP-2 (p=0.0082 for both. Using Kaplan-Meier analysis, we found that negative ER patients who were also positive for MMP-2 had even worse disease-free survival (DFS and overall survival (OS (p= 0.012 and p=0.005, respectively. Similar results were found in PR-negative patients for DFS (a trend p=0.077 and OS (p=0.038. Conclusion: Regardless of our small sample size (n=44, the data obtained strongly suggest that MMP-2 in combination with already well-established markers could help to predict the emergence of metastases and death in patients with breast cancer.
Foley, Niamh M; Coll, J M; Lowery, A J; Hynes, S O; Kerin, M J; Sheehan, M; Brodie, C; Sweeney, K J
2017-09-11
Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER-/PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management.
Peña, L; Gama, A; Goldschmidt, M H; Abadie, J; Benazzi, C; Castagnaro, M; Díez, L; Gärtner, F; Hellmén, E; Kiupel, M; Millán, Y; Miller, M A; Nguyen, F; Poli, A; Sarli, G; Zappulli, V; de las Mulas, J Martín
2014-01-01
Although there have been several studies on the use of immunohistochemical biomarkers of canine mammary tumors (CMTs), the results are difficult to compare. This article provides guidelines on the most useful immunohistochemical markers to standardize their use and understand how outcomes are measured, thus ensuring reproducibility of results. We have reviewed the biomarkers of canine mammary epithelial and myoepithelial cells and identified those biomarkers that are most useful and those biomarkers for invasion and lymph node micrometastatic disease. A 10% threshold for positive reaction for most of these markers is recommended. Guidelines on immunolabeling for HER2, estrogen receptors (ERs), and progesterone receptors (PRs) are provided along with the specific recommendations for interpretation of the results for each of these biomarkers in CMTs. Only 3+ HER2-positive tumors should be considered positive, as found in human breast cancer. The lack of any known response to adjuvant endocrine therapy of ER- and PR-positive CMTs prevents the use of the biological positive/negative threshold used in human breast cancer. Immunohistochemistry results of ER and PR in CMTs should be reported as the sum of the percentage of positive cells and the intensity of immunolabeling (Allred score). Incorporation of these recommendations in future studies, either prospective or retrospective, will provide a mechanism for the direct comparison of studies and will help to determine whether these biomarkers have prognostic significance. Finally, these biomarkers may ascertain the most appropriate treatment(s) for canine malignant mammary neoplasms.
Maxwell, Thressi; Lee, Kyu Shik; Kim, Soyoung; Nam, Kyung-Soo
2018-04-01
Arctigenin, a member of the Asteraceae family, is a biologically active lignan that is consumed worldwide due to its several health benefits. However, its use may pose a problem for patients with estrogen receptor (ER)α-positive breast cancer, since studies have shown that arctigenin is a phytoestrogen that exerts a proliferative effect by binding to the ER. Thus, in this study, we examined the effect of arctigenin on ERα-positive MCF-7 human breast cancer cells to determine whether the consumption of arctigenin is safe for patients with breast cancer. First, we found that arctigenin inhibited the viability of the MCF-7 cells, and colony formation assay confirmed that this effect was cytotoxic rather than cytostatic. The cytotoxic effects were not mediated by cell cycle arrest, apoptosis, or necroptosis, despite DNA damage, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and phosphorylated H2A.X. An increase in lipidated LC3, a marker of autophagosome formation, was observed, indicating that autophagy was induced by arctigenin, which was found to be triggered by the inhibition of the mechanistic target of rapamycin (mTOR) pathway. We then examined the effects of arctigenin on ERα expression and determined whether it affects the sensitivity of the cells to tamoxifen, as tamoxifen is commonly used against hormone-responsive cancers and is known to act via the ERα. We found that treatment with arctigenin effectively downregulated ERα expression, which was found to be a consequence of the inhibition of the mTOR pathway. However, treatment with arctigenin in combination with tamoxifen did not affect the sensitivity of the cells to tamoxifen, but instead, exerted a synergistic effect. On the whole, our data indicate that the phytoestrogen, arctigenin, mainly targeted the mTOR pathway in ERα-positive MCF-7 human breast cancer cells, leading to autophagy-induced cell death and the downregulation of ERα expression. Furthermore, the synergistic effects
Tsunashima, Ryo; Naoi, Yasuto; Shimazu, Kenzo; Kagara, Naofumi; Shimoda, Masashi; Tanei, Tomonori; Miyake, Tomohiro; Kim, Seung Jin; Noguchi, Shinzaburo
2018-05-04
Prediction models for late (> 5 years) recurrence in ER-positive breast cancer need to be developed for the accurate selection of patients for extended hormonal therapy. We attempted to develop such a prediction model focusing on the differences in gene expression between breast cancers with early and late recurrence. For the training set, 779 ER-positive breast cancers treated with tamoxifen alone for 5 years were selected from the databases (GSE6532, GSE12093, GSE17705, and GSE26971). For the validation set, 221 ER-positive breast cancers treated with adjuvant hormonal therapy for 5 years with or without chemotherapy at our hospital were included. Gene expression was assayed by DNA microarray analysis (Affymetrix U133 plus 2.0). With the 42 genes differentially expressed in early and late recurrence breast cancers in the training set, a prediction model (42GC) for late recurrence was constructed. The patients classified by 42GC into the late recurrence-like group showed a significantly (P = 0.006) higher late recurrence rate as expected but a significantly (P = 1.62 × E-13) lower rate for early recurrence than non-late recurrence-like group. These observations were confirmed for the validation set, i.e., P = 0.020 for late recurrence and P = 5.70 × E-5 for early recurrence. We developed a unique prediction model (42GC) for late recurrence by focusing on the biological differences between breast cancers with early and late recurrence. Interestingly, patients in the late recurrence-like group by 42GC were at low risk for early recurrence.
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Chen Chuang; Li Yan; Peng Jun; Xu Hao; Tang Hongwu; Zhang Zhiling; Pang Daiwen; Xia Heshun; Wu Qiongshui; Zeng Libo; Zhu Xiaobo
2010-01-01
Breast cancer (BC) is a heterogeneous tumor, and better understanding of its heterogeneity is essential to improving treatment effect. Quantum dot (QD)-based immunofluorescent nanotechnology (QD-IHC) for molecular pathology has potential advantages in delineating tumor heterogeneity. This potential is explored in this paper by QD-IHC imaging of HER2 and ER. BC heterogeneity can be displayed more clearly and sensitively by QD-IHC than conventional IHC in BC tissue microarrays. Furthermore, the simultaneous imaging of ER and HER2 might help understand their interactions during the process of evolution of heterogeneous BC.
Lee, Jun Sang; Park, Seho; Park, Ji Min; Cho, Jung Hoon; Kim, Seung Il; Park, Byeong-Woo
2013-10-01
To investigate the prognostic value of tumor markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels at diagnosis of systemic recurrence. After primary treatments of locoregional breast cancers, serum CA 15-3 and/or CEA concentrations were regularly measured, and systemic recurrences were identified in 351 patients between January 1999 and December 2009. The association between tumor marker levels at systemic recurrence and survival were investigated by univariate and multivariate analyses. Elevated CA 15-3 and CEA levels were identified in 194 of 349 (55.6 %) and 111 of 308 (36.0 %) patients, respectively, at diagnosis of systemic recurrence. Elevated levels of CA 15-3 and CEA were correlated with visceral or multiple recurrences and elevated preoperative levels. Elevation of CA 15-3 was more prominent in younger patients and in primary node-positive tumors, while CEA was elevated in older patients at diagnosis and in estrogen receptor (ER)-positive tumors. Elevated tumor markers as well as ER negativity, short disease-free interval, and advanced stage at initial diagnosis showed independent prognostic significance on multivariate analysis. Among 306 patients for whom levels of both tumor markers at recurrence were available, 106 patients without elevation of either marker showed significantly better overall survival than those with elevated levels of either one or both markers, and the significance persisted in multivariate analysis. Elevated serum CA 15-3 and CEA levels at recurrence suggest increased tumor burden and may be prognostic for survival for metastatic breast cancer patients.
Bardia, Aditya; Iafrate, John A; Sundaresan, Tilak; Younger, Jerry; Nardi, Valentina
2016-09-01
: The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the "right drug" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article. ER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment.ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER and mediate
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Klajic, Jovana; Tost, Jörg; Kristensen, Vessela N; Fleischer, Thomas; Dejeux, Emelyne; Edvardsen, Hege; Warnberg, Fredrik; Bukholm, Ida; Lønning, Per Eystein; Solvang, Hiroko; Børresen-Dale, Anne-Lise
2013-01-01
Aberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression. Quantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV. Significant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival. In the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above
Espinal, Allyson C; Wang, Dan; Yan, Li; Liu, Song; Tang, Li; Hu, Qiang; Morrison, Carl D; Ambrosone, Christine B; Higgins, Michael J; Sucheston-Campbell, Lara E
2017-02-28
DNA from archival formalin-fixed and paraffin embedded (FFPE) tissue is an invaluable resource for genome-wide methylation studies although concerns about poor quality may limit its use. In this study, we compared DNA methylation profiles of breast tumors using DNA from fresh-frozen (FF) tissues and three types of matched FFPE samples. For 9/10 patients, correlation and unsupervised clustering analysis revealed that the FF and FFPE samples were consistently correlated with each other and clustered into distinct subgroups. Greater than 84% of the top 100 loci previously shown to differentiate ER+ and ER- tumors in FF tissues were also FFPE DML. Weighted Correlation Gene Network Analyses (WCGNA) grouped the DML loci into 16 modules in FF tissue, with ~85% of the module membership preserved across tissue types. Restored FFPE and matched FF samples were profiled using the Illumina Infinium HumanMethylation450K platform. Methylation levels (β-values) across all loci and the top 100 loci previously shown to differentiate tumors by estrogen receptor status (ER+ or ER-) in a larger FF study, were compared between matched FF and FFPE samples using Pearson's correlation, hierarchical clustering and WCGNA. Positive predictive values and sensitivity levels for detecting differentially methylated loci (DML) in FF samples were calculated in an independent FFPE cohort. FFPE breast tumors samples show lower overall detection of DMLs versus FF, however FFPE and FF DMLs compare favorably. These results support the emerging consensus that the 450K platform can be employed to investigate epigenetics in large sets of archival FFPE tissues.
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Lee, D; Pollock, S; Keall, P; Greer, P; Lapuz, C; Ludbrook, J; Kim, T
2015-01-01
Purpose: Audiovisual biofeedback breath-hold (AVBH) was employed to reproduce tumor position on inhale and exhale breath-holds for 4D tumor information. We hypothesize that lung tumor position will be more consistent using AVBH compared with conventional breath-hold (CBH). Methods: Lung tumor positions were determined for seven lung cancer patients (age: 25 – 74) during to two separate 3T MRI sessions. A breathhold training session was performed prior to the MRI sessions to allow patients to become comfortable with AVBH and their exhale and inhale target positions. CBH and AVBH 4D image datasets were obtained in the first MRI session (pre-treatment) and the second MRI session (midtreatment) within six weeks of the first session. Audio-instruction (MRI: Siemens Skyra) in CBH and verbal-instruction (radiographer) in AVBH were used. A radiation oncologist contoured the lung tumor using Eclipse (Varian Medical Systems); tumor position was quantified as the centroid of the contoured tumor after rigid registration based on vertebral anatomy across two MRI sessions. CBH and AVBH were compared in terms of the reproducibility assessed via (1) the difference between the two exhale positions for the two sessions and the two inhale positions for the sessions. (2) The difference in amplitude (exhale to inhale) between the two sessions. Results: Compared to CBH, AVBH improved the reproducibility of two exhale (or inhale) lung tumor positions relative to each other by 33%, from 6.4±5.3 mm to 4.3±3.0 mm (p=0.005). Compared to CBH, AVBH improved the reproducibility of exhale and inhale amplitude by 66%, from 5.6±5.9 mm to 1.9±1.4 mm (p=0.005). Conclusions: This study demonstrated that audiovisual biofeedback can be utilized for improving the reproducibility of breath-hold lung tumor position. These results are advantageous towards achieving more accurate emerging radiation treatment planning methods, in addition to imaging and treatment modalities utilizing breath
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Lee, D; Pollock, S; Keall, P [Radiation Physics Laboratory, Sydney Medical School, The University of Sydney, NSW (Australia); Greer, P [School of Mathematical and Physical Sciences, The University of Newcastle, Newcastle, NSW (Australia); Department of Radiation Oncology, Calvary Mater Newcastle, Newcastle, NSW (Australia); Lapuz, C; Ludbrook, J [Department of Radiation Oncology, Calvary Mater Newcastle, Newcastle, NSW (Australia); Kim, T [Radiation Physics Laboratory, Sydney Medical School, The University of Sydney, NSW (Australia); Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA (United States)
2015-06-15
Purpose: Audiovisual biofeedback breath-hold (AVBH) was employed to reproduce tumor position on inhale and exhale breath-holds for 4D tumor information. We hypothesize that lung tumor position will be more consistent using AVBH compared with conventional breath-hold (CBH). Methods: Lung tumor positions were determined for seven lung cancer patients (age: 25 – 74) during to two separate 3T MRI sessions. A breathhold training session was performed prior to the MRI sessions to allow patients to become comfortable with AVBH and their exhale and inhale target positions. CBH and AVBH 4D image datasets were obtained in the first MRI session (pre-treatment) and the second MRI session (midtreatment) within six weeks of the first session. Audio-instruction (MRI: Siemens Skyra) in CBH and verbal-instruction (radiographer) in AVBH were used. A radiation oncologist contoured the lung tumor using Eclipse (Varian Medical Systems); tumor position was quantified as the centroid of the contoured tumor after rigid registration based on vertebral anatomy across two MRI sessions. CBH and AVBH were compared in terms of the reproducibility assessed via (1) the difference between the two exhale positions for the two sessions and the two inhale positions for the sessions. (2) The difference in amplitude (exhale to inhale) between the two sessions. Results: Compared to CBH, AVBH improved the reproducibility of two exhale (or inhale) lung tumor positions relative to each other by 33%, from 6.4±5.3 mm to 4.3±3.0 mm (p=0.005). Compared to CBH, AVBH improved the reproducibility of exhale and inhale amplitude by 66%, from 5.6±5.9 mm to 1.9±1.4 mm (p=0.005). Conclusions: This study demonstrated that audiovisual biofeedback can be utilized for improving the reproducibility of breath-hold lung tumor position. These results are advantageous towards achieving more accurate emerging radiation treatment planning methods, in addition to imaging and treatment modalities utilizing breath
Tracking of [18F]FDG-labeled natural killer cells to HER2/neu-positive tumors
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Meier, Reinhard; Piert, Morand; Piontek, Guido; Rudelius, Martina; Oostendorp, Robert A.; Senekowitsch-Schmidtke, Reingard; Henning, Tobias D.; Wels, Winfried S.; Uherek, Christoph; Rummeny, Ernst J.; Daldrup-Link, Heike E.
2008-01-01
Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [ 18 F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [ 18 F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [ 18 F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [ 18 F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10 6 [ 18 F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10 6 NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [ 18 F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography
Albain, Kathy S.; Barlow, William E.; Shak, Steven; Hortobagyi, Gabriel N.; Livingston, Robert B.; Yeh, I-Tien; Ravdin, Peter; Bugarini, Roberto; Baehner, Frederick L.; Davidson, Nancy E.; Sledge, George W.; Winer, Eric P.; Hudis, Clifford; Ingle, James N.; Perez, Edith A.; Pritchard, Kathleen I.; Shepherd, Lois; Gralow, Julie R.; Yoshizawa, Carl; Allred, D. Craig; Osborne, C. Kent; Hayes, Daniel F.
2010-01-01
SUMMARY Background The 21-gene Recurrence Score assay (RS) is prognostic for women with node-negative, estrogen receptor (ER)-positive breast cancer (BC) treated with tamoxifen. A low RS predicts little benefit of chemotherapy. For node-positive BC, we investigated whether RS was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher recurrence risks. Methods The phase III trial S8814 for postmenopausal women with node-positive, ER-positive BC showed that CAF chemotherapy prior to tamoxifen (CAF-T) added survival benefit to tamoxifen alone. Optional tumor banking yielded specimens for RS determination by RT-PCR. We evaluated the effect of RS on disease-free survival (DFS) by treatment group (tamoxifen versus CAF-T) using Cox regression adjusting for number of positive nodes. Findings There were 367 specimens (40% of parent trial) with sufficient RNA (tamoxifen, 148; CAF-T, 219). The RS was prognostic in the tamoxifen arm (p=0.006). There was no CAF benefit in the low RS group (logrank p=0.97; HR=1.02, 95% CI (0.54,1.93)), but major DFS improvement for the high RS subset (logrank p=.03; HR=0.59, 95% CI (0.35, 1.01)), adjusting for number of positive nodes. The RS-by-treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), though the cumulative benefit remained at 10 years. Results were similar for overall survival and BC-specific survival. Interpretation In this retrospective analysis, the RS is prognostic for tamoxifen-treated patients with positive nodes and predicts significant CAF benefit in tumors with a high RS. A low RS identifies women who may not benefit from anthracycline-based chemotherapy despite positive nodes. PMID:20005174
Large palpable ductal carcinoma in situ is Her-2 positive with high nuclear grade.
Monabati, Ahmad; Sokouti, Ali-Reza; Noori, Sadat Noori; Safaei, Akbar; Talei, Abd-Rasul; Omidvari, Shapoor; Azarpira, Negar
2015-01-01
Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group with variable clinical presentation. The exact molecular mechanism is not known why some ductal carcinomas may reach to such a large size but still remains in situ. Although, molecular classification of DCIS lesions and nuclear grading are important for identification of more aggressive lesions but it is not sufficient. Our aim was to examine the expression pattern of immunohistochemical (IHC) markers of ER, PR, HER-2 in palpable DCIS lesions and compare with clinicopathological findings. Our center is referral hospital from South of Iran. Samples were obtained from fifty four patients with a diagnosis of palpable DCIS. Equivocal (2+) case in HER-2 IHC testing was more characterized by chromogenic in situ hybridization. The positive frequency of HER2, ER, and PR was 92%, 48%, and 37% respectively. Palpable DCIS lesions were significantly more HER-2 positive (92%). The DCIS cases were more likely to be of high nuclear grade (grade III) and Her-2 positive cases were more likely to be of high nuclear grade than intermediate grade. All ER negative tumors had high nuclear grade. The Her-2 positivity is suggested as the most important factor responsible for marked in situ proliferation and production of palpable mass.
Habel, Laurel A; Shak, Steven; Jacobs, Marlena K; Capra, Angela; Alexander, Claire; Pho, Mylan; Baker, Joffre; Walker, Michael; Watson, Drew; Hackett, James; Blick, Noelle T; Greenberg, Deborah; Fehrenbacher, Louis; Langholz, Bryan; Quesenberry, Charles P
2006-01-01
The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting. A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score. After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7-3.9%), 10.7% (95% CI 6.3-14.9%), and 15.5% (95% CI 7.6-22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5-7.9%), 17.8% (95% CI 11.8-23.3%), and 19.9% (95% CI 14.2-25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values. In this large, population-based study of lymph
Directory of Open Access Journals (Sweden)
DONG Deshuo
2017-10-01
Full Text Available Hepatocellular carcinoma (HCC has an insidious onset and when a confirmed diagnosis is made, most patients lose the chance for surgery and are given transarterial chemoembolization (TACE as palliative treatment. However, repeated TACE may lead to overexpression of hypoxia-inducible factor 1α (HIF-1α and vascular endothelial growth factor (VEGF, liver injury, and reduced immune function and has poor long-term efficacy. The introduction of Huai′er granules may help to change the current status. Studies in China and foreign countries have shown that Huai′er granules exert a remarkable anti-tumor effect by blocking cell cycle, inducing cell apoptosis, inhibiting cell proliferation and invasion, and blocking the hepatitis B-hepatocellular carcinoma pathway. Meanwhile, as an adjuvant drug for HCC, Huai′er granules cover the shortcomings of TACE from multiple aspects and can effectively inhibit the overexpression of HIF-1α and VEGF, improve liver injury and immunity, enhance the effect of chemotherapy drugs, and reverse drug resistance. Many clinical studies have confirmed the remarkable advantages of Huai′er granules combined with TACE, and their synergistic effect helps to enhance anti-tumor effect and improve short- and long-term survival rates.
International Nuclear Information System (INIS)
Kim, Jisun; Kim, Lee Su; Han, Sehwan; Nam, Seok Jin; Kang, Han-Sung; Kim, Seung Il; Yoo, Young Bum; Jeong, Joon; Kim, Tae Hyun; Kang, Taewoo; Kim, Sung-Won; Lim, Woosung; Jung, Yongsik; Lee, Jeong Eon; Kim, Ku Sang; Yu, Jong-Han; Chae, Byung Joo; Jung, So-Youn; Kang, Eunyoung; Choi, Su Yun; Moon, Hyeong-Gon; Noh, Dong-Young; Kim, Eun-Kyu; Han, Wonshik; Kim, Min-Kyoon; Paik, Nam-Sun; Jeong, Sang-Seol; Yoon, Jung-han; Park, Chan Heun; Ahn, Sei Hyun
2014-01-01
Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. ClinicalTrials.gov Identifier http://clinicaltrial.gov/ct2/show/NCT01589367?term
International Nuclear Information System (INIS)
Gelman, Rebecca; Nixon, Asa J.; O'Neill, Anne; Harris, Jay R.
1996-01-01
Purpose: Most analyses of the effect of patient and tumor characteristics on long-term outcome in breast cancer use the Cox proportional hazard (prohaz) model, which assumes that hazard rates for any two subsets are proportional (i.e., hazard ratios are constant) over time. We examined whether this assumption is correct for predicting time to distant failure in breast cancer patients treated with breast-conserving therapy and speculated on the biologic implications of these findings. Materials and Methods: Between 1968 and 1986, 1081 patients treated for clinical stage I or II invasive breast cancer with a complete gross excision and ≥60 Gy to the tumor bed had pure infiltrating ductal carcinoma on central pathologic review. 37 patients (3%) were lost to followup after 7-181 months. Median followup for 694 survivors was 12 years (8-23 yrs.). Time to distant failure was defined to be time to regional nodal failure or distant metastases and was not censored for local recurrence, contralateral breast cancer, or death from other causes. We evaluated the following characteristics: histologic grade (modified Bloom-Richardson, 219 grade I, 482 grade II, 380 grade III), estrogen receptor (252 ER neg, 386 ER pos, 443 ER unk), positive axillary nodes (0,1-3,≥4, no axillary dissection in 214), adjuvant chemotherapy (in 291 patients), T stage, lymphatic vessel invasion, mononuclear cell response, clinical size in mm, age at diagnosis, and necrosis. Results: A stepwise prohaz model found all the above characteristics except the last three to be significant (all p 0 (i.e., grade III has a larger risk) but for following years, the log hazard ratio is < 0 (i.e., grade II has a large risk; see Figure for estimated log hazard ratio and 95% CI). The test for non-proportionality of grade II vs. grade I (p=0.08) and ER positive vs negative (p=0.06) were suggestive but the log hazard ratios never cross 0 (i.e., no reversal of direction of risk). Conclusions: Tumor grade clearly
Evaluation of brain tumors by simultaneous dual isotope SPECT with 201Tl-chloride and 99mTc-MIBI
International Nuclear Information System (INIS)
Nagai, Hidemasa; Yamasaki, Toshiki; Yamamoto, Yoshiaki; Takada, Daikei; Miyazaki, Takeshi; Sugimoto, Keiji; Matsumoto, Yoshifumi; Akiyama, Yasuhiko; Moritake, Kouzo
2004-01-01
Single photon emission computed tomography (SPECT) is useful for detecting brain tumors. In this study, we evaluated the utility of simultaneous dual SPECT with 201 Tl-Chloride (Tl) and 99m Tc-MIBI (MIBI) for diagnosis of brain tumors. We evaluated 20 cases, including 2 glioblastomas, 7 anaplastic astrocytomas, 2 oligodendrogliomas, 2 anaplastic ependymomas, 2 medulloblastomas, 2 meningiomas, 1 malignant meningioma, 1 pituitary adenoma, and 1 craniopharyngioma. We analyzed the uptake ratio (T/N ratio) of tracers in both Tl and MIBI at max counts/pixels ratio in the region of interest. The T/N ratios in early and delayed images were described as early ratios (ER) and delay ratios (DR), respectively. The retention index (RI) was calculated as the DR/ER ratio. Significant correlations were found between ER and DR for both Tl (DR=0.797 x ER+0.359, r=0.871), and MIBI (DR=0.961 x ER-0.191, r=0.784). Next, we analyzed the correlations between Tl and MIBI SPECT, for ER, DR, and RI. ER values for the two were strongly correlated (r=0.791), DR values were weakly correlated (r=0.556), and RI exhibited no correlation between them (r=0.328). There were no correlations between tumor volume and T/N ratio for the two (ER-Tl; r=0.0095, DR-Tl; r=0.0050, ER-MIBI; r=0.036, DR-MIBI; r=0.254). Lastly no correlation was found between RI-Tl and RI-MIBI (r=0.328). We discuss the difference in the mechanism of accumulation of two tracers and the significance of simultaneous dual SPECT using them for the differential diagnosis of pituitary tumors, regrowth of oligodendrogliomas, and multi-drug resistance of chemotherapy. Dual SPECT with Tl and MIBI appears to be useful for the diagnosis of brain tumor. (author)
Thermodynamic assessments of the Ag-Er and Er-Y systems
International Nuclear Information System (INIS)
Wang, S.L.; Wang, C.P.; Liu, X.J.; Tang, A.T.; Pan, F.S.; Ishida, K.
2010-01-01
The phase diagrams and thermodynamic properties in the Ag-Er and Er-Y binary systems have been assessed by using the CALPHAD (Calculation of Phase Diagrams) method on the basis of the experimental data including the thermodynamic properties and phase equilibria. The Gibbs free energies of the liquid, bcc, fcc, and hcp phases were described by the subregular solution model with the Redlich-Kister equation, and those of intermetallic compounds (Ag 2 Er and AgEr phases) were treated as stoichiometric compounds, and Ag 51 Er 14 phase was modeled by the sublattice model in the Ag-Er binary system. The thermodynamic parameters of the Ag-Er and Er-Y binary systems were obtained, and an agreement between the calculated results and experimental data was obtained for each binary system.
DEFF Research Database (Denmark)
Rosenbaum, Philip
2017-01-01
I en tid, hvor ”det postfaktuelle samfund” er det mest populære udtryk øst for Valby bakke, er det vigtigt for de profaktuelle fanebærere at forstå, at fakta og evidens ikke i sig selv ændrer på folks opfattelse og holdninger. For at evidensbaserede argumenter skal få en vigtig position i samfund...
International Nuclear Information System (INIS)
Kim, Mi Young; Cho, Nariya; Koo, Hye Ryoung; Yun, Bo La; Bae, Min Sun; Moon, Woo Kyung; Chie, Eui Kyu
2013-01-01
Background: The level of background parenchymal enhancement around tumor is known to be associated with breast cancer risk. However, there is no study investigating predictive power of parenchymal signal enhancement ratio (SER) around tumor for ipsilateral breast tumor recurrence (IBTR). Purpose: To investigate whether the breast parenchymal SER around the tumor on preoperative dynamic contrast-enhanced magnetic resonance imaging (MRI) is associated with subsequent IBTR in breast cancer patients who had undergone breast-conserving treatment. Material and Methods: Nineteen consecutive women (mean age, 44 years; range, 34-63 years) with breast cancer who developed IBTR following breast-conserving treatment and 114 control women matched for age, as well as T and N stages were included. We compared the clinicopathologic features of the two groups including nuclear grade, histologic grade, hormonal receptor status, human epidermal growth factor receptor-2 (HER-2) status, lymphovascular invasion, negative margin width, use of adjuvant therapy, and parenchymal SER around the tumor on preoperative DCE-MRI. The SER was measured on a slice showing the largest dimension of the tumor. Multivariate conditional logistic regression analysis was used to identify independent factors associated with IBTR. Results: In univariate analysis, ER negativity (odds ratio [OR] = 4.7; P = 0.040), PR negativity (OR = 4.0; P = 0.013), HER-2 positivity (OR = 3.6; P = 0.026), and a parenchymal SER greater than 0.53 (OR = 23.3; P = 0.011) were associated with IBTR. In multivariate analysis, ER negativity (OR = 3.8; P = 0.015) and a parenchymal SER greater than 0.53 (OR = 13.2; P = 0.040) on preoperative MRI were independent factors associated with IBTR. Conclusion: In addition to ER negativity, a higher parenchymal SER on preoperative MRI was an independent factor associated with subsequent IBTR in patients with breast cancer who had undergone breast-conserving treatment
Tracking of [{sup 18}F]FDG-labeled natural killer cells to HER2/neu-positive tumors
Energy Technology Data Exchange (ETDEWEB)
Meier, Reinhard [Department of Radiology, University of California San Francisco (United States)], E-mail: reinhardt.meier@gmail.com; Piert, Morand [Department of Radiology, Division of Nuclear Medicine, University of Michigan (United States); Piontek, Guido; Rudelius, Martina [Institute of Pathology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Oostendorp, Robert A. [3rd Department of Internal Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Senekowitsch-Schmidtke, Reingard [Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Henning, Tobias D. [Department of Radiology, University of California San Francisco (United States); Wels, Winfried S.; Uherek, Christoph [Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt am Main (Germany); Rummeny, Ernst J. [Department of Radiology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Daldrup-Link, Heike E. [Department of Radiology, University of California San Francisco (United States)
2008-07-15
Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [{sup 18}F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [{sup 18}F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [{sup 18}F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [{sup 18}F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10{sup 6} [{sup 18}F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10{sup 6} NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [{sup 18}F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography.
Loi, Sherene; Sirtaine, Nicolas; Piette, Fanny; Salgado, Roberto; Viale, Giuseppe; Van Eenoo, Françoise; Rouas, Ghizlane; Francis, Prudence; Crown, John P A; Hitre, Erika; de Azambuja, Evandro; Quinaux, Emmanuel; Di Leo, Angelo; Michiels, Stefan; Piccart, Martine J; Sotiriou, Christos
2013-03-01
Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor
DEFF Research Database (Denmark)
Skriver, Signe Korsgaard; Laenkholm, Anne-Vibeke; Rasmussen, Birgitte Bruun
2018-01-01
response and 55% of patients had partial pathological response. ER at 100%, ductal subtype, tumor size below 2 cm and lymph node-negative status was significantly associated with a better response to NET and malignancy grade 3 with a poorer response to NET. One patient progressed during treatment......INTRODUCTION: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here......, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design. MATERIAL AND METHODS: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive...
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Erica B Schleifman
Full Text Available Patients with newly diagnosed, early stage estrogen receptor positive (ER+ breast cancer often show disease free survival in excess of five years following surgery and systemic adjuvant therapy. An important question is whether diagnostic tumor tissue from the primary lesion offers an accurate molecular portrait of the cancer post recurrence and thus may be used for predictive diagnostic purposes for patients with relapsed, metastatic disease. As the class I phosphatidylinositol 3' kinase (PI3K pathway is frequently activated in ER+ breast cancer and has been linked to acquired resistance to hormonal therapy, we hypothesized pathway status could evolve over time and treatment. Biomarker analyses were conducted on matched, asynchronous primary and metastatic tumors from 77 patients with ER+ breast cancer. We examined whether PIK3CA and AKT1 alterations or PTEN and Ki67 levels showed differences between primary and metastatic samples. We also sought to look more broadly at gene expression markers reflective of proliferation, molecular subtype, and key receptors and signaling pathways using an mRNA analysis platform developed on the Fluidigm BioMark™ microfluidics system to measure the relative expression of 90 breast cancer related genes in formalin-fixed paraffin-embedded (FFPE tissue. Application of this panel of biomarker assays to matched tumor pairs showed a high concordance between primary and metastatic tissue, with generally few changes in mutation status, proliferative markers, or gene expression between matched samples. The collection of assays described here has been optimized for FFPE tissue and may have utility in exploratory analyses to identify patient subsets responsive to targeted therapies.
Rennie, P S; Mawji, N R; Coldman, A J; Godolphin, W; Jones, E C; Vielkind, J R; Bruchovsky, N
1993-12-15
Although smaller variant forms of estrogen receptor (ER) messenger RNA (mRNA) have been detected in breast tumors, neither their prevalence nor their prognostic significance have been evaluated. Similarly, TRPM-2 mRNA, the product of a gene induced principally during the onset of apoptosis, is present in mouse and human breast cancer cell lines, but whether it also occurs in primary breast tumors and is related to disease outcome is unknown. The relative expression and transcript size of ER mRNA and TRPM-2 mRNA in 126 primary breast tumors were measured by Northern analysis and compared with tumor grade, hormone receptor status, extent of tumor necrosis, and survival. In ER-positive tumors, 64% of the tumors had only the normal 6.5 kb ER mRNA, an additional 9% had the normal plus smaller ER mRNA, and 2% had variant forms. Only 8% of ER-negative tumors had ER mRNA transcripts. There were significant relationships between the occurrence of ER mRNA and low tumor grade, ER-positive receptor status, and better survival. In contrast, TRPM-2 mRNA was found in only 17% of breast tumors, none of which could be grouped with respect to grade, hormone receptor status, or survival. The presence of smaller variant forms of ER mRNA either alone or in association with the normal ER transcript is not indicative of an unfavorable prognosis, whereas TRPM-2 mRNA occurs in many primary breast tumors, but has no apparent relationship to survival.
DEFF Research Database (Denmark)
Henriksen, Katrine L; Rasmussen, Birgitte B; Lykkesfeldt, Anne E
2009-01-01
microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER...
Imaging of Hsp70-positive tumors with cmHsp70.1 antibody-conjugated gold nanoparticles
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Gehrmann MK
2015-09-01
Full Text Available Mathias K Gehrmann,1 Melanie A Kimm,2 Stefan Stangl,1 Thomas E Schmid,1 Peter B Noël,2 Ernst J Rummeny,2 Gabriele Multhoff11Department of Radiation Oncology, 2Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, GermanyAbstract: Real-time imaging of small tumors is still one of the challenges in cancer diagnosis, prognosis, and monitoring of clinical outcome. Targeting novel biomarkers that are selectively expressed on a large variety of different tumors but not normal cells has the potential to improve the imaging capacity of existing methods such as computed tomography. Herein, we present a novel technique using cmHsp70.1 monoclonal antibody-conjugated spherical gold nanoparticles for quantification of the targeted uptake of gold nanoparticles into membrane Hsp70-positive tumor cells. Upon binding, cmHsp70.1-conjugated gold nanoparticles but not nanoparticles coupled to an isotype-matched IgG1 antibody or empty nanoparticles are rapidly taken up by highly malignant Hsp70 membrane-positive mouse tumor cells. After 24 hours, the cmHsp70.1-conjugated gold nanoparticles are found to be enriched in the perinuclear region. Specificity for membrane Hsp70 was shown by using an Hsp70 knockout tumor cell system. Toxic side effects of the cmHsp70.1-conjugated nanoparticles are not observed at a concentration of 1–10 µg/mL. Experiments are ongoing to evaluate whether cmHsp70.1 antibody-conjugated gold nanoparticles are suitable for the detection of membrane-Hsp70-positive tumors in vivo.Keywords: heat shock protein 70, tumor biomarker, theranostics, multimodal CT, multispectral CT, k-edge
Brom, Maarten; Joosten, Lieke; Laverman, Peter; Oyen, Wim J.G.; Béhé, Martin; Gotthardt, Martin; Boerman, Otto C.
2011-01-01
In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor–positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET–computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor–mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor–positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor–positive tumors in humans. PMID:21439259
Directory of Open Access Journals (Sweden)
Maarten Brom
2011-03-01
Full Text Available In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0 showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET, which could improve image quality. Targeting of cholecystokinin-2 (CCK2/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g, indicating CCK2/gastrin receptor-mediated uptake (p = .0005. The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.
Li, Bei-Xu; Li, Jia; Luo, Cheng-Liang; Zhang, Ming-Chang; Li, Hui; Li, Li-Liang; Xu, Hong-Fei; Shen, Yi-Wen; Xue, Ai-Min; Zhao, Zi-Qin
2013-03-01
Jumonji Domain Containing 2A (JMJD2A) may be a cancer-associated gene involved in human breast cancer. With a view to investigating expression of JMJD2A in human breast cancer and benign lesion tissues as well as relationship between JMJD2A and tumor related proteins, histological and immunohistochemical analysis, Western blot and quantitative real-time PCR in infiltrating duct carcinoma and fibroadenoma for JMJD2A and immunohistochemical analysis and quantitative real-time PCR in infiltrating duct carcinoma for tumor related proteins (ARHI, p53, ER, PR and CerbB-2) were performed. Histological examination validated the clinical diagnosis. The JMJD2A positive rate of infiltrating duct carcinoma was significantly higher than fibroadenoma by immunohistochemical analysis. The mean optical density of JMJD2A in infiltrating duct carcinoma was higher than fibroadenoma by western blot. JMJD2A mRNA level in infiltrating duct carcinoma was higher than fibroadenoma by quantitative real-time PCR. Spearman correlation analysis revealed that the expression of JMJD2A was associated with ARHI, p53 and ER from immunohistochemical results respectively. Pearson correlation analysis revealed that the expression of JMJD2A was associated with ARHI, p53 and ER from quantitative real-time PCR results respectively. Expression of JMJD2A in infiltrating duct carcinoma was higher, and associated with ARHI, p53 and ER. The results may take JMJD2A as a potential diagnostic and therapeutic target in human breast cancer.
Zhang, Lu; Yu, Qingzhao; Wu, Xiao-Cheng; Hsieh, Mei-Chin; Loch, Michelle; Chen, Vivien W; Fontham, Elizabeth; Ferguson, Tekeda
2018-05-01
To investigate the impact of chemotherapy relative dose intensity (RDI) on cause-specific and overall survival for stage I-III breast cancer: estrogen receptor or progesterone receptor positive, human epidermal-growth factor receptor negative (ER+/PR+ and HER2-) vs. triple-negative (TNBC) and to identify the optimal RDI cut-off points in these two patient populations. Data were collected by the Louisiana Tumor Registry for two CDC-funded projects. Women diagnosed with stage I-III ER+/PR+, HER2- breast cancer, or TNBC in 2011 with complete information on RDI were included. Five RDI cut-off points (95, 90, 85, 80, and 75%) were evaluated on cause-specific and overall survival, adjusting for multiple demographic variables, tumor characteristics, comorbidity, use of granulocyte-growth factor/cytokines, chemotherapy delay, chemotherapy regimens, and use of hormone therapy. Cox proportional hazards models and Kaplan-Meier survival curves were estimated and adjusted by stabilized inverse probability treatment weighting (IPTW) of propensity score. Of 494 ER+/PR+, HER2- patients and 180 TNBC patients, RDI PR+, HER2- patients, 85% was the only cut-off point at which the low RDI was significantly associated with worse overall survival (HR = 1.93; 95% CI 1.09-3.40). Among TNBC patients, 75% was the cut-off point at which the high RDI was associated with better cause-specific (HR = 2.64; 95% CI 1.09, 6.38) and overall survival (HR = 2.39; 95% CI 1.04-5.51). Higher RDI of chemotherapy is associated with better survival for ER+/PR+, HER2- patients and TNBC patients. To optimize survival benefits, RDI should be maintained ≥ 85% in ER+/PR+, HER2- patients, and ≥ 75% in TNBC patients.
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Francescopaolo Di Cello
Full Text Available Downregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of claudin 1 via DNA promoter methylation may thus be an important determinant in breast cancer development and progression. To investigate if silencing of claudin 1 has an epigenetic etiology in breast cancer we compared gene expression and methylation data from 217 breast cancer samples and 40 matched normal samples available through the Cancer Genome Atlas (TCGA. Moreover, we analyzed claudin 1 expression and methylation in 26 breast cancer cell lines. We found that methylation of the claudin 1 promoter CpG island is relatively frequent in estrogen receptor positive (ER+ breast cancer and is associated with low claudin 1 expression. In contrast, the claudin 1 promoter was not methylated in most of the ER-breast cancers samples and some of these tumors overexpress claudin 1. In addition, we observed that the demethylating agents, azacitidine and decitabine can upregulate claudin 1 expression in breast cancer cell lines that have a methylated claudin 1 promoter. Taken together, our results indicate that DNA promoter methylation is causally associated with downregulation of claudin 1 in a subgroup of breast cancer that includes mostly ER+ tumors, and suggest that epigenetic therapy to restore claudin 1 expression might represent a viable therapeutic strategy in this subtype of breast cancer.
Du, Yinping; Yu, Jieshi; Du, Li; Tang, Jun; Feng, Wen-Hai
2016-07-01
The consistent latent presence of Epstein-Barr virus (EBV) in tumor cells offers potential for virus-targeted therapies. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. In this study, we report that a natural small molecule compound, cordycepin, can induce lytic EBV infection in tumor cells. Subsequently, we demonstrate that cordycepin can enhance EBV reactivating capacity and EBV-positive tumor cell killing ability of low dose doxorubicin. The combination of cordycepin and doxorubicin phosphorylates CCAAT/enhancer binding protein β (C/EBPβ) through protein kinase C (PKC)-p38 mitogen activated protein kinases (p38 MAPK) signaling pathway, and C/EBPβ is required for the activation of lytic EBV infection. Most importantly, an in vivo experiment demonstrates that the combination of cordycepin and doxorubicin is more effective in inhibiting tumor growth in SCID mice than is doxorubicin alone. Our findings establish that cordycepin can enhance the efficacy of conventional chemotherapy for treatment of EBV-positive tumors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
DEFF Research Database (Denmark)
Yang, Xiaohong R; Chang-Claude, Jenny; Goode, Ellen L
2011-01-01
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.......Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors....
Hvis en kartoffel er forkert, hvad er en Mars-bar så?
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Lichtenstein, Mia Beck; Thomsen, Freja; Hinze, Cecilie
2016-01-01
Danske unge er de slankeste af 41 europæiske unge, men de føler sig ofte tykke og går på slankekur. Hvad er årsagen, og hvorfor er det et problem?......Danske unge er de slankeste af 41 europæiske unge, men de føler sig ofte tykke og går på slankekur. Hvad er årsagen, og hvorfor er det et problem?...
Directory of Open Access Journals (Sweden)
Wen-Tsung Huang
2017-12-01
Full Text Available Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+ breast cancer patients. Even though dysregulations of histone deacetylases (HDACs are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan–Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.
Directory of Open Access Journals (Sweden)
Taiji Kuwata
2011-12-01
Full Text Available We present a very rare case of cerebellar metastasis of unknown origin, in which a primary lung adenocarcinoma was diagnosed by pathological examination of a cerebellar metastatic tumor, using immunohistochemical markers and epidermal growth factor receptor (EGFR mutation of primary lung cancer. A 69-year-old woman was admitted to our hospital because of a hemorrhagic cerebellar tumor and multiple small brain tumors. She underwent cerebellar tumor resection. On pathological examination, the tumor was diagnosed as adenocarcinoma. However, the primary tumor site was unidentifiable even with several imaging inspections. On immunohistochemical analysis, the resected tumor was positive for napsin A and thyroid transcription factor-1. In addition, an EGFR mutation was detected in the tumor. Therefore, primary lung cancer was diagnosed and the patient was started on gefitinib (250 mg/day therapy.
International Nuclear Information System (INIS)
Frame, C; Ding, G
2014-01-01
Purpose: To quantify patient setups errors based on bony anatomy registration rather than 3D tumor alignment for SBRT lung treatments. Method: A retrospective study was performed for patients treated with lung SBRT and imaged with kV cone beam computed tomography (kV-CBCT) image-guidance. Daily CBCT images were registered to treatment planning CTs based on bony anatomy alignment and then inter-fraction tumor movement was evaluated by comparing shift in the tumor center in the medial-lateral, anterior-posterior, and superior-inferior directions. The PTV V100% was evaluated for each patient based on the average daily tumor displacement to assess the impact of the positioning error on the target coverage when the registrations were based on bony anatomy. Of the 35 patients studied, 15 were free-breathing treatments, 10 used abdominal compression with a stereotactic body frame, and the remaining 10 were performed with BodyFIX vacuum bags. Results: For free-breathing treatments, the range of tumor displacement error is between 1–6 mm in the medial-lateral, 1–13 mm in the anterior-posterior, and 1–7 mm in the superior-inferior directions. These positioning errors lead to 6–22% underdose coverage for PTV - V100% . Patients treated with abdominal compression immobilization showed positional errors of 0–4mm mediallaterally, 0–3mm anterior-posteriorly, and 0–2 mm inferior-superiorly with PTV - V100% underdose ranging between 6–17%. For patients immobilized with the vacuum bags, the positional errors were found to be 0–1 mm medial-laterally, 0–1mm anterior-posteriorly, and 0–2 mm inferior-superiorly with PTV - V100% under dose ranging between 5–6% only. Conclusion: It is necessary to align the tumor target by using 3D image guidance to ensure adequate tumor coverage before performing SBRT lung treatments. The BodyFIX vacuum bag immobilization method has the least positioning errors among the three methods studied when bony anatomy is used for
Niemiec, Joanna; Adamczyk, Agnieszka; Harazin-Lechowska, Agnieszka; Ambicka, Aleksandra; Grela-Wojewoda, Aleksandra; Majchrzyk, Kaja; Kruczak, Anna; Sas-Korczyńska, Beata; Ryś, Janusz
2018-04-01
We compared the status of stromal podoplanin-positive cancer-associated fibroblasts (ppCAFs) between primary tumors and paired synchronous lymph node metastases (LNMs) and analyzed the prognostic significance of tumoral ppCAFs in 203 patients with human epidermal growth factor receptor 2-positive breast carcinoma. ppCAFs were found in 167/203 and in 35/87 tumors and LNM, respectively. ppCAFs were most frequently found in tumors and corresponding LNM (n=52, 59.8%; p=0.001). However, for all LNMs (n=12) without ppCAFs, their paired tumors also lacked ppCAFs. In both tumors and LNMs, ppCAFs were α-smooth muscle actin-positive and cluster of differentiation 21 protein-negative, suggesting them not to be resident lymph node cells. Moreover, in our series, the presence of ppCAFs in tumors was borderline related to poor disease-free survival (p=0.058). These results speak in favor of a hypothesis suggesting ppCAFs accompany metastatic cancer cells migrating from tumor to LNMs. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
Freund, Ariane; Chauveau, Corine; Brouillet, Jean-Paul; Lucas, Annick; Lacroix, Matthieu; Licznar, Anne; Vignon, Françoise; Lazennec, Gwendal
2003-01-01
Estrogen receptor (ER) status is an important parameter in breast cancer management as ER-positive breast cancers have a better prognosis than ER-negative tumors. This difference comes essentially from the lower aggressiveness and invasiveness of ER-positive tumors. Here, we demonstrate, that IL-8 was clearly overexpressed in most ER-negative breast, ovary cell lines and breast tumor samples tested, whereas no significant IL-8 level could be detected in ER-positive breast or ovarian cell lines. We have also cloned human IL-8 from ER-negative MDA-MB-231 cells and we show that IL-8 produced by breast cancer cells is identical to monocyte-derived IL-8. Interestingly, the invasion potential of ER-negative breast cancer cells is associated at least in part with expression of interleukin-8 (IL-8), but not with IL-8 receptors levels. Moreover, IL-8 increases the invasiveness of ER-positive breast cancer cells by 2 fold, thus confirming the invasion-promoting role of IL-8. On the other hand, exogenous expression of estrogen receptors in ER-negative cells led to a decrease of IL-8 levels. In summary, our data show that IL-8 expression is negatively linked to ER-status of breast and ovarian cancer cells. We also support the idea that IL-8 expression is associated with a higher invasiveness potential of cancer cells in vitro, which suggests that IL-8 could be a novel marker of tumor aggressiveness. PMID:12527894
ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology.
Manford, Andrew G; Stefan, Christopher J; Yuan, Helen L; Macgurn, Jason A; Emr, Scott D
2012-12-11
Endoplasmic reticulum-plasma membrane (ER-PM) junctions are conserved structures defined as regions of the ER that tightly associate with the plasma membrane. However, little is known about the mechanisms that tether these organelles together and why such connections are maintained. Using a quantitative proteomic approach, we identified three families of ER-PM tethering proteins in yeast: Ist2 (related to mammalian TMEM16 ion channels), the tricalbins (Tcb1/2/3, orthologs of the extended synaptotagmins), and Scs2 and Scs22 (vesicle-associated membrane protein-associated proteins). Loss of all six tethering proteins results in the separation of the ER from the PM and the accumulation of cytoplasmic ER. Importantly, we find that phosphoinositide signaling is misregulated at the PM, and the unfolded protein response is constitutively activated in the ER in cells lacking ER-PM tether proteins. These results reveal critical roles for ER-PM contacts in cell signaling, organelle morphology, and ER function. Copyright © 2012 Elsevier Inc. All rights reserved.
DEFF Research Database (Denmark)
Figueroa, Jonine D; Garcia-Closas, Montserrat; Humphreys, Manjeet
2011-01-01
for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling......A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer......10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11...
Emerging Role of the Unfolded Protein Response in Tumor Immunosurveillance.
Vanacker, Hélène; Vetters, Jessica; Moudombi, Lyvia; Caux, Christophe; Janssens, Sophie; Michallet, Marie-Cécile
2017-07-01
Disruption of endoplasmic reticulum (ER) homeostasis results in ER stress and activation of the unfolded protein response (UPR). This response alleviates cell stress, and is activated in both tumor cells and tumor infiltrating immune cells. The UPR plays a dual function in cancer biology, acting as a barrier to tumorigenesis at the premalignant stage, while fostering cancer maintenance in established tumors. In infiltrating immune cells, the UPR has been involved in both immunosurveillance and immunosuppressive functions. This review aims to decipher the role of the UPR at different stages of tumorigenesis and how the UPR shapes the balance between immunosurveillance and immune escape. This knowledge may improve existing UPR-targeted therapies and the design of novel strategies for cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.
DEFF Research Database (Denmark)
Widell, Peter
2012-01-01
artiklen er et bidrag til belysningen af genteori og bygger på ideen om at karakterisere skønlitteratur som et restringeret sæt af universelle tekstparametre. Artiklen fokuserer især på parametren tekstfiktion, hvor jeg forsvarer den position, at en fiktiv tekst hverken kan karakteriseres som en ...... intentioner. Det betyder dog ikke, at sandhed og mening ikke spiller noget rolle ved identifikationen af fiktion, sådan som det hævdes af Walsh og andre....
International Nuclear Information System (INIS)
Zhang Mutian; Huang Minming; Le, Carl; Zanzonico, Pat B; Ling, C Clifton; Koutcher, Jason A; Humm, John L; Claus, Filip; Kolbert, Katherine S; Martin, Kyle
2008-01-01
Dedicated small-animal imaging devices, e.g. positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) scanners, are being increasingly used for translational molecular imaging studies. The objective of this work was to determine the positional accuracy and precision with which tumors in situ can be reliably and reproducibly imaged on dedicated small-animal imaging equipment. We designed, fabricated and tested a custom rodent cradle with a stereotactic template to facilitate registration among image sets. To quantify tumor motion during our small-animal imaging protocols, 'gold standard' multi-modality point markers were inserted into tumor masses on the hind limbs of rats. Three types of imaging examination were then performed with the animals continuously anesthetized and immobilized: (i) consecutive microPET and MR images of tumor xenografts in which the animals remained in the same scanner for 2 h duration, (ii) multi-modality imaging studies in which the animals were transported between distant imaging devices and (iii) serial microPET scans in which the animals were repositioned in the same scanner for subsequent images. Our results showed that the animal tumor moved by less than 0.2-0.3 mm over a continuous 2 h microPET or MR imaging session. The process of transporting the animal between instruments introduced additional errors of ∼0.2 mm. In serial animal imaging studies, the positioning reproducibility within ∼0.8 mm could be obtained.
DEFF Research Database (Denmark)
Figueroa, Jonine D; Garcia-Closas, Montserrat; Humphreys, Manjeet
2011-01-01
A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer As...
Androgen receptor expression on circulating tumor cells in metastatic breast cancer.
Directory of Open Access Journals (Sweden)
Takeo Fujii
Full Text Available Androgen receptor (AR is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+ breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer.Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK, and biomarkers of interest (AR, estrogen receptor [ER], and HER2 on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms.Of 68 patients, 51 (75% had at least 1 CTC, and 49 of these 51 (96% had hormone-receptor-positive (HR+/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells.CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.
Feasibility of using single photon counting X-ray for lung tumor position estimation based on 4D-CT.
Aschenbrenner, Katharina P; Guthier, Christian V; Lyatskaya, Yulia; Boda-Heggemann, Judit; Wenz, Frederik; Hesser, Jürgen W
2017-09-01
In stereotactic body radiation therapy of lung tumors, reliable position estimation of the tumor is necessary in order to minimize normal tissue complication rate. While kV X-ray imaging is frequently used, continuous application during radiotherapy sessions is often not possible due to concerns about the additional dose. Thus, ultra low-dose (ULD) kV X-ray imaging based on a single photon counting detector is suggested. This paper addresses the lower limit of photons to locate the tumor reliably with an accuracy in the range of state-of-the-art methods, i.e. a few millimeters. 18 patient cases with four dimensional CT (4D-CT), which serves as a-priori information, are included in the study. ULD cone beam projections are simulated from the 4D-CTs including Poisson noise. The projections from the breathing phases which correspond to different tumor positions are compared to the ULD projection by means of Poisson log-likelihood (PML) and correlation coefficient (CC), and template matching under these metrics. The results indicate that in full thorax imaging five photons per pixel suffice for a standard deviation in tumor positions of less than half a breathing phase. Around 50 photons per pixel are needed to achieve this accuracy with the field of view restricted to the tumor region. Compared to CC, PML tends to perform better for low photon counts and shifts in patient setup. Template matching only improves the position estimation in high photon counts. The quality of the reconstruction is independent of the projection angle. The accuracy of the proposed ULD single photon counting system is in the range of a few millimeters and therefore comparable to state-of-the-art tumor tracking methods. At the same time, a reduction in photons per pixel by three to four orders of magnitude relative to commercial systems with flatpanel detectors can be achieved. This enables continuous kV image-based position estimation during all fractions since the additional dose to the
Feasibility of using single photon counting X-ray for lung tumor position estimation based on 4D-CT
Energy Technology Data Exchange (ETDEWEB)
Aschenbrenner, Katharina P.; Hesser, Juergen W. [Heidelberg Univ., Mannheim (Germany). Dept. of Experimental Radiation Oncology; Heidelberg Univ. (Germany). IWR; Guthier, Christian V. [Heidelberg Univ., Mannheim (Germany). Dept. of Experimental Radiation Oncology; Lyatskaya, Yulia [Brigham and Women' s Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Boda-Heggemann, Judit; Wenz, Frederik [Heidelberg Univ., Mannheim (Germany). Dept. of Radiation Oncology
2017-10-01
In stereotactic body radiation therapy of lung tumors, reliable position estimation of the tumor is necessary in order to minimize normal tissue complication rate. While kV X-ray imaging is frequently used, continuous application during radiotherapy sessions is often not possible due to concerns about the additional dose. Thus, ultra low-dose (ULD) kV X-ray imaging based on a single photon counting detector is suggested. This paper addresses the lower limit of photons to locate the tumor reliably with an accuracy in the range of state-of-the-art methods, i.e. a few millimeters. 18 patient cases with four dimensional CT (4D-CT), which serves as a-priori information, are included in the study. ULD cone beam projections are simulated from the 4D-CTs including Poisson noise. The projections from the breathing phases which correspond to different tumor positions are compared to the ULD projection by means of Poisson log-likelihood (PML) and correlation coefficient (CC), and template matching under these metrics. The results indicate that in full thorax imaging five photons per pixel suffice for a standard deviation in tumor positions of less than half a breathing phase. Around 50 photons per pixel are needed to achieve this accuracy with the field of view restricted to the tumor region. Compared to CC, PML tends to perform better for low photon counts and shifts in patient setup. Template matching only improves the position estimation in high photon counts. The quality of the reconstruction is independent of the projection angle. The accuracy of the proposed ULD single photon counting system is in the range of a few millimeters and therefore comparable to state-of-the-art tumor tracking methods. At the same time, a reduction in photons per pixel by three to four orders of magnitude relative to commercial systems with flatpanel detectors can be achieved. This enables continuous kV image-based position estimation during all fractions since the additional dose to the
Feasibility of using single photon counting X-ray for lung tumor position estimation based on 4D-CT
International Nuclear Information System (INIS)
Aschenbrenner, Katharina P.; Hesser, Juergen W.; Boda-Heggemann, Judit; Wenz, Frederik
2017-01-01
In stereotactic body radiation therapy of lung tumors, reliable position estimation of the tumor is necessary in order to minimize normal tissue complication rate. While kV X-ray imaging is frequently used, continuous application during radiotherapy sessions is often not possible due to concerns about the additional dose. Thus, ultra low-dose (ULD) kV X-ray imaging based on a single photon counting detector is suggested. This paper addresses the lower limit of photons to locate the tumor reliably with an accuracy in the range of state-of-the-art methods, i.e. a few millimeters. 18 patient cases with four dimensional CT (4D-CT), which serves as a-priori information, are included in the study. ULD cone beam projections are simulated from the 4D-CTs including Poisson noise. The projections from the breathing phases which correspond to different tumor positions are compared to the ULD projection by means of Poisson log-likelihood (PML) and correlation coefficient (CC), and template matching under these metrics. The results indicate that in full thorax imaging five photons per pixel suffice for a standard deviation in tumor positions of less than half a breathing phase. Around 50 photons per pixel are needed to achieve this accuracy with the field of view restricted to the tumor region. Compared to CC, PML tends to perform better for low photon counts and shifts in patient setup. Template matching only improves the position estimation in high photon counts. The quality of the reconstruction is independent of the projection angle. The accuracy of the proposed ULD single photon counting system is in the range of a few millimeters and therefore comparable to state-of-the-art tumor tracking methods. At the same time, a reduction in photons per pixel by three to four orders of magnitude relative to commercial systems with flatpanel detectors can be achieved. This enables continuous kV image-based position estimation during all fractions since the additional dose to the
Pailler, Emma; Adam, Julien; Barthélémy, Amélie; Oulhen, Marianne; Auger, Nathalie; Valent, Alexander; Borget, Isabelle; Planchard, David; Taylor, Melissa; André, Fabrice; Soria, Jean Charles; Vielh, Philippe; Besse, Benjamin; Farace, Françoise
2013-06-20
The diagnostic test for ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine-needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs). The presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter-adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib. All ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK-rearranged CTCs harbored a unique (3'5') split pattern, and heterogeneous patterns (3'5', only 3') of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib. ALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.
Case of false positive scanning observed after radiation therapy for orbital tumor
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Ohara, H [Gifu Prefectural Tajimi Hospital (Japan); Nakamura, K; Maeda, S; Watanabe, R; Miyajima, T
1978-12-01
A report was made of 56-year-old female patient of abducensparesis. In the early stage the cause remained undetermined with nothing abnormal noted in scintigraphy. Diplopia disappeared once, but right, exophalmus relapsed. In gammaencepharography, a hot spot was noted in the orbita, sinus ethmoidalis and sirus sphenoidalis. In an operation, squamous cell carcinoma was removed and radiation therapy was performed (total dose of 3520 r) and, three months later a scintigraphy disclosed a high spot of /sup 203/Hg uptake ratio in the right orbita and its lower portions. The biopsy of these portions disclosed a necrotic tissue instead of a tumor. In scintigraphy after radiation therapy against the tumor, it was reported that a positive scintigraphy was present because of the vascular trouble of said portions, although the tumor had disappeared. Attention should be given as well as an opinion of high density together with the examination by CT, especially as to enhancement.
Bassoy, Esen Yonca; Kasahara, Atsuko; Chiusolo, Valentina; Jacquemin, Guillaume; Boydell, Emma; Zamorano, Sebastian; Riccadonna, Cristina; Pellegatta, Serena; Hulo, Nicolas; Dutoit, Valérie; Derouazi, Madiha; Dietrich, Pierre Yves; Walker, Paul R; Martinvalet, Denis
2017-06-01
Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. © 2017 The Authors.
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis.
Schneeberger, Marc; Gómez-Valadés, Alicia G; Altirriba, Jordi; Sebastián, David; Ramírez, Sara; Garcia, Ainhoa; Esteban, Yaiza; Drougard, Anne; Ferrés-Coy, Albert; Bortolozzi, Analía; Garcia-Roves, Pablo M; Jones, John G; Manadas, Bruno; Zorzano, Antonio; Gomis, Ramon; Claret, Marc
2015-07-21
Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Fernand ez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, Miguel
2017-01-01
PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%. PMID:28423537
Perez, Edith A.; Ballman, Karla V.; Mashadi-Hossein, Afshin; Tenner, Kathleen S.; Kachergus, Jennifer M.; Norton, Nadine; Necela, Brian M.; Carr, Jennifer M.; Ferree, Sean; Perou, Charles M.; Baehner, Frederick; Cheang, Maggie Chon U.
2017-01-01
Background: Genomic data from human epidermal growth factor receptor 2–positive (HER2+) tumors were analyzed to assess the association between intrinsic subtype and clinical outcome in a large, well-annotated patient cohort. Methods: Samples from the NCCTG (Alliance) N9831 trial were analyzed using the Prosigna algorithm on the NanoString platform to define intrinsic subtype, risk of recurrence scores, and risk categories for 1392 HER2+ tumors. Subtypes were evaluated for recurrence-free survival (RFS) using Kaplan-Meier and Cox model analysis following adjuvant chemotherapy (n = 484) or chemotherapy plus trastuzumab (n = 908). All statistical tests were two-sided. Results: Patients with HER2+ tumors from N9831 were primarily scored as HER2-enriched (72.1%). These individuals received statistically significant benefit from trastuzumab (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52 to 0.89, P = .005), as did the patients (291 of 1392) with luminal-type tumors (HR = 0.52, 95% CI = 0.32 to 0.85, P = .01). Patients with basal-like tumors (97 of 1392) did not have statistically significantly better RFS when treated with trastuzumab and chemotherapy compared with chemotherapy alone (HR = 1.06, 95% CI = 0.53 to 2.13, P = .87). Conclusions: The majority of clinically defined HER2-positive tumors were classified as HER2-enriched or luminal using the Prosigna algorithm. Intrinsic subtype alone cannot replace conventional histopathological evaluation of HER2 status because many tumors that are classified as luminal A or luminal B will benefit from adjuvant trastuzumab if that subtype is accompanied by HER2 overexpression. However, among tumors that overexpress HER2, we speculate that assessment of intrinsic subtype may influence treatment, particularly with respect to evaluating alternative therapeutic approaches for that subset of HER2-positive tumors of the basal-like subtype. PMID:27794124
Energy Technology Data Exchange (ETDEWEB)
Kawaguchi, Hiroshi; Hirano, Yoshiyuki; Kershaw, Jeff; Yoshida, Eiji [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Shiraishi, Takahiro [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Suga, Mikio [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Center for Frontier Medical Engineering, Chiba University (Japan); Obata, Takayuki [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Ito, Hiroshi; Yamaya, Taiga [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan)
2014-07-29
In recent work, we proposed an MRI-based attenuation-coefficient (μ-value) estimation method that uses a weak fixed-position external radiation source to construct an attenuation map for PET/MRI. In this presentation we refer to this method as FixER, and perform a series of simulations to investigate the duration of the transmission scan required to accurately estimate μ-values.
International Nuclear Information System (INIS)
Kawaguchi, Hiroshi; Hirano, Yoshiyuki; Kershaw, Jeff; Yoshida, Eiji; Shiraishi, Takahiro; Suga, Mikio; Obata, Takayuki; Ito, Hiroshi; Yamaya, Taiga
2014-01-01
In recent work, we proposed an MRI-based attenuation-coefficient (μ-value) estimation method that uses a weak fixed-position external radiation source to construct an attenuation map for PET/MRI. In this presentation we refer to this method as FixER, and perform a series of simulations to investigate the duration of the transmission scan required to accurately estimate μ-values.
Van Keymeulen, Alexandra; Fioramonti, Marco; Centonze, Alessia; Bouvencourt, Gaëlle; Achouri, Younes; Blanpain, Cédric
2017-08-15
The mammary gland (MG) is composed of different cell lineages, including the basal and the luminal cells (LCs) that are maintained by distinct stem cell (SC) populations. LCs can be subdivided into estrogen receptor (ER) + and ER - cells. LCs act as the cancer cell of origin in different types of mammary tumors. It remains unclear whether the heterogeneity found in luminal-derived mammary tumors arises from a pre-existing heterogeneity within LCs. To investigate LC heterogeneity, we used lineage tracing to assess whether the ER + lineage is maintained by multipotent SCs or by lineage-restricted SCs. To this end, we generated doxycycline-inducible ER-rtTA mice that allowed us to perform genetic lineage tracing of ER + LCs and study their fate and long-term maintenance. Our results show that ER + cells are maintained by lineage-restricted SCs that exclusively contribute to the expansion of the ER + lineage during puberty and their maintenance during adult life. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
A review of 99mTc labeled myocardial imaging agents for tumor-positive imaging
International Nuclear Information System (INIS)
Xing Shian; Zhang Yongxue; An Rui
2002-01-01
The tumor-positive imaging with high sensitivity and specificity was useful in primary tumor and recurrences and metastases. The 99m Tc labeled myocardial imaging agents are easily available and stable and the radiochemical purity is high. 99m Tc is the preferred choice in routine works because its physical properties. The preparation, quality control, mechanism of accumulation and the clinical use of 99m Tc-sestamibi, 99m Tc-tetrofosmin, 99m Tc-furifosmin, and 99m Tc-N-NOET were reviewed
DEFF Research Database (Denmark)
Milne, Roger L; Goode, Ellen L; García-Closas, Montserrat
2011-01-01
-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively......BACKGROUND: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association...... and histopathology were assessed using logistic regression. RESULTS: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive...
Characterization of the ER-Targeted Low Affinity Ca2+ Probe D4ER
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Elisa Greotti
2016-09-01
Full Text Available Calcium ion (Ca2+ is a ubiquitous intracellular messenger and changes in its concentration impact on nearly every aspect of cell life. Endoplasmic reticulum (ER represents the major intracellular Ca2+ store and the free Ca2+ concentration ([Ca2+] within its lumen ([Ca2+]ER can reach levels higher than 1 mM. Several genetically-encoded ER-targeted Ca2+ sensors have been developed over the last years. However, most of them are non-ratiometric and, thus, their signal is difficult to calibrate in live cells and is affected by shifts in the focal plane and artifactual movements of the sample. On the other hand, existing ratiometric Ca2+ probes are plagued by different drawbacks, such as a double dissociation constant (Kd for Ca2+, low dynamic range, and an affinity for the cation that is too high for the levels of [Ca2+] in the ER lumen. Here, we report the characterization of a recently generated ER-targeted, Förster resonance energy transfer (FRET-based, Cameleon probe, named D4ER, characterized by suitable Ca2+ affinity and dynamic range for monitoring [Ca2+] variations within the ER. As an example, resting [Ca2+]ER have been evaluated in a known paradigm of altered ER Ca2+ homeostasis, i.e., in cells expressing a mutated form of the familial Alzheimer’s Disease-linked protein Presenilin 2 (PS2. The lower Ca2+ affinity of the D4ER probe, compared to that of the previously generated D1ER, allowed the detection of a conspicuous, more clear-cut, reduction in ER Ca2+ content in cells expressing mutated PS2, compared to controls.
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Steenbuch, Johannes Aakjær
2011-01-01
Der er ikke længere nogen højere sandhed i livet end den, flertallet bestemmer sig for – og dermed ingen del af livet, der ikke er politisk. Højre- og venstrefløjen er i bund og grund enige - enige om, at det er politikernes opgave at forære os det gode liv. Dermed bliver demokratiet totalitært. ...
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Michail Ignatiadis
Full Text Available EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC in combination with paclitaxel.HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2 every 3 weeks followed by surgery. Primary endpoint was percent (% reduction in Magnetic Resonance Imaging (MRI estimated Gadolinium (Gd enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated.Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001 for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04.The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2
Cabinakova, M; Mikulova, V; Malickova, K; Vrana, D; Pavlista, D; Petruzelka, L; Zima, T; Tesarova, P
2015-01-01
Simultaneous detection of disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) was shown to be associated with an especially poor prognosis and increased incidence of disease-related deaths in non-metastatic breast cancer patients. We analyzed the occurance of DTCs and CTCs in patients with primary breast cancer and evaluated the correlation of their presence with other prognostic markers and investigated the changes in DTCs/CTCs number at different time points during treatment.Blood of 50 patients with primary breast cancer were used for immunomagnetic separation and detection of circulating tumor cells using the commercial available system the AdnaTest Breast Cancer™ (AdnaGen GmbH, Langenhagen, Germany). Bone marrow aspirates from 50 patients were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody conjugated with FITC (Monoclonal Anti-Cytokeratin antibody F3418, Sigma Aldrich).DTCs were identified in 30% (15/50) and CTCs in 22% (11/50) of patients. We found that DTC positivity could point to a significantly high risk of larger primary tumor size (p-value 0.011) and significantly higher risk of lymph node involvement (p-value 0.002). For CTC positivity, no such relationship was proven. DTCs have shown significantly higher prevalence in ER/PR-negative females and in HER2-positive cases. CTCs were equally prevalent in patients with the presence and absence of standard prognostic and predictive markers such as ER, PR and HER2. We found no correlation between CTCs and DTCs findings (r = -0.097, p = 0.504). We used DTCs/CTCs analysis for therapy monitoring in a small group of 29 patients, who underwent neoadjuvant chemotherapy (NACT). We find out no significant correlation between DTCs/CTCs detection and the primary tumor response to NACT. A pathologic complete response (pCR) was achieved by 31% (9/29) of the patients in our study, however, no association was observed between pCR and the detection of DTCs after NACT
International Nuclear Information System (INIS)
Takada, Mamoru; Miyazaki, Masaru; Sato-Otsubo, Aiko; Ogawa, Seishi; Kaneko, Yasuhiko; Higuchi, Toru; Tozuka, Katsunori; Takei, Hiroyuki; Haruta, Masayuki; Watanabe, Junko; Kasai, Fumio; Inoue, Kenichi; Kurosumi, Masafumi
2013-01-01
Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. We
Spoelstra, F.O.B.; Sornsen de Koste, van J.R.; Vincent, A.D.; Cuijpers, J.P.; Slotman, B.J.; Senan, S.
2009-01-01
Purpose: Both carina and diaphragm positions have been used as surrogates during respiratory-gated radiotherapy. We studied the correlation of both surrogates with three-dimensional (3D) tumor position. Methods and Materials: A total of 59 repeat artifact-free four-dimensional (4D) computed
Second primary tumor in anti-Ma1/2-positive paraneoplastic limbic encephalitis.
Leyhe, T; Schüle, R; Schwärzler, F; Gasser, T; Haarmeier, T
2006-05-01
Memory loss can be a symptom of paraneoplastic limbic encephalitis (PLE) a neuropsychiatric disorder associated mostly with small-cell lung cancer and anti-Hu antibodies or with testicular tumors and anti-Ma2 antibodies. We present the case of a patient with temporal coincidence of beginning cognitive decline and diagnosis of a carcinoma of the prostate in whom we diagnosed anti-Ma1/Ma2-positive PLE. The tumor had been completely resected but memory impairment further deteriorated. As the effective treatment of the cancer is considered as the most efficient treatment of a paraneoplastic neurological syndrome (PNS) a second neoplasia was suspected in the patient. By the aid of whole body positron emission tomography with 18-fluorine fluoro-2-deoxy-glucose (FDG-PET) an adenocarcinoma of the cecum could be detected. Two months after surgery anti-Ma antibodies were negative. We conclude that a second neoplasia should be considered, if effective cancer treatment does not lead to improvement or stabilisation of a PNS. Tumor search should be exhaustive and include PET when conventional imaging fails to show a malignancy.
Directory of Open Access Journals (Sweden)
Parise Carol
2010-05-01
Full Text Available Abstract Background The 2007 St Gallen international expert consensus statement describes three risk categories and provides recommendations for treatment of early breast cancer. The set of recommendations on how to best treat primary breast cancer is recognized and used by clinicians worldwide. We now examine the variability of five-year survival of the 2007 St Gallen Risk Classifications utilizing the ER/PR/HER2 subtypes. Methods Using the population-based California Cancer Registry, 114,786 incident cases of Stages 1-3 invasive breast cancer diagnosed between 2000 and 2006 were identified. Cases were assigned to Low, Intermediate, or High Risk categories. Five-year-relative survival was computed for the three St Gallen risk categories and for the ER/PR/HER2 subtypes for further differentiation. Results and Discussion There were 9,124 (13% cases classified as Low Risk, 44,234 (65% cases as Intermediate Risk, and 14,340 (21% as High Risk. Within the Intermediate Risk group, 33,735 (76% were node-negative (Intermediate Risk 2 and 10,499 (24% were node-positive (Intermediate Risk 3. For the High Risk group, 6,149 (43% had 1 to 3 positive axillary lymph nodes (High Risk 4 and 8,191 (57% had four or more positive lymph nodes (High Risk 5. Using five-year relative survival as the principal criterion, we found the following: a There was very little difference between the Low Risk and Intermediate Risk categories; b Use of the ER/PR/HER2 subtypes within the Intermediate and High Risk categories separated each into a group with better five-year survival (ER-positive and a group with worse survival (ER-negative, irrespective of HER2-status; c The heterogeneity of the High Risk category was most evident when one examined the ER/PR/HER2 subtypes with four or more positive axillary lymph nodes; (d HER2-positivity did not always translate to worse survival, as noted when one compared the triple positive subtype (ER+/PR+/HER2+ to the triple negative subtype
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Rooijen, Dominique C van; Pool, René; Kamer, Jeroen B van de; Hulshof, Maarten CCM; Koning, Caro CE; Bel, Arjan [Department of Radiation Oncology, Academic Medical Center, Amsterdam (Netherlands)
2010-06-15
The application of lipiodol injections as markers around bladder tumors combined with the use of CBCT for image guidance enables daily on-line position correction based on the position of the bladder tumor. However, this might introduce the risk of underdosing the pelvic lymph nodes. In this study several correction strategies were compared. For this study set-up errors and tumor displacements for ten complete treatments were generated; both were based on the data of 10 bladder cancer patients. Besides, two IMRT plans were made for 20 patients, one for the elective field and a boost plan for the tumor. For each patient 10 complete treatments were simulated. For each treatment the dose was calculated without position correction (option 1), correction on bony anatomy (option 2), on tumor only (option 3) and separately on bone for the elective field (option 4). For each method we analyzed the D{sub 99%} for the tumor, bladder and lymph nodes and the V{sub 95%} for the small intestines, rectum, healthy part of the bladder and femoral heads. CTV coverage was significantly lower with options 1 and 2. With option 3 the tumor coverage was not significantly different from the treatment plan. The ΔD{sub 99%} (D{sub 99%,} {sub option} {sub n} - D{sub 99%,} {sub treatment} {sub plan}) for option 4 was small, but significant. For the lymph nodes the results from option 1 differed not significantly from the treatment plan. The median ΔD{sub 99%} of the other options were small, but significant. ΔD{sub 99%} for PTV{sub bladder} was small for options 1, 2 and 4, but decreased up to -8.5 Gy when option 3 was applied. Option 4 is the only method where the difference with the treatment plan never exceeds 2 Gy. The V{sub 95%} for the rectum, femoral heads and small intestines was small in the treatment plan and this remained so after applying the correction options, indicating that no additional hot spots occurred. Applying independent position correction on bone for the elective
Directory of Open Access Journals (Sweden)
Hulshof Maarten CCM
2010-06-01
Full Text Available Abstract Background The application of lipiodol injections as markers around bladder tumors combined with the use of CBCT for image guidance enables daily on-line position correction based on the position of the bladder tumor. However, this might introduce the risk of underdosing the pelvic lymph nodes. In this study several correction strategies were compared. Methods For this study set-up errors and tumor displacements for ten complete treatments were generated; both were based on the data of 10 bladder cancer patients. Besides, two IMRT plans were made for 20 patients, one for the elective field and a boost plan for the tumor. For each patient 10 complete treatments were simulated. For each treatment the dose was calculated without position correction (option 1, correction on bony anatomy (option 2, on tumor only (option 3 and separately on bone for the elective field (option 4. For each method we analyzed the D99% for the tumor, bladder and lymph nodes and the V95% for the small intestines, rectum, healthy part of the bladder and femoral heads. Results CTV coverage was significantly lower with options 1 and 2. With option 3 the tumor coverage was not significantly different from the treatment plan. The ΔD99% (D99%, option n - D99%, treatment plan for option 4 was small, but significant. For the lymph nodes the results from option 1 differed not significantly from the treatment plan. The median ΔD99% of the other options were small, but significant. ΔD99% for PTVbladder was small for options 1, 2 and 4, but decreased up to -8.5 Gy when option 3 was applied. Option 4 is the only method where the difference with the treatment plan never exceeds 2 Gy. The V95% for the rectum, femoral heads and small intestines was small in the treatment plan and this remained so after applying the correction options, indicating that no additional hot spots occurred. Conclusions Applying independent position correction on bone for the elective field and on
International Nuclear Information System (INIS)
Rooijen, Dominique C van; Pool, René; Kamer, Jeroen B van de; Hulshof, Maarten CCM; Koning, Caro CE; Bel, Arjan
2010-01-01
The application of lipiodol injections as markers around bladder tumors combined with the use of CBCT for image guidance enables daily on-line position correction based on the position of the bladder tumor. However, this might introduce the risk of underdosing the pelvic lymph nodes. In this study several correction strategies were compared. For this study set-up errors and tumor displacements for ten complete treatments were generated; both were based on the data of 10 bladder cancer patients. Besides, two IMRT plans were made for 20 patients, one for the elective field and a boost plan for the tumor. For each patient 10 complete treatments were simulated. For each treatment the dose was calculated without position correction (option 1), correction on bony anatomy (option 2), on tumor only (option 3) and separately on bone for the elective field (option 4). For each method we analyzed the D 99% for the tumor, bladder and lymph nodes and the V 95% for the small intestines, rectum, healthy part of the bladder and femoral heads. CTV coverage was significantly lower with options 1 and 2. With option 3 the tumor coverage was not significantly different from the treatment plan. The ΔD 99% (D 99%, option n - D 99%, treatment plan ) for option 4 was small, but significant. For the lymph nodes the results from option 1 differed not significantly from the treatment plan. The median ΔD 99% of the other options were small, but significant. ΔD 99% for PTV bladder was small for options 1, 2 and 4, but decreased up to -8.5 Gy when option 3 was applied. Option 4 is the only method where the difference with the treatment plan never exceeds 2 Gy. The V 95% for the rectum, femoral heads and small intestines was small in the treatment plan and this remained so after applying the correction options, indicating that no additional hot spots occurred. Applying independent position correction on bone for the elective field and on tumor for the boost separately gives on average the best
Time response model of ER fluids for precision control of motors
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Koyanagi, Ken' ichi [Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama (Japan)], E-mail: koyanagi@pu-toyama.ac.jp
2009-02-01
For improvement of control performance or new control demands of mechatronics devices using particle type ER fluids, it will be needed to further investigate a response time of the fluids. It is commonly said around 5-mili seconds, however, the formula structure of that delay has not been clear. This study aims to develop a functional damper (attenuators), that can control its viscous characteristics in real time using ER fluids as its working fluid. ER dampers are useful to accomplish high precision positioning not to prevent high speed movement of the motor. To realize the functional damper that can be manipulated according to situations or tasks, the modeling and control of ER fluids are necessary. This paper investigates time delay affects of ER fluids and makes an in-depth dynamic model of the fluid by utilizing simulation and experiment. The mathematical model has a dead-time and first ordered delays of the fluid and the high voltage amplifier for the fluid.
International Nuclear Information System (INIS)
Mandal, Soma; Davie, James R
2007-01-01
The sex hormone estrogen (E2) is pivotal to normal mammary gland growth and differentiation and in breast carcinogenesis. In this in silico study, we examined metabolic differences between ER(+)ve breast cancer cells during E2 deprivation. Public repositories of SAGE and MA gene expression data generated from E2 deprived ER(+)ve breast cancer cell lines, MCF-7 and ZR75-1 were compared with normal breast tissue. We analyzed gene ontology (GO), enrichment, clustering, chromosome localization, and pathway profiles and performed multiple comparisons with cell lines and tumors with different ER status. In all GO terms, biological process (BP), molecular function (MF), and cellular component (CC), MCF-7 had higher gene utilization than ZR75-1. Various analyses showed a down-regulated immune function, an up-regulated protein (ZR75-1) and glucose metabolism (MCF-7). A greater percentage of 77 common genes localized to the q arm of all chromosomes, but in ZR75-1 chromosomes 11, 16, and 19 harbored more overexpressed genes. Despite differences in gene utilization (electron transport, proteasome, glycolysis/gluconeogenesis) and expression (ribosome) in both cells, there was an overall similarity of ZR75-1 with ER(-)ve cell lines and ER(+)ve/ER(-)ve breast tumors. This study demonstrates integral metabolic differences may exist within the same cell subtype (luminal A) in representative ER(+)ve cell line models. Selectivity of gene and pathway usage for strategies such as energy requirement minimization, sugar utilization by ZR75-1 contrasted with MCF-7 cells, expressing genes whose protein products require ATP utilization. Such characteristics may impart aggressiveness to ZR75-1 and may be prognostic determinants of ER(+)ve breast tumors
Cobalt-related features of spectral and magnetic properties of RNi4Co (R=Ho, Er)
International Nuclear Information System (INIS)
Lukoyanov, A.V.; Knyazev, Yu.V.; Kuz‘min, Yu.I.; Kuchin, A.G.
2014-01-01
In this paper we investigate spectral and magnetic properties of RNi 4 Co (R=Ho, Er) intermetallics to reveal the features associated with the presence of Co substituting ion in comparison with the parent HoNi 5 and ErNi 5 compounds. Our ab initio LSDA+U calculations show that in the electronic structure Co states are strongly manifested near the Fermi energy for the case of Co in 2c position, while Co in 3g position results only in weak changes of the total DOS curve. Theoretical optical conductivity calculated assuming Co equally redistributed among 2c or 3g positions agrees well with the experimental optical conductivity. Cobalt ion in RNi 4 Co (R=Ho, Er) is characterized by magnetic moment of 1μ B that increases exchange interaction in the 3d sublattice by several times that contributes to the growth of Curie temperature in comparison with the parent compounds. - Highlights: • Electronic structure of RNi4Co (R=Ho, Er) is calculated in LSDA+U. • Cobalt ion is considered in 2c or 3g position and compared. • Experimental optical conductivity is interpreted based on the calculated one
International Nuclear Information System (INIS)
Huang, Long; Tian, Xiumei; Liu, Jun; Zheng, Cunjing; Xie, Fukang; Li, Li
2017-01-01
Our group has synthesized Gd_2O_3:Yb"3"+/Er"3"+ nanocomposites as magnetic/fluorescence imaging successfully in the previous study, which exhibit good uniformity and monodispersibility with a mean size of 7.4 nm. However, their systematic risk assessment remains unknown. In this article, the in vitro biocompatibility of the Gd_2O_3:Yb"3"+/Er"3"+ was assessed on the basis of cell viability and apoptosis. In vivo immunotoxicity was evaluated by monitoring the product of reactive oxygen species (ROS), clusters of differentiation (CD) markers, and superoxide dismutase (SOD) in Balb/c mice. No significant differences were found in cell viability, apoptosis, and immunotoxicity between our Gd_2O_3:Yb"3"+/Er"3"+ and gadodiamide which are used commonly in clinical. Few nanoprobes were localized in the phagosomes of the liver, heart, lung, spleen, kidney, brain, and tumor under the transmission electron microscopy (TEM) images. In addition, our products reveal good T_1-weighted contrast enhancement of xenografted murine tumor. Therefore, the above results may contribute to the effective application of Gd_2O_3:Yb"3"+/Er"3"+ as molecular imaging contrast agents and dual-modal nanoprobes for cancer detection.
International Nuclear Information System (INIS)
Reynisdottir, Inga; Arason, Adalgeir; Einarsdottir, Berglind O; Gunnarsson, Haukur; Staaf, Johan; Vallon-Christersson, Johan; Jonsson, Goran; Ringnér, Markus; Agnarsson, Bjarni A; Olafsdottir, Kristrun; Fagerholm, Rainer; Einarsdottir, Thorbjorg; Johannesdottir, Gudrun; Johannsson, Oskar Thor; Nevanlinna, Heli; Borg, Ake; Barkardottir, Rosa Bjork
2013-01-01
Amplification of 8p12-p11 is relatively common in breast cancer and several genes within the region have been suggested to affect breast tumor progression. The aim of the study was to map the amplified 8p12-p11 region in a large set of breast tumors in an effort to identify the genetic driver and to explore its impact on tumor progression and prognosis. Copy number alterations (CNAs) were mapped in 359 tumors, and gene expression data from 577 tumors (359 tumors included) were correlated with CNA, clinical–pathological factors, and protein expression (39 tumors). 8p12-p11 was amplified in 11.4% of tumors. The smallest region of amplification harbored one full-length gene, ZNF703. ZNF703 mRNA expression was significantly higher in estrogen receptor (ER)-positive than ER-negative tumors (P = 2 × 10 −16 ), a reflection of high expression in luminal tumors. Forty-eight percent of tumors with ZNF703 amplification were luminal B tumors in which the best correlation between DNA copy number and mRNA was seen (P = 1.2 × 10 −7 ) as well as correlation between mRNA and protein expression (P = 0.02). High ZNF703 mRNA correlated with poor survival in patients with ER-positive luminal B tumors (log rank P = 0.04). Furthermore, high ZNF703 mRNA expression correlated with poor outcome in patients with ZNF703 copy number neutral, ER-positive, luminal B tumors (log rank P = 0.004). The results support ZNF703 as the driver gene of the 8p12 amplification and suggest that independent of amplification, high expression of the gene affects prognosis in luminal B tumors. Our mapping of 8p12-p11 and analyses of ZNF703 mRNA and protein expression in breast tumors support ZNF703 as an oncogene in luminal B tumors. High ZNF703 expression, independent of the amplification, correlated with worse prognosis for the breast cancer patients with ER-positive luminal tumors, particularly of the luminal B subtype
GRP-R expression in breast cancer as target for nuclear imaging and therapy, correlation with ER
International Nuclear Information System (INIS)
Dalm, S.U.; Melis, M.; Sieuwerts, A.M.; Martens, J.W.M.; Jong, M. de
2015-01-01
Full text of publication follows. Introduction: Breast cancer (BC) is a complex and heterogeneous disease: several molecular characteristics reflect subtypes, partly overlapping with therapeutic targets. Examples include the expression of the oestrogen receptor (ER), expressed in approximately 75 % of all breast cancer cases. Currently mammography, MRI, 99m Tc-Sestamibi scintigraphy, and 18 F-FDG PET are commonly used for diagnostic imaging to accurately localize BC. Since it has been reported that the gastrin releasing peptide receptor (GRP-R) is expressed in BC, targeting this receptor with radiolabeled GRP analogues might offer opportunities for SPECT/CT or PET/CT imaging as well as radionuclide therapy in BC. In this study GRP-R expression was determined in human BC specimens and BC cell lines and correlated with ER status. Methods: GRP-R mRNA levels of 90 human breast cancer specimens, with known ER status (48 ER-positive and 42 ER-negative) were determined using qRT-PCR in a Taqman Gene expression assay. Furthermore a panel of 21 BC cell lines characterized for ER expression (13 ER-positive, 8 ER-negative) was analysed for GRP-R expression at the protein level. Internalisation studies were performed with 10-9 M 111 In-AMBA (an receptor-agonist GRP analogue) for 1 hour and 15 minutes at 37 C. degrees. Thirteen of these BC cell lines were also analyzed for GRP-R expression at mRNA level using qRT-PCR. Results: Clinical BC specimens with high GRP-R mRNA level were all ER-positive, resulting in a significant positive correlation (p=0.03). Fifty-two percent of the analyzed BC cell lines showed the ability to internalize 111 In-AMBA, although high variation between cell lines was observed. GRP-R mRNA levels of the BC cell lines significantly correlated with the internalisation rate (p=0.0003), indicating that the amount of internalized 111 In-AMBA is partly determined by the level of receptor expression. However, no correlation was found between ER status and GRP
Directory of Open Access Journals (Sweden)
Danny Lee, PhD
2017-07-01
Conclusions: This study demonstrated that audiovisual biofeedback can be used to improve the reproducibility and consistency of breath-hold lung tumor position and volume, respectively. These results may provide a pathway to achieve more accurate lung cancer radiation treatment in addition to improving various medical imaging and treatments by using breath-hold procedures.
DEFF Research Database (Denmark)
Mehlsen, Camilla
2006-01-01
Urolige elever, cyklister - der giver fuck-finger, aggressive demonstranter. Samtiden er på vej ind i en æra domineret af vrede, siger rektor Lars-Henrik Schmidt, der er aktuel med bogen 'Om vreden'. Udgivelsesdato: Juni......Urolige elever, cyklister - der giver fuck-finger, aggressive demonstranter. Samtiden er på vej ind i en æra domineret af vrede, siger rektor Lars-Henrik Schmidt, der er aktuel med bogen 'Om vreden'. Udgivelsesdato: Juni...
DEFF Research Database (Denmark)
Ahern, Thomas P; Cronin-Fenton, Deirdre P; Lash, Timothy L
2016-01-01
-/TAM - group. Pak1 cytoplasmic intensity was not associated with breast cancer recurrence in either group (ER+/TAM + ORadj for strong vs. no cytoplasmic staining = 0.91, 95% CI 0.57, 1.5; ER-/TAM - ORadj for strong vs. no cytoplasmic staining = 0.74, 95% CI 0.39, 1.4). Associations between Pak1 nuclear......Background Adjuvant tamoxifen therapy approximately halves the risk of estrogen receptor-positive (ER+) breast cancer recurrence, but many women do not respond to therapy. Observational studies nested in clinical trial populations suggest that overexpression or nuclear localization of p21-activated...... by immunohistochemical staining of primary breast tumors from recurrence cases and matched controls from two breast cancer populations; women diagnosed with ER-positive tumors who received at least one year of tamoxifen therapy (ER+/TAM+), and women diagnosed with ER-negative tumors who survived for at least one year...
Solid and Cystic Tumor (SCT of the Pancreas in an Adult Man
Directory of Open Access Journals (Sweden)
K. Ohiwa
1997-01-01
Full Text Available Solid and cystic tumor (SCT of the pancreas predominantly Occurs in women, and the occurrence in men is extremely rare. We experienced a male case of SCT. A 38-year-old man was admitted with the complaint of upper abdominal pain. CT scan showed the presence of a mass in the head of the pancreas. The mass was composed of high density areas and low density areas. Ultrasonograms revealed the mass being composed of high echoic areas and low echoic areas. The mass .was hypovascular on angiography. SCT was suspected and pancreaticoduodenectomy was performed. The cut surface of the tumor showed mainly cystic degenerative areas containing dark red hemorrhagic materials. Microscopically, there were solid areas in the periphery and pseudopapillary areas in the center. No metastasis was found in the removed lymph nodes. The tumor cells were not stained by Grimelius' silver stain. The tumor cells were positive for alpha-l-antitrypsin (AAT and neuron-specific enolase (NSE. Pancreatic hormones such as insulin, glucagon, and somatostatin were all negative. Electron micrograph showed that tumor cells were rich in mitochondria. Zymogen granules and neurosecretory granules were not detected. Estrogen receptor (ER and progesterone receptor (PR were both negative.
International Nuclear Information System (INIS)
Świerczek, Konrad; Klimkowicz, Alicja; Zheng, Kun; Dabrowski, Bogdan
2013-01-01
In this paper, we report on a synthesis procedure, structural and electrical properties of BaErMn 2 O 5 and BaErMn 2 O 6 , A-site double perovskites having layered arrangement of Ba and Er cations. These materials belong to a family of BaLnMn 2 O 5+δ oxides, which up to now were successfully synthesized for Ln=Y and La–Ho lanthanides. Up to our knowledge, this is the first report on the successful synthesis of BaErMn 2 O 5 and BaErMn 2 O 6 , yielding>95 wt% of the considered compounds. Structural characterization of the materials is given at room temperature, together with in situ XRD studies, performed during oxidation of BaErMn 2 O 5 in air, at elevated temperatures up to 500 °C. A complex structural behavior was observed, with oxidation process of BaErMn 2 O 5 occurring at around 300 °C. The oxidized BaErMn 2 O 6 shows a structural phase transition at about 225 °C. Results of structural studies are supported by thermogravimetric measurements of the oxidation process, performed in air, as well as reduction process, preformed in 5 vol% of H 2 in Ar. Additionally, isothermal oxidation/reduction cycles were measured at 500 °C, showing interesting properties of BaErMn 2 O 5+δ , from a point of view of oxygen storage technology. Electrical conductivity of BaErMn 2 O 5 is of the order of 10 −4 S cm −1 at room temperature and shows activated character on temperature with activation energy E a =0.30(1) eV. Positive sign of Seebeck coefficient for this material indicates holes as dominant charge carriers. Oxidized BaErMn 2 O 6 possesses much higher electrical conductivity, almost 0.2 S cm −1 at room temperature. Additional, about 10-fold increase of electrical conductivity, occurring in the vicinity of 225 °C for this material, can be associated with phase transition from charge/orbital-ordered insulator COI(CE) to paramagnetic metal PM phase. The highest conductivity for BaErMn 2 O 6 was measured near 500 °C and is almost equal to 40 S cm −1 , while
COPII-Dependent ER Export: A Critical Component of Insulin Biogenesis and β-Cell ER Homeostasis.
Fang, Jingye; Liu, Ming; Zhang, Xuebao; Sakamoto, Takeshi; Taatjes, Douglas J; Jena, Bhanu P; Sun, Fei; Woods, James; Bryson, Tim; Kowluru, Anjaneyulu; Zhang, Kezhong; Chen, Xuequn
2015-08-01
Pancreatic β-cells possess a highly active protein synthetic and export machinery in the endoplasmic reticulum (ER) to accommodate the massive production of proinsulin. ER homeostasis is vital for β-cell functions and is maintained by the delicate balance between protein synthesis, folding, export, and degradation. Disruption of ER homeostasis by diabetes-causing factors leads to β-cell death. Among the 4 components to maintain ER homeostasis in β-cells, the role of ER export in insulin biogenesis is the least understood. To address this knowledge gap, the present study investigated the molecular mechanism of proinsulin ER export in MIN6 cells and primary islets. Two inhibitory mutants of the secretion-associated RAS-related protein (Sar)1 small GTPase, known to specifically block coat protein complex II (COPII)-dependent ER export, were overexpressed in β-cells using recombinant adenoviruses. Results from this approach, as well as small interfering RNA-mediated Sar1 knockdown, demonstrated that defective Sar1 function blocked proinsulin ER export and abolished its conversion to mature insulin in MIN6 cells, isolated mouse, and human islets. It is further revealed, using an in vitro vesicle formation assay, that proinsulin was packaged into COPII vesicles in a GTP- and Sar1-dependent manner. Blockage of COPII-dependent ER exit by Sar1 mutants strongly induced ER morphology change, ER stress response, and β-cell apoptosis. These responses were mediated by the PKR (double-stranded RNA-dependent kinase)-like ER kinase (PERK)/eukaryotic translation initiation factor 2α (p-eIF2α) and inositol-requiring protein 1 (IRE1)/x-box binding protein 1 (Xbp1) pathways but not via activating transcription factor 6 (ATF6). Collectively, results from the study demonstrate that COPII-dependent ER export plays a vital role in insulin biogenesis, ER homeostasis, and β-cell survival.
The unpaired spectroscopy of sup 161,162 Er at spins up to 50 Dirac h
Energy Technology Data Exchange (ETDEWEB)
Riley, M.A.; Roberts, J.W.; Alderson, A.; Ali, I.; Cullen, D.M.; Fallon, P.; Forsyth, P.D.; Sharpey-Schafer, J.F. (Liverpool Univ. (UK). Oliver Lodge Lab.); Simpson, J.; Bentley, M.A.; Bruce, A.M. (Science and Engineering Research Council, Daresbury (UK). Daresbury Lab.); Chapman, R.; Lisle, J.C.; Mo, J.N. (Manchester Univ. (UK). Schuster Lab.)
1990-12-24
High spin states in {sup 161}Er and {sup 162}Er have been populated using the {sup 130}Te+{sup 36}S reaction at a bombarding energy of 170 MeV. In {sup 161}Er, three rotational bands were extended from I {approx equal} 35{Dirac h} to I {approx equal} 50{Dirac h}. In {sup 162}Er the positive parity yrast band was observed to I=44{Dirac h}. These rotational sequences are compared to a simple unpaired model which was successful in predicting the behaviour of similar high spin data on {sup 159,160}Er. These studies of the light Er isotopes constitute the highest spins observed in normal deformed nuclei and yield direct and specific information on the single-neutron spectrum of states. (orig.).
Prognostic effect of estrogen receptor status across age in primary breast cancer
DEFF Research Database (Denmark)
Bentzon, N.; During, M.; Rasmussen, B.B.
2008-01-01
prognostic factor over all age groups. This effect was limited to the first 5 years after diagnosis, RR: 2.08 (95% CI: 1.95-2.22, p ER negative tumors, RR of death: 0.89 (95% CI: 0.79-1.00, p = 0.049). Results were......Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age...... and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive...
Nitta, Hidetoshi; Nakagawa, Shigeki; Kaida, Takayoshi; Arima, Kota; Higashi, Takaaki; Taki, Katsunobu; Okabe, Hirohisa; Hayashi, Hiromitsu; Hashimoto, Daisuke; Chikamoto, Akira; Ishiko, Takatoshi; Beppu, Toru; Baba, Hideo
2017-03-01
We evaluated the therapeutic effect of radiofrequency ablation (RFA) on hepatocellular carcinoma (HCC) according to the number of positive tumor markers. The subjects of this study were 160 patients who underwent percutaneous and surgical RFA for HCC. Patients were divided into negative (n = 51), single- (n = 69), double- (n = 31), and triple-positive (n = 9) tumor marker groups according to the pre-treatment expression of these markers. We looked for any relationships among clinical parameters, outcomes, and tumor markers. The 3-year recurrence-free and overall survival rates of the negative, single-, double-, and triple-positive groups were 30, 19, 16, and 11 % (P = 0.02), and 94, 88, 67, and 37 % (P tumor marker profile was independently associated with local recurrence [hazard ratio (HR) 5.48, 95 % confidence interval (CI) 2.44-12.33, P tumor markers.
Effects of material growth technique and Mg doping on Er3+ photoluminescence in Er-implanted GaN
International Nuclear Information System (INIS)
Kim, S.; Henry, R. L.; Wickenden, A. E.; Koleske, D. D.; Rhee, S. J.; White, J. O.; Myoung, J. M.; Kim, K.; Li, X.; Coleman, J. J.
2001-01-01
Photoluminescence (PL) and photoluminescence excitation (PLE) spectroscopies have been carried out at 6 K on the ∼1540 nm 4 I 13/2 - 4 I 15/2 emissions of Er 3+ in Er-implanted and annealed GaN. These studies revealed the existence of multiple Er 3+ centers and associated PL spectra in Er-implanted GaN films grown by metalorganic chemical vapor deposition, hydride vapor phase epitaxy, and molecular beam epitaxy. The results demonstrate that the multiple Er 3+ PL centers and below-gap defect-related absorption bands by which they are selectively excited are universal features of Er-implanted GaN grown by different techniques. It is suggested that implantation-induced defects common to all the GaN samples are responsible for the Er site distortions that give rise to the distinctive, selectively excited Er 3+ PL spectra. The investigations of selectively excited Er 3+ PL and PLE spectra have also been extended to Er-implanted samples of Mg-doped GaN grown by various techniques. In each of these samples, the so-called violet-pumped Er 3+ PL band and its associated broad violet PLE band are significantly enhanced relative to the PL and PLE of the other selectively excited Er 3+ PL centers. More importantly, the violet-pumped Er 3+ PL spectrum dominates the above-gap excited Er 3+ PL spectrum of Er-implanted Mg-doped GaN, whereas it was unobservable under above-gap excitation in Er-implanted undoped GaN. These results confirm the hypothesis that appropriate codopants can increase the efficiency of trap-mediated above-gap excitation of Er 3+ emission in Er-implanted GaN. [copyright] 2001 American Institute of Physics
Anti-tumor effects of an engineered “killer” transfer RNA
International Nuclear Information System (INIS)
Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao
2012-01-01
Highlights: ► tRNA with anti-cancer effects. ► tRNA induced protein misfolding. ► tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA Ser (AAU) is an engineered human tRNA Ser with an anticodon coding for isoleucine. Here we test the possibility that tRNA Ser (AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA Ser (AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA Ser (AAU) in both tumorigenic and non-tumorigenic cells. tRNA Ser (AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA Ser (AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA Ser (AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA Ser (AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.
DEFF Research Database (Denmark)
Hoffmeyer, Jesper
2013-01-01
Nu ved vi, at der er mange slags DNA i vores krop, og at samarbejdet mellem de organismer, som bærer alt dette DNA, er essentielt for vores overlevelse" … "Kroppen er en slags økosystem, hvor alle slags samarbejde hen ad vejen bliver afprøvet"...
International Nuclear Information System (INIS)
Ravelo, Rolando; Sanchez, Iradia; Pimentel, Gilmara; Oliva, Juan; Perez, Lincidio; Ayala, Marta; Bell, Hansell; Gavilondo, Jorge
2006-01-01
The directed radiotherapy of the solid tumors with fragments recombinants of radiolabelled antibodies is a topic of current investigation, so much at preclinical level as clinical. This work describes the preclinical characterization of a new fragment type diabody of the AcMo ior CEA1 that has been labelled with 131 I for their use in the diagnosis and the therapy of CEA positive tumors. The radiolabelling methodology used allows the incorporation of more than 90% of the radio iodine to the molecule without committing the capacity of recognition of its antigen significantly. The combination of the favourable properties pharmacy kinetic and high selective accumulation in the tumor, they make of the diabody anti CEA an appropriate candidate for the radioimmunodiagnosis and the radioimmunotherapy of tumors that expresses CEA (Author)
International Nuclear Information System (INIS)
Freedman, Gary M.; Fowble, Barbara L.; Hanlon, Alexandra L.; Myint, Maung A.; Hoffman, John P.; Sigurdson, Elin R.; Eisenberg, Burton L.; Goldstein, Lori J.; Fein, Douglas A.
1998-01-01
Introduction: Indications for postmastectomy radiation include primary tumor size ≥5 cm and/or ≥4 positive axillary nodes. In clinical practice, patients with a close or positive margin after mastectomy are also often treated with postmastectomy radiation. However, there is little data regarding the risk of a chest wall recurrence in patients with close or positive margins who otherwise would be considered low risk (tumor size 50 (p = 0.04). There was no correlation with chest wall failure and number of positive nodes, ER status, lymphovascular invasion, location of primary, grade, family history, or type of tumor close to the margin. Of 5 chest wall failures, 4 were in patients who had received adjuvant systemic chemotherapy ± tamoxifen. Chest wall failures occurred in 1 patient with a positive deep margin, 3 patients with margins within 2 mm, and 1 patient with a margin of 5 mm. The estimated cumulative incidence probability of chest wall recurrence at 8 years by margin proximity was 24% ≤ 2 mm vs. 7% 2.1-6 mm (p = 0.36), and by clinical size 24% for T2 tumors vs. 7% for T1 (p = 0.98). Conclusions: A close or positive margin is uncommon (≤5%) after mastectomy in patients with tumor size <5 cm and 0-3 positive axillary nodes but, when present, it appears to be in a younger patient population. The subgroup of patients aged 50 or younger with clinical T1-T2 tumor size and 0-3 positive nodes who have a close (≤5 mm) or positive mastectomy margin are at high risk (28% at 8 years) for chest wall recurrence regardless of adjuvant systemic therapy and, therefore, should be considered for postmastectomy radiation
Directory of Open Access Journals (Sweden)
Justin Stebbing
Full Text Available Analysis of circulating tumor cells (CTCs provides real-time measures of cancer sub-populations with potential for CTC-directed therapeutics. We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR-positive pool of CTCs, which may in turn lead to clinical benefits.Patients with metastatic breast cancer and HER2 non-amplified primary tumors with EGFR-positive CTCs were recruited and lapatinib 1500 mg daily was administered, in a standard two step phase 2 trial.There were no responses leading to termination at the first analysis with 16 patients recruited out of 43 screened. In 6 out of 14 (43% individuals eligible for the efficacy analysis, a decrease in CTCs was observed with most of these having a greater decrease in their EGFR-positive CTC pool.This is one of the first studies of CTC-directed therapeutics and suggests that lapatinib monotherapy is not having any demonstrable clinical effects by reducing the EGFR-positive pool of CTCs in HER2 non-amplified primary tumors. Our attempt to expand the pool of patients eligible for a targeted therapy was unsuccessful; the role of clonal populations in cancer biology and therapeutic strategies to control them will require extensive evaluation in years to come.Clinical trials.gov NCT00820924.
Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer.
Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise
2014-01-01
The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors.
International Nuclear Information System (INIS)
Mathias, Carla J.; Wang, Susan; Low, Philip S.; Waters, David J.; Green, Mark A.
1999-01-01
The radiochemical synthesis and stability of 67 Ga-deferoxamine-folate ([ 67 Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations ≥2.5 μg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [ 67 Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were found to concentrate the 67 Ga radiolabel in a dose-dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical
Perez, Edith A; Ballman, Karla V; Mashadi-Hossein, Afshin; Tenner, Kathleen S; Kachergus, Jennifer M; Norton, Nadine; Necela, Brian M; Carr, Jennifer M; Ferree, Sean; Perou, Charles M; Baehner, Frederick; Cheang, Maggie Chon U; Thompson, E Aubrey
2017-02-01
Genomic data from human epidermal growth factor receptor 2-positive (HER2+) tumors were analyzed to assess the association between intrinsic subtype and clinical outcome in a large, well-annotated patient cohort. Samples from the NCCTG (Alliance) N9831 trial were analyzed using the Prosigna algorithm on the NanoString platform to define intrinsic subtype, risk of recurrence scores, and risk categories for 1392 HER2+ tumors. Subtypes were evaluated for recurrence-free survival (RFS) using Kaplan-Meier and Cox model analysis following adjuvant chemotherapy (n = 484) or chemotherapy plus trastuzumab (n = 908). All statistical tests were two-sided. Patients with HER2+ tumors from N9831 were primarily scored as HER2-enriched (72.1%). These individuals received statistically significant benefit from trastuzumab (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52 to 0.89, P = .005), as did the patients (291 of 1392) with luminal-type tumors (HR = 0.52, 95% CI = 0.32 to 0.85, P = .01). Patients with basal-like tumors (97 of 1392) did not have statistically significantly better RFS when treated with trastuzumab and chemotherapy compared with chemotherapy alone (HR = 1.06, 95% CI = 0.53 to 2.13, P = .87). The majority of clinically defined HER2-positive tumors were classified as HER2-enriched or luminal using the Prosigna algorithm. Intrinsic subtype alone cannot replace conventional histopathological evaluation of HER2 status because many tumors that are classified as luminal A or luminal B will benefit from adjuvant trastuzumab if that subtype is accompanied by HER2 overexpression. However, among tumors that overexpress HER2, we speculate that assessment of intrinsic subtype may influence treatment, particularly with respect to evaluating alternative therapeutic approaches for that subset of HER2-positive tumors of the basal-like subtype. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions
Energy Technology Data Exchange (ETDEWEB)
Yi, B; Hu, E; Yu, C; Lee, M; Lasio, G [Univ. of Maryland School Of Medicine, Baltimore, MD (United States)
2015-06-15
Purpose: A Tomo-Cinegraphy (TC) is a method to generate a series of temporal tomographic images from projection images of the on-board imager (OBI) while gantry is moving. It is to test if this technique is useful to determine a lung tumor position during treatments. Methods: Tomographic image via background subtraction, TIBS uses a priori anatomical information from a previous CT scan to isolate a SOI from a planar kV image by factoring out the attenuations by tissues outside the SOI (background). This idea was extended to a TC, which enables to generate tomographic images of same geometry from the projection of different gantry angles and different breathing phases. Projection images of a lung patient for CBCT acquisition are used to generate TC images. A region of interest (ROI) is selected around a tumor adding 2cm margins. Center of mass (COM) of the ROI is traced to determine tumor position for every projection images. Results: Tumor is visible in the TC images while the OBI projections are not. The coordinates of the COMs represent the temporal tumor positions. While, it is not possible to trace the tumor motion using the projection images. A source of time delay is the time to acquire projection images, which is always less than a second. Conclusion: TC allows tracking the tumor positions without fiducial markers in real time for some lung patients, if the projection images are acquired during treatments. Partially supported by NIH R01CA133539.
International Nuclear Information System (INIS)
Duursen, Majorie B.M. van; Smeets, Evelien E.J.W.; Rijk, Jeroen C.W.; Nijmeijer, Sandra M.; Berg, Martin van den
2013-01-01
Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: • Supplements containing phytoestrogens are commonly used by women with breast cancer. • Phytoestrogens alter steroidogenesis in a co-culture breast
Energy Technology Data Exchange (ETDEWEB)
Duursen, Majorie B.M. van, E-mail: M.vanDuursen@uu.nl [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands); Smeets, Evelien E.J.W. [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands); Rijk, Jeroen C.W. [RIKILT - Institute for Food Safety, Wageningen UR, P.O. Box 230, 6700 AE, Wageningen (Netherlands); Nijmeijer, Sandra M.; Berg, Martin van den [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands)
2013-06-01
Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: • Supplements containing phytoestrogens are commonly used by women with breast cancer. • Phytoestrogens alter steroidogenesis in a co-culture breast
International Nuclear Information System (INIS)
Chang, Yeun-Chung; Huang, Yao-Sian; Huang, Chiun-Sheng; Chen, Jeon-Hor; Chang, Ruey-Feng
2014-01-01
Purpose: This study aimed to investigate the three-dimensional (3-D) power Doppler ultrasonographic (PDUS) vascular features of breast carcinoma according to intrinsic subtypes, nodal stage, and tumor grade. Materials and methods: Total 115 receiving mastectomy breast carcinomas (mean size, 2.5 cm; range, 0.7–6.5 cm), including 102 invasive ductal carcinomas (IDC), 10 ductal carcinomas in situ (DCIS), and 3 invasive lobular carcinomas (ILC) diagnosed after mastectomy, were used in this retrospective study. Sixty IDC had nodal status and histopathologic tumor grades available for analysis. Vascular features, including number of vascular trees (NV), longest path length (LPL), total vessel length (TVL), number of bifurcations (NB), distance metric (DM), inflection count metric (ICM), vessel diameter (VD), and vessel-to-volume ratio (VVR) were extracted using 3-D thinning method. The Mann–Whitney U test, Student's t-test, one-way ANOVA, and Kruskal–Wallis test were performed as appropriate. Results: There was no significant difference of vascular features among IDC, DCIS and ILC. Except VD, vascular features in luminal type were significantly lower compared to HER2-enriched or triple negative types (p < 0.05). Compared to ER+ (estrogen receptor positive) tumors, all features in ER− (estrogen receptor negative) tumors were significantly higher (p < 0.01). Despite some significantly higher vascular features in high grade IDC compared to low and intermediate grade, there was no significant correlation between vascular features and nodal stages. Conclusion: Differences in 3-D PDUS vascular features among intrinsic types of IDC are attributed to their ER status. Vascular features extracted by 3-D PDUS correlate with tumor grades but not nodal stage in IDC
Energy Technology Data Exchange (ETDEWEB)
Chang, Yeun-Chung [Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10041, Taiwan, ROC (China); Huang, Yao-Sian [Department of Computer Science and Information Engineering, National Taiwan University, Taipei 10617, Taiwan, ROC (China); Huang, Chiun-Sheng [Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10041, Taiwan, ROC (China); Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan, ROC (China); Chen, Jeon-Hor [Center for Functional Onco-Imaging and Department of Radiological Science, University of California Irvine, California, CA 92868 (United States); Department of Radiology, E-Da Hospital and I-Shou University, Kaohsiung 82445, Taiwan, ROC (China); Chang, Ruey-Feng, E-mail: rfchang@csie.ntu.edu.tw [Department of Computer Science and Information Engineering, National Taiwan University, Taipei 10617, Taiwan, ROC (China); Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan, ROC (China)
2014-08-15
Purpose: This study aimed to investigate the three-dimensional (3-D) power Doppler ultrasonographic (PDUS) vascular features of breast carcinoma according to intrinsic subtypes, nodal stage, and tumor grade. Materials and methods: Total 115 receiving mastectomy breast carcinomas (mean size, 2.5 cm; range, 0.7–6.5 cm), including 102 invasive ductal carcinomas (IDC), 10 ductal carcinomas in situ (DCIS), and 3 invasive lobular carcinomas (ILC) diagnosed after mastectomy, were used in this retrospective study. Sixty IDC had nodal status and histopathologic tumor grades available for analysis. Vascular features, including number of vascular trees (NV), longest path length (LPL), total vessel length (TVL), number of bifurcations (NB), distance metric (DM), inflection count metric (ICM), vessel diameter (VD), and vessel-to-volume ratio (VVR) were extracted using 3-D thinning method. The Mann–Whitney U test, Student's t-test, one-way ANOVA, and Kruskal–Wallis test were performed as appropriate. Results: There was no significant difference of vascular features among IDC, DCIS and ILC. Except VD, vascular features in luminal type were significantly lower compared to HER2-enriched or triple negative types (p < 0.05). Compared to ER+ (estrogen receptor positive) tumors, all features in ER− (estrogen receptor negative) tumors were significantly higher (p < 0.01). Despite some significantly higher vascular features in high grade IDC compared to low and intermediate grade, there was no significant correlation between vascular features and nodal stages. Conclusion: Differences in 3-D PDUS vascular features among intrinsic types of IDC are attributed to their ER status. Vascular features extracted by 3-D PDUS correlate with tumor grades but not nodal stage in IDC.
DEFF Research Database (Denmark)
Bech, Henning; Necef, Mehmet Ümit
Igennem de seneste årtier er det blevet almindeligt at tale om, at der er en udbredt racisme i Danmark. Påstande om danskernes racisme, fremmedhad og diskrimination optræder dagligt i offentligheden og i medierne, og der henvises ofte til, hvad ’forskerne’ og de ’videnskabelige undersøgelser’ siger...... om emnet. Der kan da næppe heller være tvivl om, at der forekommer racistiske holdninger hos nogle danskere. Men er problemet så stort, som det gøres til i den offentlige debat? Bogen ønsker at afklare, hvorvidt der er videnskabelig dokumentation for påstandene om danskernes racisme. Den går i dybden...... med en række forskeres og eksperters udtalelser på området og præsenterer en grundig analyse af deres fremstilling af dansk racisme i forhold til emner som kultur, seksualitet, kriminalitet og arbejdsmarked....
Directory of Open Access Journals (Sweden)
Skoog Lambert
2006-06-01
Full Text Available Abstract Background Postmenopausal hormone-replacement therapy (HRT increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. Methods We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. Results HRT use in patients with estrogen receptor (ER protein positive tumors (n = 72 was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. Conclusion Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.
Induction of ER stress in macrophages of tuberculosis granulomas.
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Tracie A Seimon
2010-09-01
Full Text Available The endoplasmic reticulum (ER stress pathway known as the Unfolded Protein Response (UPR is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection.Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153, phosphorylated inositol-requiring enzyme 1 alpha (Ire1α and eukaryotic initiation factor 2 alpha (eIF2α, and activating transcription factor 3 (ATF3 are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb. These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation.In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in
Cobalt-related features of spectral and magnetic properties of RNi{sub 4}Co (R=Ho, Er)
Energy Technology Data Exchange (ETDEWEB)
Lukoyanov, A.V., E-mail: lukoyanov@imp.uran.ru [Institute of Metal Physics, Russian Academy of Sciences–Ural Branch, 620990 Yekaterinburg (Russian Federation); Ural Federal University, 620002 Yekaterinburg (Russian Federation); Knyazev, Yu.V.; Kuz‘min, Yu.I.; Kuchin, A.G. [Institute of Metal Physics, Russian Academy of Sciences–Ural Branch, 620990 Yekaterinburg (Russian Federation)
2014-11-15
In this paper we investigate spectral and magnetic properties of RNi{sub 4}Co (R=Ho, Er) intermetallics to reveal the features associated with the presence of Co substituting ion in comparison with the parent HoNi{sub 5} and ErNi{sub 5} compounds. Our ab initio LSDA+U calculations show that in the electronic structure Co states are strongly manifested near the Fermi energy for the case of Co in 2c position, while Co in 3g position results only in weak changes of the total DOS curve. Theoretical optical conductivity calculated assuming Co equally redistributed among 2c or 3g positions agrees well with the experimental optical conductivity. Cobalt ion in RNi{sub 4}Co (R=Ho, Er) is characterized by magnetic moment of 1μ{sub B} that increases exchange interaction in the 3d sublattice by several times that contributes to the growth of Curie temperature in comparison with the parent compounds. - Highlights: • Electronic structure of RNi4Co (R=Ho, Er) is calculated in LSDA+U. • Cobalt ion is considered in 2c or 3g position and compared. • Experimental optical conductivity is interpreted based on the calculated one.
Mast cells: potential positive and negative roles in tumor biology.
Marichal, Thomas; Tsai, Mindy; Galli, Stephen J
2013-11-01
Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. ©2013 AACR.
Den sproglige leg er super fly
DEFF Research Database (Denmark)
Just, Sine Nørholm
2013-01-01
Man kan rappe om alt. I hvert fald hvis man er Marvelous Mosell. I spændingsfeltet mellem fiktion og virkelighed skaber Mosell sin persona i et forjættende 80' er-univers der på en og samme tid er vildt overdrevet og helt autentisk.......Man kan rappe om alt. I hvert fald hvis man er Marvelous Mosell. I spændingsfeltet mellem fiktion og virkelighed skaber Mosell sin persona i et forjættende 80' er-univers der på en og samme tid er vildt overdrevet og helt autentisk....
Cao, Pengfei; Renna, Luciana; Stefano, Giovanni; Brandizzi, Federica
2016-12-05
The endoplasmic reticulum (ER) is an essential organelle that spreads throughout the cytoplasm as one interconnected network of narrow tubules and dilated cisternae that enclose a single lumen. The ER network undergoes extensive remodeling, which critically depends on membrane-cytoskeleton interactions [1]. In plants, the ER is also highly mobile, and its streaming contributes significantly to the movement of other organelles [2, 3]. The remodeling and motility of the plant ER rely mainly on actin [4] and to a minor extent on microtubules [5]. Although a three-way interaction between the ER, cytosolic myosin-XI, and F-actin mediates the plant ER streaming [6], the mechanisms underlying stable interaction of the ER membrane with actin are unknown. Early electron microscopy studies suggested a direct attachment of the plant ER with actin filaments [7, 8], but it is plausible that yet-unknown proteins facilitate anchoring of the ER membrane with the cytoskeleton. We demonstrate here that SYP73, a member of the plant Syp7 subgroup of SNARE proteins [9] containing actin-binding domains, is a novel ER membrane-associated actin-binding protein. We show that overexpression of SYP73 causes a striking rearrangement of the ER over actin and that, similar to mutations of myosin-XI [4, 10, 11], loss of SYP73 reduces ER streaming and affects overall ER network morphology and plant growth. We propose a model for plant ER remodeling whereby the dynamic rearrangement and streaming of the ER network depend on the propelling action of myosin-XI over actin coupled with a SYP73-mediated bridging, which dynamically anchors the ER membrane with actin filaments. Copyright © 2016 Elsevier Ltd. All rights reserved.
Site of Er ions in silica layers codoped with Si nanoclusters and Er
International Nuclear Information System (INIS)
Pellegrino, P.; Garrido, B.; Arbiol, J.; Garcia, C.; Lebour, Y.; Morante, J.R.
2006-01-01
Silica layers implanted with Si and Er ions to various doses and annealed at 950 deg. C have been investigated by means of energy-filtered transmission electron microscopy (EFTEM) and high annular angle dark field (HAADF). EFTEM analysis reveals Si nanoclusters (Si-nc) with an average size around 3 nm for high Si content (15 at. %) whereas no clusters can be imaged for the lowest Si excess (5 at. %). Raman scattering supports that amorphous Si precipitates are present in all the samples. Moreover, the filtered images show that Er ions appear preferentially located outside the Si-nc. HAADF analysis confirms that the Er atoms form agglomerations of 5-10 nm size when the Er concentration exceeds 1x10 20 cm -3 . This observation correlates well with the reduction of the Er population excitable by Si nanoclusters, in the best case corresponding to 10% of the total. A suitable tuning of the annealing drastically reduces this deleterious effect
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G. A. Sobral
2015-01-01
Full Text Available Fluorescence intensity ratio (FIR technique, based on the thermal coupling of H11/22 and S3/24 energy levels of erbium ions, was used to study the optical heating behavior of rare earth doped yttrium oxide nanophosphors (Y2O3:Er3+, Y2O3:Er3+-Eu3+, Y2O3:Er3+-Tb3+, and Y2O3:Er3+-Eu3+-Tb3+ synthesized via PVA-assisted sol-gel route. The samples were optically heated by an 800 nm CW diode laser, while the upconverted green emissions were used to measure their temperatures in real time. The experimental results indicate that the studied nanoparticles are promising candidates to applications such as photothermal treatments and hyperthermia.
DEFF Research Database (Denmark)
van der Meijden, Peter Alexander
2008-01-01
"Fluxus-øer" er en introduktion til Fluxus med udgangspunkt i den tyske galleri-ejer René Blocks samling, som udstillingen "Food for Thought" i Sukkerfabrikken i Stege (Møn) præsenterede et udvalg af. Artiklen beskriver Fluxus som et heterotopi som beskrevet af Michel Foucault i "Of Other Spaces"...
International Nuclear Information System (INIS)
Freedman, G.M.; Fowble, B.L.; Hanlon, A.L.; Myint, M.A.; Hoffman, J.P.; Sigurdson, E.R.; Eisenberg, B.L.; Goldstein, L.J.; Fein, D.A.
1997-01-01
Purpose: Indications for postmastectomy radiation include primary tumor size > 5 cm and ≥ 4 positive axillary nodes. In clinical practice, patients with a close or positive margin after mastectomy are also often treated with postmastectomy radiation. However, there is little data regarding the risk of a chest wall recurrence in patients with this pathologic feature who otherwise would be considered low risk (tumor size 25% at 8 years: Age ≤ 50 years was 28% vs. 0% for age > 50 (p=0.08). There was no correlation with chest wall failure and number of nodes, ER status, lymphovascular invasion, location of primary, grade, family history or type of tumor close to the margin. All four chest wall failures were in patients who had received adjuvant systemic chemotherapy ± Tamoxifen. Chest wall failures occurred in patients with margins within 1-2 mm in three patients and 5 mm in one patient. The cumulative chest wall recurrence at 8 years by margin proximity was 24% ≤ 2mm vs. 7% 2.1-6 mm (p=0.44), and by clinical size 24% for T2 tumors vs. 7% for T1 (p=0.55). Conclusions: A close or positive margin is uncommon (< 5%) after mastectomy in patients with tumor size < 5 cm and 0-3 positive axillary nodes, but when present it appears to be in a younger patient population. The subgroup of patients aged 50 or younger with clinical T1-T2 tumor size and 0-3 positive nodes who have a close (≤ 5 mm) or positive mastectomy margin are at high risk (28% at 8 years) for chest wall recurrence regardless of adjuvant systemic therapy, and therefore we recommend they be considered for postmastectomy radiation. This high risk of local failure was not observed in patients over age 50, suggesting this subgroup may not require adjuvant chest wall irradiation
Shaheen, Alaa
2018-05-05
The unfolded protein response (UPR) is an adaptive cellular response that aims to relieve endoplasmic reticulum (ER) stress via several mechanisms, including inhibition of protein synthesis and enhancement of protein folding and degradation. There is a controversy over the effect of the UPR on ER protein export. While some investigators suggested that ER export is inhibited during ER stress, others suggested the opposite. In this article, their conflicting studies are analyzed and compared in attempt to solve this controversy. The UPR appears indeed to enhance ER export, possibly via multiple mechanisms. However, another factor, which is the integrity of the folding machinery/environment inside ER, determines whether ER export will appear increased or decreased during experimentation. Also, different methods of stress induction appear to have different effects on ER export. Thus, improvement of ER export may represent a new mechanism by which the UPR alleviates ER stress. This may help researchers to understand how the UPR works inside cells and how to manipulate it to alter cell fate during stress, either to promote cell survival or death. This may open up new approaches for the treatment of ER stress-related diseases.
Domingo, Laia; Salas, Dolores; Zubizarreta, Raquel; Baré, Marisa; Sarriugarte, Garbiñe; Barata, Teresa; Ibáñez, Josefa; Blanch, Jordi; Puig-Vives, Montserrat; Fernández, Ana; Castells, Xavier; Sala, Maria
2014-01-10
Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories. We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd's scale and was conflated into: 75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided. Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; cancers, extreme breast density being strongly associated with occult tumors (OR
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AYESHA AMIR SIDDIQI
2017-01-01
Full Text Available Segmentation of brain tumors has been found challenging throughout in the field of image processing. Different algorithms have been applied to the segmentation of solid or cystic tumors individually but little work has been done for solid cum cystic tumor. The papers reviewed in this article only deal with the case study of patients suffering from solid cum cystic brain tumor as this type of tumor is rarely found for the purpose of research. The research work conducted so far on this topic has been reviewed. The study begins with 2D (Two Dimensional segmentation of tumor using MATLAB. It is then extended to study of slices of tumor and its volume calculation using open source software named 3D Slicer which represents the tumor in 3D. This software can intake the 2D slices and process them to give a combined 3D view. Various techniques are available in the software. According to the particular requirement an appropriate algorithm can be chosen. This paper gives a promising hierarchy for volume calculation of tumor and the three dimensional view. Further we can also find the position of tumor in the skull using the same software. This piece of work is a valuable guideline for the researchers interested in segmentation and three dimensional representations of different areas of human body. The models extracted out using the given algorithms can also be treated for matching and comparison of any future research. This will also aid surgeons and physicians in efficient analysis and reporting techniques.
Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.
Busam, Klaus J; Pulitzer, Melissa P; Coit, Daniel C; Arcila, Maria; Leng, Danielle; Jungbluth, Achim A; Wiesner, Thomas
2017-06-01
Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.
Anti-tumor effects of an engineered 'killer' transfer RNA
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Zhou, Dong-hui [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Lee, Jiyoung; Frankenberger, Casey [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Geslain, Renaud, E-mail: rgeslain@depaul.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Department of Biology, DePaul University, Chicago, IL 60614 (United States); Rosner, Marsha, E-mail: m-rosner@uchicago.edu [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Pan, Tao, E-mail: taopan@uchicago.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States)
2012-10-12
Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.
DEFF Research Database (Denmark)
Schilling, Benedicte; Jacobsen, Claus Haugaard; Nielsen, Jan
2010-01-01
Kontrol, kontrakt og kontekst er supervisionens tre k'er. Men hvad er supervision i det hele taget for en størrelse, der spillerså central en rolle for den psykologfaglige profession?......Kontrol, kontrakt og kontekst er supervisionens tre k'er. Men hvad er supervision i det hele taget for en størrelse, der spillerså central en rolle for den psykologfaglige profession?...
Kaaks, Rudolf; Johnson, Theron; Tikk, Kaja; Sookthai, Disorn; Tjønneland, Anne; Roswall, Nina; Overvad, Kim; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Dossus, Laure; Rinaldi, Sabina; Romieu, Isabelle; Boeing, Heiner; Schütze, Madlen; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Grioni, Sara; Tumino, Rosario; Sacerdote, Carlotta; Panico, Salvatore; Buckland, Genevieve; Argüelles, Marcial; Sánchez, María-José; Amiano, Pilar; Chirlaque, Maria-Dolores; Ardanaz, Eva; Bueno-de-Mesquita, H Bas; van Gils, Carla H; Peeters, Petra H; Andersson, Anne; Sund, Malin; Weiderpass, Elisabete; Gram, Inger Torhild; Lund, Eiliv; Khaw, Kay-Tee; Wareham, Nick; Key, Timothy J; Travis, Ruth C; Merritt, Melissa A; Gunter, Marc J; Riboli, Elio; Lukanova, Annekatrin
2014-06-01
Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older. © 2013 UICC.
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Yanke Chen
Full Text Available Tumor angiogenesis is a complex process based upon a sequence of interactions between tumor cells and endothelial cells. Previous studies have shown that CD147 was correlated with tumor angiogenesis through increasing tumor cell secretion of vascular endothelial growth factor (VEGF and matrix metalloproteinases (MMPs. In this study, we made a three-dimensional (3D tumor angiogenesis model using a co-culture system of human hepatocellular carcinoma cells SMMC-7721 and humanumbilical vein endothelial cells (HUVECs in vitro. We found that CD147-expressing cancer cells could promote HUVECs to form net-like structures resembling the neo-vasculature, whereas the ability of proliferation, migration and tube formation of HUVECs was significantly decreased in tumor conditioned medium (TCM of SMMC-7721 cells transfected with specific CD147-siRNA. Furthermore, by assaying the change of pro-angiogenic factors in TCM, we found that the inhibition of CD147 expression led to significant decrease of VEGF and insulin-like growth factor-I (IGF-I secretion. Interestingly, we also found that IGF-I up-regulated the expression of CD147 in both tumor cells and HUVECs. These findings suggest that there is a positive feedback between CD147 and IGF-I at the tumor-endothelial interface and CD147 initiates the formation of an angiogenesis niche.
Coronavirus infection, ER stress and Apoptosis
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TO SING eFUNG
2014-06-01
Full Text Available The replication of coronavirus, a family of important animal and human pathogens, is closely associated with the cellular membrane compartments, especially the endoplasmic reticulum (ER. Coronavirus infection of cultured cells was previously shown to cause ER stress and induce the unfolded protein response (UPR, a process that aims to restore the ER homeostasis by global translation shutdown and increasing the ER folding capacity. However under prolonged ER stress, UPR can also induce apoptotic cell death. Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus-host interaction. Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP kinases activation, autophagy, apoptosis and innate immune response. ER stress and UPR activation may therefore contribute significantly to the viral replication and pathogenesis during coronavirus infection. In this review, we summarize current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.
Real-time tumor-tracking radiotherapy for adrenal tumors
International Nuclear Information System (INIS)
Katoh, Norio; Onimaru, Rikiya; Sakuhara, Yusuke; Abo, Daisuke; Shimizu, Shinichi; Taguchi, Hiroshi; Watanabe, Yoshiaki; Shinohara, Nobuo; Ishikawa, Masayori; Shirato, Hiroki
2008-01-01
Purpose: To investigate the three-dimensional movement of internal fiducial markers near the adrenal tumors using a real-time tumor-tracking radiotherapy (RTRT) system and to examine the feasibility of high-dose hypofractionated radiotherapy for the adrenal tumors. Materials and methods: The subjects considered in this study were 10 markers of the 9 patients treated with RTRT. A total of 72 days in the prone position and 61 treatment days in the supine position for nine of the 10 markers were analyzed. All but one patient were prescribed 48 Gy in eight fractions at the isocenter. Results: The average absolute amplitude of the marker movement in the prone position was 6.1 ± 4.4 mm (range 2.3-14.4), 11.1 ± 7.1 mm (3.5-25.2), and 7.0 ± 3.5 mm (3.9-12.5) in the left-right (LR), craniocaudal (CC), and anterior-posterior (AP) directions, respectively. The average absolute amplitude in the supine position was 3.4 ± 2.9 mm (0.6-9.1), 9.9 ± 9.8 mm (1.1-27.1), and 5.4 ± 5.2 mm (1.7-26.6) in the LR, CC, and AP directions, respectively. Of the eight markers, which were examined in both the prone and supine positions, there was no significant difference in the average absolute amplitude between the two positions. No symptomatic adverse effects were observed within the median follow-up period of 16 months (range 5-21 months). The actuarial freedom-from-local-progression rate was 100% at 12 months. Conclusions: Three-dimensional motion of a fiducial marker near the adrenal tumors was detected. Hypofractionated RTRT for adrenal tumors was feasible for patients with metastatic tumors
Purple perilla extracts allay ER stress in lipid-laden macrophages.
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Sin-Hye Park
Full Text Available There is a growing body of evidence that excess lipids, hypoxic stress and other inflammatory signals can stimulate endoplasmic reticulum (ER stress in metabolic diseases. However, the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. The current study investigated that 50 ng/ml oxidized LDL promoted unfolded protein response (UPR and ER stress in J774A1 murine macrophages, which was blocked by extracts (PPE of purple Perilla frutescens, a plant of the mint family Lamiaceae. The ER stressor tunicamycin was employed as a positive control. Treating 1-10 µg/ml oxidized LDL for 24 h elicited lipotoxic apoptosis in macrophages with obvious nuclear condensation and DNA fragmentation, which was inhibited by PPE. Tunicamycin and oxidized LDL activated and induced the UPR components of activating transcription factor 6 and ER resident chaperone BiP/Grp78 in temporal manners and such effects were blocked by ≥5 µg/ml PPE. In addition, PPE suppressed the enhanced mRNA transcription and splicing of X-box binding protein 1 (XBP1 by tunicamycin and oxidized LDL. The protein induction and nuclear translocation of XBP1 were deterred in PPE-treated macrophages under ER stress. The induction of ATP-binding cassette transporter A1 (ABCA1, scavenger receptor-B1 (SR-B1 and intracellular adhesion molecule-1 (ICAM-1 was abolished by the ER stressor in activated macrophages. The protein induction of ABCA1 and ICAM1 but not SR-B1 was retrieved by adding 10 µg/ml PPE to cells. These results demonstrate that PPE inhibited lipotoxic apoptosis and demoted the induction and activation of UPR components in macrophages. PPE restored normal proteostasis in activated macrophages oxidized LDL. Therefore, PPE was a potent agent antagonizing macrophage ER stress due to lipotoxic signals associated with atherosclerosis.
Tang, Gong; Cuzick, Jack; Costantino, Joseph P.; Dowsett, Mitch; Forbes, John F.; Crager, Michael; Mamounas, Eleftherios P.; Shak, Steven; Wolmark, Norman
2011-01-01
Purpose The 21-gene breast cancer assay recurrence score (RS) is widely used for assessing recurrence risk and predicting chemotherapy benefit in patients with estrogen receptor (ER) –positive breast cancer. Pathologic and clinical factors such as tumor size, grade, and patient age also provide independent prognostic utility. We developed a formal integration of these measures and evaluated its prognostic and predictive value. Patients and Methods From the National Surgical Adjuvant Breast and Bowel (NSABP) B-14 and translational research cohort of the Arimidex, Tamoxifen Alone or in Combination (TransATAC) studies, we included patients who received hormonal monotherapy, had ER-positive tumors, and RS and traditional clinicopathologic factors assessed (647 and 1,088, respectively). Individual patient risk assessments from separate Cox models were combined using meta-analysis to form an RS-pathology-clinical (RSPC) assessment of distant recurrence risk. Risk assessments by RS and RSPC were compared in node-negative (N0) patients. RSPC was compared with RS for predicting chemotherapy benefit in NSABP B-20. Results RSPC had significantly more prognostic value for distant recurrence than did RS (P < .001) and showed better separation of risk in the study population. RSPC classified fewer patients as intermediate risk (17.8% v 26.7%, P < .001) and more patients as lower risk (63.8% v 54.2%, P < .001) than did RS among 1,444 N0 ER-positive patients. In B-20, the interaction of RSPC with chemotherapy was not statistically significant (P = .10), in contrast to the previously reported significant interaction of RS with chemotherapy (P = .037). Conclusion RSPC refines the assessment of distant recurrence risk and reduces the number of patients classified as intermediate risk. Adding clinicopathologic measures did not seem to enhance the value of RS alone nor the individual biology RS identifies in predicting chemotherapy benefit. PMID:22010013
Tang, Gong; Cuzick, Jack; Costantino, Joseph P; Dowsett, Mitch; Forbes, John F; Crager, Michael; Mamounas, Eleftherios P; Shak, Steven; Wolmark, Norman
2011-11-20
The 21-gene breast cancer assay recurrence score (RS) is widely used for assessing recurrence risk and predicting chemotherapy benefit in patients with estrogen receptor (ER) -positive breast cancer. Pathologic and clinical factors such as tumor size, grade, and patient age also provide independent prognostic utility. We developed a formal integration of these measures and evaluated its prognostic and predictive value. From the National Surgical Adjuvant Breast and Bowel (NSABP) B-14 and translational research cohort of the Arimidex, Tamoxifen Alone or in Combination (TransATAC) studies, we included patients who received hormonal monotherapy, had ER-positive tumors, and RS and traditional clinicopathologic factors assessed (647 and 1,088, respectively). Individual patient risk assessments from separate Cox models were combined using meta-analysis to form an RS-pathology-clinical (RSPC) assessment of distant recurrence risk. Risk assessments by RS and RSPC were compared in node-negative (N0) patients. RSPC was compared with RS for predicting chemotherapy benefit in NSABP B-20. RSPC had significantly more prognostic value for distant recurrence than did RS (P < .001) and showed better separation of risk in the study population. RSPC classified fewer patients as intermediate risk (17.8% v 26.7%, P < .001) and more patients as lower risk (63.8% v 54.2%, P < .001) than did RS among 1,444 N0 ER-positive patients. In B-20, the interaction of RSPC with chemotherapy was not statistically significant (P = .10), in contrast to the previously reported significant interaction of RS with chemotherapy (P = .037). RSPC refines the assessment of distant recurrence risk and reduces the number of patients classified as intermediate risk. Adding clinicopathologic measures did not seem to enhance the value of RS alone nor the individual biology RS identifies in predicting chemotherapy benefit.
Root canal preparation with Er:YSGG laser
Benthin, Hartmut; Ertl, Thomas P.; Onal, B.; Schruender, Stephan; Mueller, Gerhard J.
1994-12-01
The high level of efficiency of hard tissue ablation with Er:YAG and Er:YSGG lasers is well known. Of these lasers it is possible only to transmit Er:YSGG laser radiation with OH reduced quartz fibers. Most of the fibers we use in this study were prepared as hemispherical fiber tips. Fifty single rooted teeth were divided into ten groups (n equals 5). After conventional opening of the pulp chamber, root canal preparation was performed in five groups under water only using the laser. In the other five groups preparation with K-files to size 35 was performed before treatment with laser radiation. All teeth were axially separated with direct access to the root canal and examined in SEM investigations. The groups were compared by measuring the areas with patent dentin tubules. Representative areas were examined by TEM. The temperature at the root surface was measured during laser irradiation with thermocouples positioned at several points. The in-vitro study of the effect of the high delivered energy (50 - 100 mJ per pulse) in the root canal showed a good ablation effect. Most of the dentin tubules were opened. The increase in temperature at the root surface was tolerable.
Croce, Sabrina; de Kock, Leanne; Boshari, Talia; Hostein, Isabelle; Velasco, Valerie; Foulkes, William D; McCluggage, W Glenn
2016-07-01
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm which morphologically and immunohistochemically exhibits overlap with an ovarian sex cord tumor. Although many of these neoplasms are positive with markers of ovarian sex cord-stromal tumors, staining is often limited and the pathogenesis of UTROSCT is unknown. To further explore the sex cord lineage of UTROSCT, we studied 19 of these neoplasms and examined the expression of 2 recently described markers of ovarian sex cord-stromal tumors, FOXL2, and steroidogenic factor-1. We also undertook FOXL2 and DICER1 mutation analysis in these cases; a somatic missense mutation in codon C134W (402C→G) of FOXL2 gene has been demonstrated in the vast majority (>95%) of ovarian adult granulosa cell tumors and somatic DICER1 mutations are found in approximately 60% of ovarian Sertoli-Leydig cell tumors. Ten of 19 cases (53%) exhibited nuclear immunoreactivity with FOXL2 and 11 of 19 (58%) exhibited nuclear staining with steroidogenic factor-1. Neither FOXL2 nor DICER1 mutations were identified in any case where there was sufficient tumor tissue for analysis (18 and 9 cases, respectively). Despite exhibiting an immunophenotype characteristic of a sex cord-stromal tumor, mutations in FOXL2 and DICER1, the 2 most common mutations hitherto reported in ovarian sex cord-stromal tumors, are not a feature of UTROSCT.
Shibuya, Makoto
2018-04-01
The fourth edition of the World Health Organization classification of endocrine tumors (EN-WHO2017) was released in 2017. In this new edition, changes in the classification of non-neuroendocrine tumors are proposed particularly in tumors arising in the posterior pituitary. These tumors are a distinct group of low-grade neoplasms of the sellar region that express thyroid transcription factor-1, and include pituicytoma, granular cell tumor of the sellar region, spindle cell oncocytoma, and sellar ependymoma. This short review focuses on the classification of posterior pituitary tumors newly proposed in EN-WHO2017, and controversies in their pathological differential diagnosis are discussed based on recent cases.
DEFF Research Database (Denmark)
Poulfelt, Flemming
2015-01-01
HR: Er der behov for nytænkning i HR-land? Artikler i Harvard Business Review - bakket op af en dansk undersøgelse - konkluderer, at HR stadig mangler gennemslagskraft i virksomhederne. Er HR ude i tovene? ... For i undersøgelsen "Ny Dansk Ledelse" (maj 2015), som er baseret på danske lederes...
DEFF Research Database (Denmark)
Pedersern, Birger
2010-01-01
Forskningen i fødevarer har fået et potent redskab i hånden. Metabolomics er vejen frem, mener professor Søren Balling Engelsen fra Københavns Universitet......Forskningen i fødevarer har fået et potent redskab i hånden. Metabolomics er vejen frem, mener professor Søren Balling Engelsen fra Københavns Universitet...
DEFF Research Database (Denmark)
Helms, Niels Henrik
2008-01-01
Brugerdreven innovation er blevet svaret på mange af de udfordringer, som vores moderne samfund står overfor.Det er skrevet ind i såvel regeringsgrundlaget som i de forskellige tiltag, som skal ruste Danmark i forhold til globaliseringen. Vi har ifølge argumentationen her enrække særlige forudsæt....... Udgivelsesdato: marts 2008...
DEFF Research Database (Denmark)
Jensen, J. P.; Søndergaard, M.; Jeppesen, E.
styrke det fagli-ge grundlag for de mil-jøpolitiske prioriteringer og beslut-ninger. En væsentlig del af denne opgave er overvågning af miljø og natur. Det er derfor et naturligt led i Danmarks Miljø-undersø-gelsers opgave at forestå den landsdækkende rapportering af overvågnings-program-met inden...
International Nuclear Information System (INIS)
Sanlioglu, Ahter D.; Korcum, Aylin F.; Pestereli, Elif; Erdogan, Gulgun; Karaveli, Seyda; Savas, Burhan; Griffith, Thomas S.; Sanlioglu, Salih V.
2007-01-01
Purpose: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells, and a number of clinical trials have recently been initiated to test the safety and antitumoral potential of TRAIL in cancer patients. Four different receptors have been identified to interact with TRAIL: two are death-inducing receptors (TRAIL-R1 [DR4] and TRAIL-R2 [DR5]), whereas the other two (TRAIL-R3 [DcR1] and TRAIL-R4 [DcR2]) do not induce death upon ligation and are believed to counteract TRAIL-induced cytotoxicity. Because high levels of DcR2 expression have recently been correlated with carcinogenesis in the prostate and lung, this study investigated the importance of TRAIL and TRAIL receptor expression in breast cancer patients with invasive ductal carcinoma, taking various prognostic markers into consideration. Methods and Materials: Immunohistochemical analyses were performed on 90 breast cancer patients with invasive ductal carcinoma using TRAIL and TRAIL receptor-specific antibodies. Age, menopausal status, tumor size, lymph node status, tumor grade, lymphovascular invasion, perineural invasion, extracapsular tumor extension, presence of an extensive intraductal component, multicentricity, estrogen and progesterone receptor status, and CerbB2 expression levels were analyzed with respect to TRAIL/TRAIL receptor expression patterns. Results: The highest TRAIL receptor expressed in patients with invasive ductal carcinoma was DR4. Although progesterone receptor-positive patients exhibited lower DR5 expression, CerbB2-positive tissues displayed higher levels of both DR5 and TRAIL expressions. Conclusions: DR4 expression positively correlates with the tumor grade in breast cancer patients with invasive ductal carcinoma
DEFF Research Database (Denmark)
Andersson, Lasse
2014-01-01
afhængig af Frank Underwood fra serien House of Cards på den fremadstormende TV-streamingstjenesten Netflix. Jeg har opdaget et nyt internetbaseret datingforhold. Et surrealt, fedt miks af det kyniske og joviale personificeret i karakteren Frank Underwood, som er helt igennem ubehagelig, men fantastisk...... spillet af Kevin Spacey. Og tak til Spacey der for en tid har forladt teateret ’The Old Vic’ i London for at begejstre mig. Der er generelt to årsager til mine FRANKofile tilbøjeligheder. For det første er Netflix’s remake af den tyve år gamle BBC serie House of Cards efter min menig et stykke tv...... anden grund, til at jeg er blevet Frankofil, er, at jeg ikke skal sidde og vente på næste søndag efter søndag efter søndag for at få lov at se næste afsnit. Netflix lagde alle tretten timer af sæson 2 ud på nettet. Jeg afgør selv, hvornår jeg skal have mere Frank! Men på trods af mit narkomanlignende...
Expression of NgBR Is Highly Associated with Estrogen Receptor Alpha and Survivin in Breast Cancer
North, Paula; Kong, Amanda; Huang, Jian; Miao, Qing Robert
2013-01-01
NgBR is a type I receptor with a single transmembrane domain and was identified as a specific receptor for Nogo-B. Our recent findings demonstrated that NgBR binds farnesylated Ras and recruits Ras to the plasma membrane, which is a critical step required for the activation of Ras signaling in human breast cancer cells and tumorigenesis. Here, we first use immunohistochemistry and real-time PCR approaches to examine the expression patterns of Nogo-B and NgBR in both normal and breast tumor tissues. Then, we examine the relationship between NgBR expression and molecular subtypes of breast cancer, and the roles of NgBR in estrogen-dependent survivin signaling pathway. Results showed that NgBR and Nogo-B protein were detected in both normal and breast tumor tissues. However, the expression of Nogo-B and NgBR in breast tumor tissue was much stronger than in normal breast tissue. The statistical analysis demonstrated that NgBR is highly associated with ER-positive/HER2-negative breast cancer. We also found that the expression of NgBR has a strong correlation with the expression of survivin, which is a well-known apoptosis inhibitor. The correlation between NgBR and survivin gene expression was further confirmed by real-time PCR. In vitro results also demonstrated that estradiol induces the expression of survivin in ER-positive T47D breast tumor cells but not in ER-negative MDA-MB-468 breast tumor cells. NgBR knockdown with siRNA abolishes estradiol-induced survivin expression in ER-positive T47D cells but not in ER-negative MDA-MB-468 cells. In addition, estradiol increases the expression of survivin and cell growth in ER-positive MCF-7 and T47D cells whereas knockdown of NgBR with siRNA reduces estradiol-induced survivin expression and cell growth. In summary, these results indicate that NgBR is a new molecular marker for breast cancer. The data suggest that the expression of NgBR may be essential in promoting ER-positive tumor cell proliferation via survivin induction
Felsberg, Jörg; Hentschel, Bettina; Kaulich, Kerstin; Gramatzki, Dorothee; Zacher, Angela; Malzkorn, Bastian; Kamp, Marcel; Sabel, Michael; Simon, Matthias; Westphal, Manfred; Schackert, Gabriele; Tonn, Jörg C; Pietsch, Torsten; von Deimling, Andreas; Loeffler, Markus; Reifenberger, Guido; Weller, Michael
2017-11-15
Purpose: Approximately 40% of all glioblastomas have amplified the EGFR gene, and about half of these tumors express the EGFRvIII variant. The prognostic role of EGFRvIII in EGFR -amplified glioblastoma patients and changes in EGFRvIII expression in recurrent versus primary glioblastomas remain controversial, but such data are highly relevant for EGFRvIII-targeted therapies. Experimental Design: EGFR -amplified glioblastomas from 106 patients were assessed for EGFRvIII positivity. Changes in EGFR amplification and EGFRvIII status from primary to recurrent glioblastomas were evaluated in 40 patients with EGFR -amplified tumors and 33 patients with EGFR -nonamplified tumors. EGFR single-nucleotide variants (SNV) were assessed in 27 patients. Data were correlated with outcome and validated in 150 glioblastoma patients from The Cancer Genome Atlas (TCGA) consortium. Results: Sixty of 106 EGFR -amplified glioblastomas were EGFRvIII-positive (56.6%). EGFRvIII positivity was not associated with different progression-free or overall survival. EGFRvIII status was unchanged at recurrence in 35 of 40 patients with EGFR -amplified primary tumors (87.5%). Four patients lost and one patient gained EGFRvIII positivity at recurrence. None of 33 EGFR- nonamplified glioblastomas acquired EGFR amplification or EGFRvIII at recurrence. EGFR SNVs were frequent in EGFR -amplified tumors, but were not linked to survival. Conclusions: EGFRvIII and EGFR SNVs are not prognostic in EGFR -amplified glioblastoma patients. EGFR amplification is retained in recurrent glioblastomas. Most EGFRvIII-positive glioblastomas maintain EGFRvIII positivity at recurrence. However, EGFRvIII expression may change in a subset of patients at recurrence, thus repeated biopsy with reassessment of EGFRvIII status is recommended for patients with recurrent glioblastoma to receive EGFRvIII-targeting agents. Clin Cancer Res; 23(22); 6846-55. ©2017 AACR . ©2017 American Association for Cancer Research.
Peripheral epithelial odontogenic tumor
International Nuclear Information System (INIS)
Carzoglio, J.; Tancredi, N.; Capurro, S.; Ravecca, T.; Scarrone, P.
2006-01-01
A new case of peripheral epithelial odontogenic tumor (Pindborg tumor) is reported. It is localized in the superior right gingival region, a less frequent site, and has the histopathological features previously reported. Immunochemical studies were performed, revealing a differential positive stain to cytokeratins in tumor cells deeply seated in the tumor mass, probably related to tumoral cell heterogeneity.Interestingly, in this particular case S-100 protein positive reactivity was also detected in arborescent cells intermingled with tumoral cells, resembling Langerhans cells. Even though referred in the literature in central Pindborg tumors, no references were found about their presence in peripheral tumors, like the one that is presented here
Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer.
Candido Dos Reis, Francisco J; Lynn, Stuart; Ali, H Raza; Eccles, Diana; Hanby, Andrew; Provenzano, Elena; Caldas, Carlos; Howat, William J; McDuffus, Leigh-Anne; Liu, Bin; Daley, Frances; Coulson, Penny; Vyas, Rupesh J; Harris, Leslie M; Owens, Joanna M; Carton, Amy F M; McQuillan, Janette P; Paterson, Andy M; Hirji, Zohra; Christie, Sarah K; Holmes, Amber R; Schmidt, Marjanka K; Garcia-Closas, Montserrat; Easton, Douglas F; Bolla, Manjeet K; Wang, Qin; Benitez, Javier; Milne, Roger L; Mannermaa, Arto; Couch, Fergus; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Cox, Angela; Cross, Simon S; Blows, Fiona M; Sanders, Joyce; de Groot, Renate; Figueroa, Jonine; Sherman, Mark; Hooning, Maartje; Brenner, Hermann; Holleczek, Bernd; Stegmaier, Christa; Lintott, Chris; Pharoah, Paul D P
2015-07-01
Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface. From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists. The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists. Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input.
DEFF Research Database (Denmark)
Gundelach, Peter; Nørregård-Nielsen, Esther C.
2002-01-01
Hvornår er man ung, og hvornår er man voksen? Er der forskelle i befolkningens værdier i forhold til arbejde og politik, når det undersøges ud fra henholdsvis et alders- eller generationsperspektiv? Baseret på data fra den danske del af den internationale værdiundersøgelse vises at der er så store...
DEFF Research Database (Denmark)
Jensen, J. P.; Søndergaard, M.; Jeppesen, E.
små cladoceer og hjuldyr, og især er maksimumsforekom-sterne af calanoide vandlopper og de små og store cladoceer og daf-nier gået tilbage. Den gennemsnitlige biomasse af dafnier er derimod øget især p.g.a. stigning i de 25 % af søerne med størst forekomster. Dyreplanktons græsning Betragtet under et...
Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L.; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Spurdle, Amanda; Robson, Mark; Sherman, Mark; Mulligan, Anna Marie; Couch, Fergus J.; Engel, Christoph; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Southey, Melissa C.; Terry, Mary Beth; Goldgar, David; O’Malley, Frances; John, Esther M.; Janavicius, Ramunas; Tihomirova, Laima; Hansen, Thomas v O; Nielsen, Finn C.; Osorio, Ana; Stavropoulou, Alexandra; Benítez, Javier; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Volorio, Sara; Pasini, Barbara; Dolcetti, Riccardo; Putignano, Anna Laura; Ottini, Laura; Radice, Paolo; Hamann, Ute; Rashid, Muhammad U.; Hogervorst, Frans B.; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Brewer, Carole; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Houghton, Catherine; Weaver, JoEllen; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Kast, Karin; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Doroteha; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schönbuchner, Ines; Gevensleben, Heidrun; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Barjhoux, Laure; Isaacs, Claudine; Peshkin, Beth N.; Caldes, Trinidad; de al Hoya, Miguel; Cañadas, Carmen; Heikkinen, Tuomas; Heikkilä, Päivi; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.; Dumont, Martine; Simard, Jacques; Montagna, Marco; Agata, Simona; D’Andrea, Emma; Yan, Max; Fox, Stephen; Rebbeck, Timothy R.; Rubinstein, Wendy; Tung, Nadine; Garber, Judy E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia M.; Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine; Mai, Phuong L.; Greene, Mark H.; Sokolenko, Anna; Imyanitov, Evgeny; Toland, Amanda Ewart; Senter, Leigha; Sweet, Kevin; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben; Caligo, Maria; Aretini, Paolo; Rantala, Johanna; von Wachenfeld, Anna; Henriksson, Karin; Steele, Linda; Neuhausen, Susan L.; Nussbaum, Bob; Beattie, Mary; Odunsi, Kunle; Sucheston, Lara; Gayther, Simon A; Nathanson, Kate; Gross, Jenny; Walsh, Christine; Karlan, Beth; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.
2011-01-01
Background Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers. Results There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%). Conclusions/Impact Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis. PMID:22144499
International Nuclear Information System (INIS)
Onishi, Hiroshi; Kuriyama, Kengo; Komiyama, Takafumi; Tanaka, Shiho; Ueki, Junko; Sano, Naoki; Araki, Tsutomu; Ikenaga, Satoshi; Tateda, Yoshihito; Aikawa, Yoshihito
2003-01-01
The aim of the present study was to evaluate the reproducibility of tumor position under patient deep inspiration self-breath-holding in the absence of respiratory monitoring devices, as well as to compare the reproducibility of deep inspiration self-breath-holding on the verbal command of a radiation technologist (Passive mode) with that initiated by patients' own estimation (Active mode). Twenty patients with lung cancer were shown how the tumor and diaphragm move during the respiration cycle. Patients were instructed to hold their breath during deep inspiration and reproduce identical tumor position as well as possible either by the Active mode or by the Passive mode. After patients had practiced self-breath-holding during deep inspiration, a set of three CT scans was obtained for each of the two modes of self-breath-holding (6 CT scans total) to obtain randomly timed images of 2 mm thickness in the vicinity of the tumor. The first three scans were performed during breath-hold using the Active mode, and next three scans were using the Passive mode. Maximum difference in tumor position for the three CT scans was then calculated along three axes: cranial-caudal (C-C); anterior-posterior (A-P); and right-left (R-L). In the 20 patients who underwent analysis of self-breath-holding, mean maximum difference in tumor position obtained under breath-hold using the Active and the Passive modes were: 2.2 and 3.1 mm along the C-C axis; 1.4 and 2.4 mm along the A-P axis; and 1.3 and 2.2 mm along the R-L axis, respectively. These differences in all axes were significantly smaller (p<0.05) for the Active mode than for the Passive mode. Most tumors displayed maximal respiratory movement along the C-C axis, and minimal movement along the R-L axis, but tumors located in the upper lung displayed maximal movement along the A-P axis. Significant correlation (p<0.05) was observed between differences along three axes in either mode of breath-hold. In conclusion, the reproducibility of
Directory of Open Access Journals (Sweden)
Lipika Lipi
2014-01-01
Full Text Available A 50-year-old male patient presented with pain abdomen of 6 months duration. Computed tomography scan revealed a large mass in the stomach occluding the lumen. Histopathology revealed a triple composite tumor comprising of tubular adenocarcinoma arising on a background of high-grade dysplasia, hepatoid adenocarcinoma (positive for Hep Par-1 and alpha fetoprotein and large cell neuroendocrine carcinoma (positive for synaptophysin and chromogranin with nodal metastasis.Triple composite tumors are distinctly rare with few reports in literature.
Treating ER+ Breast Cancer with CDK4/6 Inhibitors.
2017-08-01
Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment. ©2017 American Association for Cancer Research.
Excitation mechanism of Er{sup 3+} in a-Si:H; Anregungsmechanismus von Er{sup 3+} in a-Si:H
Energy Technology Data Exchange (ETDEWEB)
Kuehne, H.
2004-07-01
assisted through PL measurements at a-Si{sub 1-x}C{sub x}:H (Er) films which show change in energetic Position of defects in dependence of the amount of carbon. Samples of different deposition processes: Sputtering and deposition of an organic molecule with PECVD Process show identical PL intensities even though EXAFS measurements show that a great peace of the organic material is implemented. This suggests a relatively high range of the energy transfer which is a disagreement to the discussed excitation model with Auger excitation. This model requires a special overlap of the wave function of electron, dangling bond and Erbium. The resonant Foerster transfer is suggested as excitation transfer. The energy is transported through dipole-dipole interaction with a range of 50A. (orig.)
Endoplasmic Reticulum (ER Stress and Endocrine Disorders
Directory of Open Access Journals (Sweden)
Daisuke Ariyasu
2017-02-01
Full Text Available The endoplasmic reticulum (ER is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR, which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI, Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2 are discussed in this article.
Endoplasmic Reticulum (ER) Stress and Endocrine Disorders
Ariyasu, Daisuke; Yoshida, Hiderou; Hasegawa, Yukihiro
2017-01-01
The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article. PMID:28208663
Directory of Open Access Journals (Sweden)
Yohei Fujita
Full Text Available PURPOSE: We investigated whether serum interleukin (IL-8 reflects the tumor microenvironment and has prognostic value in patients with oral squamous cell carcinoma (OSCC. EXPERIMENTAL DESIGN: Fifty OSCC patients who received radical resection of their tumor(s were enrolled. Preoperative sera were measured for IL-8 by ELISA. Expression of IL-8 and the infiltration of immune cells in tumor tissues were analyzed by an immunohistochemical staining of surgical specimens. RESULTS: We found that disease-free survival (DFS was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p = 0.001. The tumor expression of IL-8, i.e., IL-8(T and the density of CD163-positive cells in the tumor invasive front, i.e., CD163(IF were correlated with the serum IL-8 level (p = 0.033 and p = 0.038, respectively, and they were associated with poor clinical outcome (p = 0.007 and p = 0.002, respectively, in DFS in all patients. A multivariate analysis revealed that N status, IL-8(T and CD163(IF significantly affected the DFS of the patients. Further analysis suggested that combination of N status with serum IL-8, IL-8(T or CD163(IF may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Interestingly, the in vitro experiments demonstrated that IL-8 enhanced generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10. CONCLUSIONS: These findings indicate that IL-8 may be involved in poor clinical outcomes via generation of CD163-positive M2 macrophages, and that these factors in addition to N status may have prognostic value in patients with resectable OSCSS.
Directory of Open Access Journals (Sweden)
Fuminori Sakurai
2016-01-01
Full Text Available Circulating tumor cells (CTCs are promising biomarkers in several cancers, and thus methods and apparatuses for their detection and quantification in the blood have been actively pursued. A novel CTC detection system using a green fluorescence protein (GFP–expressing conditionally replicating adenovirus (Ad (rAd-GFP was recently developed; however, there is concern about the production of false-positive cells (GFP-positive normal blood cells when using rAd-GFP, particularly at high titers. In addition, CTCs lacking or expressing low levels of coxsackievirus–adenovirus receptor (CAR cannot be detected by rAd-GFP, because rAd-GFP is constructed based on Ad serotype 5, which recognizes CAR. In order to suppress the production of false-positive cells, sequences perfectly complementary to blood cell–specific microRNA, miR-142-3p, were incorporated into the 3′-untranslated region of the E1B and GFP genes. In addition, the fiber protein was replaced with that of Ad serotype 35, which recognizes human CD46, creating rAdF35-142T-GFP. rAdF35-142T-GFP efficiently labeled not only CAR-positive tumor cells but also CAR-negative tumor cells with GFP. The numbers of false-positive cells were dramatically lower for rAdF35-142T-GFP than for rAd-GFP. CTCs in the blood of cancer patients were detected by rAdF35-142T-GFP with a large reduction in false-positive cells.
Wang, Shanshan; Zheng, Shanshan; Zhou, Hong; Pan, Anlian; Wu, Guangheng; Liu, Jun-ming
2015-11-01
Here, we demonstrate outstanding temperature-sensing properties from Na0.5Bi0.49Er0.01TiO3 (NBT:Er) thin films. The perovskite phase for them is stable in the temperature range from 80 to 440 K. Interestingly, the Er doping enhances the ferroelectric polarization and introduces local dipolar, which are positive for temperature sensing. Pumped by a 488-nm laser, the NBT:Er thin films show strong green luminescence with two bands around 525 and 548 nm. The intensity ratio I 525/ I 548 can be used for temperature sensing, and the maximum sensitivity is about 2.3 × 10-3 K-1, higher than that from Er-doped silicon oxide. These suggest NBT:Er thin film is a promising candidate for temperature sensor.
Energy Technology Data Exchange (ETDEWEB)
Huang, Long [Sun Yat-sen University, Department of Histology and Embryology, Zhongshan School of Medicine (China); Tian, Xiumei [Guangzhou Medical University, Department of Biomedical Engineering (China); Liu, Jun [Guangdong Ocean University, School of Electronics and Information Technology (China); Zheng, Cunjing; Xie, Fukang, E-mail: frankxie2000@yahoo.com [Sun Yat-sen University, Department of Histology and Embryology, Zhongshan School of Medicine (China); Li, Li, E-mail: li2@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Imaging Diagnosis and Interventional Center (China)
2017-02-15
Our group has synthesized Gd{sub 2}O{sub 3}:Yb{sup 3+}/Er{sup 3+} nanocomposites as magnetic/fluorescence imaging successfully in the previous study, which exhibit good uniformity and monodispersibility with a mean size of 7.4 nm. However, their systematic risk assessment remains unknown. In this article, the in vitro biocompatibility of the Gd{sub 2}O{sub 3}:Yb{sup 3+}/Er{sup 3+} was assessed on the basis of cell viability and apoptosis. In vivo immunotoxicity was evaluated by monitoring the product of reactive oxygen species (ROS), clusters of differentiation (CD) markers, and superoxide dismutase (SOD) in Balb/c mice. No significant differences were found in cell viability, apoptosis, and immunotoxicity between our Gd{sub 2}O{sub 3}:Yb{sup 3+}/Er{sup 3+} and gadodiamide which are used commonly in clinical. Few nanoprobes were localized in the phagosomes of the liver, heart, lung, spleen, kidney, brain, and tumor under the transmission electron microscopy (TEM) images. In addition, our products reveal good T{sub 1}-weighted contrast enhancement of xenografted murine tumor. Therefore, the above results may contribute to the effective application of Gd{sub 2}O{sub 3}:Yb{sup 3+}/Er{sup 3+} as molecular imaging contrast agents and dual-modal nanoprobes for cancer detection.
Cordina-Duverger, Emilie; Koudou, Yves; Truong, Thérèse; Arveux, Patrick; Kerbrat, Pierre; Menegaux, Florence; Guénel, Pascal
Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.
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Rennison, Betina Wolfgang
2017-01-01
Ledere skal i dag selv skabe deres eget rum til ledelse, men hvad er med til at sætte det, hvilke betingelser og udfordringer er der, og hvordan kan lederne skabe sig selv i et hav af forventninger? Dette katalog inviterer til refleksion herom....
International Nuclear Information System (INIS)
Artagaveytia, N.; Román, E.; Alonso, I.; Sabini, G.; Garófalo, E.
2004-01-01
The aim of this study was to investigate retrospectively the presence of ER, PR, Db Receptor and Epidermal Growth Factor (EGFR) in 678 patients carrying primary breast cancer, its correlation with clinic pathological parameters and evolution. the determination of ER, PR and EGFR was performed by Scatchard biochemical technique, based cutoff 10 fmoles / mg of protein. The RE-b detection performed by RT-PCR from total RNA, using the GAPDH gene as a control. Statistical analyzes were applied the Chi2 tests, Spearman and Kruskal-Wallis. The disease-free survival (SVLE) and survival overall (SVG) were analyzed using Kaplan Meier / Log Rank Test and analysis Cox regression. Median follow-up was 28 months (range 1-218 months). sixty Four percent of the patients were post-menopausal and 83% occurred in stages Early disease (I-II, pTNM UICC). The receptor positivity was 68%, 47%, 23% and 58% for ER, PR, EGFR and ER-b-mRNA, respectively. A correlation was found positive between the content of ER and PR (p = 1.10-5) and negative between these receptors and EGFR (n = 359, p = 0.014 and p = 0.018, respectively). We observed a trend to increased expression ER-b when ER, PR or both receptors were negative comparable to that observed with EGFR. Also, a gradual decrease in the content of ER and PR was observed with the progression to more advanced stages (p = 0.04 and p = 0.03). Of a total of 501 evaluable patients 23% relapsed and 12% died. ER positivity was associated with a greater SVLE and SVG 24 and 60 months follow up (p = 0.06). A major impact did the RE content, levels less than 45 fmol / mg protein were associated with disease recurrence (p = 0.03 and p = 0.006 for 24 and 60 months). Although less significant EGFR status influenced SVLE and SVG. In particular, the presence of EGFR in ER + group affected the evolution tripling relapses and deaths (p = 0.058). The presence of ER-b also had a negative impact on this patient group. In Cox regression analysis, N + and T> 2cm
Effect of Er3+ Concentration on Upconversion in Hexagonal-Phase NaYF4:Er3+ Nanocrystals
International Nuclear Information System (INIS)
Luo, X J; Yuminami, R; Sakurai, T; Akimoto, K
2013-01-01
A facile synthesis method was developed to produce hexagonal-phase of NaYF 4 nanocrystals (NCs) doped with Er 3+ in different concentration, which showed upconversion (UC) emission from infrared to visible spectral region. This proposed method is simple and less toxic compared with generally used method so far. It was found that up-conversion emission spectra of NaYF 4 :Er 3+ NCs, excited at 1550 nm, included four peaks at about 980 nm, 800 nm, 660 nm and 540 nm. The effect of Er 3+ concentration on UC in β-phase NaYF 4 :Er 3+ NCs were discussed based on the excitation power dependence. The optimum Er 3+ concentration for 2-step and 3-step UC was found to be around 10∼30%.
Nielsen, Jon Magne
2006-01-01
Denne oppgaven ser på bruken av elektronisk ID i statlige etater i Norge i dag. Det ses spesielt på om bruken av tekologien PKI er en god løsning på etatenes behov på dette området. Som utgangspunkt for analysen er det sett spesielt på to statlige etater. Disse etatenes behov og bruk av elektronisk ID generelt og PKI spesielt blir undersøkt. Det er videre gjort rede for hvilke lover, forskrifter og andre førende dokumenter som danner de formelle rammebetingelsene for etaters bruk av PKI. ...
2014-01-01
Introduction Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories. Methods We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd’s scale and was conflated into: 75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided. Results Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; screening-detected cancers, extreme breast density
Li, Jun; Yang, Shengke; Hu, Junjie; Liu, Hao; Du, Feng; Yin, Jie; Liu, Sai; Li, Ci; Xing, Shasha; Yuan, Jiatian; Lv, Bo; Fan, Jun; Leng, Shusheng; Zhang, Xin; Wang, Bing
2016-04-05
We investigated the possibility of counting tumor deposits (TDs) as positive lymph nodes (pLNs) in the pN category and evaluated its prognostic value for colorectal cancer (CRC) patients. A new pN category (npN category) was calculated using the numbers of pLNs plus TDs. The npN category included 4 tiers: npN1a (1 tumor node), npN1b (2-3 tumor nodes), npN2a (4-6 tumor nodes), and npN2b (≥7 tumor nodes). We identified 4,121 locally advanced CRC patients, including 717 (11.02%) cases with TDs. Univariate and multivariate analyses were performed to evaluate the disease-free and overall survival (DFS and OS) for npN and pN categories. Multivariate analysis showed that the npN and pN categories were both independent prognostic factors for DFS (HR 1.614, 95% CI 1.541 to 1.673; HR 1.604, 95% CI 1.533 to 1.679) and OS (HR 1.633, 95% CI 1.550 to 1.720; HR 1.470, 95% CI 1.410 to 1.532). However, the npN category was superior to the pN category by Harrell's C statistic. We conclude that it is thus feasible to consider TDs as positive lymph nodes in the pN category when evaluating the prognoses of CRC patients, and the npN category is potentially superior to the TNM (7th edition) pN category for predicting DFS and OS among advanced CRC patients.
Huang, Haitao; Yue, Tao; Xu, Ke; Golzarian, Jafar; Yu, Jiahui; Huang, Jin
2015-07-01
Gd(III) chelate is currently used as positive magnetic resonance imaging (MRI) contrast agent in clinical diagnosis, but generally induces the risk of nephrogenic systemic fibrosis (NSF) due to the dissociated Gd(3+) from Gd(III) chelates. To develop a novel positive MRI contrast agent with low toxicity and high sensitivity, ultrasmall MnO nanoparticles were PEGylated via catechol-Mn chelation and conjugated with cRGD as active targeting function to tumor. Particularly, the MnO nanoparticles with a size of ca. 5nm were modified by α,β-poly(aspartic acid)-based graft polymer containing PEG and DOPA moieties and, meanwhile, conjugated with cRGD to produce the contrast agent with a size of ca. 100nm and a longitudinal relaxivity (r1) of 10.2mM(-1)S(-1). Such nanoscaled contrast agent integrated passive- and active-targeting function to tumor, and its efficient accumulation behavior in tumor was verified by in vivo distribution study. At the same time, the PEG moiety played a role of hydrophilic coating to improve the biocompatibility and stability under storing and physiological conditions, and especially might guarantee enough circulation time in blood. Moreover, in vivo MRI revealed a good and long-term effect of enhancing MRI signal for as-fabricated contrast agent while cell viability assay proved its acceptable cytotoxicity for MRI application. On the whole, the as-fabricated PEGylated and cRGD-functionalized contrast agent based on ultrasmall MnO nanoparticles showed a great potential to the T1-weighted MRI diagnosis of tumor. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.
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Rydén, Pernille; Ringberg, Torsten; Wilke, Ricky
En forskningsrapport fra CBS om danske lederes opfattelse af sociale medier i detail- og servicebranchen. Rapporten er udarbejdet i regi af Service Platform.......En forskningsrapport fra CBS om danske lederes opfattelse af sociale medier i detail- og servicebranchen. Rapporten er udarbejdet i regi af Service Platform....
International Nuclear Information System (INIS)
Sakitani, Kosuke; Hirata, Yoshihiro; Hikiba, Yohko; Hayakawa, Yoku; Ihara, Sozaburo; Suzuki, Hirobumi; Suzuki, Nobumi; Serizawa, Takako; Kinoshita, Hiroto; Sakamoto, Kei; Nakagawa, Hayato; Tateishi, Keisuke; Maeda, Shin; Ikenoue, Tsuneo; Kawazu, Shoji; Koike, Kazuhiko
2015-01-01
Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer. We crossed K19 CreERT and Atg5 flox/flox mice to generate Atg5 flox/flox /K19 CreERT mice. Atg5 flox/flox /K19 CreERT mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins. Colon tumors in Atg5 flox/flox /K19 CreERT mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 flox/flox /K19 CreERT mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 flox/flox /K19 CreERT mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells. Blocking autophagy
An approach to malignant mammary phyllodes tumors detection
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Ilić Ivan
2009-01-01
Full Text Available Background/Aim. Mammary phyllodes tumors (MPT are uncommon fibroepithelial (biphasic neoplasms whose clinical behavior is difficult to predict on the basis of histological criteria only. They are divided into benign, borderline malignant and malignant groups. Sometimes it appears difficult to distinguish these tumors from other types of soft tissue sarcomas. Because of the relatively scant data on the role of biological markers in MPT histogenesis, we have decided to undertake the following study, trying to shed more light on the issue by investigating the following elements that make up MPT: their histological patterns, biological behavior, enzymohistochemical, histochemical and immunohistochemical characteristics (ICH together with the mast cell analysis. Methods. We examined the biopsy material of 35 MPT in our laboratory. Enzymohistochemistry was performed on frozen sections (method of Crowford, Nachlas and Seligman. The used methods were classical hematoxylin-eosin (H&E; histochemical Massontrichrome, Alcian-blue, Periodic acid Schiff and immunohistochemical LSAB2 method (DacoCytomation. Ki-67, ckit, vimentin, estrogen receptor (ER, progesterone receptor (PR and Her-2 oncoprotein immunohistochemistry was performed on all tumors. Results. The patients were ranged per age from 30-62 years (mean 43.3 years, median 39 years. A total of 35 cases of MPT were included: 20 benign (57%, 6 borderline malignant (17% and 9 malignant (26%. Twenty-two patients (62.8 % underwent segmental mastectomy, while 13 (37.2% had total mastectomies. Twenty-eight patients had negative surgical margins at original resection. The mean size of malignant MPT (7.8 cm was larger than that of benign MPT (4.5 cm. Significant features of the malignant MPT were: stromal cellularity, stromal cellular atypism, high mitotic activity, atypic mitoses, stromal overgrowth, infiltrative tumor contour and heterologous stromal elements. Benign MPT showed strong enzymohistochemical
Anjana, R.; Jayaraj, M. K.; Yadav, A. K.; Jha, S. N.; Bhattacharyya, D.
2018-04-01
The local structure around Er and Yb centre in ZnO favouring upconversion luminescence was studied using EXAFS (Extended X-ray absorption fine structure spectroscopy). Due to the ionic radii difference between Zn and Er, Yb ions, the dopants cannot replace Zn in the ZnO lattice properly. Er2O3 and Yb2O3 impurity phases are formed at the grain boundaries of ZnO. It is found that the local structure around the Er centre in ZnO is modified on annealing in air. The symmetry around both erbium and ytterbium reduces with increase in annealing temperature. Symmetry reduction will favour the intra-4f transition and the energy transitions causing upconversion luminescence. By fitting the EXAFS data with theoretically simulated data, it is found that the Er centre forms a local structure similar to C4ν symmetry which is a distorted octahedron. On annealing the sample to 1200 °C, all the erbium centres are transformed to C4ν symmetry causing enhanced upconversion emission. Yb centre has also been modified on annealing. The decrease in co-ordination number with annealing temperature will decrease the symmetry and increase the near infrared absorption cross section. The decrease in symmetry around both the erbium and ytterbium centre and formation of C4ν symmetry around Er centre is the reason behind the activation of upconversion luminescence with high temperature annealing in both Er doped and Er, Yb co-doped ZnO samples. The study will be useful for the synthesis of high efficiency upconversion materials.
International Nuclear Information System (INIS)
Mera, Kentaro; Kawahara, Ko-ichi; Tada, Ko-ichi; Kawai, Kazuhiro; Hashiguchi, Teruto; Maruyama, Ikuro; Kanekura, Takuro
2010-01-01
Proteins are folded properly in the endoplasmic reticulum (ER). Various stress such as hypoxia, ischemia and starvation interfere with the ER function, causing ER stress, which is defined by the accumulation of unfolded protein (UP) in the ER. ER stress is prevented by the UP response (UPR) and ER-associated degradation (ERAD). These signaling pathways are activated by three major ER molecules, ATF6, IRE-1 and PERK. Using HaCaT cells, we investigated ER signaling in human keratinocytes irradiated by environmental doses of ultraviolet B (UVB). The expression of Ero1-Lα, an upstream signaling molecule of ER stress, decreased at 1-4 h after 10 mJ/cm 2 irradiation, indicating that the environmental dose of UVB-induced ER stress in HaCaT cells, without growth retardation. Furthermore, expression of intact ATF6 was decreased and it was translocated to the nuclei. The expression of XBP-1, a downstream molecule of IRE-1, which is an ER chaperone whose expression is regulated by XBP-1, and UP ubiquitination were induced by 10 mJ/cm 2 UVB at 4 h. PERK, which regulates apoptosis, was not phosphorylated. Our results demonstrate that UVB irradiation generates UP in HaCaT cells and that the UPR and ERAD systems are activated to protect cells from UVB-induced ER stress. This is the first report to show ER signaling in UVB-irradiated keratinocytes.
DEFF Research Database (Denmark)
Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B
2009-01-01
BACKGROUND: New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear...... whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved...... of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate...
Directory of Open Access Journals (Sweden)
Obacz J
2015-06-01
Full Text Available Joanna Obacz,1 Veronika Brychtova,1 Jan Podhorec,1 Pavel Fabian,2 Petr Dobes,1 Borivoj Vojtesek,1 Roman Hrstka1 1Regional Centre for Applied Molecular Oncology (RECAMO, 2Department of Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic Abstract: Anterior gradient protein (AGR 3 is a highly related homologue of pro-oncogenic AGR2 and belongs to the family of protein disulfide isomerases. Although AGR3 was found in breast, ovary, prostate, and liver cancer, it remains of yet poorly defined function in tumo-rigenesis. This study aimed to determine AGR3 expression in a cohort of 129 primary breast carcinomas and evaluate the clinical and prognostic significance of AGR3 in these tumors. The immunohistochemical analysis revealed the presence of AGR3 staining to varying degrees in 80% of analyzed specimens. The percentage of AGR3-positive cells significantly correlated with estrogen receptor, progesterone receptor (both P<0.0001 as well as low histological grade (P=0.003, and inversely correlated with the level of Ki-67 expression (P<0.0001. In the whole cohort, AGR3 expression was associated with longer progression-free survival (PFS, whereas AGR3-positive subgroup of low-histological grade tumors showed both significantly longer PFS and overall survival. In conclusion, AGR3 is associated with the level of differentiation, slowly proliferating tumors, and more favorable prognosis of breast cancer patients. Keywords: AGR3, patient survival, protein disulfide isomerase, ER-positive breast cancer, immunohistochemistry
ER Stress: A Therapeutic Target in Rheumatoid Arthritis?
Rahmati, Marveh; Moosavi, Mohammad Amin; McDermott, Michael F
2018-04-22
Diverse physiological and pathological conditions that impact on protein folding of the endoplasmic reticulum (ER) cause ER stress. The unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway are activated to cope with ER stress. In rheumatoid arthritis (RA), inflammation and ER stress work in parallel by driving inflammatory cells to release cytokines that induce chronic ER stress pathways. This chronic ER stress may contribute to the pathogenesis of RA through synoviocyte proliferation and proinflammatory cytokine production. Therefore, ER stress pathways and their constituent elements are attractive targets for RA drug development. In this review, we integrate current knowledge of the contribution of ER stress to the overall pathogenesis of RA, and suggest some therapeutic implications of these discoveries. Copyright © 2018 Elsevier Ltd. All rights reserved.
Fremtidens undervisningsmiljøer
DEFF Research Database (Denmark)
2013-01-01
Som oplægget til dette temanummer af LOM også indikerede, så sætter vi fokus på fremtidens undervisningsmiljøer på universiteter og UCer. Fremtidens undervisningsmiljøer har mange facetter, hvilket samlingen af artikler også illustrerer. “Fremtidens Undervisningsmiljø” handler om eksisterende erf...
Directory of Open Access Journals (Sweden)
Bondarenko I.N.
2016-05-01
Full Text Available Extreme heterogeneity of breast cancer (BC is considered to be one of the reasons that affects the success of treatment. According to current classifications, there are 4 molecular subtypes (MS. The basis for subtypes division is immunohistochemical testing of tumor cell receptors - estrogen (ER, progesterone (PR, HER2-neu and Ki-67. The doctrine of the tumor MS was the basis for the individualization of therapeutic tactics in patients with breast cancer. It was studied that luminal A subtype is the most common and the most favorable, with hormone therapy being a highly effective treatment method. Luminal B subtype, HER2 - positive and triple negative MS is characterized by a high aggressiveness, worse survival rate of patients and better prognostic effect of chemotherapy. The importance of determining the level of Ki-67 for assessment of tumor aggressiveness was revealed. Significant differences in receptor status of the primary tumor and metastases were proven. Data on the impact of changes in receptor status of the tumor prognosis are ambiguous and need further study. The use of targeted agents in the treatment of HER2 + patients can significantly improve treatment outcomes, turning this MS from historically aggressive subgroup to quite favorable.
Suppression of concentration quenching of Er-related luminescence in Er-doped GaN
International Nuclear Information System (INIS)
Chen Shaoqiang; Tomita, Shigeo; Kudo, Hiroshi; Akimoto, Katsuhiro; Dierre, Benjamin; Lee, Woong; Sekiguchi, Takashi
2010-01-01
Erbium-doped GaN with different doping concentrations were grown by ammonia-source molecular beam epitaxy. The intra-4f-shell transitions related green luminescence were observed by both photoluminescence (PL) and cathodoluminescence (CL) measurements. It was found that concentration quenching of Er-related luminescence was observed in PL measurements while not in CL measurements. The different excitation and relaxation processes are suggested as the cause of the concentration quenching characteristics between PL and CL. The strong Er-related CL intensity in highly doped GaN demonstrates that high energy excitation is a promising approach to suppress the concentration quenching in Er-doped GaN.
Hofvind, Solveig; Sagstad, Silje; Sebuødegård, Sofie; Chen, Ying; Roman, Marta; Lee, Christoph I
2018-04-01
Purpose To compare rates and tumor characteristics of interval breast cancers (IBCs) detected after a negative versus false-positive screening among women participating in the Norwegian Breast Cancer Screening Program. Materials and Methods The Cancer Registry Regulation approved this retrospective study. Information about 423 445 women aged 49-71 years who underwent 789 481 full-field digital mammographic screening examinations during 2004-2012 was extracted from the Cancer Registry of Norway. Rates and odds ratios of IBC among women with a negative (the reference group) versus a false-positive screening were estimated by using logistic regression models adjusted for age at diagnosis and county of residence. Results A total of 1302 IBCs were diagnosed after 789 481 screening examinations, of which 7.0% (91 of 1302) were detected among women with a false-positive screening as the most recent breast imaging examination before detection. By using negative screening as the reference, adjusted odds ratios of IBCs were 3.3 (95% confidence interval [CI]: 2.6, 4.2) and 2.8 (95% CI: 1.8, 4.4) for women with a false-positive screening without and with needle biopsy, respectively. Women with a previous negative screening had a significantly lower proportion of tumors that were 10 mm or less (14.3% [150 of 1049] vs 50.0% [seven of 14], respectively; P false-positive screening with benign biopsy. A retrospective review of the screening mammographic examinations identified 42.9% (39 of 91) of the false-positive cases to be the same lesion as the IBC. Conclusion By using a negative screening as the reference, a false-positive screening examination increased the risk of an IBC three-fold. The tumor characteristics of IBC after a negative screening were less favorable compared with those detected after a previous false-positive screening. © RSNA, 2017 Online supplemental material is available for this article.
The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer
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Malgorzata Banys
2014-01-01
Full Text Available Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly worse clinical outcome than DTC-negative patients. Since DTC phenotype may differ from the primary tumor with regard to ER and HER2 status, reevaluation of predictive markers on DTCs may optimize treatment choices. In the present review, we report on the clinical relevance of DTC detection in breast cancer.
International Nuclear Information System (INIS)
Parise, C. A.; Caggiano, V.Caggiano
2015-01-01
Background. The eight ER/PR/HER2 breast cancer subtypes vary widely in demographic and clinico pathologic characteristics and survival. This study assesses the contribution of SES to the risk of mortality for blacks, Hispanics, Asian/Pacific Islanders, and American Indians when compared with white women for each ER/PR/HER2 subtype. Methods. We identified 143,184 cases of first primary female invasive breast cancer from the California Cancer Registry between 2000 and 2012. The risk of mortality was computed for each race/ethnicity within each ER/PR/HER2 subtype. Models were adjusted for tumor grade, year of diagnosis, and age. SES was added to a second set of models. Analyses were conducted separately for each stage. Results. Race/ethnicity did not contribute to the risk of mortality for any subtype in stage 1 when adjusted for SES. In stages 2, 3, and 4, race/ethnicity was associated with risk of mortality and adjustment for SES changed the risk only in some subtypes. SES reduced the risk of mortality by over 45% for American Indians with stage 2 ER+/PR+/HER2-cancer, but it decreased the risk of mortality for blacks with stage 2 triple negative cancer by less than 4%. Conclusions. Racial/ethnic disparities do not exist in all ER/PR/HER2 subtypes and, in general, SES modestly alters these disparities.
DEFF Research Database (Denmark)
Thomsen, Frej Klem
2014-01-01
Hvis man er skeptiker, så er moral nemlig altid kun et udtryk for psykologi og kultur, også når det handler om for eksempel misbrug af børn i Tønder-sagen eller terror-angreb i Madrid, London og Mumbai .......Hvis man er skeptiker, så er moral nemlig altid kun et udtryk for psykologi og kultur, også når det handler om for eksempel misbrug af børn i Tønder-sagen eller terror-angreb i Madrid, London og Mumbai ....
International Nuclear Information System (INIS)
Brandes, S.J.; Katzenellenbogen, J.A.
1986-01-01
The assay of progesterone receptor (PR) concentration in breast tumors and androgen receptor (AR) concentration in prostate tumors enables hormone responsive neoplasms to be distinguished from those that are non-responsive. In principle, a positron-emitting progestin or androgen with suitably high affinity and selectivity for PR and AR, respectively, and an adequately high specific activity might provide a means for imaging receptor-positive tumors and quantifying their receptor content in vivo. The use of fluorine-18 as a radiolabel, coupled with the use of positron emission transaxial tomography, appears to be a most favorable approach in the development of receptor binding radiopharmaceuticals for in vivo imaging. Therefore, we have begun a systematic investigation of the development of fluorine-substituted androgens and progestins that might be prepared in F-18 labeled form as probes for AR and PR. (author)
Jin, Peng; van der Horst, Astrid; de Jong, Rianne; van Hooft, Jeanin E.; Kamphuis, Martijn; van Wieringen, Niek; Machiels, Melanie; Bel, Arjan; Hulshof, Maarten C. C. M.; Alderliesten, Tanja
2015-01-01
The aim of this study was to quantify interfractional esophageal tumor position variation using markers and investigate the use of markers for setup verification. Sixty-five markers placed in the tumor volumes of 24 esophageal cancer patients were identified in computed tomography (CT) and follow-up
Petit, F G; Métivier, R; Valotaire, Y; Pakdel, F
1999-01-01
In all oviparous, liver represents one of the main E2-target tissues where estrogen receptor (ER) constitutes the key mediator of estrogen action. The rainbow trout estrogen receptor (rtER) gene expression is markedly up-regulated by estrogens and the sequences responsible for this autoregulation have been located in a 0.2 kb upstream transcription start site within - 40/- 248 enhancer region. Absence of interference with steroid hormone receptors and tissue-specific factors and a conserved basal transcriptional machinery between yeast and higher eukaryotes, make yeast a simple assay system that will enable determination of important cis-acting regulatory sequences within rtER gene promoter and identification of transcription factors implicated in the regulation of this gene. Deletion analysis allowed to show a synergistic effect between an imperfect estrogen-responsive element (ERE) and a consensus half-ERE to achieve a high hormone-dependent transcriptional activation of the rtER gene promoter in the presence of stably expressed rtER. As in mammalian cells, here we observed a positive regulation of the rtER gene promoter by the chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) through enhancing autoregulation. Using a point mutation COUP-TFI mutant unable to bind DNA demonstrates that enhancement of rtER gene autoregulation requires the interaction of COUP-TFI to the DNA. Moreover, this enhancement of transcriptional activation by COUP-TFI requires specifically the AF-1 transactivation function of ER and can be observed in the presence of E2 or 4-hydroxytamoxifen but not ICI 164384. Thus, this paper describes the reconstitution of a hormone-responsive transcription unit in yeast in which the regulation of rtER gene promoter could be enhanced by the participation of cis-elements and/or trans-acting factors, such as ER itself or COUP-TF.
DEFF Research Database (Denmark)
Klebaner, Daniella; Hamilton-Dutoit, Stephen; Ahern, Thomas P
2017-01-01
confounding using logistic regression. RESULTS: Cytoplasmic ApoD expression was seen in 68% of ER+ tumors, in 66% of ER- tumors, and in 66% of controls across both groups. In women with ER+ tumors, the associations of cytoplasmic ApoD expression with recurrence (OR = 1.0; 95% CI = 0.7 to 1.4) and increasing...... cytoplasmic expression with recurrence (OR = 1.0; 95% CI = 0.996 to 1.003) were null, as were those for women with ER- tumors. Associations for nuclear ApoD expression and combined nuclear and cytoplasmic expression were similarly near-null. CONCLUSION: ApoD expression is likely not a predictor of recurrence......BACKGROUND: Apolipoprotein D (ApoD) has been proposed as a predictor of breast cancer recurrence among estrogen receptor-positive (ER+), tamoxifen-treated patients. METHODS: We conducted a population-based case-control study nested in a population of 11,251 women aged 35-69 years at diagnosis...
Self-diffusion of Er and Hf inpure and HfO2-doped polycrystalline Er2O3
International Nuclear Information System (INIS)
Scheidecker, R.W.
1979-01-01
Using a tracer technique, self-diffusion of Er and Hf was measured over the approximate temperature interval of 1600 to 1970 0 C in pure and HfO 2 -doped polycryatalline Er 2 O 3 . Up to about 10 m/o HfO 2 dopant level, the Er self-diffusion coefficients followed a relationship based on cation vacancies. Above 10 m/o HfO 2 , deviation from this relationship occurred, apparently due to clustering of cation vacancies and oxygen interstitials around the dopant hafnia ion. The activation energy for the self-diffusion of Er in pure Er 2 O 3 was 82.2 Kcal/mole and increased with the HfO 2 dopant level present. Self-diffusion of Hf was measured in pure Er 2 O 3 having two impurity levels, and a separation of the grain boundary. The volume diffusion of Hf showed both extrinsic and intrinsic behavior with the transition temperature increasing with the impurity level present in Er 2 O 3 . The activation energy for Hf volume diffusion in the intrinsic region was high, i.e. 235 -+ 9.5 Kcal/mole. The grain boundary diffusion was apparently extrinsic over the entire temperature interval Very low Hf self diffusion rates were found in both pure and HfO 2 doped Er 2 O 3 compositions. Despite a clustering effect, the HfO 2 dopant increased the Hf volume diffusion coefficients
Directory of Open Access Journals (Sweden)
Tomohisa Mori
Full Text Available The membrane of the endoplasmic reticulum (ER of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.
Mori, Tomohisa; Hayashi, Teruo; Hayashi, Eri; Su, Tsung-Ping
2013-01-01
The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.
Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics
Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E.; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F.G.; Rothermel, Beverly A.; Lavandero, Sergio
2014-01-01
Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER–mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245
DEFF Research Database (Denmark)
Nielsen, Rikke Kristine
2013-01-01
Færdigheder: Oftest er lederne langtfra de første til at kaste sig over ny teknologi. It-kundskaberne på chefgangen trænger til en opgradering.......Færdigheder: Oftest er lederne langtfra de første til at kaste sig over ny teknologi. It-kundskaberne på chefgangen trænger til en opgradering....
A novel resveratrol-salinomycin combination sensitizes ER-positive breast cancer cells to apoptosis.
Venkatadri, Rajkumar; Iyer, Anand Krishnan V; Kaushik, Vivek; Azad, Neelam
2017-08-01
Resveratrol is a dietary compound that has been widely reported for its anticancer activities. However, successful extrapolation of its effects to pre-clinical studies is met with limited success due to inadequate bioavailability. We investigated the potential of combination therapy to improve the efficacy of resveratrol in a more physiologically relevant dose range. The effect of resveratrol on canonical Wnt signaling was evaluated by Western blotting. Wnt modulators HLY78 (activator) and salinomycin (inhibitor) were evaluated in combination with resveratrol for their effect on breast cancer cell viability (MTT assay), cell cycle progression and apoptosis (Western blotting). Bliss independency model was used to evaluate combinatorial effects of resveratrol-salinomycin combination. Resveratrol downregulated canonical Wnt signaling proteins in treated breast cancer cells (MCF-7, MDA-MB-231 and MDA-MB-468) in the dose range of 50-200μM, which also affected cellular viability. However, at very low doses (0-50μM), resveratrol exhibited no cellular toxicity. Co-treatment with salinomycin significantly potentiated the anti-cancer effects of resveratrol, whereas HLY78 co-treatment had minimal effect. Bliss independency model revealed that Wnt inhibition synergistically potentiates the effects of resveratrol in MCF-7 and BT474 cells. Significantly downregulated canonical Wnt signaling proteins and marker of epithelial-mesenchymal transition (EMT), vimentin were observed in cells treated with resveratrol-salinomycin combination. Cell cycle arrest, caspase activation and apoptosis induction in cells treated with resveratrol-salinomycin combination further confirmed the efficacy of the combination. We report a novel resveratrol-salinomycin combination for targeting ER-positive breast cancer cells and present evidence for successful pre-clinical implementation of resveratrol. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban
Synthesis of Er and Er : Yb doped sol–gel derived silica glass and ...
Indian Academy of Sciences (India)
Unknown
Materials Science Centre, †Central Research Facility, Optical Fibre Unit, Indian Institute of Technology,. Kharagpur 721 302, India. MS received 1 March 2004; revised 4 July 2004. Abstract. Er3+ and Er3+ : Yb3+ doped optical quality, crack and bubble free glasses for possible use in mak- ing laser material have been ...
Energy Technology Data Exchange (ETDEWEB)
Cervia, Davide, E-mail: d.cervia@unitus.it [Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), University of Tuscia, Viterbo (Italy); Department of Biomedical and Clinical Sciences, “Luigi Sacco” University Hospital, University of Milan, Milano (Italy); Catalani, Elisabetta; Belardinelli, Maria Cristina [Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), University of Tuscia, Viterbo (Italy); Perrotta, Cristiana [Department of Biomedical and Clinical Sciences, “Luigi Sacco” University Hospital, University of Milan, Milano (Italy); Picchietti, Simona [Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), University of Tuscia, Viterbo (Italy); Alimenti, Claudio [Department of Environmental and Natural Sciences, University of Camerino, Camerino (Italy); Casini, Giovanni; Fausto, Anna Maria [Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), University of Tuscia, Viterbo (Italy); Vallesi, Adriana [Department of Environmental and Natural Sciences, University of Camerino, Camerino (Italy)
2013-02-01
Water-soluble protein signals (pheromones) of the ciliate Euplotes have been supposed to be functional precursors of growth factors and cytokines that regulate cell–cell interaction in multi-cellular eukaryotes. This work provides evidence that native preparations of the Euplotes raikovi pheromone Er-1 (a helical protein of 40 amino acids) specifically increases viability, DNA synthesis, proliferation, and the production of interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-2, and IL-13 in human Jurkat T-cells. Also, Er-1 significantly decreases the mRNA levels of the β and γ subunits of IL-2 receptor (IL-2R), while the mRNA levels of the α subunit appeared to be not affected. Jurkat T-cell treatments with Er-1 induced the down-regulation of the IL-2Rα subunit by a reversible and time-dependent endocytosis, and increased the levels of phosphorylation of the extracellular signal-regulated kinases (ERK). The cell-type specificity of these effects was supported by the finding that Er-1, although unable to directly influence the growth of human glioma U-373 cells, induced Jurkat cells to synthesize and release factors that, in turn, inhibited the U-373 cell proliferation. Overall, these findings imply that Er-1 coupling to IL-2R and ERK immuno-enhances T-cell activity, and that this effect likely translates to an inhibition of glioma cell growth. -- Highlights: ► Euplotes pheromone Er-1 increases the growth of human Jurkat T-cells. ► Er-1 increases the T-cell production of specific cytokines. ► Er-1 activates interleukin-2 receptor and extracellular signal-regulated kinases. ► The immuno-enhancing effect of Er-1 on Jurkat cells translates to an inhibition of human glioma cell growth.
Expression profiling on soybean leaves reveals integration of ER- and osmotic-stress pathways
Directory of Open Access Journals (Sweden)
Dewey Ralph E
2007-11-01
downstream targets were inversely regulated by osmotic stress. Conclusion The present ER-stress- and osmotic-stress-induced transcriptional studies demonstrate a clear predominance of stimulus-specific positive changes over shared responses on soybean leaves. This scenario indicates that polyethylene glycol (PEG-induced cellular dehydration and ER stress elicited very different up-regulated responses within a 10-h stress treatment regime. In addition to identifying ER-stress and osmotic-stress-specific responses in soybean (Glycine max, our global expression-profiling analyses provided a list of candidate regulatory components, which may integrate the osmotic-stress and ER-stress signaling pathways in plants.
Novikov, Olga; Wang, Zhongyan; Stanford, Elizabeth A; Parks, Ashley J; Ramirez-Cardenas, Alejandra; Landesman, Esther; Laklouk, Israa; Sarita-Reyes, Carmen; Gusenleitner, Daniel; Li, Amy; Monti, Stefano; Manteiga, Sara; Lee, Kyongbum; Sherr, David H
2016-11-01
The endogenous ligand-activated aryl hydrocarbon receptor (AHR) plays an important role in numerous biologic processes. As the known number of AHR-mediated processes grows, so too does the importance of determining what endogenous AHR ligands are produced, how their production is regulated, and what biologic consequences ensue. Consequently, our studies were designed primarily to determine whether ER - /PR - /Her2 - breast cancer cells have the potential to produce endogenous AHR ligands and, if so, how production of these ligands is controlled. We postulated that: 1) malignant cells produce tryptophan-derived AHR ligand(s) through the kynurenine pathway; 2) these metabolites have the potential to drive AHR-dependent breast cancer migration; 3) the AHR controls expression of a rate-limiting kynurenine pathway enzyme(s) in a closed amplification loop; and 4) environmental AHR ligands mimic the effects of endogenous ligands. Data presented in this work indicate that primary human breast cancers, and their metastases, express high levels of AHR and tryptophan-2,3-dioxygenase (TDO); representative ER - /PR - /Her2 - cell lines express TDO and produce sufficient intracellular kynurenine and xanthurenic acid concentrations to chronically activate the AHR. TDO overexpression, or excess kynurenine or xanthurenic acid, accelerates migration in an AHR-dependent fashion. Environmental AHR ligands 2,3,7,8-tetrachlorodibenzo[p]dioxin and benzo[a]pyrene mimic this effect. AHR knockdown or inhibition significantly reduces TDO2 expression. These studies identify, for the first time, a positive amplification loop in which AHR-dependent TDO2 expression contributes to endogenous AHR ligand production. The net biologic effect of AHR activation by endogenous ligands, which can be mimicked by environmental ligands, is an increase in tumor cell migration, a measure of tumor aggressiveness. Copyright © 2016 by The Author(s).
Directory of Open Access Journals (Sweden)
Deepankar Misra
2014-01-01
Full Text Available Cone-beam computed tomography (CBCT is an advanced imaging modality, with its application in all branches of dentistry. Of all the imaging modalities available, CBCT, with minimum required exposure, provides the best image quality and helps in arriving at a correct diagnosis and in treatment planning. An odontogenic keratocyst, reclassified as a keratocystic odontogenic tumor (KCOT, has an aggressive behavior, is prone to recur, and thus, has been classified as a tumor. Here, we discuss a rare case of a keratocystic odontogenic tumor occurring in the maxilla, with an ectopic tooth position mimicking a dentigerous cyst.
Vidensledelse er også en social praksis
DEFF Research Database (Denmark)
Lauring, Jakob; Waldstrøm, Christian
2006-01-01
lys er det utroligt vigtigt at personalefunktionen i virksomheden er klar over de processer der udspiller sig, og aktivt tager fat om problemerne der ligger i disse barrierer. Vores egne undersøgelser viser, at på trods af opstillingen af teknologiske systemer til vidensdeling, er der stadig...... væsentlige ledelsesmæssige opgaver i forhold til sociale aspekter ved arbejdet i en organisation, som skal varetages hvis vidensdelingen skal fremmes succesfuldt. Det er væsentligt at forstå, at vidensledelse ikke blot handler om cirkulering af information, men også er forbundet mere generelt til ledelse som...
DEFF Research Database (Denmark)
Bentzen, Tina Øllgaard
2017-01-01
At fjerne styring er det, man ofte forbinder med afbureaukratisering, men det er ikke tilstrækkeligt, når man vil gå fra flotte ambitioner til en styring, som reelt opleves enklere. For at forenkle må man også forandre, forankre og fastholde styring, og det må ske i et samspil mellem de aktører, ...
International Nuclear Information System (INIS)
Niewald, M.; Uhlmann, U.; Schnabel, K.; Lehmann, W.; Leetz, H.K.
1988-01-01
In radiotherapy of cerebral tumors in the occipital, central and parietal area it can be favourable to fix the patient's head in frontal or lateral position. It is true that this problem can be solved by manufacturing individual face masks of PVC with the vacuum deep-drawing method, but this method is very time- and cost-consuming. The present study suggests a simplified method using the thermoplastic polyester 'Orifit'. Such a mask provides a good immobilization and can be manufactured in 10 to 15 minutes without bothering much the patient. Simulation and computed tomography are not substantially affected by the material. (orig.) [de
ER Consolidated Quarterly Report October 2014
Energy Technology Data Exchange (ETDEWEB)
Cochran, John R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
2014-10-01
This Environmental Restoration Operations (ER) Consolidated Quarterly Report (ER Quarterly Report) provides the status of ongoing corrective actions and related Long- Term Stewardship (LTS) activities being implemented by Sandia National Laboratories, New Mexico (SNL/NM) ER for the April, May, and June 2014 quarterly reporting period. Section 2.0 provides the status of ER Operations activities including closure activities for the Mixed Waste Landfill (MWL), project management and site closure, and hydrogeologic characterizations. Section 3.0 provides the status of LTS activities that relate to the Chemical Waste Landfill (CWL) and the associated Corrective Action Management Unit (CAMU). Section 4.0 provides the references noted in Section I of this report.
DEFF Research Database (Denmark)
Bjerre-Harpøth, Vibeke; Damgaard, Birthe Marie
2013-01-01
Et forsøg har vist, at køer på lavt energiniveau i goldperioden var fysiologisk sundere og havde mindre risiko for at udvikle stofskiftesygdomme end køer på et højt energiniveau. Forsøget viste også, at køer på et normalt energiniveau i senlaktationen gav mere mælk i den efterfølgende laktation e...
DEFF Research Database (Denmark)
Olden-Jørgensen, Sebastian
2009-01-01
Ansatte på KU mobber hverken mere eller mindre end på andre danske arbejdspladser. Mediernes dækning af APV-undersøgelsens resultater mht. mobning er sensationalistisk og delvis vildledende.......Ansatte på KU mobber hverken mere eller mindre end på andre danske arbejdspladser. Mediernes dækning af APV-undersøgelsens resultater mht. mobning er sensationalistisk og delvis vildledende....
International Nuclear Information System (INIS)
Sparks, Rachel; Yuan, Xiaopu; Lin, Ming Gang; McVarish, Lynda; Aiello, Erin J; McTiernan, Anne; Ulrich, Cornelia M; Bigler, Jeannette; Tworoger, Shelley S; Yasui, Yutaka; Rajan, Kumar B; Porter, Peggy; Stanczyk, Frank Z; Ballard-Barbash, Rachel
2004-01-01
UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA) 6 /(TA) 7 ), UGT2B4 (Asp 458 Glu), UGT2B7 (His 268 Tyr), UGT2B15 (Asp 85 Tyr), and SULT1A1 (Arg 213 His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER - ) or progesterone receptor-negative (PR - ) tumor. Logistic regression analysis was used to estimate the odds ratios of an ER - or PR - tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89). The variant allele of UGT1A1 was associated with reduced risk of an ER - tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). The risk of ER - breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes
Energy Technology Data Exchange (ETDEWEB)
Freyschmidt, J. [Beratungsstelle und Referenzzentrum fuer Osteoradiologie, Bremen (Germany); Ostertag, H. [Klinikum Region Hannover GmbH, Pathologisches Institut, Hannover (Germany)
2016-06-15
Radiological imaging only reflects the anatomy and its pathological abnormalities. Therefore, the radiologist should be able to recognize the basic features of the pathological anatomy of bone tumors. This can only be learned working closely with a pathologist who is experienced in this field. On the other hand, the pathologist needs from the radiologist their diagnostic assessment with information on size, location, aggressiveness and the existence of a bone tumor's matrix, of the whole lesion, because he usually only receives a small part for examination in the form of a biopsy. In this article, the features and fundamentals (standards) of radiological-pathological cooperation as the mainstay for a precise diagnosis in bone tumors are outlined. The radiological appearance and the histopathological features behind it are presented for Ewing's sarcoma, fibrogenic tumors, giant cell tumor, and hemangioma of the bone. (orig.) [German] Radiologische Bilder spiegeln nichts anderes als die Anatomie und ihre pathologischen Abweichungen wider. Deshalb sollte der Radiologe die Grundzuege der pathologischen Anatomie auch von Knochentumoren kennen. Das kann er nur durch eine enge Zusammenarbeit mit einem auf diesem Gebiet erfahrenen Pathologen erlernen. Andererseits braucht der Pathologe vom Radiologen dessen diagnostische Einschaetzung mit Informationen ueber die Groesse, Lage, Aggressivitaet und das Vorhandensein einer Matrix eines Knochentumors und zwar von der gesamten Laesion, denn er bekommt inform einer Biopsie i. d. R. nur einen mehr oder weniger kleinen Teil zur Untersuchung. In diesem Beitrag werden die Grundzuege und Standards der radiologisch-pathologischen Zusammenarbeit aufgezeigt, auf denen eine praezise Diagnosestellung beruht. Radiologisches Erscheinungsbild und die dahintersteckenden - und erklaerenden - histopathologischen Merkmale werden fuer das Ewing-Sarkom, fuer fibrogene Tumoren, den Riesenzelltumor und das Haemangiom des Knochens
Enrichment of tumor cells for cell kinetic analysis in human tumor biopsies using cytokeratin gating
International Nuclear Information System (INIS)
Haustermans, K.; Hofland, I.; Ramaekers, M.; Ivanyi, D.; Balm, A.J.M.; Geboes, K.; Lerut, T.; Schueren, E. van der; Begg, A.C.
1996-01-01
Purpose: To determine the feasibility of using cytokeratin antibodies to distinguish normal and malignant cells in human tumors using flow cytometry. The goal was ultimately to increase the accuracy of cell kinetic measurements on human tumor biopsies. Material and methods: A panel of four antibodies was screened on a series of 48 tumors from two centres; 22 head and neck tumors (Amsterdam) and 26 esophagus carcinomas (Leuven). First, screening was carried out by immunohistochemistry on frozen sections to test intensity of staining and the fraction of cytokeratin-positive tumor cells. The antibody showing the most positive staining was then used for flow cytometry on the same tumor. Results: The two broadest spectrum antibodies (AE1/AE3, E3/C4) showed overall the best results with immunohistochemical staining, being positive in over 95% of tumors. Good cell suspensions for DNA flow cytometry could be made from frozen material by a mechanical method, whereas enzymatic methods with trypsin or collagenase were judged failures in almost all cases. >From fresh material, both collagenase and trypsin produced good suspensions for flow cytometry, although the fraction of tumor cells, judged by proportion aneuploid cells, was markedly higher for trypsin. Using the best cytokeratin antibody for each tumor, two parameter flow cytometry was done (cytokeratin versus DNA content). Enrichment of tumor cells was then tested by measuring the fraction of aneuploid cells (the presumed malignant population) of cytokeratin-positive cells versus all cells. An enrichment factor ranging between 0 (no enrichment) and 1 (perfect enrichment, tumor cells only) was then calculated. The average enrichment was 0.60 for head and neck tumors and 0.59 for esophagus tumors. Conclusions: We conclude that this method can substantially enrich the proportion of tumor cells in biopsies from carcinomas. Application of this method could significantly enhance accuracy of tumor cell kinetic measurements
Spectral-converting behaviors of Er{sup 3+} and Er{sup 3+}–Yb{sup 3+} doped YOCl phosphors
Energy Technology Data Exchange (ETDEWEB)
Park, Sangmoon, E-mail: spark@silla.ac.kr [Center for Green Fusion Technology and Department of Engineering in Energy and Applied Chemistry, Silla University, Busan 617-736 (Korea, Republic of); Cho, So-Hye [Center for Materials Architecturing, Institute of Multidisciplinary Convergence of Materials, Korea Institute of Science and Technology, Seoul 130-650 (Korea, Republic of)
2014-01-25
Highlights: • Luminescent materials of YOCl:Er,Yb were prepared using NH{sub 4}Cl flux. • Interesting spectral-converting behaviors were observed in the phosphors. • 980 or 1550 nm diode laser was irradiated for up-converting study. • A multi-photon process in the phosphors was calculated. -- Abstract: Luminescent materials composed of Y{sub 1−m−n}Er{sub m}Yb{sub n}OCl (m = 0.001–0.1, n = 0.005–0.1) were prepared via a solid-state reaction using NH{sub 4}Cl flux. Photoluminescence spectra, the dependence of the luminescent intensity as a function of Er{sup 3+} content, and their CIE coordinates of the Er{sup 3+}-doped layered YOCl compounds were also investigated under near-ultraviolet (NUV) and visible lights. The spectral up-converting properties of Er{sup 3+} and Er{sup 3+}–Yb{sup 3+} in YOCl phosphors were elucidated under 980 and 1550 nm diode laser irradiations. This up-conversion emission spectra and the pump power dependence versus emission intensity observed in the Y{sub 0.9}Er{sub 0.1}OCl up-conversion phosphors gave rise to one- and two-photon processes. The up-conversion mechanism of Er{sup 3+} and Yb{sup 3+} ions in YOCl was described by a schematic energy-level diagram. Through the use of these up-conversion luminescent materials, the desired emitting lights throughout the orange and red regions of the spectra were achieved.
International Nuclear Information System (INIS)
Katoh, Hironori; Fujita, Keiko; Takuhara, Yuki; Ogawa, Atsushi; Suzuki, Shunji
2011-01-01
Highlights: → VIGG is an ER stress-induced protein in plant. → We examine the characteristics of VIGG-overexpressing Arabidopsis plants. → VIGG-overexpressing plants reveal growth retardation and robustness to ER stress. → VIGG disturbs cation homeostasis in plant. -- Abstract: VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. The overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42 days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation.
Energy Technology Data Exchange (ETDEWEB)
Katoh, Hironori; Fujita, Keiko; Takuhara, Yuki [Laboratory of Fruit Genetic Engineering, The Institute of Enology and Viticulture, University of Yamanashi, Kofu, Yamanashi 400-0005 (Japan); Ogawa, Atsushi [Department of Biological Production, Akita Prefectural University, Shimosinjyou-nakano 241-438, Akita 010-0195 (Japan); Suzuki, Shunji, E-mail: suzukis@yamanashi.ac.jp [Laboratory of Fruit Genetic Engineering, The Institute of Enology and Viticulture, University of Yamanashi, Kofu, Yamanashi 400-0005 (Japan)
2011-02-18
Highlights: {yields} VIGG is an ER stress-induced protein in plant. {yields} We examine the characteristics of VIGG-overexpressing Arabidopsis plants. {yields} VIGG-overexpressing plants reveal growth retardation and robustness to ER stress. {yields} VIGG disturbs cation homeostasis in plant. -- Abstract: VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. The overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42 days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation.
Pæren er faldet langt fra stammen
DEFF Research Database (Denmark)
Haarder, Jon Helt
2013-01-01
Roman: Hassan Preislers vellykkede debutroman udleverer ikke bare multikulti-industrien. Den er også en rablende diagnosticering af det moderne menneskes livsvilkår HASSAN PREISLER BRUN MANDS BYRDE 224 sider, 249,95 Lindhardt og Ringhof Er udkommet 4......Roman: Hassan Preislers vellykkede debutroman udleverer ikke bare multikulti-industrien. Den er også en rablende diagnosticering af det moderne menneskes livsvilkår HASSAN PREISLER BRUN MANDS BYRDE 224 sider, 249,95 Lindhardt og Ringhof Er udkommet 4...
Er Web 2.0 klar til mainstream?
DEFF Research Database (Denmark)
Ivang, Reimer
2009-01-01
BLOG: Spørgsmålene der relateres til Web 2.0 er mange. Men en af de mest signifikante er om netop din virksomhed skal anvende Web 2.0 teknologier? Hvad kan I få ud af det?......BLOG: Spørgsmålene der relateres til Web 2.0 er mange. Men en af de mest signifikante er om netop din virksomhed skal anvende Web 2.0 teknologier? Hvad kan I få ud af det?...
MIT HJEM ER HVOR MIT HJERTE ER
DEFF Research Database (Denmark)
Høst, Jeppe Engset
2014-01-01
Ideen om at arbejde med det man kalder de stedbundne ressourcer på en ny måde, er relevant på Bornholm hvor events som blandt andet festivalen ’Wonderfestiwall’, strandfesten ’Vang Pier Beach Party’, karnevallet ’Svaneke Beach Party, kokkekonkurrencen ’Sol over Gudhjem’ og filmfestivalen ’Bornsho...
Directory of Open Access Journals (Sweden)
Montserrat Garcia-Closas
2008-04-01
Full Text Available A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs in five loci (fibroblast growth receptor 2 (FGFR2, trinucleotide repeat containing 9 (TNRC9, mitogen-activated protein kinase 3 K1 (MAP3K1, 8q24, and lymphocyte-specific protein 1 (LSP1 associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI = 1.31 (1.27-1.36 than ER-negative (1.08 (1.03-1.14 disease (P for heterogeneity = 10(-13. This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5, 10(-8, 0.013, respectively. The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4, respectively. The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312 showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21. rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97. The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding
Markgraf, Daniel F; Klemm, Robin W; Junker, Mirco; Hannibal-Bach, Hans K; Ejsing, Christer S; Rapoport, Tom A
2014-01-16
Eukaryotic cells store neutral lipids such as triacylglycerol (TAG) in lipid droplets (LDs). Here, we have addressed how LDs are functionally linked to the endoplasmic reticulum (ER). We show that, in S. cerevisiae, LD growth is sustained by LD-localized enzymes. When LDs grow in early stationary phase, the diacylglycerol acyl-transferase Dga1p moves from the ER to LDs and is responsible for all TAG synthesis from diacylglycerol (DAG). During LD breakdown in early exponential phase, an ER membrane protein (Ice2p) facilitates TAG utilization for membrane-lipid synthesis. Ice2p has a cytosolic domain with affinity for LDs and is required for the efficient utilization of LD-derived DAG in the ER. Ice2p breaks a futile cycle on LDs between TAG degradation and synthesis, promoting the rapid relocalization of Dga1p to the ER. Our results show that Ice2p functionally links LDs with the ER and explain how cells switch neutral lipid metabolism from storage to consumption. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Daniel F. Markgraf
2014-01-01
Full Text Available Eukaryotic cells store neutral lipids such as triacylglycerol (TAG in lipid droplets (LDs. Here, we have addressed how LDs are functionally linked to the endoplasmic reticulum (ER. We show that, in S. cerevisiae, LD growth is sustained by LD-localized enzymes. When LDs grow in early stationary phase, the diacylglycerol acyl-transferase Dga1p moves from the ER to LDs and is responsible for all TAG synthesis from diacylglycerol (DAG. During LD breakdown in early exponential phase, an ER membrane protein (Ice2p facilitates TAG utilization for membrane-lipid synthesis. Ice2p has a cytosolic domain with affinity for LDs and is required for the efficient utilization of LD-derived DAG in the ER. Ice2p breaks a futile cycle on LDs between TAG degradation and synthesis, promoting the rapid relocalization of Dga1p to the ER. Our results show that Ice2p functionally links LDs with the ER and explain how cells switch neutral lipid metabolism from storage to consumption.
Ochi, Nobuaki; Isozaki, Hideko; Takeyama, Masami; Singer, Jack W; Yamane, Hiromichi; Honda, Yoshihiro; Kiura, Katsuyuki; Takigawa, Nagio
2016-06-10
The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance. Copyright © 2016 Elsevier Inc. All rights reserved.
ER Stress and Lipid Metabolism in Adipocytes
Directory of Open Access Journals (Sweden)
Beth S. Zha
2012-01-01
Full Text Available The role of endoplasmic reticulum (ER stress is a rapidly emerging field of interest in the pathogenesis of metabolic diseases. Recent studies have shown that chronic activation of ER stress is closely linked to dysregulation of lipid metabolism in several metabolically important cells including hepatocytes, macrophages, β-cells, and adipocytes. Adipocytes are one of the major cell types involved in the pathogenesis of the metabolic syndrome. Recent advances in dissecting the cellular and molecular mechanisms involved in the regulation of adipogenesis and lipid metabolism indicate that activation of ER stress plays a central role in regulating adipocyte function. In this paper, we discuss the current understanding of the potential role of ER stress in lipid metabolism in adipocytes. In addition, we touch upon the interaction of ER stress and autophagy as well as inflammation. Inhibition of ER stress has the potential of decreasing the pathology in adipose tissue that is seen with energy overbalance.
DEFF Research Database (Denmark)
Schubart, Rikke
2013-01-01
Indlæg om tv-serien Once Upon a Time (2011-), der hører til genren fairytale fantasy, der blander eventyr og fantasy. Her bliver alle eventyr brugt i en fortælling om alle beboere i en lille by, der ikke ved, at de i virkeligheden er eventyr-karakterer.......Indlæg om tv-serien Once Upon a Time (2011-), der hører til genren fairytale fantasy, der blander eventyr og fantasy. Her bliver alle eventyr brugt i en fortælling om alle beboere i en lille by, der ikke ved, at de i virkeligheden er eventyr-karakterer....
Directory of Open Access Journals (Sweden)
Marina Mihaela
2012-07-01
Full Text Available Abstract MEK Partner 1 (MP1 or MAPKSP1 is a scaffold protein that has been reported to function in multiple signaling pathways, including the ERK, PAK and mTORC pathways. Several of these pathways influence the biology of breast cancer, but MP1’s functional significance in breast cancer cells has not been investigated. In this report, we demonstrate a requirement for MP1 expression in estrogen receptor (ER positive breast cancer cells. MP1 is widely expressed in both ER-positive and negative breast cancer cell lines, and in non-tumorigenic mammary epithelial cell lines. However, inhibition of its expression using siRNA duplexes resulted in detachment and apoptosis of several ER-positive breast cancer cell lines, but not ER-negative breast cancer cells or non-tumorigenic mammary epithelial cells. Inhibition of MP1 expression in ER-positive MCF-7 cells did not affect ERK activity, but resulted in reduced Akt1 activity and reduced ER expression and activity. Inhibition of ER expression did not result in cell death, suggesting that decreased ER expression is not the cause of cell death. In contrast, pharmacological inhibition of PI3K signaling did induce cell death in MCF-7 cells, and expression of a constitutively active form of Akt1 partially rescued the cell death observed when the MP1 gene was silenced in these cells. Together, these results suggest that MP1 is required for pro-survival signaling from the PI3K/Akt pathway in ER-positive breast cancer cells.
International Nuclear Information System (INIS)
Akane, T.; Jinno, S.; Yang, Y.; Kuno, T.; Hirata, T.; Isogai, Y.; Watanabe, N.; Fujiwara, Y.; Nakamura, A.; Takeda, Y.
2003-01-01
ErP has been grown on InP(0 0 1) substrates by organometallic vapor phase epitaxy (OMVPE) using a new liquid organic Er source: tris(ethylcyclopentadienyl)erbium (Er(EtCp) 3 ). Morphological change of an ErP layer on InP(0 0 1) is investigated together with that of an overgrown capping InP layer. Optimum growth condition of InP causes islanding on over-monolayer-ErP. A relatively low overgrowth temperature of InP is a key factor for attaining complete capping coverage on ErP
One-Step 18F-Labeling of Estradiol Derivative for PET Imaging of Breast Cancer
Directory of Open Access Journals (Sweden)
Hongbo Huang
2018-01-01
Full Text Available Positron emission tomography (PET imaging is a useful method to evaluate in situ estrogen receptor (ER status for the early diagnosis of breast cancer and optimization of the appropriate treatment strategy. The 18F-labeled estradiol derivative has been successfully used to clinically assess the ER level of breast cancer. In order to simplify the radiosynthesis process, one-step 18F-19F isotope exchange reaction was employed for the 18F-fluorination of the tracer of [18F]AmBF3-TEG-ES. The radiotracer was obtained with the radiochemical yield (RCY of ~61% and the radiochemical purity (RCP of >98% within 40 min. Cell uptake and blocking assays indicated that the tracer could selectively accumulate in the ER-positive human breast cancer cell lines MCF-7 and T47D. In vivo PET imaging on the MCF-7 tumor-bearing mice showed relatively high tumor uptake (1.4~2.3 %D/g and tumor/muscle uptake ratio (4~6. These results indicated that the tracer is a promising PET imaging agent for ER-positive breast cancers.
[Isolation and identification of brain tumor stem cells from human brain neuroepithelial tumors].
Fang, Jia-sheng; Deng, Yong-wen; Li, Ming-chu; Chen, Feng-Hua; Wang, Yan-jin; Lu, Ming; Fang, Fang; Wu, Jun; Yang, Zhuan-yi; Zhou, Xang-yang; Wang, Fei; Chen, Cheng
2007-01-30
To establish a simplified culture system for the isolation of brain tumor stem cells (BTSCs) from the tumors of human neuroepithelial tissue, to observe the growth and differentiation pattern of BTSCs, and to investigate their expression of the specific markers. Twenty-six patients with brain neuroepithelial tumors underwent tumor resection. Two pieces of tumor tissues were taken from each tumor to be dissociated, triturated into single cells in sterile DMEM-F12 medium, and then filtered. The tumor cells were seeded at a concentration of 200,000 viable cells per mL into serum-free DMEM-F12 medium simply supplemented with B27, human basic fibroblast growth factor (20 microg/L), human epidermal growth factor (20 microg /L), insulin (4 U/L), L-glutamine, penicillin and streptomycin. After the primary brain tumor spheres (BTSs) were generated, they were triturated again and passed in fresh medium. Limiting dilution assay was performed to observe the monoclone formation. 5-bromodeoxyuridine (BrdU) incorporation test was performed to observe the proliferation of the BTS. The BTSCs were cultured in mitogen-free DMEM-F12 medium supplemented with 10% fetal bovine serum to observe their differentiation. Immunocytochemistry was used to examine the expression of CD133 and nestin, specific markers of BTSC, and the rate of CD133 positive cells. Only a minority of subsets of cells from the tumors of neuroepithelial tissue had the capacity to survive, proliferate, and generate free-floating neurosphere-like BTSs in the simplified serum-free medium. These cells attached to the poly-L-lysine coated coverslips in the serum-supplemented medium and differentiated. The BTSCs were CD133 and nestin positive. The rate of CD133 positive cells in the tumor specimens was (21 +/- 6.2)% - (38 +/- 7.0)%. A new simplified culture system for the isolation of BTSCs is established. The tumors of human neuroepithelial tissue contain CD133 and nestin positive tumor stem cells which can be isolated
BOREAS Level-0 ER-2 Navigation Data
Strub, Richard; Dominguez, Roseanne; Newcomer, Jeffrey A.; Hall, Forrest G. (Editor)
2000-01-01
The BOREAS Staff Science effort covered those activities that were BOREAS community-level activities or required uniform data collection procedures across sites and time. These activities included the acquisition, processing, and archiving of aircraft navigation/attitude data to complement the digital image data. The level-0 ER-2 navigation data files contain aircraft attitude and position information acquired during the digital image and photographic data collection missions. Temporally, the data were acquired from April to September 1994. Data were recorded at intervals of 5 seconds. The data are stored in tabular ASCII files.
International Nuclear Information System (INIS)
Vojtechova, Zuzana; Sabol, Ivan; Salakova, Martina; Smahelova, Jana; Zavadil, Jiri; Turek, Lubomir; Grega, Marek; Klozar, Jan; Prochazka, Bohumir; Tachezy, Ruth
2016-01-01
Better insights into the molecular changes involved in virus-associated and -independent head and neck cancer may advance our knowledge of HNC carcinogenesis and identify critical disease biomarkers. Here we aimed to characterize the expression profiles in a matched set of well-characterized HPV-dependent and HPV-independent tonsillar tumors and equivalent immortalized keratinocyte clones to define potential and clinically relevant biomarkers of HNC of different etiology. Fresh frozen tonsillar cancer tissues were analyzed together with non-malignant tonsillar tissues and compared with cervical tumors and normal cervical tissues. Furthermore, relative miRNAs abundance levels of primary and immortalized human keratinocyte clones were evaluated. The global quantitation of miRNA gene abundance was performed using a TaqMan Low Density Array system. The confirmation of differentially expressed miRNAs was performed on a set of formalin-fixed paraffin-embedded tumor samples enriched for the tumor cell fraction by macrodissection. We defined 46 upregulated and 31 downregulated miRNAs characteristic for the HPV-positive tonsillar tumors and 42 upregulated miRNAs and 42 downregulated miRNAs characteristic for HPV-independent tumors. In comparison with the expression profiles in cervical tumors, we defined miR-141-3p, miR-15b-5p, miR-200a-3p, miR-302c-3p, and miR-9-5p as specific for HPV induced malignancies. MiR-335-5p, miR-579-3p, and miR-126-5p were shared by the expression profiles of HPV-positive tonsillar tumors and of the HPV immortalized keratinocyte clones, whereas miR-328-3p, miR-34c-3p, and miR-885-5p were shared by the miRNA profiles of HPV-negative tonsillar tumors and the HPV-negative keratinocytes. We identified the miRNAs characteristic for HPV-induced tumors and tonsillar tumors of different etiology, and the results were compared with those of the model system. Our report presents the basis for further investigations leading to the identification of
Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations.
Kirma, Nameer B; Tekmal, Rajeshwar R
2012-09-01
Mouse models of breast cancer, especially transgenic and knockout mice, have been established as valuable tools in shedding light on factors involved in preneoplastic changes, tumor development and malignant progression. The majority of mouse transgenic models develop estrogen receptor (ER) negative tumors. This is seen as a drawback because the majority of human breast cancers present an ER positive phenotype. On the other hand, several transgenic mouse models have been developed that produce ER positive mammary tumors. These include mice over-expressing aromatase, ERα, PELP-1 and AIB-1. In this review, we will discuss the value of these models as physiologically relevant in vivo systems to understand breast cancer as well as some of the pitfalls involving these models. In all, we argue that the use of transgenic models has improved our understanding of the molecular aspects and biology of breast cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.
Miyazaki, Yoshiaki; Tabata, Nobuyuki; Taroura, Tomomi; Shinozaki, Kenji; Kubo, Yuichiro; Tokunaga, Eriko; Taguchi, Kenichi
We propose a computer-aided diagnostic (CAD) system that uses time-intensity curves to distinguish between benign and malignant mammary tumors. Many malignant tumors show a washout pattern in time-intensity curves. Therefore, we designed a program that automatically detects the position with the strongest washout effect using the technique, such as the subtraction technique, which extracts only the washout area in the tumor, and by scanning data in 2×2 pixel region of interest (ROI). Operation of this independently developed program was verified using a phantom system that simulated tumors. In three cases of malignant tumors, the washout pattern detection rate in images with manually set ROI was ≤6%, whereas the detection rate with our novel method was 100%. In one case of a benign tumor, when the same method was used, we checked that there was no washout effect and detected the persistent pattern. Thus, the distinction between benign and malignant tumors using our method was completely consistent with the pathological diagnoses made. Our novel method is therefore effective for differentiating between benign and malignant mammary tumors in dynamic magnetic resonance images.
Hvorfor er sygeplejersker usynlige i offentlige medier?
DEFF Research Database (Denmark)
Joensen, Annemi Lund; Hall, Elisabeth
2015-01-01
Når der er sygeplejerelevante emner til debat i de offentlige medier på Færøerne, bærer debatten præg af sygeplejerskers manglende deltagelse. Sygeplejerskerne er usynlige. Et eksempel på dette er en debat om besparelser inden for ældreomsorgen. Til trods for at besparelsen fik omfattende konsekv...
Hayashi, Naoki; Niikura, Naoki; Masuda, Norikazu; Takashima, Seiki; Nakamura, Rikiya; Watanabe, Ken-ichi; Kanbayashi, Chizuko; Ishida, Mayumi; Hozumi, Yasuo; Tsuneizumi, Michiko; Kondo, Naoto; Naito, Yoichi; Honda, Yayoi; Matsui, Akira; Fujisawa, Tomomi; Oshitanai, Risa; Yasojima, Hiroyuki; Yamauchi, Hideko; Saji, Shigehira; Iwata, Hiroji
2015-01-01
The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20-86 years). Of the patients, 162 patients (37.5 %) had ER-positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER-negative/HER2-positive (ER-HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER-HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival.
Reversal of the sign of giant magnetoresistance upon boron filling in RPd{sub 3} compounds (R=Tb,Er)
Energy Technology Data Exchange (ETDEWEB)
Pandey, Abhishek [S. N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata-700098 (India); Mazumdar, Chandan; Ranganathan, R, E-mail: abhishek.phy@gmail.co, E-mail: chandan.mazumar@saha.ac.i, E-mail: r.ranganathan@saha.ac.i [Experimental Condensed Matter Physics Division, Saha Institute of Nuclear Physics, 1/AF, Bidhannagar, Kolkata-700064 (India)
2010-01-01
We report the study of magnetic and transport properties of binary intermetallic compounds RPd{sub 3} (R: Tb and Er) and boron-filled perovskite compounds RPd{sub 3}B. Our results suggest that the magnetic and transport behavior of boron-filled compositions is substantially different compared to that of undoped compounds. For example, TbPd{sub 3} and ErPd{sub 3} exhibit negative magnetoresistance, while boron-filled TbPd{sub 3}B and ErPd{sub 3}B shows positive magnetoresistance. In addition, our results also suggest that there exists a strong correlation between magnetic and electrical-transport behavior of these systems.
Zilli, Alessandra; Fanetti, Ilaria; Conte, Dario; Massironi, Sara
Gallium-68 DOTA-peptide positron emission tomography/computed tomography ( 68 Ga-PET/CT) has emerged as a promising tool for the diagnosis and staging of gastro-entero-pancreatic neoplasms, thanks to its high sensitivity and specificity. Heterotopic pancreas, which is relatively rare, has never been reported as a possible cause of false positives of 68 Ga-PET/CT. We report on the first case of a heterotopic pancreas showing pathological uptake at 68 Ga-PET/CT, thus mimicking an intestinal neuroendocrine tumor. The present case suggests that heterotopic pancreas should be included among the possible causes of false positives at 68 Ga PET. Copyright © 2018 Elsevier Inc. All rights reserved.
International Nuclear Information System (INIS)
AlJammaz, I.; Al-Otaibi, B.; Al-Rumayan, F.; Al-Yanbawi, S.; Amer, S.; Okarvi, S.M.
2014-01-01
In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [ 124 I]-SIB- and [ 124 I]-SIP-folate conjugates using a straightforward and two-step simple reactions. Radiochemical yields for [ 124 I]-SIB- and [ 124 I]-SIP-folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30–40 min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for 124 I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [ 124 I]-SIP-folate conjugate over [ 124 I]-SIB-folate conjugate. Biodistribution studies of [ 124 I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [ 124 I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment
Brandulykker er et socialt problem
DEFF Research Database (Denmark)
Leth, Peter Mygind
1999-01-01
Det er de gamle, de syge, de handicappede og alkoholikerne, der brænder inde. Typisk har de tabt en cigaret eller tændstik på tøjet. En del af disse brandulykker opstår på plejehjem og andre institutioner, hvor det ofte er plejepersonalet, der opdager og slukker branden....
DEFF Research Database (Denmark)
Jensen, J. P.; Jeppesen, E.; Søndergaard, M.
Forord: Denne rapport er udarbej-det af Danmarks Mil-jøunder-søgelser som et led i den lands-dæk-ken-de rapportering af Vand-miljøpla-nens Over-vågningspro-gram. Over-vågningsprogram-met blev iværksat efteråret 1988. Hensigten med Vand-miljøplanens over-vågningsprogram er at undersøge effekten af......-miljøet med nærings-salte. Danmarks Miljøundersø-gelser har som sektor-forskningsinstitu-tion i Miljø- og Energiministeriet til opgave at forbedre og styrke det fagli-ge grundlag for de mil-jøpolitiske prioriteringer og beslut-ninger. En væsentlig del af denne opgave er overvågning af miljø og natur. Det er...
Arctigenin alleviates ER stress via activating AMPK
Gu, Yuan; Sun, Xiao-xiao; Ye, Ji-ming; He, Li; Yan, Shou-sheng; Zhang, Hao-hao; Hu, Li-hong; Yuan, Jun-ying; Yu, Qiang
2012-01-01
Aim: To investigate the protective effects of arctigenin (ATG), a phenylpropanoid dibenzylbutyrolactone lignan from Arctium lappa L (Compositae), against ER stress in vitro and the underlying mechanisms. Methods: A cell-based screening assay for ER stress regulators was established. Cell viability was measured using MTT assay. PCR and Western blotting were used to analyze gene and protein expression. Silencing of the CaMKKβ, LKB1, and AMPKα1 genes was achieved by RNA interference (RNAi). An ATP bioluminescent assay kit was employed to measure the intracellular ATP levels. Results: ATG (2.5, 5 and 10 μmol/L) inhibited cell death and unfolded protein response (UPR) in a concentration-dependent manner in cells treated with the ER stress inducer brefeldin A (100 nmol/L). ATG (1, 5 and 10 μmol/L) significantly attenuated protein synthesis in cells through inhibiting mTOR-p70S6K signaling and eEF2 activity, which were partially reversed by silencing AMPKα1 with RNAi. ATG (1-50 μmol/L) reduced intracellular ATP level and activated AMPK through inhibiting complex I-mediated respiration. Pretreatment of cells with the AMPK inhibitor compound C (25 μmol/L) rescued the inhibitory effects of ATG on ER stress. Furthermore, ATG (2.5 and 5 μmol/L) efficiently activated AMPK and reduced the ER stress and cell death induced by palmitate (2 mmol/L) in INS-1 β cells. Conclusion: ATG is an effective ER stress alleviator, which protects cells against ER stress through activating AMPK, thus attenuating protein translation and reducing ER load. PMID:22705729
International Nuclear Information System (INIS)
La Roca, Ricardo L.R. Felts de; Fonseca, Francisco Paula da; Cunha, Isabela Werneck da; Bezerra, Stephania Martins
2013-01-01
Introduction: positive surgical margins (PSMs) are common adverse factors to predict the outcome of a patient submitted to radical prostatectomy (PR). However, not all of these men will follow with biochemical (BCR) or clinical (CR) recurrence. Relationship between PSMs with these recurrent events has to be correlated with other clinicopathological findings in order to recognize more aggressive tumors in order to recommend complementary treatment to these selected patients. Materials and methods: we retrospectively reviewed the outcome of 228 patients submitted to open retropubic RP between March 1991 and June 2008, where 161 had and 67 did not have PSMs. Minimum follow-up time was considered 2 years after surgery. BCR was considered when PSA ≥ 0.2 ng/ml. CR was determined when clinical evidence of tumor appeared. Chi-square test was used to correlate clinical and pathologic variables with PSMs. The estimated 5-year risk of BCR and CR in presence of PSMs was determined using the Kaplan-Meier method and compared to log-rank tests. Results: from the total of 228 patients, 161 (71%) had PSMs, while 67 (29%) had negative surgical margins (NSMs). Prostatic circumferential margin was the most common (43.4%) site. Univariate analysis showed statistically significant (p < 0.001) associations between the presence of PSMs and BCR, but not with CR (p = 0.06). Among 161 patients with PSMs, 61 (37.8%) presented BCR, while 100 (62.8%) did not. Predicting progression-free survival for 5 years, BCR was correlated with pathological stage; Gleason score; pre-treatment PSA; tumor volume in specimen; capsular and perineural invasion; presence and number of PSMs. RC correlated only with angiolymphatic invasion and Gleason score. Considering univariate analyses the clinicopathological factors predicting BCR for 5 years, results statistically significant links with prostate weight; pre-treatment PSA; Gleason score; pathological stage; tumor volume; PSMs; capsular and perineural
Energy Technology Data Exchange (ETDEWEB)
La Roca, Ricardo L.R. Felts de, E-mail: Ricardo@delarocaurologia.com.br [Hospital do Cancer A.C. Camargo, Sao Paulo, SP (Brazil); Fonseca, Francisco Paula da, E-mail: fpf@uol.com.br [Hospital do Cancer A.C. Camargo, Sao Paulo, SP (Brazil). Divisao de Urologia. Dept. de Cirurgia Pelvica; Cunha, Isabela Werneck da; Bezerra, Stephania Martins, E-mail: iwerneck@gmail.com, E-mail: stephaniab@gmail.com [Hospital do Cancer A.C. Camargo, Sao Paulo, SP (Brazil). Dept. de Patologia
2013-07-01
Introduction: positive surgical margins (PSMs) are common adverse factors to predict the outcome of a patient submitted to radical prostatectomy (PR). However, not all of these men will follow with biochemical (BCR) or clinical (CR) recurrence. Relationship between PSMs with these recurrent events has to be correlated with other clinicopathological findings in order to recognize more aggressive tumors in order to recommend complementary treatment to these selected patients. Materials and methods: we retrospectively reviewed the outcome of 228 patients submitted to open retropubic RP between March 1991 and June 2008, where 161 had and 67 did not have PSMs. Minimum follow-up time was considered 2 years after surgery. BCR was considered when PSA {>=} 0.2 ng/ml. CR was determined when clinical evidence of tumor appeared. Chi-square test was used to correlate clinical and pathologic variables with PSMs. The estimated 5-year risk of BCR and CR in presence of PSMs was determined using the Kaplan-Meier method and compared to log-rank tests. Results: from the total of 228 patients, 161 (71%) had PSMs, while 67 (29%) had negative surgical margins (NSMs). Prostatic circumferential margin was the most common (43.4%) site. Univariate analysis showed statistically significant (p < 0.001) associations between the presence of PSMs and BCR, but not with CR (p = 0.06). Among 161 patients with PSMs, 61 (37.8%) presented BCR, while 100 (62.8%) did not. Predicting progression-free survival for 5 years, BCR was correlated with pathological stage; Gleason score; pre-treatment PSA; tumor volume in specimen; capsular and perineural invasion; presence and number of PSMs. RC correlated only with angiolymphatic invasion and Gleason score. Considering univariate analyses the clinicopathological factors predicting BCR for 5 years, results statistically significant links with prostate weight; pre-treatment PSA; Gleason score; pathological stage; tumor volume; PSMs; capsular and perineural
Kim, Woo Hyoung; Kim, Chang Guhn; Kim, Myoung Hyoun; Kim, Dae-Weung; Park, Cho Rong; Park, Ji Yong; Lee, Yun-Sang; Youn, Hyewon; Kang, Keon Wook; Jeong, Jae Min; Chung, June-Key
2016-06-01
The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model. Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE. The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95 % for up to 4 h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4 h after injection in KB tumor was 16.4, 23.2, and 17.6 % injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4 % when excess free folate was co-administered. Tumor:normal organ ratios at 4 h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16 h after injection was 17.4, 21.7, 24.1, and 15.6 %ID/g, respectively. Tumor:normal organ ratios at 8 h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re
Hvad er ledelse af brugerinddragelse?
DEFF Research Database (Denmark)
Holm-Petersen, Christina; Navne, Laura Emdal
2015-01-01
Brugerinddragelse i det danske sundhedsvæsen står højt på den politiske dagsorden, men det er stadig en udfordring at implementere visionen i klinisk praksis. Ledelse af brugerinddragelse bliver aktuelt udpeget som en central nøgle til at føre visionen ud i livet. Samtidig er der kun relativt lidt......, at brugerinddragelse skal implementeres i en verden, hvor der allerede er en række andre mål tilstede. En central ledelsesudfordring er derfor, at nogle af målene med brugerinddragelse forudsætter nye måder at organisere ikke bare arbejdet og kompetencer på, men også relationer til patienter og pårørende. En væsentlig...... that organize relations Patient involvement in the health services in Denmark is high on the political agenda, though continues to be a challenge to implement. It is increasingly said that leadership is crucial to the implementation process. However, research into the role of leaders in patient involvement...
DEFF Research Database (Denmark)
Gravgaard Thomsen, Karina Hedelund; Lyng, Maria Bibi; Elias, Daniel
2015-01-01
predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated...... by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p ....05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen...
Directory of Open Access Journals (Sweden)
Atsunobu Masuno
2016-02-01
Full Text Available Glasses with the composition xBaO–(99.9 − xSiO2–0.1ErO3/2 (0 ≤x ≤ 34.9 were fabricated by a levitation technique. The glasses in the immiscibility region were opaque due to chemical inhomogeneity, while the other glasses were colorless and transparent. The scanning electron microscope observations and electron probe microanalysis scan profiles revealed that more Er3+ ions were preferentially distributed in the regions where more Ba2+ ions existed in the chemically inhomogeneous glasses. The synchronicity of the spatial distributions of the two ions initially increased with increasing x and then decreased when the Ba2+ concentration exceeded a certain value. The peak shape and lifetime of the fluorescence at 1.55 μm depended on x as well as the spatial distribution of both ions. These results indicate that although ErOn polyhedra are preferentially coordinated with Ba2+ ions and their local structure is affected by the coordination of Ba2+, there is a maximum in the amount of Ba2+ ions that can coordinate ErOn polyhedra since the available space for Ba2+ ions is limited. These findings provide us with efficient ways to design the chemical composition of glasses with superior Er3+ fluorescence properties for optical communication network systems.
International Nuclear Information System (INIS)
Martínez-Galán, Joaquina; Ríos, Sandra; Delgado, Juan Ramón; Torres-Torres, Blanca; Núñez, María Isabel; López-Peñalver, Jesús; Del Moral, Rosario; Ruiz De Almodóvar, José Mariano; Menjón, Salomón; Concha, Ángel; Chamorro, Clara
2014-01-01
Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5′ CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients. Patients (n = 110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique). Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p = 0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients, 60% of HER2 patients, compared to 28% and 5.9% of patients with better prognosis such as luminal A and luminal B, respectively. Silencing, by methylation, of the promoter region of the ESR1 affects the expression of the estrogen receptor protein in tumors of breast cancer patients; high methylation of ESR1-DNA is associated with estrogen receptor negative status which, in turn, may be implicated in the patient’s resistance to hormonal treatment in breast cancer. As such, epigenetic markers in plasma may be of interest as new targets for anticancer therapy, especially with respect to endocrine treatment
International Nuclear Information System (INIS)
Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B; Sasano, Hironobu; Evans, Dean B; Møller, Susanne; Ejlertsen, Bent; Mouridsen, Henning T
2009-01-01
New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer
Den rige personlighed er livsduelig
DEFF Research Database (Denmark)
Holm, Claus
2015-01-01
For omtrent 160 år siden formulerede Karl Marx forestillingen om en rig individualitet som det kommunistiske samfunds individideal. I dag får forestillingen relevans. Lyder det lidt besynderligt, er det ikke mærkeligt. For de fleste af os går næppe rundt og tror, at vi er lige på trapperne til...
Hvilke Dødehavstekster er "sekteriske"?
DEFF Research Database (Denmark)
Holst, Søren
2003-01-01
Skønt Dødehavsrullerne antageligt tilhørte en gruppering, der boede i Qumran, tyder alt på, at mange af teksterne er forfattet andre steder. Artiklen undersøger den særlige sprogbrug, som antageligt er typisk for Qumran-samfundet, og som præger forbavsende få af tekserne. En meget stor del af...
DEFF Research Database (Denmark)
Søltoft, Pia
2016-01-01
I modsætning til ironi er humor for Kierkegaard fællesskabsgivende – ironikeren hævder sig selv, men humoristen har sympati med den, man ler med. Humor er hos Kierkegaard udtryk for, at humoristen forliger sig med tilværelsen og dens luner, og dermed grænser humoren hos Kierkegaard op til det...
Energy Technology Data Exchange (ETDEWEB)
Peterson, Lanell M. [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Department of Radiology, Seattle Cancer Care Alliance, Seattle WA (United States); Kurland, Brenda F. [Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA (United States); Link, Jeanne M. [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Schubert, Erin K. [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Department of Radiology, Seattle Cancer Care Alliance, Seattle WA (United States); Stekhova, Svetlana [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Linden, Hannah M. [Department of Medical Oncology, University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA (United States); Mankoff, David A., E-mail: dam@u.washington.edu [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Department of Radiology, Seattle Cancer Care Alliance, Seattle WA (United States)
2011-10-15
Introduction: {sup 18}F-Fluoroestradiol (FES) PET imaging provides a non-invasive method to measure estrogen receptor (ER) expression in tumors. Assessment of factors that could affect the quantitative level of FES uptake is important as part of the validation of FES PET for evaluating regional ER expression in breast cancer. Methods: This study examines FES uptake in tumors from 312 FES PET scans (239 patients) with documented ER+ primary breast cancer. FES uptake was compared to clinical and laboratory data, treatment prior to or at time of scan, and properties of FES and its metabolism and transport. Linear mixed models were used to explore univariate, threshold-based and multivariate associations. Results: Sex hormone-binding globulin (SHBG) was inversely associated with FES SUV. Average FES uptake did not differ by levels of plasma estradiol, age or rate of FES metabolism. FES tumor uptake was greater for patients with a higher body mass index (BMI), but this effect did not persist when SUV was corrected for lean body mass (LBM). In multivariate analysis, only plasma SHBG binding was an independent predictor of LBM-adjusted FES SUV. Conclusions: Calculation of FES SUV, possibly adjusted for LBM, should be sufficient to assess FES uptake for the purpose of inferring ER expression. Pre-menopausal estradiol levels do not appear to interfere with FES uptake. The availability and binding properties of SHBG influence FES uptake and should be measured. Specific activity did not have a clear influence on FES uptake, except perhaps at higher injected mass per kilogram. These results suggest that FES imaging protocols may be simplified without sacrificing the validity of the results.
Microtubule and Cell Contact Dependency of ER-bound PTP1B Localization in Growth Cones
Fuentes, Federico
2009-01-01
PTP1B is an ER-bound protein tyrosine phosphatase implied in the regulation of cell adhesion. Here we investigated mechanisms involved in the positioning and dynamics of PTP1B in axonal growth cones and evaluated the role of this enzyme in axons. In growth cones, PTP1B consistently localizes in the central domain, and occasionally at the peripheral region and filopodia. Live imaging of GFP-PTP1B reveals dynamic excursions of fingerlike processes within the peripheral region and filopodia. PTP1B and GFP-PTP1B colocalize with ER markers and coalign with microtubules at the peripheral region and redistribute to the base of the growth cone after treatment with nocodazole, a condition that is reversible. Growth cone contact with cellular targets is accompanied by invasion of PTP1B and stable microtubules in the peripheral region aligned with the contact axis. Functional impairment of PTP1B causes retardation of axon elongation, as well as reduction of growth cone filopodia lifetime and Src activity. Our results highlight the role of microtubules and cell contacts in the positioning of ER-bound PTP1B to the peripheral region of growth cones, which may be required for the positive role of PTP1B in axon elongation, filopodia stabilization, and Src activity. PMID:19158394
2006-08-01
ta-l] tam com 0unds havy be• fond to f dr.fce apoptosis in a number of tumor cell lines, such as the huijian leukeihia Ju•at i ls, yeast ani er (MCF-7...uptake and distribution in yeast . Trends Microbiol.12: 500-505 (1999) 2. Aggett, P.J. and S. Fairweather-Tait, Adaptation to high and low copper...Wilding, Angiogenesis inhibitors. New agents in cancer therapy. Drugs Aging.4: 249-255 (2000) 17. Brewer , G.J., Copper control as an antiangiogenic
Employer branding er også intern kommunikation
DEFF Research Database (Denmark)
Hansen, Heidi
2016-01-01
I videnssamfundet og serviceøkonomien er medarbejderne virksomhedens vigtigste ressource, men milleniumgenerationen er ikke trofaste overfor deres arbejdsplads – de har typisk 15-20 jobs i løbet af deres livstid. Et stærkt employer brand bidrager til at fastholde medarbejdere – og dermed...... kompetencer – i virksomheden, og medarbejderne er dermed en central målgruppe for employer branding....
Hvorfor er danske fødevarer dyre?
DEFF Research Database (Denmark)
Hansen, Henning Otte
2015-01-01
De danske fødevarepriser er generelt høje set i forhold til resten af EU og også i forhold til lande uden for EU. Overordnet set er der en række forklaringer på internationale prisforskelle, og der er også flere mulige årsager til de høje danske fødevarepriser. Forskelle i moms, kvalitet...
International Nuclear Information System (INIS)
Jo, I; Kim, Sung Hoon; Kim, Hae Won; Kang, Sung Hee; Zeon, Seok Kil; Kim, Su Jin
2015-01-01
The purpose of this study was to investigate the correlation of primary tumor FDG uptake to clinicopathological prognostic factors in invasive ductal carcinoma of the breast. We retrospectively reviewed 136 of 215 female patients with pathologically proven invasive ductal breast cancer from January 2008 to December 2011 who underwent F-18 FDG PET/CT for initial staging and follow-up after curative treatment with analysis of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). The maximum standardized uptake value (SUV max ) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status. The high SUV max of primary breast tumors is significantly correlated with the clinicopathological factors: tumor size, histologic grade, TNM stage, negativity of ER, negativity of PR, HER2 overexpression and triple negativity. The recurrent group with non-triple negative cancer had a higher SUV max compared with the non-recurrent group, though no significant difference in FDG uptake was noted between the recurrence and non-recurrent groups in subjects with triple-negative cancer. Lymph node involvement was the independent risk factor for cancer recurrence in the multivariate analysis. In conclusion, high FDG uptake in primary breast tumors is significantly correlated with clinicopathological factors, such as tumor size, histologic grade, TNM stage, negativity of the hormonal receptor, HER2 overexpression and triple negativity. Therefore, FDG PET/CT is a helpful prognostic tool to direct the further management of patients with breast cancer
Energy Technology Data Exchange (ETDEWEB)
Ewan, Kenneth B.R.; Oketch-Rabah, Hellen A.; Ravani, Shraddha A.; Shyamala, G.; Moses, Harold L.; Barcellos-Hoff, Mary Helen
2005-03-03
Transforming growth factor {beta}1 (TGF{beta}1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor {alpha} (ER{alpha}) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF{beta}1 is necessary for the quiescence of ER{alpha}-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF{beta}1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF{beta} signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER{alpha}. To test whether TGF{beta} was functional, we examined genetically engineered mice with different levels of TGF{beta}1. ER{alpha} co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf{beta}1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF{beta}1 via the MMTV promoter suppressed proliferation of ER{alpha} positive cells. Thus, TGF{beta}1 activation functionally restrains ER{alpha} positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF{beta}1 dysregulation may promote proliferation of ER{alpha} positive cells associated with breast cancer risk in humans.
Ytringsfriheden er ikke nødvendig
DEFF Research Database (Denmark)
Lauritzen, Pia
2008-01-01
nemlig godt konstatere, at ytringsfriheden ikke er nødvendig uden dermed at give afkald på frihed og demokrati.Vi kan oven i købet mene, at ytringsfriheden ophører med at være frihed, når vi betragter den som nødvendig. Og det er lige nøjagtig det, jeg efterlyser: at vi bruger filosoffer som Immanuel...... Kant og Luigi Pareyson til at forstå, at friheden er betydelig mere kompleks, end vi gør den til i øjeblikket....
TCSP ER-2 DOPPLER RADAR (EDOP) V1
National Aeronautics and Space Administration — The TCSP ER-2 DOPPLER RADAR (EDOP) dataset was collected by the ER-2 Doppler radar (EDOP), which is an X-band (9.6 GHz) Doppler radar mounted in the nose of the ER-2...
National Aeronautics and Space Administration — The CAMEX-4 ER-2 Doppler Radar dataset was collected by the ER-2 Doppler radar (EDOP), which is an X-band (9.6 GHz) Doppler radar mounted in the nose of ER-2. The...
68Ga-DOTA-NGR as a novel molecular probe for APN-positive tumor imaging using MicroPET.
Zhang, Jun; Lu, Xiaoli; Wan, Nan; Hua, Zichun; Wang, Zizheng; Huang, Hongbo; Yang, Min; Wang, Feng
2014-03-01
-DOTA-NGR was easily synthesized and showed favorable biodistribution and kinetics. (68)Ga-DOTA-NGR could also specifically bind to the APN receptor in vitro and in vivo, and might be a potential molecular probe for the noninvasive detection of APN-positive tumors and neovasculature. Copyright © 2014 Elsevier Inc. All rights reserved.
Expression of melatonin receptor MT1 in cells of human invasive ductal breast carcinoma.
Jablonska, Karolina; Pula, Bartosz; Zemla, Agata; Owczarek, Tomasz; Wojnar, Andrzej; Rys, Janusz; Ambicka, Aleksandra; Podhorska-Okolow, Marzena; Ugorski, Maciej; Dziegiel, Piotr
2013-04-01
In humans, two main types of membrane melatonin receptors have been identified, MT1 and MT2. Expression of MT1 in neoplastic cells seems to increase the efficacy of melatonin's oncostatic activity. The purpose of this study was to determine the distribution and the intensity of MT1 expression in breast cancer cells and to correlate it with clinicopathological factors. Immunohistochemical studies (IHC) were conducted on 190 cases of invasive ductal breast carcinomas (IDC) and molecular studies were performed on 29 cases of frozen tumor fragments and selected breast cancer cell lines. Most of the studied tumors manifested a membranous/cytoplasmic IHC expression of MT1. In IDC, the MT1 expression was higher than in fibrocystic breast disease. MT1 expression was higher in estrogen receptor positive (ER+) and HER2 positive (HER2+) tumors. Triple negative tumors (TN) manifested the lowest MT1 expression level. The lowest MT1 protein expression level was noted in the TN breast cancer cell line MDA-MB-231 compared with ER+ cell lines MCF-7 and SK-BR-3. MT1 mRNA expression was negatively correlated with the malignancy grade of the studied IDC cases. Moreover, higher MT1 expression was associated with patients' longer overall survival (OS) in the group of ER+ breast cancers and treated with tamoxifen. Multivariate analysis indicated that MT1 was an independent prognostic factor in the ER+ tumors for OS and event-free survival in the ER+ tumors. The results of this study may point to a potential prognostic and therapeutic significance of MT1 in IDC. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
DEFF Research Database (Denmark)
Olsen, Poul Bitsch
2008-01-01
Dansk håndbold er en kæmpemæssig succeshistorie. Ser man snævert på den udvikling, elitedelen af sporten har gennemlevet de seneste 15 år, viser stort set alle tænkelige parametre fremgang. De internationale resultater for lands og klubhold er med få udfald blevet stadigt bedre, omsætningen i klu...
International Nuclear Information System (INIS)
Polyakova, I. N.; Baulin, V. E.; Ivanova, I. S.; Pyatova, E. N.; Sergienko, V. S.; Tsivadze, A. Yu.
2015-01-01
The coordination compounds of Er 3+ with 1-(methoxydiphenylphosphoryl)-2-diphenylphosphorylbenzene [ErL 2 1 (NO 3 ) 2 ] 2 [Er(NO 3 ) 2 (H 2 O) 5 ] 0.333 (NO 3 ) 2.333 · 2.833H 2 O (I) and its ethyl substituted derivative [ErL 2 2 (NO 3 ) 2 ][Er(NO 3 ) 5 ] 0.5 · 0.5H 2 O (II) are synthesized and their crystal structures are studied. I and II contain [ErL 2 (NO 3 ) 2 ] + complex cations of identical composition and close structure. The eight-vertex polyhedron of the Er atom in the shape of a distorted octahedron with two split trans vertices is formed by the O atoms of the phosphoryl groups of L ligands and nitrate anions. L ligands close nine-membered metallocycles. The structures contain spacious channels which are populated differently, namely, by disordered [Er(NO 3 ) 2 (H 2 O) 5 ] + complex cations, NO 3 − anions, and crystallization water molecules in I and disordered [Er(NO 3 ) 5 ] 2− complex anions and crystallization water molecules in II. The IR spectra of I and II are studied
International Nuclear Information System (INIS)
Chung, Jin Il; Lee, Jong Tae; Yoo, Hyung Sik; Lee, Byung Hee; Bae, Jong Yup
1994-01-01
To evaluate the accuracy of CT using water as an oral contrast material in a prone position in determining the depth of tumor invasion in gastric cancer patients. Thirty three patients(19 male, 14 female) with surgically confirmed gastric cancer were studied. We performed CT in a prone position after ingestion of 1 liter of pure water. CT findings were classified into 4 groups by the morphologic appearance of infiltrates in the perigastric fat plane: normal perigastric fat(S0), fine mottled densities(S1), irregular aggregated or liner densities(S2) and direct extension and invasion of tumor into contiguous structures(S3). Also we prospectively compared the CT staging with pathologic T staging according to the TNM systems. The overall accuracy of CT staging in determining the pathologic T factor was 69.6%. As we regarded T1 and T2 lesions as one group on CT, the accuracy of CT staging was increased to 80.2% because of a limitation of CT for distinguishing T1 from T2 lesions. Prone position CT using water as an oral contrast agent is quite accurate in determining the T staging of gastric carcinoma
Maxwell, Thressi; Chun, So-Young; Lee, Kyu-Shik; Kim, Soyoung; Nam, Kyung-Soo
2017-02-01
Arctigenin is a plant lignan extracted from Arctium lappa that has been shown to have estrogenic properties. In spite of the health benefits of phytoestrogens reducing the risk of osteoporosis, heart disease, and menopausal symptoms, its benefits against the risk of breast cancer have not been fully elucidated. Thus, we investigated the effects of arctigenin on metastasis of breast cancer using both estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cell lines to see if the effects are dependent on the status of ER expression. In ER-positive MCF-7 cells, arctigenin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and invasion. The activity of crucial metastatic protease matrix metalloprotease (MMP)-9 in gelatin zymography was also efficiently decreased by arctigenin, as well as its mRNA expression. Notably, arctigenin exhibited similar anti-metastatic effects even in ER-negative MDA-MB-231 cells, suggesting that the anti-metastatic effects of arctigenin were not exerted via the ER. The upstream signaling pathways involved in the regulation of MMP-9 and urokinase plasminogen activator (uPA) were analyzed using western blotting. The activation of Akt, NF-κB and MAPK (ERK 1/2 and JNK 1/2) was found to be inhibited. Taken together, these data suggest that arctigenin confers anti-metastatic effects by inhibiting MMP-9 and uPA via the Akt, NF-κB and MAPK signaling pathways on breast cancer, regardless of ER expression. Therefore, we propose that the intake of arctigenin could be an effective supplement for breast cancer patients.
Stemmer, Salomon M; Steiner, Mariana; Rizel, Shulamith; Geffen, David B; Nisenbaum, Bella; Peretz, Tamar; Soussan-Gutman, Lior; Bareket-Samish, Avital; Isaacs, Kevin; Rosengarten, Ora; Fried, Georgeta; McCullough, Debbie; Svedman, Christer; Shak, Steven; Liebermann, Nicky; Ben-Baruch, Noa
2017-01-01
The Recurrence Score® is increasingly used in node-positive ER+ HER2-negative breast cancer. This retrospective analysis of a prospectively designed registry evaluated treatments/outcomes in node-positive breast cancer patients who were Recurrence Score-tested through Clalit Health Services from 1/2006 through 12/2011 ( N = 709). Medical records were reviewed to verify treatments/recurrences/survival. Median follow-up, 5.9 years; median age, 62 years; 53.9% grade 2; 69.8% tumors ≤ 2 cm; 84.5% invasive ductal carcinoma; 42.0% N1mi, and 37.2%/15.5%/5.2% with 1/2/3 positive nodes; 53.4% Recurrence Score < 18, 36.4% Recurrence Score 18-30, and 10.2% Recurrence Score ≥ 31. Overall, 26.9% received adjuvant chemotherapy: 7.1%, 39.5%, and 86.1% in the Recurrence Score < 18, 18-30, and ≥ 31 group, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 3.2%, 6.3%, and 16.9% for these respective groups and the corresponding 5-year breast cancer death estimates were 0.5%, 3.4%, and 5.7%. In Recurrence Score < 18 patients, 5-year distant-recurrence rates for N1mi/1 positive node/2-3 positive nodes were 1.2%/4.4%/5.4%. As patients were not randomized to treatment and treatment decision is heavily influenced by Recurrence Score, analysis of 5-year distant recurrence by chemotherapy use was exploratory and should be interpreted cautiously: In Recurrence Score < 18, recurrence rate was 7.7% in chemotherapy-treated ( n = 27) and 2.9% in chemotherapy-untreated patients ( n = 352); P = 0.245. In Recurrence Score 18-30, recurrence rate in chemotherapy-treated patients ( n = 102) was significantly lower than in untreated patients ( n = 156) (1.0% vs. 9.7% P = 0.019); in Recurrence Score ≤ 25 (the RxPONDER study cutoff), recurrence rate was 2.3% in chemotherapy-treated ( n = 89) and 4.4% in chemotherapy-untreated patients ( n = 488); P = 0.521. In conclusion, our findings
Parotid tumor statistics for the past five years
International Nuclear Information System (INIS)
Yamaguchi, Soichi; Sueno, Kohei; Yamaguchi, Takeshi; Asano, Yukimi; Shiba, Kazutaka; Sekiguchi, Nao; Masuda, Takeshi
2004-01-01
We reviewed the case of 40 patients with parotid tumor who underwent an operation in the past five years. The patients included 23 (57.5%) males and 17 (42.5%) females. The average age was 53.4 years old with a range of 19 to 71 years. Thirty eight (95.0%) had benign tumor, and 2 (5.0%) had malignant tumor. Tc scintigraphy was performed in 37 out of the 40 patients, and 9 patients showed positive results. Six patients had warthin's tumor, and 3 had pleomorphic adenoma. In other words, 66.7% were positive for warthin's tumor. Ga scintigraphy was performed in 31 out of the 40 patients. Nine were positive out of the 10 benign tumor that showed a positive result. None of the cases had permanent facial palsy as a postoperative complication. Transient facial palsy was exhibited by 13 patients (32.5%), but they all improved 2 weeks to 6 months. In addition, we experienced 1 case of salivary fistula. Pleomorphic adenoma was noted in 63.2%, and warthin's tumor in 23.7%. There was no gender difference for pleomorphic adenoma, but 8 out of the 9 patients with warthin's tumor were men. The average age was 47.0 for pleomorphic adenoma and 58.7 for warthin's tumor which was in accordance with conventional reports. The Tc scintigraphy positive rate of warthin's tumor was low, 66.7%, in comparison with that in conventional reports. In addition, 90% of the tumors that showed positive results in Ga scintigraphy were preoperatively positive tumors, indicating the diagnostic usefulness of this. Transient facial palsy was a complication in 32.5% of the patients, which was similar to the rate in the conventional report. We experienced 1 case salivary fistula, which did not improve with conservative treatment. We opened the wounded area, and drained it by pressing. (author)
International Nuclear Information System (INIS)
Chouairy, Camil J.; Bechara, Elie A.; Ghabril, Ramy H.; Gebran, Sleiman J.
2008-01-01
Inflammatory myofibroblastic tumor (IMT) is associated in 15-30% of cases with systemic symptomatology , such as prolonged fever, weight loss, elevated erythrocyte sedimentation rate (ESR) , anemia, thrombocytosis and leukocytosis. We report the case of a 4-year-old Lebanese boy who presented with high-grade fever of long duration and a single (unpaired) positive Widal agglutination test. Blood culture was negative. A diagnosis of typhoid fever was made. An abdominal (mesenteric) IMT was incidentally discovered, 30 days after the fever had appeared. After surgery, the fever disappeared immediately, and the ESR returned. We strongly favor the possibility of a false positive Widal test, due to polyclonal increase in serum immunoglobulins, which often occurs in IMT. We also think that IMT might be a mimicker of typhoid fever, both clinically and serologically. Physicians, especially pediatricians practicing in endemic areas, should probably be aware of this mimicry. (author)
Energy Technology Data Exchange (ETDEWEB)
Chouairy, Camil J [Dept. of Pathology, Saint George Hospital, Beirut (Lebanon); Bechara, Elie A; Ghabril, Ramy H [Dept. of Pediatrics, Saint George Hospital, Beirut (Lebanon); Gebran, Sleiman J [Dept. of Pediatric Surgery, AlHada Armed Forces Hospital, Taif (Saudi Arabia)
2008-07-01
Inflammatory myofibroblastic tumor (IMT) is associated in 15-30% of cases with systemic symptomatology , such as prolonged fever, weight loss, elevated erythrocyte sedimentation rate (ESR) , anemia, thrombocytosis and leukocytosis. We report the case of a 4-year-old Lebanese boy who presented with high-grade fever of long duration and a single (unpaired) positive Widal agglutination test. Blood culture was negative. A diagnosis of typhoid fever was made. An abdominal (mesenteric) IMT was incidentally discovered, 30 days after the fever had appeared. After surgery, the fever disappeared immediately, and the ESR returned. We strongly favor the possibility of a false positive Widal test, due to polyclonal increase in serum immunoglobulins, which often occurs in IMT. We also think that IMT might be a mimicker of typhoid fever, both clinically and serologically. Physicians, especially pediatricians practicing in endemic areas, should probably be aware of this mimicry. (author)
Local microstructure and photoluminescence of Er-doped 12CaO·7Al2O3 powder
Institute of Scientific and Technical Information of China (English)
WANG Dan; LIU Yuxue; XU Changshan; LIU Yichun; WANG Guorui; LI Xinghua
2008-01-01
Er-doped 12CaO·7Al2O3 (C12A7:Er) powders were prepared using the sol-gel method followed by annealing inorganic precursors. X-ray diffraction (XRD), Raman and absorption spectra revealed that Er ions existed and substituted Ca2+ lattice site in C12A7. The photoluminescence of C12A7:Er at room temperature was observed in the visible and infrared region using 488 nm (2.54 eV) Ar+ line as excitation source, respectively. The sharp and intense green emission bands with multi-peaks around 520 nm and 550 nm correspond to the transitions from the excited states 2H11/2 and 4S3/2 to the ground state 4I15/2, respectively. Furthermore, red emission band around 650 nm was also observed. It was attributed to the electronic transition from excited states 4F9/2 to the ground state 4I15/2 inside 4f-shell of Er3+ ions. The intensive infrared emission at 1.54μm was attributed to the transition from the first excited states of 4I13/2 to the ground state (4I15/2). The temperature dependent photoluminescence of infrared emission showed that the integrated intensity reached a maximum value at near room temperature. The forbidden transitions of intra-4f shell electrons in free Er3+ ions were allowed in C12A7 owing to lack of the inversion symmetry in the Er3+ position in C12A7 crystal field. Our results suggested that C12A7:Er was a candidate for applications in Er-doped laser materials, and full color display.
Dietary toxins, endoplasmic reticulum (ER) stress and diabetes.
Hettiarachchi, Kalindi D; Zimmet, Paul Z; Myers, Mark A
2008-05-01
The incidence of Type 1 diabetes has been increasing at a rate too rapid to be due to changes in genetic risk. Instead changes in environmental factors are the likely culprit. The endoplasmic reticulum (ER) plays an important role in the production of newly synthesized proteins and interference with these processes leads to ER stress. The insulin-producing beta cells are particularly prone to ER stress as a result of their heavy engagement in insulin production. Increasing evidence suggests ER stress is central to initiation and progression of Type 1 diabetes. An early environmental exposure, such as toxins and viral infections, can impart a significant physiological load on beta cells to initiate abnormal processing of proinsulin, ER stress and insulin secretory defects. Release of altered proinsulin from the beta cells early in life may trigger autoimmunity in those with genetic susceptibility leading to cytokine-induced nitric oxide production and so exacerbating ER stress in beta cells, ultimately leading to apoptosis of beta cells and diabetes. Here we suggest that ER stress is an inherent cause of beta cell dysfunction and environmental factors, in particular dietary toxins derived from Streptomyces in infected root vegetables, can impart additional stress that aggravates beta cell death and progression to diabetes. Furthermore, we propose that the increasing incidence of Type 1 diabetes may be accounted for by increased dietary exposure to ER-stress-inducing Streptomyces toxins.
Variations in tumor size and position due to irregular breathing in 4D-CT: A simulation study
International Nuclear Information System (INIS)
Sarker, Joyatee; Chu, Alan; Mui, Kit; Wolfgang, John A.; Hirsch, Ariel E.; Chen, George T. Y.; Sharp, Gregory C.
2010-01-01
Purpose: To estimate the position and volume errors in 4D-CT caused by irregular breathing. Methods: A virtual 4D-CT scanner was designed to reproduce axial mode scans with retrospective resorting. This virtual scanner creates an artificial spherical tumor based on the specifications of the user, and recreates images that might be produced by a 4D-CT scanner using a patient breathing waveform. 155 respiratory waveforms of patients were used to test the variability of 4D-CT scans. Each breathing waveform was normalized and scaled to 1, 2, and 3 cm peak-to-peak motion, and artificial tumors with 2 and 4 cm radius were simulated for each scaled waveform. The center of mass and volume of resorted 4D-CT images were calculated and compared to the expected values of center of mass and volume for the artificial tumor. Intrasubject variability was investigated by running the virtual scanner over different subintervals of each patient's breathing waveform. Results: The average error in the center of mass location of an artificial tumor was less than 2 mm standard deviation for 2 cm motion. The corresponding average error in volume was less than 4%. In the worst-case scenarios, a center of mass error of 1.0 cm standard deviation and volume errors of 30%-60% at inhale were found. Systematic errors were observed in a subset of patients due to irregular breathing, and these errors were more pronounced when the tumor volume is smaller. Conclusions: Irregular breathing during 4D-CT simulation causes systematic errors in volume and center of mass measurements. These errors are small but depend on the tumor size, motion amplitude, and degree of breathing irregularity.
International Nuclear Information System (INIS)
Olsson, Eleonor; Lövgren, Kristina; Fernö, Mårten; Grabau, Dorthe; Borg, Åke; Hegardt, Cecilia; Honeth, Gabriella; Bendahl, Pär-Ola; Saal, Lao H; Gruvberger-Saal, Sofia; Ringnér, Markus; Vallon-Christersson, Johan; Jönsson, Göran; Holm, Karolina
2011-01-01
The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes. We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA. Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44 + /CD24 - phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival. We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to
Directory of Open Access Journals (Sweden)
Vallon-Christersson Johan
2011-09-01
Full Text Available Abstract Background The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes. Methods We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA. Results Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44+/CD24- phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival. Conclusions We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in
Ikon. iPod er kongen over mp3. Hvad er hemmeligheden?
DEFF Research Database (Denmark)
Dickson, Thomas
2005-01-01
iPod er blevet ikonet for det 21. århundrede. Men iPod var hverken den første mp3-afspiller eller den første veldesignede af slagsen. Før iPod så dagens lys var Bang & Olufsen på banen med sin næsten lige så lækre BeoSound2.......iPod er blevet ikonet for det 21. århundrede. Men iPod var hverken den første mp3-afspiller eller den første veldesignede af slagsen. Før iPod så dagens lys var Bang & Olufsen på banen med sin næsten lige så lækre BeoSound2....
Directory of Open Access Journals (Sweden)
Xiaohua Pan
2016-02-01
Full Text Available Epigallocatechin-3-gallate (EGCG is a type of catechin extracted from green tea, which is reported to have anticancer effects. EGCG is also reported to inhibit the cancer stem/progenitor cells in several estrogen receptor (ER-negative breast cancer cell lines, such as SUM-149, SUM-190 and MDA-MB-231. And all these cancer cells are highly expressed a new variant of ER-α, ER-α36. The aim of our present study is to determine the role of ER-α36 in the growth inhibitory activity of EGCG towards ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells. We found that EGCG potently inhibited the growth of cancer stem/progenitor cells in MDA-MB-231 and MDA-MB-436 cells, and also reduced the expression of ER-α36 in these cells. However, in ER-α36 knocked-down MDA-MB-231 and MDA-MB-436 cells, no significant inhibitory effects of EGCG on cancer stem/progenitor cells were observed. We also found that down-regulation of ER-α36 expression was in accordance with down-regulation of EGFR, which further verified a loop between ER-α36 and EGFR. Thus, our study indicated ER-α36 is involved in EGCG's inhibitory effects on ER-negative breast cancer stem/progenitor cells, which supports future preclinical and clinical evaluation of EGCG as a therapeutic option for ER-α36 positive breast cancer.
DEFF Research Database (Denmark)
2016-01-01
Valg af materiale/medie/form: YouTube Valg af arbejdsform: Videoerne kan bruges som caseundervisning Begrundelse for valg af materiale/medie/form/arbejdsform: Caseundervisning er velegnet til at lære om praksis......Valg af materiale/medie/form: YouTube Valg af arbejdsform: Videoerne kan bruges som caseundervisning Begrundelse for valg af materiale/medie/form/arbejdsform: Caseundervisning er velegnet til at lære om praksis...
Energy Technology Data Exchange (ETDEWEB)
Roman, Nicholas O., E-mail: nroman@mcvh-vcu.edu [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA (United States); Shepherd, Wes [Department of Pulmonology, Virginia Commonwealth University, Richmond, VA (United States); Mukhopadhyay, Nitai [Department of Biostatistics, Virginia Commonwealth University, Richmond, VA (United States); Hugo, Geoffrey D.; Weiss, Elisabeth [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA (United States)
2012-08-01
Purpose: To evaluate implanted markers as a surrogate for tumor-based setup during image-guided lung cancer radiotherapy with audiovisual biofeedback. Methods and Materials: Seven patients with locally advanced non-small-cell lung cancer were implanted bronchoscopically with gold coils. Markers, tumor, and a reference bony structure (vertebra) were contoured for all 10 phases of the four-dimensional respiration-correlated fan-beam computed tomography and weekly four-dimensional cone-beam computed tomography. Results: The systematic/random interfractional marker-to-tumor centroid displacements were 2/3, 2/2, and 3/3 mm in the x (lateral), y (anterior-posterior), and z (superior-inferior) directions, respectively. The systematic/random interfractional marker-to-bone displacements were 2/3, 2/3, and 2/3 mm in the x, y, and z directions, respectively. The systematic/random tumor-to-bone displacements were 2/3, 2/4, and 4/4 mm in the x, y, and z directions, respectively. All displacements changed significantly over time (p < 0.0001). Conclusions: Although marker-based image guidance may decrease the risk for geometric miss compared with bony anatomy-based positioning, the observed displacements between markers and tumor centroids indicate the need for repeated soft tissue imaging, particularly in situations with large tumor volume change and large initial marker-to-tumor centroid distance.
International Nuclear Information System (INIS)
Roman, Nicholas O.; Shepherd, Wes; Mukhopadhyay, Nitai; Hugo, Geoffrey D.; Weiss, Elisabeth
2012-01-01
Purpose: To evaluate implanted markers as a surrogate for tumor-based setup during image-guided lung cancer radiotherapy with audiovisual biofeedback. Methods and Materials: Seven patients with locally advanced non-small-cell lung cancer were implanted bronchoscopically with gold coils. Markers, tumor, and a reference bony structure (vertebra) were contoured for all 10 phases of the four-dimensional respiration-correlated fan-beam computed tomography and weekly four-dimensional cone-beam computed tomography. Results: The systematic/random interfractional marker-to-tumor centroid displacements were 2/3, 2/2, and 3/3 mm in the x (lateral), y (anterior–posterior), and z (superior–inferior) directions, respectively. The systematic/random interfractional marker-to-bone displacements were 2/3, 2/3, and 2/3 mm in the x, y, and z directions, respectively. The systematic/random tumor-to-bone displacements were 2/3, 2/4, and 4/4 mm in the x, y, and z directions, respectively. All displacements changed significantly over time (p < 0.0001). Conclusions: Although marker-based image guidance may decrease the risk for geometric miss compared with bony anatomy–based positioning, the observed displacements between markers and tumor centroids indicate the need for repeated soft tissue imaging, particularly in situations with large tumor volume change and large initial marker-to-tumor centroid distance.
A Role for MEK-Interacting Protein 1 In Hormone Responsiveness of ER Positive Breast Cancer Cells
2011-10-01
48 hours, ER- positiv e cell lines tran sfected with MP1siRNA (but not control siR NA) rounded up and detached fr om the plate, and trypan blue...phenotype to MCF-7. To quantitate the effect of MP1 knockdown, attached and detached cells were collected at 48 h following siRNA transfection, stained...Immunoblot from a representative experiment. Lower panel: Quantitation of MP1/Actin ratios in three independent experiments (mean ± SD, *pɘ.05). Figure
Mungle, T; Tewary, S; DAS, D K; Arun, I; Basak, B; Agarwal, S; Ahmed, R; Chatterjee, S; Chakraborty, C
2017-08-01
Molecular pathology, especially immunohistochemistry, plays an important role in evaluating hormone receptor status along with diagnosis of breast cancer. Time-consumption and inter-/intraobserver variability are major hindrances for evaluating the receptor score. In view of this, the paper proposes an automated Allred Scoring methodology for estrogen receptor (ER). White balancing is used to normalize the colour image taking into consideration colour variation during staining in different labs. Markov random field model with expectation-maximization optimization is employed to segment the ER cells. The proposed segmentation methodology is found to have F-measure 0.95. Artificial neural network is subsequently used to obtain intensity-based score for ER cells, from pixel colour intensity features. Simultaneously, proportion score - percentage of ER positive cells is computed via cell counting. The final ER score is computed by adding intensity and proportion scores - a standard Allred scoring system followed by pathologists. The classification accuracy for classification of cells by classifier in terms of F-measure is 0.9626. The problem of subjective interobserver ability is addressed by quantifying ER score from two expert pathologist and proposed methodology. The intraclass correlation achieved is greater than 0.90. The study has potential advantage of assisting pathologist in decision making over manual procedure and could evolve as a part of automated decision support system with other receptor scoring/analysis procedure. © 2017 The Authors Journal of Microscopy © 2017 Royal Microscopical Society.
International Nuclear Information System (INIS)
Kubota, N.; Griffin, R.J.; Williams, B.W.; Song, C.W.; Yahiro, T.
2003-01-01
Full text: We previously have reported the radiosensitizing capability of Doranidazole (PR-350) on SCCVII cells and tumors (Puerto Rico, 2001). In the present study, we have investigated the efficacy of PR-350 as a hypoxic cell radiosensitizer using human lung cancer cells (RERF-LC-AI) in vitro and also RERF-LC-AI tumors grown s.c. in Balb/c nude mice. Using the micronucleus assay method, we determined the effect of PR-350 on the response of RERF-LC-AI cells to radiation under hypoxic conditions and enhancement ratios (ER) of 1.45∼2.26 were obtained. The in vivo radiosensitizing effect was studied by irradiating RERF-LC-AI tumors with 15 Gy at 20 min. after i.v. injection of PR-350 (200mg/kg) and measuring the tumor growth delay. Significant growth delay occurred after i.v. injection of PR-350 before irradiation compared to radiation alone. We measured tumor pO 2 at 3, 7 and 14 days after treatment using an Eppendorf pO 2 histograph. The frequency of pO 2 values 2 in tumors treated with radiation plus PR-350 were higher than that in tumors treated with radiation plus saline. These data suggest that the O 2 consumption in tumors treated with radiation plus PR-350 was less than that in tumors treated with radiation plus saline due to greater drug and radiation-induced cell death. This hypothesis is supported by the fact that the tumor size in the combined treatment group was smaller than in radiation alone. These results suggest that PR-350 may improve the response of tumors to radiotherapy not only by increasing the radiosensitivity of hypoxic cells but also by improving tumor oxygenation over many days during fractionated radiotherapy
Shieh, Yiwey; Hu, Donglei; Ma, Lin; Huntsman, Scott; Gard, Charlotte C; Leung, Jessica W T; Tice, Jeffrey A; Ziv, Elad; Kerlikowske, Karla; Cummings, Steven R
2017-11-01
Models that predict the risk of estrogen receptor (ER)-positive breast cancers may improve our ability to target chemoprevention. We investigated the contributions of sex hormones to the discrimination of the Breast Cancer Surveillance Consortium (BCSC) risk model and a polygenic risk score comprised of 83 single nucleotide polymorphisms. We conducted a nested case-control study of 110 women with ER-positive breast cancers and 214 matched controls within a mammography screening cohort. Participants were postmenopausal and not on hormonal therapy. The associations of estradiol, estrone, testosterone, and sex hormone binding globulin with ER-positive breast cancer were evaluated using conditional logistic regression. We assessed the individual and combined discrimination of estradiol, the BCSC risk score, and polygenic risk score using the area under the receiver operating characteristic curve (AUROC). Of the sex hormones assessed, estradiol (OR 3.64, 95% CI 1.64-8.06 for top vs bottom quartile), and to a lesser degree estrone, was most strongly associated with ER-positive breast cancer in unadjusted analysis. The BCSC risk score (OR 1.32, 95% CI 1.00-1.75 per 1% increase) and polygenic risk score (OR 1.58, 95% CI 1.06-2.36 per standard deviation) were also associated with ER-positive cancers. A model containing the BCSC risk score, polygenic risk score, and estradiol levels showed good discrimination for ER-positive cancers (AUROC 0.72, 95% CI 0.65-0.79), representing a significant improvement over the BCSC risk score (AUROC 0.58, 95% CI 0.50-0.65). Adding estradiol and a polygenic risk score to a clinical risk model improves discrimination for postmenopausal ER-positive breast cancers.
DEFF Research Database (Denmark)
Møberg, Rasmus Juul
normativ fordring. Kohlis (2007) formulering af normalbiografien er en tredeling af livsforløbet (uddannelse – arbejdsliv - pension). En tredeling der bliver kritiseret for at være køns- og familieblind, hvorfor linked lives-begrebet bliver introduceret. Begrebet har den teoretiske implikation...... analyser tager højde for afhængighed over tid i den afhængige variabel. Overordnet set er det tre aspekter af datas karakteristika, der fordrer specielle metoder. Det er censurering af data, tidsmæssig variation i de uafhængige variable samt potentiel korrelation mellem målingerne af den afhængige variabel...... for disse ændringer, hvorved risikoen for en given transition beregnes mere præcist. Afhandlingens empiriske grundlag er registerdata for alle personer i Danmark, der tilhører fødselskohorterne 1968, 1972 og 1976. Data dækker over personlige, familiære forhold og oplysninger på arbejdspladsniveau, hvor den...
Hirschler-Guttenberg, Yael; Golan, Ofer; Ostfeld-Etzion, Sharon; Feldman, Ruth
2015-05-01
Children with autism spectrum disorder (ASD) exhibit difficulties in regulating emotions and authors have called to study the specific processes underpinning emotion regulation (ER) in ASD. Yet, little observational research examined the strategies preschoolers with ASD use to regulate negative and positive emotions in the presence of their mothers and fathers. Forty preschoolers with ASD and 40 matched typically developing children and their mothers and fathers participated. Families were visited twice for identical battery of paradigms with mother or father. Parent-child interactions were coded for parent and child behaviors and children engaged in ER paradigms eliciting negative (fear) and positive (joy) emotions with each parent. ER paradigms were microcoded for negative and positive emotionality, ER strategies, and parent regulation facilitation. During free play, mothers' and fathers' sensitivity and warm discipline were comparable across groups; however, children with ASD displayed lower positive engagement and higher withdrawal. During ER paradigms, children with ASD expressed less positive emotionality overall and more negative emotionality during fear with father. Children with ASD used more simple self-regulatory strategies, particularly during fear, but expressed comparable levels of assistance seeking behavior toward mother and father in negative and positive contexts. Parents of children with ASD used less complex regulation facilitation strategies, including cognitive reappraisal and emotional reframing, and employed simple tactics, such as physical comforting to manage fear and social gaze to maintain joy. Findings describe general and parent- and emotion-specific processes of child ER and parent regulation facilitation in preschoolers with ASD. Results underscore the ability of such children to seek parental assistance during moments of high arousal and the parents' sensitive adaptation to their children's needs. Reduced positive emotionality
ER2OWL: Generating OWL Ontology from ER Diagram
Fahad, Muhammad
Ontology is the fundamental part of Semantic Web. The goal of W3C is to bring the web into (its full potential) a semantic web with reusing previous systems and artifacts. Most legacy systems have been documented in structural analysis and structured design (SASD), especially in simple or Extended ER Diagram (ERD). Such systems need up-gradation to become the part of semantic web. In this paper, we present ERD to OWL-DL ontology transformation rules at concrete level. These rules facilitate an easy and understandable transformation from ERD to OWL. The set of rules for transformation is tested on a structured analysis and design example. The framework provides OWL ontology for semantic web fundamental. This framework helps software engineers in upgrading the structured analysis and design artifact ERD, to components of semantic web. Moreover our transformation tool, ER2OWL, reduces the cost and time for building OWL ontologies with the reuse of existing entity relationship models.
Penault-Llorca, Frédérique; Filleron, Thomas; Asselain, Bernard; Baehner, Frederick L; Fumoleau, Pierre; Lacroix-Triki, Magali; Anderson, Joseph M; Yoshizawa, Carl; Cherbavaz, Diana B; Shak, Steven; Roca, Lise; Sagan, Christine; Lemonnier, Jérôme; Martin, Anne-Laure; Roché, Henri
2018-05-04
The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m 2 ) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p < 0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p < 0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. Not applicable.
Multiple band structure in 156Er
International Nuclear Information System (INIS)
Sunyar, A.W.; Der Mateosian, E.; Kistner, O.C.; Johnson, A.; Lumpkin, A.H.; Thieberger, P.
1976-01-01
The 142 Nd( 18 O,4n) 156 Er reaction at 90-95 MeV was used to study 156 Er high-spin states to spin 24. In addition to the background ground-state band, two well developed off-spin side bands, one of each parity, were observed. (Auth.)
Er formen blevet vigtigst i politik?
DEFF Research Database (Denmark)
Etemadi, Maziar Haghpaidar
2005-01-01
RETORIK: Retorikken er kunsten at tage ordet - skriftligt eller mundtligt - og udtrykke sig smukt og velformuleret. Gorgias (ca. 490-ca. 390 f. Kr.) fra Leontinoi på Sicilien betragtes som ophavsmanden til den første endelige formulering af retorikkens virke og muligheder: "Talen er en mægtig...
DEFF Research Database (Denmark)
Klausen, Kurt Klaudi
2017-01-01
Artiklen gennemgår kort de tre F'er: at fremskrive, forudse og forestille som strategiske værktøjer til strategic forecast......Artiklen gennemgår kort de tre F'er: at fremskrive, forudse og forestille som strategiske værktøjer til strategic forecast...
DEFF Research Database (Denmark)
Korshoej, Anders Rosendal; Hansen, Frederik Lundgaard; Thielscher, Axel
2017-01-01
and in deep tumors embedded in white matter. The field strength was not higher for tumors close to the active electrode. Left/right field directions were generally superior to anterior/posterior directions. Central necrosis focally enhanced the field near tumor boundaries perpendicular to the applied field...
Heggen, Vilde Stuvøy
2014-01-01
Det er kanskje ingen overraskelse at man i internettalderen har funnet på en valuta som kun eksisterer på nett. Per i dag eksisterer det flere slike nettvalutaer, med varierende grad av oppslutning. Spørsmålet som stilles i oppgaven er hva slags formuerettslig objekt digital valuta er. Jeg regner digital valuta som alle valutaer som hovedsakelig er å finne på nett og som ikke utstedes av eller på vegne av en statsmakt. Definisjonen omfatter både kryptovalutaer som Bitcoin, som nok er mest kje...
Correlation of expression of BP1, a homeobox gene, with estrogen receptor status in breast cancer
International Nuclear Information System (INIS)
Fu, Sidney W; Poola, Indira; Stephan, Dietrich A; Berg, Patricia E; Schwartz, Arnold; Stevenson, Holly; Pinzone, Joseph J; Davenport, Gregory J; Orenstein, Jan M; Gutierrez, Peter; Simmens, Samuel J; Abraham, Jessy
2003-01-01
BP1 is a novel homeobox gene cloned in our laboratory. Our previous studies in leukemia demonstrated that BP1 has oncogenic properties, including as a modulator of cell survival. Here BP1 expression was examined in breast cancer, and the relationship between BP1 expression and clinicopathological data was determined. Total RNA was isolated from cell lines, tumors, and matched normal adjacent tissue or tissue from autopsy. Reverse transcription polymerase chain reaction was performed to evaluate BP1 expression. Statistical analysis was accomplished with SAS. Analysis of 46 invasive ductal breast tumors demonstrated BP1 expression in 80% of them, compared with a lack of expression in six normal breast tissues and low-level expression in one normal breast tissue. Remarkably, 100% of tumors that were negative for the estrogen receptor (ER) were BP1-positive, whereas 73% of ER-positive tumors expressed BP1 (P = 0.03). BP1 expression was also associated with race: 89% of the tumors of African American women were BP1-positive, whereas 57% of those from Caucasian women expressed BP1 (P = 0.04). However, there was no significant difference in BP1 expression between grades I, II, and III tumors. Interestingly, BP1 mRNA expression was correlated with the ability of malignant cell lines to cause breast cancer in mice. Because BP1 is expressed abnormally in breast tumors, it could provide a useful target for therapy, particularly in patients with ER-negative tumors. The frequent expression of BP1 in all tumor grades suggests that activation of BP1 is an early event
Luczynska, Elzbieta; Niemiec, Joanna; Heinze, Sylwia; Adamczyk, Agnieszka; Ambicka, Aleksandra; Marcyniuk, Paulina; Rudnicki, Wojciech; Mitus, Jerzy W; Dyczek, Sonia; Rys, Janusz; Sas-Korczynska, Beata
2018-02-01
It is possible that the degree of enhancement on contrast-enhanced spectral mammography (CESM), a new diagnostic method, might provide prognostic information for breast cancer patients. Therefore, in a group of 82 breast cancer patients, we analyzed the prognostic significance of degree and pattern of enhancement on CESM as well as its relation to: (a) breast cancer immunophenotype (based on ER/PR/HER2 status) (b) podoplanin expression in cancer stroma (lymphatic vessel density plus podoplanin-positivity of cancer-associated fibroblasts), and (c) other histological parameters. For each tumor the intensity of enhancement on CESM was qualitatively assessed as strong or weak/medium, while the pattern - as homogenous and heterogenous. Herein we report, for the first time, that strong and heterogenous enhancement on CESM was related to unfavorable disease-free survival of breast cancer patients (p=0.005). Moreover, the strong enhancement was more frequent in large and node-positive tumors (pT>1, pN>0) (p=0.002), as well as in carcinomas with podoplanin-sparse stroma (p=0.008). Intensity and pattern of enhancement on CESM might provide (together with the results of other diagnostic imaging methods) not only the confirmation of presence or absence of tumor, but also prognostic information. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
MicroRNAs meet calcium: joint venture in ER proteostasis.
Finger, Fabian; Hoppe, Thorsten
2014-11-04
The endoplasmic reticulum (ER) is a cellular compartment that has a key function in protein translation and folding. Maintaining its integrity is of fundamental importance for organism's physiology and viability. The dynamic regulation of intraluminal ER Ca(2+) concentration directly influences the activity of ER-resident chaperones and stress response pathways that balance protein load and folding capacity. We review the emerging evidence that microRNAs play important roles in adjusting these processes to frequently changing intracellular and environmental conditions to modify ER Ca(2+) handling and storage and maintain ER homeostasis. Copyright © 2014, American Association for the Advancement of Science.
Córdoba, Rodrigo; Cano, Juan Fernando; Arango-Dávila, César Augusto; Miranda, Carlos; Holguín, Jorge; Fernández, Darío; Márquez, Miguel; Lupo, Christian; Gargoloff, Pedro; Petracca, Gustavo; Lucchetti, César
2012-06-01
Extended-release (ER) paliperidone is an innovative atypical antipsychotic that allows minimal peak-to-through fluctuations with once-daily dosing. To evaluate effectiveness, safety and tolerability of flexible, once-daily doses of paliperidone ER (3-12 mg/day) in patients with schizophrenia from Argentina and Colombia who had previously failed treatment with other antipsychotic agents. The authors conducted a 6-month, open-label, prospective and multicentric study. Effectiveness was assessed with Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance scale (PSP). Other measures of effectiveness, safety and tolerability, were also conducted. Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end (p < 0,001). In the PANSS total score, the mean change from baseline (83, 9 units) to end point (53,7 units) was significant (p < 0,001). Flexible doses of paliperidone ER demonstrated a ≥20% reduction in the PANSS total score (p<0.001) in almost two-thirds of patients. PSP mean change from baseline (52 units) to end point (85 units) was significant (p < 0,001). Secondary effectiveness assessments, as well as safety and tolerability measures, demonstrated favourable results throughout the study. Flexible doses of paliperidone ER over 6 months were effective, safe and well tolerated in patients with schizophrenia from Argentina and Colombia. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
Tumor detection using feature extraction
International Nuclear Information System (INIS)
Sankar, A.S.; Amudhavalli, N.; Sivakolundu, M.K.
2008-01-01
The assistance system for brain tumor detection helps the doctor to analyse the brain tumor in MRI image and help to make decision. The manual detection system takes 3 -5 hours time to analyse the tumor. Doctors are in a position to analyze the tumor faster and make a correct decision with an assistance system
Cross-presentation: how to get there – or how to get the ER
Directory of Open Access Journals (Sweden)
Christoph eKreer
2012-01-01
Full Text Available Antigen cross-presentation enables dendritic cells to present extracellular antigens on MHC I molecules, a process that plays an important role in the induction of immune responses against viruses and tumors and in the induction of peripheral tolerance.In order to allow intracellular processing for cross-presentation, internalized antigens are targeted by distinct endocytic receptors towards specific endosomal compartments, where they are protected from rapid lysosomal degradation. From these compartments, antigens are processed for loading onto MHC I molecules. Such processing generally includes antigen transport into the cytoplasm, a process that is regulated by members of the ER-associated degradation (ERAD machinery. After proteasomal degradation in the cytoplasm, antigen-derived peptides have been shown to be re-imported into the same endosomal compartment by endosomal TAP, another ER protein, which is recruited towards the endosomes after DC maturation. In our review, we highlight the recent advances on the molecular mechanisms of cross-presentation. We focus on the necessity of such antigen storage compartments and point out important parallels to MHC I-restricted presentation of endogenous antigens. We discuss the composition of such endosomes and the targeting of extracellular antigens into this compartment by specific endocytic receptors. Finally, we highlight recent advances on the recruitment of the cross-presentation machinery, like the members of the MHC I loading complex and the ERAD machinery, from the ER towards these storage compartments, a process that can be induced by antigen encounter or by activation of the dendritic cell after contact with endotoxins.
Norona, A N; Baker, B L
2017-02-01
Emotion regulation has been identified as a robust predictor of adaptive functioning across a variety of domains (Aldao et al. ). Furthermore, research examining early predictors of competence and deficits in ER suggests that factors internal to the individual (e.g. neuroregulatory reactivity, behavioural traits and cognitive ability) and external to the individual (e.g. caregiving styles and explicit ER training) contribute to the development of ER (Calkins ). Many studies have focused on internal sources or external sources; however, few have studied them simultaneously within one model, especially in studies examining children with developmental delays (DD). Here, we addressed this specific research gap and examined the contributions of one internal factor and one external factor on emotion dysregulation outcomes in middle childhood. Specifically, our current study used structural equation modelling (SEM) to examine prospective, predictive relationships between DD status, positive parenting at age 4 years and child emotion dysregulation at age 7 years. Participants were 151 families in the Collaborative Family Study, a longitudinal study of young children with and without DD. A positive parenting factor was composed of sensitivity and scaffolding scores from mother-child interactions at home and in the research centre at child age 4 years. A child dysregulation factor was composed of a dysregulation code from mother-child interactions and a parent-report measure of ER and lability/negativity at age 7 years. Finally, we tested the hypothesis that positive parenting would mediate the relationship between DD and child dysregulation. Mothers of children with DD exhibited fewer sensitive and scaffolding behaviours compared with mothers of typically developing children, and children with DD were more dysregulated on all measures of ER. SEM revealed that both DD status and early positive parenting predicted emotion dysregulation in middle childhood. Furthermore
DEFF Research Database (Denmark)
Schilhab, Theresa
2014-01-01
Hvor ’konkret’ skal en oplevelse være, for at intuitionen om, at det selvoplevede styrker læringen, holder? Er brug af tablets (e.g. iPads) et ligebyrdigt alternativ til den konkrete oplevelse?......Hvor ’konkret’ skal en oplevelse være, for at intuitionen om, at det selvoplevede styrker læringen, holder? Er brug af tablets (e.g. iPads) et ligebyrdigt alternativ til den konkrete oplevelse?...
Hatta, Taku; Yamamoto, Nobuyuki; Sano, Hirotaka; Itoi, Eiji
2017-03-01
Immobilization with shoulder braces is used for conservative treatment of an initial shoulder dislocation. Various arm positions have been investigated to determine optimal position in terms of the anatomical reduction of the Bankart lesion. Recently, the effect of immobilization in shoulder abduction as well as in external rotation has been reported. However, there are few studies assessing subjects' acceptability of the brace in various arm positions. We hypothesized that a certain arm position regarding abduction or external rotation for immobilization would induce significant discomfort during activities of daily living. A dominant arm of 20 healthy participants was immobilized with a shoulder brace in 4 different positions; adduction and internal rotation (Add-IR), adduction and external rotation (Add-ER), 30° of abduction and 30° of external rotation (Abd-30ER), and 30° of abduction and 60° of external rotation (Abd-60ER). After completing immobilization for 24 h, subjects were asked to assess the discomfort of bracing for overall and individual activities, using a visual analogue scale. Data were compared among the four positions. For overall activities and several activities (eating, reading books, and removing and putting on pants), Abd-60ER was significantly more uncomfortable than adducted arm positions. Abd-30ER did not show any differences compared to the other arm positions. Immobilization in abduction and external rotation seems to be acceptable although the arm position in 30° of abduction and 60° of external rotation is less comfortable than the others. Our results might be useful in determining and developing the ideal shoulder brace which could keep patients' compliance and improve their outcomes. Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
Nascimbeni, Anna Chiara; Giordano, Francesca; Dupont, Nicolas; Grasso, Daniel; Vaccaro, Maria I; Codogno, Patrice; Morel, Etienne
2017-07-14
The double-membrane-bound autophagosome is formed by the closure of a structure called the phagophore, origin of which is still unclear. The endoplasmic reticulum (ER) is clearly implicated in autophagosome biogenesis due to the presence of the omegasome subdomain positive for DFCP1, a phosphatidyl-inositol-3-phosphate (PI3P) binding protein. Contribution of other membrane sources, like the plasma membrane (PM), is still difficult to integrate in a global picture. Here we show that ER-plasma membrane contact sites are mobilized for autophagosome biogenesis, by direct implication of the tethering extended synaptotagmins (E-Syts) proteins. Imaging data revealed that early autophagic markers are recruited to E-Syt-containing domains during autophagy and that inhibition of E-Syts expression leads to a reduction in autophagosome biogenesis. Furthermore, we demonstrate that E-Syts are essential for autophagy-associated PI3P synthesis at the cortical ER membrane via the recruitment of VMP1, the stabilizing ER partner of the PI3KC3 complex. These results highlight the contribution of ER-plasma membrane tethers to autophagosome biogenesis regulation and support the importance of membrane contact sites in autophagy. © 2017 The Authors.
Li, Hui; Fan, Ming; Zhang, Peng; Li, Yuanzhe; Cheng, Hu; Zhang, Juan; Shao, Guoliang; Li, Lihua
2018-03-01
Breast cancer, with its high heterogeneity, is the most common malignancies in women. In addition to the entire tumor itself, tumor microenvironment could also play a fundamental role on the occurrence and development of tumors. The aim of this study is to investigate the role of heterogeneity within a tumor and the surrounding stromal tissue in predicting the Ki-67 proliferation status of oestrogen receptor (ER)-positive breast cancer patients. To this end, we collected 62 patients imaged with preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for analysis. The tumor and the peritumoral stromal tissue were segmented into 8 shells with 5 mm width outside of tumor. The mean enhancement rate in the stromal shells showed a decreasing order if their distances to the tumor increase. Statistical and texture features were extracted from the tumor and the surrounding stromal bands, and multivariate logistic regression classifiers were trained and tested based on these features. An area under the receiver operating characteristic curve (AUC) were calculated to evaluate performance of the classifiers. Furthermore, the statistical model using features extracted from boundary shell next to the tumor produced AUC of 0.796+/-0.076, which is better than that using features from the other subregions. Furthermore, the prediction model using 7 features from the entire tumor produced an AUC value of 0.855+/-0.065. The classifier based on 9 selected features extracted from peritumoral stromal region showed an AUC value of 0.870+/-0.050. Finally, after fusion of the predictive model obtained from entire tumor and the peritumoral stromal regions, the classifier performance was significantly improved with AUC of 0.920. The results indicated that heterogeneity in tumor boundary and peritumoral stromal region could be valuable in predicting the indicator associated with prognosis.
En hat er vel en hat ... eller?
DEFF Research Database (Denmark)
Bøilerehauge, Dorrit
2007-01-01
Mens vi kører i høj fart på "the information highway" - i den helt store bus midt på vejen - glemmer vi ofte noget meget vigtigt i vores glæde over, at verden tilsyneladende åbner sig for os, og vi kan kommunikere med hele verden med ét klik. Vi glemmer, at selvom trafikskilte som oftest er ens -...... - så er selve trafikken og forventningerne blandt medtrafikanterne helt forskellige fra det, vi er vant til. Udgivelsesdato: Februar...
Interlayer exchange coupling in Er|Tb superlattices mediated by short range incommensurate Er order
International Nuclear Information System (INIS)
Pfuhl, E; Brueckel, T; Voigt, J; Mattauch, S; Korolkov, D
2010-01-01
We study the magnetic correlations in Er|Tb superlattices by means of off-specular scattering of polarized neutrons. We show here the co-existence of inhomogeneous magnetic states: i) ferromagnetic order of moments within the Tb layers below 230 K (FM), correlation length of about 10 bilayer, ii) an incommensurate modulated magnetic order, restricted to single Er layers and iii) antiferromagnetic coupling of ferromagnetic layers below 70K (AFC). Polarised off-specular neutron scattering under grazing incidence reveals that i) magnetic fluctuations appear when the sample is cooled below 70 K, ii) these fluctuations lead to AFC, when the sample is cooled to 10 K, which iii) persists, when the sample is subsequently heated up to 45 K, while the order is not present during the cooling cycle. Also the short range incommensurate order changes accordingly, implying that the magnetic order in the Er layers mediates the interlayer coupling between ferromagnetic Tb layers.
International Nuclear Information System (INIS)
Chen Baojun; Hu Ji; Liang Jixin; Li Hongyu; Luo Lianzhe; Shen Langtao; Luo Zhifu; Chen Yang
2007-01-01
The Cys-RGD peptide is labelled with 99 Tc m -nitrido core combined with PNP6 lig- and (PNP6=bis (diethoxypropylphosphino ethyl) ethoxy ethylamine) to investigate the possibility of radiolabelled RGD peptides for tumor α v β 3 integrin receptor scintigraphy. The radiochemical purity is measured with HPLC, the in vitro stability is investigated at room temperature and at 37 degree C incubated in the cystein and serum solution. Biodistribution studies and gamma camera imaging are performed in normal mice and nude mice bearing FWK-1 pancreatic tumor xenografts. More than 92% radiolabelling yield is achieved under optimized condition. The high in vitro stability is found for 99 Tc m (N) (PNP6) (Cys-RGD). In vivo biodistribution studies indicate the radiolabelled peptide is cleared rapidly from blood and mainly excreted via urinary system. Tumor uptake is 2.92 ± 0.71%/g at 1 h after injection. The uptake ratios of tumor to blood and tumor to muscle (T/NT) are 11.0 and 3. 1 at 4 h after injection, respectively. Scintigraphic imaging allows contrasting visualisation of α v β 3 -expressed tumors at 1 h after injection. The results suggest 99 Tc m (N) (PNP6) (Cys- RGD) may be the potential agent for α v β 3 -positive tumor imaging. (authors)
DEFF Research Database (Denmark)
Schrohl, Anne-Sofie; Look, Maxime P.; Gelder, Marion E. Meijer-van
2009-01-01
BACKGROUND: We have previously demonstrated that high tumor tissue levels of TIMP-1 are associated with no or limited clinical benefit from chemotherapy with CMF and anthracyclines in metastatic breast cancer patients. Here, we extend our investigations to the adjuvant setting studying outcome...... an association between shorter survival after treatment in TIMP-1 high patients compared with TIMP-1 low patients, especially in patients receiving anthracycline-based therapy. This suggests that high tumor tissue levels of TIMP-1 might be associated with reduced benefit from classical adjuvant chemotherapy. Our...... after adjuvant chemotherapy in premenopausal lymph node-positive patients. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and accordingly that high tumor tissue levels are associated with shorter survival. METHODS: From our original retrospectively collected tumor samples we...
Directory of Open Access Journals (Sweden)
Yukihiko Hiroshima
Full Text Available We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1 no treatment; (2 carboplatinum (30 mg/kg, ip, weekly, 5 weeks; (3 trastuzumab (20 mg/kg, ip, weekly, 5 weeks; (4 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks; (5 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks + trastuzumab (20 mg/kg, ip, weekly, 5 weeks. All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007 and S. typhimurium A1-R alone (p = 0.039. No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021. Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.
Mukherjee, Subhendu; Saha, Achintya; Roy, Kunal
2005-02-15
Considering importance of developing selective estrogen receptor modulators (SERMs), the present paper explores selectivity requirements of tetrahydroisoquinoline derivatives for binding with ER(alpha) versus ER(beta) receptors using E-state index and physicochemical parameters. The best model [n=21, Q(2)=0.512, R(a)(2)=0.613, R=0.819, F=11.6 (df 3,17)] for ER(alpha) binding data obtained from radioligand binding assay showed importance of C(1), C(15) and lipophilicity (logP) while the best model [n=21, Q(2)=0.768, R(a)(2)=0.796, R=0.904, F=40.1 (df 2,18)] for ER(beta) binding data showed importance of C(1) and molar refractivity (MR). While modeling ER(alpha)/ER(beta) selectivity [n=21, Q(2)=0.695, R(a)(2)=0.739, R=0.882, F=19.8 (df 3,17)], C(1), C(15) and molar refractivity were found to be significant contributors. The data obtained from cellular transcription assay were also modeled. In case of ER(alpha), the best equation involving E-state values of C(1) and C(14) and logP explained 62.1% of the variance while the best equation for ER(beta) involving E-state values of C(1) and C(15) and MR explained 64.6% of the variance of the response variable. In case of ER(alpha)/ER(beta) selectivity, the best equation involving E-state values of O(8), C(14) and N(27) showed 48.3% explained variance, which increased to 63.5% on deletion of single outlier. From the analysis it appears that the nitrogen atom of the aminoethoxyphenyl substituent and 6-hydroxy substituent of the tetrahydroisoquinoline nucleus play important roles for ER(alpha)/ER(beta) selectivity in addition to R(1) and R(2) substituents.
Erfani, Mostafa; Shafiei, Mohammad; Mazidi, Mohammad; Goudarzi, Mostafa
2013-04-01
Somatostatin-derived analogues play an important role in the diagnosis and treatment of neuroendocrine tumors. The aim of this study was to evaluate a new somatostatin analogue designed for labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), β-(3-benzothienyl)-Ala (BzThi(3))]-octreotide ([HYNIC]-BOC), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was performed on a solid phase using a standard Fmoc strategy. The HYNIC-peptide conjugate was radiolabeled with (99m)Tc and characterized by ITLC and high-performance liquid chromatography (HPLC). In vitro studies were carried out in sstr2 expressing AR4-2J cell lines. In vivo distribution studies were performed in rats bearing the AR4-2J tumor. The radiolabeled complex could be prepared at high-specific activities and >95% radiochemical yield as determined by HPLC. The peptide conjugate showed high-affinity binding for sstr2. The radioligand showed high and specific internalization into AR4-2J cells (18.19%±0.21% at 4 hours). In vivo distribution studies in rats bearing tumor have shown a receptor-specific uptake of radioactivity in somatostatin receptor-positive organs. After 4 hours, uptake in the AR4-2J tumor was 1.71%±0.36% injected dose per gram tissue (%ID/g). These data show that [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide is a specific radioligand for the somatostatin receptor-positive tumors and is a suitable candidate for clinical studies.
International Nuclear Information System (INIS)
Daldrup-Link, Heike E.; Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J.; Rudelius, Martina; Piontek, Guido; Schlegel, Juergen; Piert, Morand; Uherek, Christoph; Wels, Winfried
2005-01-01
The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P 6 NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10 6 parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently labeled with clinically applicable iron-oxide contrast
Energy Technology Data Exchange (ETDEWEB)
Daldrup-Link, Heike E. [UCSF Medical Center, Department of Radiology, San Francisco, CA (United States); Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J. [Technical University Munich, Department of Radiology, Munich (Germany); Rudelius, Martina; Piontek, Guido; Schlegel, Juergen [Technical University Munich, Institute of Pathology, Division of Neuropathology, Munich (Germany); Piert, Morand [Technical University Munich, Department of Nuclear Medicine, Munich (Germany); Uherek, Christoph; Wels, Winfried [University of Frankfurt, Georg Speyer House, Frankfurt (Germany)
2005-01-01
The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P<0.05). After intravenous injection of 5 x 10{sup 6} NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10{sup 6} parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently
Operational durability of a giant ER valve for Braille display
Luning, Xu; Han, Li; Yufei, Li; Shen, Rong; Kunquan, Lu
2017-05-01
The compact configuration of giant ER (electrorheological) valves provides the possibility of realizing a full-page Braille display. The operational durability of ER valves is a key issue in fulfilling a Braille display. A giant ER valve was used to investigate the variations in pressure drops and critical pressure drops of the valves over a long period under some typical operational parameters. The results indicate that neither the pressure drops nor critical pressure drops of giant ER valves show apparent deterioration over a long period. Without ER fluid exchange, a blockage appears in the channel of the valve because the ER structures induced by an external electric field cannot be broken by the Brownian motion of hydraulic oil molecules when the external electric field is removed. Forcing ER fluid flow is an effective and necessary method to keep the channel of the valve unblocked. Thus the operational durability of the valve using giant ER fluids is able to meet the demands of Braille display.
Kündig, Pascale; Giesen, Charlotte; Jackson, Hartland; Bodenmiller, Bernd; Papassotirolopus, Bärbel; Freiberger, Sandra Nicole; Aquino, Catharine; Opitz, Lennart; Varga, Zsuzsanna
2018-05-08
Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p < 0.05) with histopathological grading both in central and peripheral areas. Our results suggest that intra-tumoral heterogeneity of stem-cell and tumor-progression markers cannot be reliably addressed in tissue-micro-array samples in breast cancer. However, most markers correlated strongly with histopathological grading confirming prognostic information as expression profiles were independent on the site of the
Red shifts of the Eg(1) Raman mode of nanocrystalline TiO2:Er monoliths grown by sol-gel process
Palomino-Merino, R.; Trejo-Garcia, P.; Portillo-Moreno, O.; Jiménez-Sandoval, S.; Tomás, S. A.; Zelaya-Angel, O.; Lozada-Morales, R.; Castaño, V. M.
2015-08-01
Nanocrystalline monoliths of Er doped TiO2 were prepared by the sol-gel technique, by controlling the Er-doping levels into the TiO2 precursor solution. As-prepared and annealed in air samples showed the anatase TiO2 phase. The average diameter of the nanoparticles ranged from 19 to 2.6 nm as the nominal concentration of Er varies from 0% to 7%, as revealed by EDS analysis in an electron microscope. Photo Acoustic Spectroscopy (PAS) allowed calculate the forbidden band gap, evidencing an absorption edge at around 300 nm, attributed to TiO2 and evidence of electronic transitions or Er3+. The Raman spectra, corresponding to the anatase phase, show the main phonon mode Eg(1) band position at 144 cm-1 with a red shift for the annealing samples.
Heat capacity and thermal diffusivity of ScD/sub x/ and ErD/sub x/
International Nuclear Information System (INIS)
Moss, M.
1979-04-01
The heat capacity, C/sub p/ (T = 298-1000 K), and the thermal diffusivity, α(T = 623-773 K), of ScD/sub x/ and ErD/sub x/ (x = 0-1.83) have been measured. C/sub p/ of ScD/sub x/ increases with x for x = 0-1.59 over the entire temperature range, but then declines for x = 1.83. ErD/sub x/ shows a monotonic increase of C/sub p/ with x, and exhibits a sharp positive anomaly at 910 K for x = 1.82. Both materials display an excess heat capacity which is attributed to disorder in the deuterium sublattice. A minimum in α is observed for ScD/sub x/ and ErD/sub x/ at mid-range values of x where disorder is greatest; α for all samples is fairly constant with T in this limited temperature range
Hvordan er det å leve med CRPS?
Hovind, Thomas
2014-01-01
Hensikten med denne studien er å se på hvordan pasienter med komplekst regionalt smertesyndrom (CRPS) opplever å leve med tilstanden og hvordan disse pasientene har opplevd å bli møtt i helsevesenet. CRPS er en langvarig tilstand med sterke smerter som kan medføre økt smerterespons, redusert funksjon og nedsatt livskvalitet hos pasientene. Studien er en kvalitativ undersøkelse basert på dybdeintervju av fire pasienter med CRPS. Pasientene ble rekruttert fra en smerteavdeling i Nord-Norge og u...
Branding er ikke til at komme udenom
DEFF Research Database (Denmark)
Hermansen, Judy
2008-01-01
Søren Askegaard definerer branding som "et iscenesat og afkodet symbolunivers". Det vil sige, at vi på den ene side har virksomhedens strategiske profilering, hvor den forsøger at skabe sig en særlig differentieret og positioneret profil, som adskiller den fra andre virksomheder. "Og det er denne...... strategiske kommunikation, der gør at branding er et ledelsesbegreb og ikke kun et markedsføringsbegreb. Det er ikke staffage, men værdier, som skal gennemsyre alle organisationens aktiviteter." Udgivelsesdato: maj...
Er der en underviser til stede?
DEFF Research Database (Denmark)
Christiansen, René Boyer; Nortvig, Anne-Mette; Rosenlund, Lea Tilde
2015-01-01
I de senere år er MOOC (Massive Open Online Courses) blevet en faktor på uddannelsesområdet. MOOC-forskning er et forholdsvist nyt felt, men har inden for de seneste 2-3 år udviklet sig med hastige skridt (Liyanagunawardena et al. 2013, Bayne & Ross 2014). En stor del af denne forskning har haft...
"Det man siger er man selv..."
DEFF Research Database (Denmark)
Næsby, Torben; Nørgaard, Britta; Uddholm, Mats
forhold, der er hermeneutisk, strukturelt og relationelt bestemt. Praksisviden kan ikke være objektiv i gængs forstand, men det behøver ikke at diskvalificere denne viden. Forståelse er altid knyttet til den sag og bundet til den situation man står overfor og i som professionel og som menneske....
Ehrke, M J; Verstovsek, S; Ujházy, P; Meer, J M; Eppolito, C; Maccubbin, D L; Mihich, E
1998-02-01
The therapeutic efficacy of a total of 42 single-agent or combination protocols involving doxorubicin (Adriamycin, ADM) and tumor necrosis factor alpha (TNFalpha) were evaluated in the syngeneic murine lymphoma model, C57BL/6-EL4. Combination treatments were the most effective and the therapeutic effects were schedule-dependent; e.g. it was generally advantageous for ADM to precede TNFalpha administration. Two protocols selected for further study were 4 mg/kg ADM i.v. on days 1 and 8 plus TNFalpha, i.v., at either 16000 U (7 microg)/injection, on days 1 and 8 or 4000 U (1.7 microg)/injection, on days 11-15. Survival of mice bearing one of four EL4 sublines having different in vitro drug sensitivities was assessed. These sublines were E10 (ADM-sensitive/TNFalpha-resistant), E16 (sensitive/sensitive), ER2 (ADM-resistant/TNFalpha-sensitive) and ER13 (resistant/resistant). Between 80% and 100% long-term survivors (i.e. tumor free on day 60) were obtained with the two treatments in mice bearing ADM-sensitive sublines, even though one of these sublines, E10, was resistant to TNFalpha in vitro. Induction of long-term survival appeared, therefore, to correlate with in vitro defined sensitivity/resistance to ADM, but not to TNFalpha Treatment-induced modulations of tumoricidal immune effector functions were also examined. Taken together, the results indicated that induction of long-term survival involved complex interactions of: (1) ADM-induced tumor modifications, including, but not limited to, tumor debulking, (2) combination-treatment-induced modifications of splenic cytolytic T cell and macrophage activities, and (3) the restoration of thymus cellularity. Finally, when long-term survivors resulting from treatment of E10- or E16-bearing mice were implanted with ER2 on day 120, the majority survived, indicating that long-term immune memory, capable of recognizing drug resistant variants, had been established.
Barz, W P; Walter, P
1999-04-01
Many eukaryotic cell surface proteins are anchored in the lipid bilayer through glycosylphosphatidylinositol (GPI). GPI anchors are covalently attached in the endoplasmic reticulum (ER). The modified proteins are then transported through the secretory pathway to the cell surface. We have identified two genes in Saccharomyces cerevisiae, LAG1 and a novel gene termed DGT1 (for "delayed GPI-anchored protein transport"), encoding structurally related proteins with multiple membrane-spanning domains. Both proteins are localized to the ER, as demonstrated by immunofluorescence microscopy. Deletion of either gene caused no detectable phenotype, whereas lag1Delta dgt1Delta cells displayed growth defects and a significant delay in ER-to-Golgi transport of GPI-anchored proteins, suggesting that LAG1 and DGT1 encode functionally redundant or overlapping proteins. The rate of GPI anchor attachment was not affected, nor was the transport rate of several non-GPI-anchored proteins. Consistent with a role of Lag1p and Dgt1p in GPI-anchored protein transport, lag1Delta dgt1Delta cells deposit abnormal, multilayered cell walls. Both proteins have significant sequence similarity to TRAM, a mammalian membrane protein thought to be involved in protein translocation across the ER membrane. In vivo translocation studies, however, did not detect any defects in protein translocation in lag1Delta dgt1Delta cells, suggesting that neither yeast gene plays a role in this process. Instead, we propose that Lag1p and Dgt1p facilitate efficient ER-to-Golgi transport of GPI-anchored proteins.
Die HECT-Ligase Hul5, eine neue Komponente der ER-assoziierten Proteindegradation
Kohlmann, Sonja
2007-01-01
Die meisten sekretorischen Proteine der eukaryontischen Zellen erreichen durch das endoplasmatische Retikulum (ER) den sekretorischen Signalweg. Sie gelangen vom Zytoplasma durch einen Kanal in der ER-Membran in das ER, wo sie ihre native Konformation erhalten. Das ER enthält ein strenges Qualitätskontrollsystem, welches fehlgefaltete Proteine erkennt, im ER zurückhält und letztendlich der ER-assoziierten Degradation (ERAD) zuführt. Die ER-Qualitätskontrolle und die ER-assoziierte Degradation...
Androgen Receptor Expression in Thai Breast Cancer Patients
Directory of Open Access Journals (Sweden)
Suthat Chottanapund
2016-09-01
Full Text Available The aim of this study was to investigate prevalence and related factors of androgen receptor (AR expression in Thai breast cancer patients. A descriptive study was done in 95 patients, who were admitted to Charoenkrung Pracharak Hospital, Bangkok (2011–2013. Statistical relationships were examined between AR protein expression, tumor status, and patient characteristics. Compared with those from Western countries, ethnic Thai patients were younger at age of diagnosis and had a higher proliferative index (high Ki-67 expression, which indicates unfavorable prognosis. In addition, 91% of the Thai breast tumors that were positive for any of the following receptors, estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2 also expressed the AR protein, while in triple negative breast tumors only 33% were AR positive. ER and PR expression was positively related with AR expression, while AR expression was inversely correlated to Ki-67 expression. AR status was strongly correlated with ER and PR status in Thai patients. There is an inverse relationship between Ki-67 and AR, which suggests that AR may be a prognostic factor for breast cancer.
Directory of Open Access Journals (Sweden)
George Fountzilas
Full Text Available BACKGROUND: The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded (FFPE tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER, progesterone receptor (PgR, HER2, Ki67, cytokeratin 5 (CK5, and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low; luminal B (ER/PgR-positive, HER2-negative, Ki67(high; luminal-HER2 (ER/PgR-positive, HER2-positive; HER2-enriched (ER-negative, PgR-negative, HER2-positive; triple-negative (TNBC (ER-negative, PgR-negative, HER2-negative; and basal core phenotype (BCP (TNBC, CK5-positive and/or EGFR-positive. RESULTS: After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS and overall survival (OS rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001 and for death 2.53 (95% CI: 1.62-3.60, p<0.001. Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors
Bjørklund, Sunniva Stordal; Kristensen, Vessela N; Seiler, Michael; Kumar, Surendra; Alnæs, Grethe I Grenaker; Ming, Yao; Kerrigan, John; Naume, Bjørn; Sachidanandam, Ravi; Bhanot, Gyan; Børresen-Dale, Anne-Lise; Ganesan, Shridar
2015-07-17
Alternate transcripts from a single gene locus greatly enhance the combinatorial flexibility of the human transcriptome. Different patterns of exon usage have been observed when comparing normal tissue to cancers, suggesting that variant transcripts may play a role in the tumor phenotype. Ribonucleic acid-sequencing (RNA-seq) data from breast cancer samples was used to identify an intronic start variant transcript of Acyl-CoA oxidase 2, ACOX2 (ACOX2-i9). Difference in expression between Estrogen Receptor (ER) positive and ER negative patients was assessed by the Wilcoxon rank sum test, and the findings validated in The Cancer Genome Atlas (TCGA) breast cancer dataset (BRCA). ACOX2-i9 expression was also assessed in cell lines using both quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot analysis. Knock down by short hairpin RNA (shRNA) and colony formation assays were used to determine whether ACOX2-i9 expression would influence cellular fitness. The effect of ACOX2-i9 expression on patient survival was assessed by the Kaplan-Meier survival function, and association to clinical parameters was analyzed using a Fisher exact test. The expression and translation of ACOX2-i9 into a 25 kDa protein was demonstrated in HepG2 cells as well as in several breast cancer cell lines. shRNA knock down of the ACOX2-i9 variant resulted in decreased cell viability of T47D and MDA-MB 436 cells. Moreover, expression of ACOX2-i9 was shown to be estrogen regulated, being induced by propyl pyrazoletriol and inhibited by tamoxifen and fulvestrant in ER+ T47D and Mcf-7 cells, but not in the ER- MDA-MB 436 cell line. This variant transcript showed expression predominantly in ER-positive breast tumors as assessed in our initial set of 53 breast cancers and further validated in 87 tumor/normal pairs from the TCGA breast cancer dataset, and expression was associated with better outcome in ER positive patients. ACOX2-i9 is specifically enriched in ER+ breast
Petruolo, Oriana A; Pilewskie, Melissa; Patil, Sujata; Barrio, Andrea V; Stempel, Michelle; Wen, Hannah Y; Morrow, Monica
2017-09-01
The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR). The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC. Patients with stage I-III ER+, HER2- breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP). From 2007 to 2016, 402 ER+/HER2- cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II-III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p benefit from NAC are those with PR- and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach.
Vejen til helvede er brolagt med frelste intentioner
DEFF Research Database (Denmark)
Vestenskov, David
2013-01-01
Det åbenlyse spørgsmål omkring, hvorfor vi er i Afghanistan (eller hvorfor vi bliver?) er bestemt et relevant spørgsmål, men at klæbe et prædikat på om krigens manglende moralske troværdighed kræver mere end blot sure opstød. Er vi netop ikke blevet i Afghanistan grundet moralske principper?...
International Nuclear Information System (INIS)
Kitamura, Kei; Shirato, Hiroki; Seppenwoolde, Yvette; Onimaru, Rikiya; Oda, Makoto; Fujita, Katsuhisa; Shimizu, Shinichi; Shinohara, Nobuo; Harabayashi, Toru; Miyasaka, Kazuo
2002-01-01
Purpose: To quantify three-dimensional (3D) movement of the prostate gland with the patient in the supine and prone positions and to analyze the movement frequency for each treatment position. Methods and Materials: The real-time tumor-tracking radiotherapy (RTRT) system was developed to identify the 3D position of a 2-mm gold marker implanted in the prostate 30 times/s using two sets of fluoroscopic images. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within the region of the planned coordinates relative to the isocenter. Ten patients with prostate cancer treated with RTRT were the subjects of this study. The coordinates of the gold marker were recorded every 0.033 s during RTRT in the supine treatment position for 2 min. The patient was then moved to the prone position, and the marker was tracked for 2 min to acquire data regarding movement in this position. Measurements were taken 5 times for each patient (once a week); a total of 50 sets for the 10 patients was analyzed. The raw data from the RTRT system were filtered to reduce system noise, and the amplitude of movement was then calculated. The discrete Fourier transform of the unfiltered data was performed for the frequency analysis of prostate movement. Results: No apparent difference in movement was found among individuals. The amplitude of 3D movement was 0.1-2.7 mm in the supine and 0.4-24 mm in the prone positions. The amplitude in the supine position was statistically smaller in all directions than that in the prone position (p < 0.0001). The amplitude in the craniocaudal and AP directions was larger than in the left-right direction in the prone position (p < 0.0001). No characteristic movement frequency was detected in the supine position. The respiratory frequency was detected for all patients regarding movement in the craniocaudal and AP directions in the prone position. The results of the frequency analysis suggest that prostate movement is
International Nuclear Information System (INIS)
Delgado, L; Richardet, E; Pallotta, G; Fresco, R; Aguiar, S; Camejo, N; Gonzalez, V; Ferrero, L; Heinzen, S; Martinez, A. and others
2010-01-01
Introduction: the study of biological subtype of breast cancer (B C) given by the expression tumor estrogen receptors (E R), progesterone (P R) and growth factor receptor and evolutionary. Objective: To know the profile of tumor expression of HER2, ER and P R and their relation with to characteristics clinico pathological characteristics in Uruguayan and Argentine patients with breast cancer. Material and Methods: The medical records of patients who underwent analyzed C M I-III invasive stages between 03/2006 and 03/2008 and assisted in Oncology Services where the authors are performing, which had selected determination ER, P R and HER2 by immunohistochemistry. The expression profile of these was markers compared with age at diagnosis, type and histological grade (GH) and pathological stage (TNM). Results: 291 patients (197 Uruguayan and 94 Argentine) were included whose characteristics were: mean age: 56 years, ductal carcinoma: 85%, GH 1-2: 55% stage I-II: 70%, metastasis axillary: 51%, ER / P R +: 78% HER2 + 12%. Three subtypes were defined: HER2 ER / P R + (71%), HER2 + (12% Uruguayan patients: 10%, Argentine patients: 17%) and negative Triple (TN) (17%). The joint analysis of the patients in both countries showed that subtypes TN and HER2 is associated with greater histological grade (p <0.05). Furthermore, in the group of patients Uruguayan, TN subtype was associated with younger age at diagnosis (p <0.05) subtype HER2, ER / PR +. Conclusions: The percentage of patients with CM Uruguayan invasive HER2 + subtype (10%) is smaller than that reported by other studies (17-28%) and that observed in our study Argentine group of patients. Consistent with previous studies, TN subtypes and HER2 + correlated with more undifferentiated tumors and in the group of Uruguayan patients TN appeared in younger patients
Excitation of spin-1 states in 166168170Er using bremsstrahlung
International Nuclear Information System (INIS)
Metzger, F.R.
1976-01-01
Some 40 states in 166 , 168 , 170 Er, most of them previously unknown, have been excited using bremsstrahlung with < or =4.2 MeV endpoint energy. For all but three of these levels, the angular distribution of the resonantly scattered radiation favors the assignment of spin 1. For some of the strongly excited levels, linear polarization measurements have been performed. They indicate that these levels have positive parity. The branching ratios further characterize them as K=1 excitations
Feng, Xiaolan; Li, Haocheng; Kornaga, Elizabeth N; Dean, Michelle; Lees-Miller, Susan P; Riabowol, Karl; Magliocco, Anthony M; Morris, Don; Watson, Peter H; Enwere, Emeka K; Bebb, Gwyn; Paterson, Alexander
2016-12-27
This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02). These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.
Vascular measurements correlate with estrogen receptor status
International Nuclear Information System (INIS)
Lloyd, Mark C; Alfarouk, Khalid O; Verduzco, Daniel; Bui, Marilyn M; Gillies, Robert J; Ibrahim, Muntaser E; Brown, Joel S; Gatenby, Robert A
2014-01-01
Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, although ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. Here we view cellular evolution within tumors as a classical Darwinian system in which variations in molecular properties represent predictable adaptations to spatially heterogeneous environmental selection forces. We hypothesize that ER expression is a successful adaptive strategy only if estrogen is present in the microenvironment. Since the dominant source of estrogen is blood flow, we hypothesized that, in general, intratumoral regions with higher blood flow would contain larger numbers of ER + cells when compared to areas of low blood flow and in turn necrosis. This study used digital pathology whole slide image acquisition and advanced image analysis algorithms. We examined the spatial distribution of ER + and ER- cells, vascular density, vessel area, and tissue necrosis within histological sections of 24 breast cancer specimens. These data were correlated with the patients ER status and molecular pathology report findings. ANOVA analyses revealed a strong correlation between vascular area and ER expression and between high fractional necrosis and absent ER expression (R 2 = 39%; p < 0.003 and R 2 = 46%; p < 0.001), respectively). ER expression did not correlate with tumor grade or size. We conclude that ER expression can be understood as a Darwinian process and linked to variations in estrogen delivery by temporal and spatial heterogeneity in blood flow. This correlation suggests strategies to promote intratumoral blood flow or a cyclic introduction of estrogen in the treatment schedule could be explored as a counter-intuitive approach to increase the efficacy of anti
Child abuse inventory at emergency rooms: CHAIN-ER rationale and design
Directory of Open Access Journals (Sweden)
Nieuwenhuis Edward ES
2011-10-01
Full Text Available Abstract Background Child abuse and neglect is an important international health problem with unacceptable levels of morbidity and mortality. Although maltreatment as a cause of injury is estimated to be only 1% or less of the injured children attending the emergency room, the consequences of both missed child abuse cases and wrong suspicions are substantial. Therefore, the accuracy of ongoing detection at emergency rooms by health care professionals is highly important. Internationally, several diagnostic instruments or strategies for child abuse detection are used at emergency rooms, but their diagnostic value is still unknown. The aim of the study 'Child Abuse Inventory at Emergency Rooms' (CHAIN-ER is to assess if active structured inquiry by emergency room staff can accurately detect physical maltreatment in children presenting at emergency rooms with physical injury. Methods/design CHAIN-ER is a multi-centre, cross-sectional study with 6 months diagnostic follow-up. Five thousand children aged 0-7 presenting with injury at an emergency room will be included. The index test - the SPUTOVAMO-R questionnaire- is to be tested for its diagnostic value against the decision of an expert panel. All SPUTOVAMO-R positives and a 15% random sample of the SPUTOVAMO-R negatives will undergo the same systematic diagnostic work up, which consists of an adequate history being taken by a pediatrician, inquiry with other health care providers by structured questionnaires in order to obtain child abuse predictors, and by additional follow-up information. Eventually, an expert panel (reference test determines the true presence or absence of child abuse. Discussion CHAIN-ER will determine both positive and negative predictive value of a child abuse detection instrument used in the emergency room. We mention a benefit of the use of an expert panel and of the use of complete data. Conducting a diagnostic accuracy study on a child abuse detection instrument is also
Mechanisms of ER Stress-Mediated Mitochondrial Membrane Permeabilization.
LENUS (Irish Health Repository)
Gupta, Sanjeev
2010-01-01
During apoptosis, the process of mitochondrial outer membrane permeabilization (MOMP) represents a point-of-no-return as it commits the cell to death. Here we have assessed the role of caspases, Bcl-2 family members and the mitochondrial permeability transition pore on ER stress-induced MOMP and subsequent cell death. Induction of ER stress leads to upregulation of several genes such as Grp78, Edem1, Erp72, Atf4, Wars, Herp, p58ipk, and ERdj4 and leads to caspase activation, release of mitochondrial intermembrane proteins and dissipation of mitochondrial transmembrane potential (DeltaPsim). Mouse embryonic fibroblasts (MEFs) from caspase-9, -2 and, -3 knock-out mice were resistant to ER stress-induced apoptosis which correlated with decreased processing of pro-caspase-3 and -9. Furthermore, pretreatment of cells with caspase inhibitors (Boc-D.fmk and DEVD.fmk) attenuated ER stress-induced loss of DeltaPsim. However, only deficiency of caspase-9 and -2 could prevent ER stress-mediated loss of DeltaPsim. Bcl-2 overexpression or pretreatment of cells with the cell permeable BH4 domain (BH4-Tat) or the mitochondrial permeability transition pore inhibitors, bongkrekic acid or cyclosporine A, attenuated the ER stress-induced loss of DeltaPsim. These data suggest a role for caspase-9 and -2, Bcl-2 family members and the mitochondrial permeability transition pore in loss of mitochondrial membrane potential during ER stress-induced apoptosis.
International Nuclear Information System (INIS)
Erridge, Sara C.; Seppenwoolde, Yvette; Muller, Sara H.; Herk, Marcel van; Jaeger, Katrien de; Belderbos, Jose S.A.; Boersma, Liesbeth J.; Lebesque, Joos V.
2003-01-01
Purpose: To investigate patient set-up, tumor movement and shrinkage during 3D conformal radiotherapy for non-small cell lung cancer. Materials and methods: In 97 patients, electronic portal images (EPIs) were acquired and corrected for set-up using an off-line correction protocol based on a shrinking action level. For 25 selected patients, the orthogonal EPIs (taken at random points in the breathing cycle) throughout the 6-7 week course of treatment were assessed to establish the tumor position in each image using both an overlay and a delineation technique. The range of movement in each direction was calculated. The position of the tumor in the digitally reconstructed radiograph (DRR) was compared to the average position of the lesion in the EPIs. In addition, tumor shrinkage was assessed. Results: The mean overall set-up errors after correction were 0, 0.6 and 0.2 mm in the x (left-right), y (cranial-caudal) and z (anterior-posterior) directions, respectively. After correction, the standard deviations (SDs) of systematic errors were 1.4, 1.5 and 1.3 mm and the SDs of random errors were 2.9, 3.1 and 2.0 mm in the x-, y- and z-directions, respectively. Without correction, 41% of patients had a set-up error of more than 5 mm vector length, but with the set-up correction protocol this percentage was reduced to 1%. The mean amplitude of tumor motion was 7.3 (SD 2.7), 12.5 (SD 7.3) and 9.4 mm (SD 5.2) in the x-, y- and z-directions, respectively. Tumor motion was greatest in the y-direction and in particular for lower lobe tumors. In 40% of the patients, the projected area of the tumor regressed by more than 20% during treatment in at least one projection. In 16 patients it was possible to define the position of the center of the tumor in the DRR. There was a mean difference of 6 mm vector length between the tumor position in the DRR and the average position in the portal images. Conclusions: The application of the correction protocol resulted in a significant
Tumor PIK3CA genotype and prognosis in early-stage breast cancer
DEFF Research Database (Denmark)
Zardavas, Dimitrios; Te Marvelde, Luc; Milne, Roger L.
2018-01-01
% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P, .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR...... points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors....
Directory of Open Access Journals (Sweden)
Lundberg Cathryn
2008-01-01
Full Text Available Abstract Background Gene expression measurements from breast cancer (BrCa tumors are established clinical predictive tools to identify tumor subtypes, identify patients showing poor/good prognosis, and identify patients likely to have disease recurrence. However, diverse breast cancer datasets in conjunction with diagnostic clinical arrays show little overlap in the sets of genes identified. One approach to identify a set of consistently dysregulated candidate genes in these tumors is to employ meta-analysis of multiple independent microarray datasets. This allows one to compare expression data from a diverse collection of breast tumor array datasets generated on either cDNA or oligonucleotide arrays. Results We gathered expression data from 9 published microarray studies examining estrogen receptor positive (ER+ and estrogen receptor negative (ER- BrCa tumor cases from the Oncomine database. We performed a meta-analysis and identified genes that were universally up or down regulated with respect to ER+ versus ER- tumor status. We surveyed both the proximal promoter and 3' untranslated regions (3'UTR of our top-ranking genes in each expression group to test whether common sequence elements may contribute to the observed expression patterns. Utilizing a combination of known transcription factor binding sites (TFBS, evolutionarily conserved mammalian promoter and 3'UTR motifs, and microRNA (miRNA seed sequences, we identified numerous motifs that were disproportionately represented between the two gene classes suggesting a common regulatory network for the observed gene expression patterns. Conclusion Some of the genes we identified distinguish key transcripts previously seen in array studies, while others are newly defined. Many of the genes identified as overexpressed in ER- tumors were previously identified as expression markers for neoplastic transformation in multiple human cancers. Moreover, our motif analysis identified a collection of
International Nuclear Information System (INIS)
Awde, Ali R.; Boisgard, Raphael; Theze, Benoit; Dubois, Albertine; Zheng, Jinzi; Winkeler, Alexandra; Dolle, Frederic; Jacobs, Andreas H.; Tavitian, Bertrand
2013-01-01
On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2- 18 F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ( 18 F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkyl-phosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using 18 F-DPA-714 PET. Methods: In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with 18 F-DPA-714 for the time of treatment. Results: A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in 18 F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive micro-glia/macrophages and glial fibrillary acidic protein-positive astrocytes. Conclusion: Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using 18 F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas. (authors)
International Nuclear Information System (INIS)
Minacheva, L.Kh.; Ivanova, I.S.; Kireeva, I.K.; Sakharova, V.G.; Tsivadze, A.Yu.; Sergienko, V.S.; Baulin, V.E.
2000-01-01
Synthesis of podandocoronand on the basis of diazo-18-crown-6 (DA18K6) 1,4,10,13-tetraoxi-7,16-diazo (diphenylphosphynylmethyl)cyclooctadecane (L) and erbium nitrate complex with L of the [ErL(H 2 O)(NO 3 ) 3 ] (I) composition is described. The IR-spectra of the free ligand L and complex I are studied and interpreted.The crystals are monoclinic: a = 10.432(2), b = 19.909(4), c = 21.361(4), β = 100.39(3) Deg, V = 4364(2) A 3 , sp. gr. P2 1 /n, Z = 4, ρ = 1.617 g/cm 3 . The structure I is formed of discrete molecular complexes. The Er atom coordination number is equal to 9. Three nitrate groups are bidentate-cyclic coordinated; two of them are in trans-position to each other; the H 2 O molecule is trans-position to the third NO 3 -group. The ligand L is coordinated by metal through two oxygen phosphoryl atoms. Thus, the Er atom coordination polyhedron may be described as octahedron, if each NO 3 -group occupies one coordination position. The Er-O(L) and Er-O(NO 3 ) overage distances are equal to 2.25 and 2.43 A correspondingly. Er-O(H 2 O) - 2.29 A. The H 2 O coordinated molecule forms intermolecular hydrogen atom and two oxygen atoms of the DA18K6 macrocycle [ru
Formålet er trivsel – om brain breaks i undervisningen
DEFF Research Database (Denmark)
Christiansen, Lars Breum Skov; Holt, Anne-Didde
2017-01-01
Brain breaks, defineret som korte aktive pauser i klasseundervisningen, er en af indsatserne i Trivsel og Bevægelse i Skolen. Med brug af forskellige typer af brain breaks blev der arbejdet med at skabe øget motivation og energi, styrke fællesskabet, og give kropsligt velvære. Mange lærere...... tilkendegiver positive erfaringer med brain breaks og en oplevelse af, at brain breaks kan fremme trivslen. Andre lærere oplever, at mangel på tid og øget uro i forbindelse med gennemførelse af brain breaks er væsentlige barrierer i bestræbelserne på at indfri de faglige mål i undervisningen. Succesfuld...... integration af bevægelse i undervisningen forudsætter en klar didaktisk rammesætning såvel som en tilvænningsperiode for både lærere og elever....
The new ternary pnictides Er12Ni30P21 and Er13Ni25As19: Crystal structures and magnetic properties
International Nuclear Information System (INIS)
Oryshchyn, Stepan; Babizhetskyy, Volodymyr; Zhak, Olga; Zelinska, Mariya; Pivan, Jean-Yves; Duppel, Viola; Simon, Arndt; Kienle, Lorenz
2010-01-01
The new ternary pnictides Er 12 Ni 30 P 21 and Er 13 Ni 25 As 19 have been synthesized from the elements. They crystallize with hexagonal structures determined from single-crystal X-ray data for Er 12 Ni 30 P 21 (space group P6 3 /m, a=1.63900(3) nm, c=0.37573(1) nm, Z=1, R F =0.062 for 1574 F-values and 74 variable parameters), and for Er 13 Ni 25 As 19 (Tm 13 Ni 25 As 19 -type structure, space group P6-bar , a=1.6208(1) nm, c=0.38847(2) nm, Z=1, R F =0.026 for 1549 F-values and 116 variable parameters). These compounds belong to a large family of hexagonal structures with a metal-metalloid ratio of 2:1. HRTEM investigations were conducted to probe for local ordering of the disordered structure at the nanoscale. The magnetic properties of the phosphide Er 12 Ni 30 P 21 have been studied in the temperature of range 2 eff =9.59 μ B corresponds to the theoretical value of Er 3+ . - Graphical abstract: The new ternary pnictides Er 12 Ni 30 P 21 and Er 13 Ni 25 As 19 have been synthesized from the elements. They crystallize with hexagonal structures determined from single-crystal X-ray data. The compounds belong to a large family of structures with a metal-metalloid ratio of 2:1. HRTEM investigations were conducted to probe for local ordering of the disordered structure at the nanoscale. Display Omitted
Structural and spectroscopic studies on Er3+ doped boro-tellurite glasses
Selvaraju, K.; Marimuthu, K.
2012-04-01
Er3+ doped boro-tellurite glasses with the chemical composition (69-x)B2O3-xTeO2-15MgO-15K2O-1Er2O3 (where x=0, 10, 20, 30 and 40 wt%) have been prepared and their structural and spectroscopic behavior were studied and reported. The varying tellurium dioxide content in the host matrix that results, changes in structural and spectroscopic behavior around Er3+ ions are explored through XRD, FTIR, UV-VIS-NIR and luminescence measurements. The XRD pattern confirms the amorphous nature of the prepared glasses and the FTIR spectra explore the fundamental groups and the local structural units in the prepared boro-tellurite glasses. The bonding parameters (βbar and δ) have been calculated from the observed band positions of the absorption spectra to claim the ionic/covalent nature of the prepared glasses. The Judd-Ofelt (JO) intensity parameters Ωλ (λ=2, 4 and 6) were determined through experimental and calculated oscillator strengths obtained from the absorption spectra and their results are studied and compared with reported literature. The variation in the JO parameters Ωλ (λ=2, 4 and 6) with the change in chemical composition have been discussed in detail. The JO parameters have also been used to derive the important radiative properties like transition probability (A), branching ratio (βR) and peak stimulated emission cross-section (σPE) for the excited state transitions 2H9/2→4I15/2 and 2H11/2 and 4S3/2→4I15/2 of the Er3+ ions and the results were studied and reported. Using Davis and Mott theory, optical band gap energy (Eopt) values for the direct and indirect allowed transitions have been calculated and discussed along with the Urbach energy values for the prepared Er3+ doped boro-tellurite glasses in the present study. The optical properties of the prepared glasses with the change in tellurium dioxide have been studied and compared with similar results.
International Nuclear Information System (INIS)
Ma, Junliang; Liu, Lunxu; Che, Guowei; Yu, Nanbin; Dai, Fuqiang; You, Zongbing
2010-01-01
were positively associated with patient's survival time in a univariate analysis (P < 0.01 or 0.001). In a multivariate Cox proportional hazards analysis, the M1 macrophage density in the tumor islets was an independent predictor of patient's survival time. The M1 macrophage density in the tumor islets is an independent predictor of survival time in NSCLC patients
DEFF Research Database (Denmark)
Wind, P.
resultaterne af orkidéovervågningen (Wind 2001). Hertil kommer præsentationen af projektet og dets resultater efter forløbet af de første tre år (Løjtnant 1991a) og en bearbejdning af projektets resultater for årene 1987-1995 (Wind 1997). I nærværende rapport undersøges skov-hullæbe for en eventuel sammenhæng...... mellem skudanlæggelsen udtrykt ved antallet af blomstrende og vegetative skud i et givet år og nedbørsmængder i august og september året før. Det er en udbredt antagelse at der er en sammenhæng mellem skudanlæggelse og mængden af nedbør det foregående år. Undersøgelser af skov-hullæbe populationer i...... truet og sårbar samt de to arter der er omfattet af Habitatdirektivets bilag 2. I 2000 kan det i forhold til 1999 konstateres at der i 15 bestande er optalt et øget antal skud. I 11 bestande er der noteret en nedgang i antallet af skud sammenlignet med optællingerne i 1999. Af disse er der 2 be...
DEFF Research Database (Denmark)
Bach-Nielsen, Carsten
2015-01-01
Om et kors, der er rejst uden for den danske kirke i Bruxelles; formodentlig en afledning af det såkaldte Brabanterkors.......Om et kors, der er rejst uden for den danske kirke i Bruxelles; formodentlig en afledning af det såkaldte Brabanterkors....
Design Program in Graphic User Interface Environment for Automobile ER Devices
Lim, S. C.; Park, J. S.; Sohn, J. W.; Choi, S. B.
This work presents a design and analysis program for vehicle devices utilizing an electrorheological (ER) fluid. The program is operated in graphic user interface (GUI) environment and the initial window is consisted of four subprogram modules which are related to ER shock absorber, ER seat damper, ER engine mount, and ER anti-lock brake system (ABS), respectively. In order to execute each module, both material properties and design parameters are to be chosen by the user. Then, the output display window shows the field-dependent performance characteristics to be considered as design criteria. In addition, control performances of the vehicle system equipped with ER devices are displayed in time and frequency domain. In order to demonstrate the effectiveness of the proposed program, ER shock absorber and ER ABS are designed and manufactured and their performance characteristics are evaluated.
International Nuclear Information System (INIS)
Parr, A.F.; Beihn, R.M.; Franz, R.M.; Szpunar, G.J.; Jay, M.
1987-01-01
External gamma scintigraphy was used to monitor the gastrointestinal (GI) transit of radiolabeled sustained-release tablets containing 800 mg ibuprofen in eight fasted healthy volunteers. Ibuprofen serum concentrations were determined from blood samples drawn sequentially over a 24-hr period. Serum concentrations and related parameters were correlated to the position of the dosage form in the GI tract from the scintiphotos. The sustained-release tablets were radiolabeled intact utilizing a neutron activation procedure, by incorporating 0.18% of 170 Er2O3 (enriched to greater than 96% 170 Er) into the bulk formulation. After manufacture of the final dosage forms, the tablets were irradiated in a neutron flux (4.4 x 10(13) n/cm2.sec) for 2 min, converting the stable 170 Er to radioactive 171 Er (t1/2 = 7.5 hr). Each tablet contained 50 microCi of 171 Er at the time of administration. The scintigraphy studies suggested that the greatest proportion of ibuprofen was absorbed from this dosage form while the tablet was in the large bowel. The dosage forms eroded slowly in the small bowel and appeared to lose their integrity in the large bowel. In vitro studies showed only minimal effects of the neutron irradiation procedure on the dosage form performance
Structural and electronic properties of Er-monopnictides under high pressure
International Nuclear Information System (INIS)
Pandit, Premlata; Srivastava, Vipul; Rajagopalan, M.; Sanyal, Sankar P.
2010-01-01
We present the results of theoretical calculations on the structural, magnetic and electronic properties of Er-monopnictides using self-consistent first principles tight-binding linear-muffin-tin-orbital (TB-LMTO) method within the atomic-sphere approximation (ASA). Both spin-polarized and non-spin-polarized calculations are performed to check the magnetic stability of these compounds. We find that ErN, ErP and ErAs are metallic in ferromagnetic (FM) phase in both the spin channels and stable in NaCl-type (B 1 ) structure at ambient pressure. We predict NaCl-type (B 1 ) to CsCl-type (B 2 ) structural phase transition in ErN, ErP and ErAs at pressures of 146.1, 60.2 and 53.2 GPa, respectively and remain metallic ferromagnetic at high pressure. We calculate equilibrium lattice constants (a), bulk modulus (B), magnetic moments (μ B ) and electronic properties of these compounds in B 1 and B 2 phases and compare with available experimental and theoretical results.
International Nuclear Information System (INIS)
Wang, Ying; Xie, Xiumin; Qi, Jianqi; Wang, Shanshan; Wei, Nian; Lu, Zhongwen; Chen, Xingtao; Lu, Tiecheng
2016-01-01
We report on the sintering promoting and fluorescent activator roles of Er 3+ in AlON:Er 3+ transparent ceramics prepared by pressureless sintering with Er 2 O 3 and AlON powder. There shows that the transparency of samples varied with the content of Er 2 O 3 additive. The AlON:Er 3+ ceramics showed upconversion luminescence peaking at 546 nm, 662 nm and 840 nm under the 980 nm excitation due to transition of 4 S 3/2 / 2 H 11/2 → 4 I 15/2 , 4 F 9/2 → 4 I 15/2 and 4 S 3/2 / 2 H 11/2 → 4 I 13/2 of Er 3+ ions, respectively. The infrared spectra exhibited strong emission at 1534 nm corresponds to 4 I 13/2 → 4 I 15/2 transition. The mechanism of the IR and visible emission bands in AlON:Er 3+ ceramics are discussed, which suggest it should be attractive for lighting and display devices applications.
International Nuclear Information System (INIS)
Miquel-Cases, Anna; Steuten, Lotte M. G.; Rigter, Lisanne S.; Harten, Wim H. van
2016-01-01
Response-guided neoadjuvant chemotherapy (RG-NACT) with magnetic resonance imaging (MRI) is effective in treating oestrogen receptor positive/human epidermal growth factor receptor-2 negative (ER-positive/HER2-negative) breast cancer. We estimated the expected cost-effectiveness and resources required for its implementation compared to conventional-NACT. A Markov model compared costs, quality-adjusted-life-years (QALYs) and costs/QALY of RG-NACT vs. conventional-NACT, from a hospital perspective over a 5-year time horizon. Health services required for and health outcomes of implementation were estimated via resource modelling analysis, considering a current (4 %) and a full (100 %) implementation scenario. RG-NACT was expected to be more effective and less costly than conventional NACT in both implementation scenarios, with 94 % (current) and 95 % (full) certainty, at a willingness to pay threshold of €20.000/QALY. Fully implementing RG-NACT in the Dutch target population of 6306 patients requires additional 5335 MRI examinations and an (absolute) increase in the number of MRI technologists, by 3.6 fte (full-time equivalent), and of breast radiologists, by 0.4 fte. On the other hand, it prevents 9 additional relapses, 143 cancer deaths, 23 congestive heart failure events and 2 myelodysplastic syndrome/acute myeloid leukaemia events. Considering cost-effectiveness, RG-NACT is expected to dominate conventional-NACT. While personnel capacity is likely to be sufficient for a full implementation scenario, MRI utilization needs to be intensified
DEFF Research Database (Denmark)
Tække, Jesper
2014-01-01
Den store vision for world wide web var, at alle kunne få ubegrænset adgang til alverdens information. www var mangfoldigt og anarkistisk. I dag er der rigtig mange, der kun bruger nettet til at være på Facebook. Hvad bruger Facebook det til? Og hvad gør det ved vores udsyn?......Den store vision for world wide web var, at alle kunne få ubegrænset adgang til alverdens information. www var mangfoldigt og anarkistisk. I dag er der rigtig mange, der kun bruger nettet til at være på Facebook. Hvad bruger Facebook det til? Og hvad gør det ved vores udsyn?...
Proliferation of human mammary cancer cells exposed to 27-hydroxycholesterol.
Cruz, Pamela; Torres, Cristian; Ramírez, María Eugenia; Epuñán, María José; Valladares, Luis Emilio; Sierralta, Walter Daniel
2010-05-01
The aim of the present study was to identify the possible mechanisms by which certain estradiol receptor (ER)-positive mammary tumor cells remain resistant to treatment with anti-estrogens or inhibitors of local estradiol (E(2)) production. To this end, we compared the proliferative effects on mammary cancer cells of the novel selective ER modulator 27-hydroxycholesterol (27OHC) to those of E(2), and evaluated their inhibition by ICI 182,780 (ICI). Analysis of the effects on the cell cycle of 27OHC and E(2) in the absence or presence of ICI was conducted. In ER-positive mammary tumor cells, we detected the blocking of 27OHC proliferation-stimulatory activity by simvastatin, as well as the inhibition of E(2)-stimulated proliferation by an α-fetoprotein-derived cyclic nonapeptide. The effects reported herein may be extrapolated to infiltrating mammary cancer, where the activity of local macrophages may stimulate tumor growth. We suggest that increased breast cancer growth in obese patients may be related to increased 27OHC circulatory levels.
Trump er godt nyt for verdensfreden
DEFF Research Database (Denmark)
Jakobsen, Peter Viggo
2017-01-01
Trumps uberegnelighed øger ikke risikoen for krig. Den mindsker den ved at få de allierede til at gøre mere og modstanderne til at forhandle. Det er godt for verdensfreden......Trumps uberegnelighed øger ikke risikoen for krig. Den mindsker den ved at få de allierede til at gøre mere og modstanderne til at forhandle. Det er godt for verdensfreden...
Optical energy gaps and photoluminescence peaks of BaGa2S4:Er3+ and BaGa2Se4:Er3+ single crystals
International Nuclear Information System (INIS)
Choe, Sung-Hyu; Jin, Moon-Seog; Kim, Wha-Tek
2005-01-01
BaGa 2 S 4 :Er 3+ and BaGa 2 Se 4 :Er 3+ single crystals were grown by using the chemical transport reaction method. The optical energy gaps of the BaGa 2 S 4 :Er 3+ and the BaGa 2 Se 4 :Er 3+ single crystals were found to be 4.045 eV and 3.073 eV, respectively, at 11 K. The temperature dependence of the optical energy gap was well fitted by the Varshni equation. Sharp emission peaks were observed in the photoluminescence spectra of the single crystals and assigned to radiation recombination between split Stark levels of the Er 3+ ion.
Er{sup 3+} Doping conditions of planar porous silicon waveguides
Energy Technology Data Exchange (ETDEWEB)
Najar, A. [Laboratoire d' Optronique UMR 6082-FOTON, Universite de Rennes 1, 6 rue de Kerampont, B. P. 80518, 22305 Lannion Cedex (France); Laboratoire de Spectroscopie Raman, Faculte des Sciences de Tunis, 2092 El Manar, Tunis (Tunisia); Lorrain, N., E-mail: nathalie.lorrain@univ-rennes1.fr [Laboratoire d' Optronique UMR 6082-FOTON, Universite de Rennes 1, 6 rue de Kerampont, B. P. 80518, 22305 Lannion Cedex (France); Ajlani, H. [Laboratoire de Spectroscopie Raman, Faculte des Sciences de Tunis, 2092 El Manar, Tunis (Tunisia); Charrier, J. [Laboratoire d' Optronique UMR 6082-FOTON, Universite de Rennes 1, 6 rue de Kerampont, B. P. 80518, 22305 Lannion Cedex (France); Oueslati, M. [Laboratoire de Spectroscopie Raman, Faculte des Sciences de Tunis, 2092 El Manar, Tunis (Tunisia); Haji, L. [Laboratoire d' Optronique UMR 6082-FOTON, Universite de Rennes 1, 6 rue de Kerampont, B. P. 80518, 22305 Lannion Cedex (France)
2009-11-15
EDX and infrared photoluminescence (IR PL) analyses performed on erbium-doped porous silicon waveguides (PSWG) were studied using different doping conditions. Both parameters of the cathodisation electrochemical method used for Er incorporation and parameters of thermal treatments required for Er optical activation were taken into consideration. Firstly, by varying the current density and the time of cathodisation, we have shown that a current density of 0.1 mA/cm{sup 2} for 10 min allows homogeneous Er doping to be achieved throughout the depth of the guiding layer. Then, the PL intensity at 1.53 {mu}m was studied as a function of the oxidation time at 900 deg. C and Er diffusion temperature for 60 min. Increasing the oxidation time up to 1 h allows PL to be enhanced due to active Si-O-Er complex formation whereas an oxidation time of 2 h induces a decrease in PL because of Er segregation. Moreover, an increase in the diffusion temperature induces an optimal distribution of optically active Si-Er-O complexes inside the crystallites. When the temperature is too high, a PSWG densification and Er segregation occurs inducing a decrease in PL due to energy transfer phenomena.
Directory of Open Access Journals (Sweden)
Girdhari Rijal
2017-01-01
Full Text Available Preparation of three-dimensional (3D porous scaffolds from synthetic polymers is a challenge to most laboratories conducting biomedical research. Here, we present a handy and cost-effective method to fabricate polymeric hydrogel and porous scaffolds using poly(lactic-co-glycolic acid (PLGA or polycaprolactone (PCL. Breast cancer cells grown on 3D polymeric scaffolds exhibited distinct survival, morphology, and proliferation compared to those on 2D polymeric surfaces. Mammary epithelial cells cultured on PLGA- or PCL-coated slides expressed extracellular matrix (ECM proteins and their receptors. Estrogen receptor- (ER- positive T47D breast cancer cells are less sensitive to 4-hydroxytamoxifen (4-HT treatment when cultured on the 3D porous scaffolds than in 2D cultures. Finally, cancer cell-laden polymeric scaffolds support consistent tumor formation in animals and biomarker expression as seen in human native tumors. Our data suggest that the porous synthetic polymer scaffolds satisfy the basic requirements for 3D tissue cultures both in vitro and in vivo. The scaffolding technology has appealing potentials to be applied in anticancer drug screening for a better control of the progression of human cancers.
Forbruget af træer og buske i Danmark
DEFF Research Database (Denmark)
Jensen, Jan Svejgaard; Laursen, Allan Bach; Kjær, Erik Dahl
Træer og buske er vigtige elementer i byen og landskabet, og i Danmark bruges der mellem 60 og 80 millioner vedplanter hvert år. Forbruget har været konstant stigende og der er sket store forskydninger i forbrugsmønstret i retning af større fokus på mangfoldighed og autencitet. Undersøgelsen...... klarlægger forbrugsmønstret for træer og buske og undersøger, hvad brugerne lægger vægt på i deres valg af planter....
Preparation of Erbium-169 (169Er) Using Natural Erbium Target
International Nuclear Information System (INIS)
Azmairit Aziz; Nana Suherman
2009-01-01
The therapeutic radiopharmaceuticals which is labelled by β-particle emission are now increasingly used in nuclear medicine. Erbium-169 ('1 69 Er) is one of radioisotopes that can be used for radiation synovectomy (radio synovectomy) in the treatment of inflammatory joint diseases (arthritis) due to its β- particle emission (T 1/2 =9.4 days, E β maximum =0.34 MeV). The preliminary study on preparation of 169 Er by using natural erbium oxide (Er 2 O 3 ) target irradiated at TRIGA 2000 Bandung reactor has been carried out. The irradiated target was dissolved in hydrochloric acid solution and gentle warming. The optimum condition of 169 Er preparation was obtained by dissolution of 169 Er 2 O 3 by using 1N HCl solution. The radiochemical purity of 169 ErCl 3 was determined by paper chromatography, thin layer chromatography and paper electrophoresis techniques. The solution of 169 ErCl 3 formed was obtained with the pH of 1.5 – 2, clear, with the specific activity of 0.48 – 0.71 MBq/mg Er. The solution has the radiochemical purity of 98.32 ± 1.28% and the radionuclide purity of 99.98%. Study on the stability of 169 ErCl 3 solution showed that the solution was still stable for 4 days at room temperature with the radiochemical purity more than 95%. (author)
Gingival melanin depigmentation by Er:YAG laser: A literature review.
Pavlic, Verica; Brkic, Zlata; Marin, Sasa; Cicmil, Smiljka; Gojkov-Vukelic, Mirjana; Aoki, Akira
2018-04-01
Laser ablation is recently suggested as a most effective and reliable technique for depigmentation of melanin hyperpigmented gingiva. To date, different lasers have been used for gingival depigmentation (CO 2 , diode, Nd:YAG, Er:YAG and Er,Cr:YSGG lasers). The use of Er:YAG laser for depigmentation of melanin hyperpigmented gingiva has gained increasing importance in recent years. The purpose of this study was to report removal of gingival melanin pigmentation using an Er:YAG laser in a literature review. The main outcomes, such as improvement of signs (clinical parameters of bleeding, erythema, swelling and wound healing), symptoms (pain) and melanin recurrence/repigmentation were measured. The literature demonstrated that depigmentation of gingival melanin pigmentation can be performed safely and effectively by Er:YAG laser resulting in healing and an esthetically significant improvement of gingival discoloration. Thus, Er:YAG laser seems to be safe and useful in melanin depigmentation procedure. However, the main issue in giving the final conclusion of the optimal Er:YAG laser use in melanin depigmentation is that, to date, studies are offering completely discrepant Er:YAG laser procedure protocols (complex settings of laser parameters), and different criteria for the assessment of depigmentation and repigmentation (recurrence), thus hampering the comparison of the results. Therefore, further studies are necessary to give an optimal recommendation on the use of Er:YAG laser in gingival melanin hyperpigmentation.
International Nuclear Information System (INIS)
Chang, Jenghwa; Mageras, Gig S.; Yorke, Ellen; De Arruda, Fernando; Sillanpaa, Jussi; Rosenzweig, Kenneth E.; Hertanto, Agung; Pham, Hai; Seppi, Edward; Pevsner, Alex; Ling, C. Clifton; Amols, Howard
2007-01-01
Purpose: To evaluate the use of megavoltage cone-beam computed tomography (MV CBCT) to measure interfractional variation in lung tumor position. Methods and Materials: Eight non-small-cell lung cancer patients participated in the study, 4 with respiratory gating and 4 without. All patients underwent MV CBCT scanning at weekly intervals. Contoured planning CT and MV CBCT images were spatially registered based on vertebral anatomy, and displacements of the tumor centroid determined. Setup error was assessed by comparing weekly portal orthogonal radiographs with digitally reconstructed radiographs generated from planning CT images. Hypothesis testing was performed to test the statistical significance of the volume difference, centroid displacement, and setup uncertainty. Results: The vertebral bodies and soft tissue portions of tumor within lung were visible on the MV CBCT scans. Statistically significant systematic volume decrease over the course of treatment was observed for 1 patient. The average centroid displacement between simulation CT and MV CBCT scans were 2.5 mm, -2.0 mm, and -1.5 mm with standard deviations of 2.7 mm, 2.7 mm, and 2.6 mm in the right-left, anterior-posterior and superior-inferior directions. The mean setup errors were smaller than the centroid shifts, while the standard deviations were comparable. In most cases, the gross tumor volume (GTV) defined on the MV CBCT was located on average at least 5 mm inside a 10 mm expansion of the GTV defined on the planning CT scan. Conclusions: The MV CBCT technique can be used to image lung tumors and may prove valuable for image-guided radiotherapy. Our conclusions must be verified in view of the small patient number
Hooshmand, Somayeh; Ghaderi, Abbas; Yusoff, Khatijah; Thilakavathy, Karuppiah; Rosli, Rozita; Mojtahedi, Zahra
2014-01-01
The consequence of Rho GDP dissociation inhibitor alpha (RhoGDIα) activity on migration and invasion of estrogen receptor positive (ER+) and negative (ER-) breast cancer cells has not been studied using the proteomic approach. Changes in expression of RhoGDIα and other proteins interacting directly or indirectly with RhoGDIα in MCF7 and MDA-MB-231, with different metastatic potentials is of particular interest. ER+ MCF7 and ER- MDA-MB-231 cell lines were subjected to two-dimensional electrophoresis (2-DE) and spots of interest were identified by matrix-assisted laser desorption/ionization time of- flight/time- of-flight (MALDI-TOF/TOF) mass spectrometry (MS) analysis after downregulation of RhoGDIα using short interfering RNA (siRNA) and upregulated using GFP-tagged ORF clone of RhoGDIα. The results showed a total of 35 proteins that were either up- or down-regulated in these cells. Here we identifed 9 and 15 proteins differentially expressed with silencing of RhoGDIα in MCF-7 and the MDA-MB-231 cells, respectively. In addition, 10 proteins were differentially expressed in the upregulation of RhoGDIα in MCF7, while only one protein was identified in the upregulation of RhoGDIα in MDA-MB-231. Based on the biological functions of these proteins, the results revealed that proteins involved in cell migration are more strongly altered with RhoGDI-α activity. Although several of these proteins have been previously indicated in tumorigenesis and invasiveness of breast cancer cells, some ohave not been previously reported to be involved in breast cancer migration. Hence, these proteins may serve as useful candidate biomarkers for tumorigenesis and invasiveness of breast cancer cells. Future studies are needed to determine the mechanisms by which these proteins regulate cell migration. The combination of RhoGDIα with other potential biomarkers may be a more promising approach in the inhibition of breast cancer cell migration.
Directory of Open Access Journals (Sweden)
Muralidhar K
2008-01-01
Full Text Available The purpose of this study was to evaluate the reproducibility and magnitude of shift of tumor position by using active breathing control and iView-GT for patients with lung cancer with moderate deep-inspiration breath-hold (mDIBH technique. Eight patients with 10 lung tumors were studied. CT scans were performed in the breath-holding phase. Moderate deep-inspiration breath-hold under spirometer-based monitoring system was used. Few important bony anatomic details were delineated by the radiation oncologist. To evaluate the interbreath-hold reproducibility of the tumor position, we compared the digital reconstruction radiographs (DRRs from planning system with the DRRs from the iView-GT in the machine room. We measured the shift in x, y, and z directions. The reproducibility was defined as the difference between the bony landmarks from the DRR of the planning system and those from the DRR of the iView-GT. The maximum shift of the tumor position was 3.2 mm, 3.0 mm, and 2.9 mm in the longitudinal, lateral, and vertical directions. In conclusion, the moderated deep-inspiration breath-hold method using a spirometer is feasible, with relatively good reproducibility of the tumor position for image-guided radiotherapy in lung cancers.
Nie, Yong-Zhan; He, Feng-Tian; Li, Zhi-Kui; Wu, Kai-Chun; Cao, Yun-Xin; Chen, Bao-Jun; Fan, Dai-Ming
2002-01-01
AIM: To study the feasibility of panning and screening phage-displaying recombinant single-chain variable fragment (ScFv) of anti-tumor monoclonal antibodies for fixed whole cells as the carriers of mAb-binding antigens. METHODS: The recombinant phage displaying libraries for anti-colorectal tumor mAb MC3Ab, MC5Ab and anti-gastric tumor mAb MGD1 was constructed. Panning and screening were carried out by means of modified fixation of colorectal and gastric tumor cells expressed the mAb-binding antigens. Concordance of binding specificity to tumor cells between phage clones and parent antibodies was analyzed. The phage of positive clones was identified with competitive ELISA, and infected by E. coli HB2151 to express soluble ScFv. RESULTS: The ratio of positive clones to MC3-ScF-MC5-ScFv and MGD1-ScFv were 60%, 24% and 30%. MC3-ScFv had Mr 32000 confirmed by Western blot. The specificity to antigen had no difference between 4 positive recombinant phage antibodies and MC3Ab. CONCLUSION: The modified process of fixing whole tumor cells is efficient, convenient and feasible to pan and screen the phage-displaying ScFv of anti-tumor monoclonal antibodies. PMID:12174367
Directory of Open Access Journals (Sweden)
Zhifu Sun
Full Text Available We used deep sequencing technology to profile the transcriptome, gene copy number, and CpG island methylation status simultaneously in eight commonly used breast cell lines to develop a model for how these genomic features are integrated in estrogen receptor positive (ER+ and negative breast cancer. Total mRNA sequence, gene copy number, and genomic CpG island methylation were carried out using the Illumina Genome Analyzer. Sequences were mapped to the human genome to obtain digitized gene expression data, DNA copy number in reference to the non-tumor cell line (MCF10A, and methylation status of 21,570 CpG islands to identify differentially expressed genes that were correlated with methylation or copy number changes. These were evaluated in a dataset from 129 primary breast tumors. Gene expression in cell lines was dominated by ER-associated genes. ER+ and ER- cell lines formed two distinct, stable clusters, and 1,873 genes were differentially expressed in the two groups. Part of chromosome 8 was deleted in all ER- cells and part of chromosome 17 amplified in all ER+ cells. These loci encoded 30 genes that were overexpressed in ER+ cells; 9 of these genes were overexpressed in ER+ tumors. We identified 149 differentially expressed genes that exhibited differential methylation of one or more CpG islands within 5 kb of the 5' end of the gene and for which mRNA abundance was inversely correlated with CpG island methylation status. In primary tumors we identified 84 genes that appear to be robust components of the methylation signature that we identified in ER+ cell lines. Our analyses reveal a global pattern of differential CpG island methylation that contributes to the transcriptome landscape of ER+ and ER- breast cancer cells and tumors. The role of gene amplification/deletion appears to more modest, although several potentially significant genes appear to be regulated by copy number aberrations.
International Nuclear Information System (INIS)
Linxweiler, Maximilian; Greiner, Markus; Schorr, Stefan; Schäuble, Nico; Jung, Martin; Linxweiler, Johannes; Langer, Frank; Schäfers, Hans-Joachim; Cavalié, Adolfo; Zimmermann, Richard
2013-01-01
Tumor cells benefit from their ability to avoid apoptosis and invade other tissues. The endoplasmic reticulum (ER) membrane protein Sec62 is a key player in these processes. Sec62 is essential for cell migration and protects tumor cells against thapsigargin-induced ER stress, which are both linked to cytosolic Ca 2+ . SEC62 silencing leads to elevated cytosolic Ca 2+ and increased ER Ca 2+ leakage after thapsigargin treatment. Sec62 protein levels are significantly increased in different tumors, including prostate, lung and thyroid cancer. In lung cancer, the influence of Sec62 protein levels on patient survival was analyzed using the Kaplan-Meier method and log-rank test. To elucidate the underlying pathophysiological functions of Sec62, Ca 2+ imaging techniques, real-time cell analysis and cell migration assays were performed. The effects of treatment with the calmodulin antagonists, trifluoperazine (TFP) and ophiobolin A, on cellular Ca 2+ homeostasis, cell growth and cell migration were compared with the effects of siRNA-mediated Sec62 depletion or the expression of a mutated SEC62 variant in vitro. Using Biacore analysis we examined the Ca 2+ -sensitive interaction of Sec62 with the Sec61 complex. Sec62 overproduction significantly correlated with reduced patient survival. Therefore, Sec62 is not only a predictive marker for this type of tumor, but also an interesting therapeutic target. The present study suggests a regulatory function for Sec62 in the major Ca 2+ leakage channel in the ER, Sec61, by a direct and Ca 2+ -sensitive interaction. A Ca 2+ -binding motif in Sec62 is essential for its molecular function. Treatment of cells with calmodulin antagonists mimicked Sec62 depletion by inhibiting cell migration and rendering the cells sensitive to thapsigargin treatment. Targeting tumors that overproduce Sec62 with calmodulin antagonists in combination with targeted thapsigargin analogues may offer novel personalized therapeutic options
Growth process and structure of Er/Si(100) thin film
International Nuclear Information System (INIS)
Fujii, S.; Michishita, Y.; Miyamae, N.; Suto, H.; Honda, S.; Okado, H.; Oura, K.; Katayama, M.
2006-01-01
The solid-phase reactive epitaxial growth processes and structures of Er/Si(100) thin films were investigated by coaxial impact-collision ion scattering spectroscopy (CAICISS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The as-deposited Er film grown at room temperature was transformed into crystalline rectangular-shaped islands after annealing at 900 deg. C. These islands have a hexagonal AlB 2 -type structure and the epitaxial relationship is determined to be ErSi 2 (011-bar0)[0001]//Si(100)[011-bar]. It has been revealed that the surface of the Er silicide island is terminated with an Er plane
Krigens første offer er også truet i fredstid
DEFF Research Database (Denmark)
Serritzlev, Jeanette
2018-01-01
Sandheden er krigens første offer, lyder det. Men informationskrig finder også sted i fredstid, og også her er sandheden jaget vildt. ’Fake News’ er det nye modeord, selv om det ikke er nyt. Det behøver ikke at være værre, end vi selv gør det. Det farlige opstår først, når vi er ligeglade....
Directory of Open Access Journals (Sweden)
Minsi Zhang
2015-09-01
Full Text Available Novel genetically engineered mouse models using the Cre-loxP or the Flp-FRT systems have generated useful reagents to manipulate the mouse genome in a temporally-regulated and tissue-specific manner. By incorporating a constitutive Cre driver line into a mouse model in which FRT-regulated genes in other cell types are regulated by Flp-FRT recombinase, gene expression can be manipulated simultaneously in separate tissue compartments. This application of dual recombinase technology can be used to dissect the role of stromal cells in tumor development and cancer therapy. Generating mice in which Cre-ERT2 is expressed under Flp-FRT-mediated regulation would enable step-wise manipulation of the mouse genome using dual recombinase technology. Such next-generation mouse models would enable sequential mutagenesis to better model cancer and define genes required for tumor maintenance. Here, we generated novel genetically engineered mice that activate or delete Cre-ERT2 in response to Flp recombinase. To potentially utilize the large number of Cre-loxP-regulated transgenic alleles that have already been targeted into the Rosa26 locus, such as different reporters and mutant genes, we targeted the two novel Cre-ERT2 alleles into the endogenous Col1a1 locus for ubiquitous expression. In the Col1a1FRT-Cre-ER-T2-FRT mice, Flp deletes Cre-ERT2, so that Cre-ERT2 is only expressed in cells that have never expressed Flp. In contrast, in the Col1a1FRT-STOP-FRT-Cre-ER-T2 mice, Flp removes the STOP cassette to allow Cre-ERT2 expression so that Cre-ERT2 is only expressed in cells that previously expressed Flp. These two new novel mouse strains will be complementary to each other and will enable the exploration of complex biological questions in development, normal tissue homeostasis and cancer.
Zhang, Minsi; Kirsch, David G.
2015-01-01
ABSTRACT Novel genetically engineered mouse models using the Cre-loxP or the Flp-FRT systems have generated useful reagents to manipulate the mouse genome in a temporally-regulated and tissue-specific manner. By incorporating a constitutive Cre driver line into a mouse model in which FRT-regulated genes in other cell types are regulated by Flp-FRT recombinase, gene expression can be manipulated simultaneously in separate tissue compartments. This application of dual recombinase technology can be used to dissect the role of stromal cells in tumor development and cancer therapy. Generating mice in which Cre-ERT2 is expressed under Flp-FRT-mediated regulation would enable step-wise manipulation of the mouse genome using dual recombinase technology. Such next-generation mouse models would enable sequential mutagenesis to better model cancer and define genes required for tumor maintenance. Here, we generated novel genetically engineered mice that activate or delete Cre-ERT2 in response to Flp recombinase. To potentially utilize the large number of Cre-loxP-regulated transgenic alleles that have already been targeted into the Rosa26 locus, such as different reporters and mutant genes, we targeted the two novel Cre-ERT2 alleles into the endogenous Col1a1 locus for ubiquitous expression. In the Col1a1FRT-Cre-ER-T2-FRT mice, Flp deletes Cre-ERT2, so that Cre-ERT2 is only expressed in cells that have never expressed Flp. In contrast, in the Col1a1FRT-STOP-FRT-Cre-ER-T2 mice, Flp removes the STOP cassette to allow Cre-ERT2 expression so that Cre-ERT2 is only expressed in cells that previously expressed Flp. These two new novel mouse strains will be complementary to each other and will enable the exploration of complex biological questions in development, normal tissue homeostasis and cancer. PMID:26183214
Biocompatible Er:(Na,K)NbO3 nanofibers
Markova, N. P.; Grishin, A. M.
2017-11-01
Dense homogeneous fabric composed from continuous bead-free erbium-doped sodium potassium niobate (Er:NKN) 100 μm long and 100-200 nm in diameter nanofibers was sintered by sol-gel calcination assisted electrospinning technique. Er doping with the concentration of 2 at.% provides readily detectable room-temperature broad-band photoluminescence (PL) centered at λPL = 0.55 and 0.98 μm being pumped, respectively, with 532 and 785 nm lasers. Electric field induced resistance switching and strong electric rectification effect were found in nanoporous sandwich Au/Er:NKN/Pt capacitive cell. Memristor-type current-voltage I-V characteristics originate from the electrochemical migration of oxygen vacancies at the n-type Er:NKN oxide/high work function Pt cathode junction interface.
Æstetik er tilbage som nøgle til at forstå samtiden
DEFF Research Database (Denmark)
Sharma, Devika
2013-01-01
Casper Christensen er gakket, Hello Kitty er nuttet og konceptkunsten er interessant. Her er tre nye kategorier at forstå senkapitalismen med. I anledning af Sianne Ngais bog "Our aesthetic categories: zany, cute, interesting" .......Casper Christensen er gakket, Hello Kitty er nuttet og konceptkunsten er interessant. Her er tre nye kategorier at forstå senkapitalismen med. I anledning af Sianne Ngais bog "Our aesthetic categories: zany, cute, interesting" ....
Når mindset er nøglen til succes
DEFF Research Database (Denmark)
Nielsen, Jeppe Agger; Karlsmose, Jens; Kortnum, Allan
2016-01-01
Hvordan skaber man en arbejdspladskultur, hvor medarbejderne trives med forandringer, er udholdende og indstillede på at lære nyt? Det er for mange virksomheder et af de helt store aktuelle spørgsmål, og i flere af dem er svaret ledelse med mindsetbaserede principper. Læs her om mindset-tanketank...
Rantong, Gaolathe; Evans, Rodger; Gunawardena, Arunika H L A N
2015-10-01
The lace plant, Aponogeton madagascariensis, is an aquatic monocot that forms perforations in its leaves as part of normal leaf development. Perforation formation occurs through developmentally regulated programmed cell death (PCD). The molecular basis of PCD regulation in the lace plant is unknown, however ethylene has been shown to play a significant role. In this study, we examined the role of ethylene receptors during perforation formation. We isolated three lace plant ethylene receptors AmERS1a, AmERS1b and AmERS1c. Using quantitative PCR, we examined their transcript levels at seven stages of leaf development. Through laser-capture microscopy, transcript levels were also determined in cells undergoing PCD and cells not undergoing PCD (NPCD cells). AmERS1a transcript levels were significantly lower in window stage leaves (in which perforation formation and PCD are occurring) as compared to all other leaf developmental stages. AmERS1a and AmERS1c (the most abundant among the three receptors) had the highest transcript levels in mature stage leaves, where PCD is not occurring. Their transcript levels decreased significantly during senescence-associated PCD. AmERS1c had significantly higher transcript levels in NPCD compared to PCD cells. Despite being significantly low in window stage leaves, AmERS1a transcripts were not differentially expressed between PCD and NPCD cells. The results suggested that ethylene receptors negatively regulate ethylene-controlled PCD in the lace plant. A combination of ethylene and receptor levels determines cell fate during perforation formation and leaf senescence. A new model for ethylene emission and receptor expression during lace plant perforation formation and senescence is proposed.
Herp enhances ER-associated protein degradation by recruiting ubiquilins
International Nuclear Information System (INIS)
Kim, Tae-Yeon; Kim, Eunmin; Yoon, Sungjoo Kim; Yoon, Jong-Bok
2008-01-01
ER-associated protein degradation (ERAD) is a protein quality control system of ER, which eliminates misfolded proteins by proteasome-dependent degradation and ensures export of only properly folded proteins from ER. Herp, an ER membrane protein upregulated by ER stress, is implicated in regulation of ERAD. In the present study, we show that Herp interacts with members of the ubiquilin family, which function as a shuttle factor to deliver ubiquitinated substrates to the proteasome for degradation. Knockdown of ubiquilin expression by small interfering RNA stabilized the ERAD substrate CD3δ, whereas it did not alter or increased degradation of non-ERAD substrates tested. CD3δ was stabilized by overexpressed Herp mutants which were capable of binding to ubiquilins but were impaired in ER membrane targeting by deletion of the transmembrane domain. Our data suggest that Herp binding to ubiquilin proteins plays an important role in the ERAD pathway and that ubiquilins are specifically involved in degradation of only a subset of ubiquitinated targets, including Herp-dependent ERAD substrates
DEFF Research Database (Denmark)
Markgraf, Daniel F; Klemm, Robin W; Junker, Mirco
2014-01-01
Eukaryotic cells store neutral lipids such as triacylglycerol (TAG) in lipid droplets (LDs). Here, we have addressed how LDs are functionally linked to the endoplasmic reticulum (ER). We show that, in S. cerevisiae, LD growth is sustained by LD-localized enzymes. When LDs grow in early stationary...... phase, the diacylglycerol acyl-transferase Dga1p moves from the ER to LDs and is responsible for all TAG synthesis from diacylglycerol (DAG). During LD breakdown in early exponential phase, an ER membrane protein (Ice2p) facilitates TAG utilization for membrane-lipid synthesis. Ice2p has a cytosolic...... and explain how cells switch neutral lipid metabolism from storage to consumption....
Energy Technology Data Exchange (ETDEWEB)
Burck, Andreas
2008-11-04
This thesis describes the development of large-area magnetic calorimeters which could for example be used for the investigation of the dissociative recombination or the measurement of the Lamb-shift for hydrogenlike heavy ions. The detectors consist of two meandershaped niobium thin film pickup coils and a paramagnetic sensor. The deposition of energy in the sensor results in a temperature change and therefore in a change of magnetisation of the sensor, which can be measured by a SQUID-magnetometer with high precision. As sensormaterials a dilute alloy of gold-erbium (Au:Er) as well as silver-erbium (Ag:Er) were used. Whereas the Ag:Er-sensor was glued on the pickup coil the Au:Er-sensor was for the first time microstructured by a novel microstructuring process established in this thesis. For the characterisation of the detectors and the sensormaterials a fluorescence source and a {sup 55}Fe source were used. The thermodynamic properties of the Au:Er-sensors thereby show promising results, as the magnetisation shows bulk properties down to 20 mK. The measurements of the signalize and the magnetisation with the detector which was equipped with a Ag:Er-sensor showed that the thermodynamic properties of the Ag:Eralloy could be fully described. Furthermore the shape of the pulses, the noise and the energy resolution of both detectors will be discussed. (orig.)
International Nuclear Information System (INIS)
Medrek, Catharina; Pontén, Fredrik; Jirström, Karin; Leandersson, Karin
2012-01-01
Tumor associated macrophages (TAMs) are alternatively activated macrophages that enhance tumor progression by promoting tumor cell invasion, migration and angiogenesis. TAMs have an anti-inflammatory function resembling M2 macrophages. CD163 is regarded as a highly specific monocyte/macrophage marker for M2 macrophages. In this study we evaluated the specificity of using the M2 macrophage marker CD163 as a TAM marker and compared its prognostic value with the more frequently used pan-macrophage marker CD68. We also analyzed the prognostic value of the localization of CD163 + and CD68 + myeloid cells in human breast cancer. The extent of infiltrating CD163 + or CD68 + myeloid cells in tumor nest versus tumor stroma was evaluated by immunohistochemistry in tissue microarrays with tumors from 144 breast cancer cases. Spearman’s Rho and χ 2 tests were used to examine the correlations between CD163 + or CD68 + myeloid cells and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the impact of CD163 + and CD68 + myeloid cells in tumor stroma and tumor nest, respectively, on recurrence free survival, breast cancer specific and overall survival. We found that infiltration of CD163 + and CD68 + macrophages into tumor stroma, but not into tumor nest, were of clinical relevance. CD163 + macrophages in tumor stroma positively correlated with higher grade, larger tumor size, Ki67 positivity, estrogen receptor negativity, progesterone receptor negativity, triple-negative/basal-like breast cancer and inversely correlated with luminal A breast cancer. Some CD163 + areas lacked CD68 expression, suggesting that CD163 could be used as a general anti-inflammatory myeloid marker with prognostic impact. CD68 + macrophages in tumor stroma positively correlated to tumor size and inversely correlated to luminal A breast cancer. More importantly, CD68 in tumor stroma was an independent prognostic factor for reduced breast cancer
Snip snap snude - dobbelthagerne er ude
DEFF Research Database (Denmark)
Larsen, Malene Charlotte; Kofoed, Jette
2015-01-01
Det handler om at være grim. Det står i skarp kontrast til det pæne og polerede på Instagram. Det er flygtigt, useriøst og ligegyldigt. Og så forsvinder det heldigvis igen, så man behøver kun at forholde sig til det i de få sekunder, det foregår. Snapchat vokser i popularitet og er nu det...