bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delivery of four‐dimensional radiotherapy with TrackBeam for moving target using a dual‐layer MLC: dynamic phantoms study
Authors: Liu Yaxi , Shi Chengyu , Lin Bryan , Ha Chul Soo , Papanikolaou Niko 
Published: May 2009

Respiratory motion has been considered a clinical challenge for lung tumor treatments due to target motion. In this study, we aimed to perform an experimental evaluation based on dynamic phantoms using MLC‐based beam tracking. TrackBeam, a prototype real‐time beam tracking system, has been assembled and evaluated in our clinic. TrackBeam includes an orthogonal dual‐layer micro multileaf collimator (DmMLC), an on‐board mega‐voltage (MV) portal imaging device, and an image processing workstation. With a fiducial marker implanted in a moving target, the onboard imaging device can capture the motion. The TrackBeam workstation processes the online MV fluence and detects and predicts tumor motion. The DmMLC system then dynamically repositions each leaf to form new beam apertures based on the movement of the fiducial marker. In this study, a dynamic phantom was used for the measurements. Three delivery patterns were evaluated for dosimetric verification based on radiographic films: no‐motion lung‐tumor (NMLT), three‐dimensional conformal radiotherapy (3DCRT), and four‐dimensional tracking radiotherapy (4DTRT). The displacement between the DmMLC dynamic beam isocenter and the fiducial marker was in the range of 0.5 mm to 1.5 mm. With radiographic film analysis, the planar dose histogram difference between 3DCRT and NLMT was 48.6% and 38.0% with dose difference tolerances of 10% and 20%, respectively. The planar dose histogram difference between 4DTRT and NLMT was 15.2% and 4.0%, respectively. Based on dose volume histogram analysis, 4DTRT reduces the mean dose for the surrounding tissue from 35.4 Gy to 19.5 Gy, reduces the relative volume of the total lung from 28% to 18% at V20, and reduces the amount of dose from 35.2 Gy to 15.0 Gy at D20. The experimental results show that MLC‐based real‐time beam tracking delivery provides a potential solution to respiratory motion control. Beam tracking delivers a highly conformal dose to a moving target, while sparing surrounding normal tissue.PACS number: 87.55.de, 87.55.ne, 87.56.nk
Characterization and clinical evaluation of a novel IMRT quality assurance system
Authors: Sadagopan Ramaswamy , Bencomo Jose A. , Martin Rafael L. , Nilsson Gorgen , Matzen Thomas , Balter Peter A. 
Published: May 2009

Intensity‐modulated radiation therapy (IMRT) is a complex procedure that involves the delivery of complex intensity patterns from various gantry angles. Due to the complexity of the treatment plans, the standard care is to perform measurement‐based, patient‐specific quality assurance (QA). IMRT QA is traditionally done with film for relative dose in a plane and with an ion chamber for absolute dose. This is a laborious and time‐consuming process. In this work, we characterized, commissioned, and evaluated the QA capabilities of a novel commercial IMRT device, Delta4, (ScandiDos, Uppsala, Sweden). This device consists of diode matrices in two orthogonal planes inserted in a cylindrical acrylic phantom that is 22 cm in diameter. Although the system has detectors in only two planes, it provides a novel interpolation algorithm that is capable of estimating doses at points where no detectors are present. Each diode is sampled per beam pulse so that the dose distribution can be evaluated on segment‐by‐segment, beam‐by‐beam, or as a composite plan from a single set of measurements. The end user can calibrate the system to perform absolute dosimetry, eliminating the need for additional ion chamber measurements. The patient's IMRT plan is imported into the device over the hospital LAN and the results of the measurements can be displayed as gamma profiles, distance‐to‐agreement maps, dose difference maps, or the measured dose distribution can be superimposed on the patient's anatomy to display an as‐delivered plan. We evaluated the system's reproducibility, stability, pulse‐rate dependence, dose‐rate dependence, angular dependence, linearity of dose response, and energy response using carefully planned measurements. We also validated the system's interpolation algorithm by measuring a complex dose distribution from an IMRT treatment. Several simple and complex isodose distributions planned using a treatment planning system were delivered to the QA device; the planned and measured dose distributions were then compared and analyzed. In addition, the dose distributions measured by conventional IMRT QA, which uses an ion chamber and film, were compared. We found that the Delta4 device is accurate and reproducible and that its interpolation algorithm is valid. In addition, the supplied software and network interface allow a streamlined IMRT QA process.PACS number: 87.56Fc
Comparison of two commercial detector arrays for IMRT quality assurance
Authors: Li Jonathan G. , Yan Guanghua , Liu Chihray 
Published: May 2009

Two commercially available detector arrays were compared for their use in the quality assurance of patient‐specific IMRT treatment plans: one a diode‐based array (MapCHECK) and the other an ion chamber‐based array (MatriXX). The dependence of the response of detectors on field size, dose rate, and radiation energy was measured and compared with reference measurements using a Farmer‐type ionization chamber. The linearity of the detector response, short‐term and long‐term reproducibility, statistical uncertainty as a function of delivered dose, and the validity of the array calibration were also examined to understand the stability and uncertainty of the systems. No field size or SSD dependence was observed within the range of the field sizes and SSDs used in the study at both 6 MV and 18 MV photon energies. Both detector arrays showed negligible errors when measuring doses of more than , but exhibited errors of when measuring doses on the order of 1 cGy. While the MapCHECK showed a stable short‐term reproducibility to within measurement error, the MatriXX showed a slow but continuous increase in readings during the initial one‐hour period (about 0.8%). The MapCHECK also showed a slightly better array sensitivity correction with all the detectors having less than 1% discrepancy and more than 90% of the detectors within 0.5% variation, whereas about 60% of the MatriXX detectors showed a less than 0.5% variation and exhibited a larger than 1% discrepancy. MatriXX detectors also displayed a volume‐averaging effect consistent with its detector size of in diameter. Excellent passing rates were obtained for both detector arrays when compared with the planar dose distributions from the treatment planning system for three 6 MV IMRT fields and three 18 MV IMRT fields after the volume‐averaging effect of the MatriXX was taken into account.PACS number: 87.55.km; 87.55.Qr; 87.56.Fc
Parameter optimization in HN‐IMRT for Elekta linacs
Authors: Worthy Danielle , Wu Qiuwen 
Published: May 2009

Planning and delivery in HN‐IMRT has been challenging for the Elekta linac because of numerous machine limitations. Direct aperture optimization (DAO) algorithms have had success in simplifying the planning process and improving plan quality. Commercial adaptations of DAO allow for widespread use in many clinics; however clinical validation of these methods is still needed. In this work we evaluated Pinnacle3 commercial software for HN‐IMRT on the Elekta linac. The purpose was to find a set of planning parameters that are applicable to most patients and optimal in terms of plan quality, delivery efficiency, and dosimetric accuracy. Four types of plans were created for each of 12 patients: ideal fluence optimization (FO), conventional two‐step optimization (TS), segment weight optimization (SW), and direct machine parameter optimization (DMPO). Maximum number of segments (NS) and minimum segment area (MSA) were varied in DMPO. Results showed DMPO plans have the best optimization scores and dosimetric indices, and the most consistent IMRT output among patients. At larger NS , plan quality decreases with increasing MSA as expected, except for , suggesting presence of local minima in DMPO. Segment area and MUs can vary significantly between optimization methods and parameter settings; however, the quantity ‘integral MU’ remains constant. Irradiation time is linearly proportional to total plan segments, weakly dependent on MUs and independent of MSA. Dosimetric accuracy is independent of DMPO parameters. The superior quality of DMPO makes it the choice for HN‐IMRT on Elekta linacs and its consistency allows development of ‘class solutions’. However, planners should be aware of the local minima issue when pushing parameters to the limit such as and . The optimal set of parameters should be chosen to balance plan quality and delivery efficiency based on a systematic evaluation of the planning technique and system constraints.PACS number: PACS: 87.55.D, 87.55.de
Fibroblast Growth Factor Receptor 1 Promotes Proliferation and Survival via Activation of the Mitogen-Activated Protein Kinase Pathway in Bladder Cancer
Authors: Tomlinson Darren C. , Lamont Fiona R. , Shnyder Steve D. , Knowles Margaret A. 
Published: May 2009

Abstract
Fibroblast growth factor receptors (FGFR) play key roles in proliferation, differentiation, and tumorigenesis. Many urothelial carcinomas contain activating point mutations or increased expression of FGFR3. However, little is known about the role of other FGFRs. We examined FGFR expression in telomerase-immortalized normal human urothelial cells, urothelial carcinoma cell lines, and tumor samples and showed that FGFR1 expression is increased in a high proportion of cell lines and tumors independent of stage and grade. To determine the role of FGFR1 in low-stage bladder cancer, we overexpressed FGFR1 in telomerase-immortalized normal human urothelial cells and examined changes in proliferation and cell survival in response to FGF2. FGFR1 stimulation increased proliferation and reduced apoptosis. To elucidate the mechanistic basis for these alterations, we examined the signaling cascades activated by FGFR1. FRS2α and PLCγ were activated in response to FGF2, leading to activation of the mitogen-activated protein kinase pathway. The level of mitogen-activated protein kinase activation correlated with the level of cyclin D1, MCL1, and phospho-BAD, which also correlated with FGFR-induced proliferation and survival. Knockdown of FGFR1 in urothelial carcinoma cell lines revealed differential FGFR1 dependence. JMSU1 cells were dependent on FGFR1 expression for survival but three other cell lines were not. Two cell lines (JMSU1 and UMUC3) were dependent on FGFR1 for growth in soft agar. Only one of the cell lines tested (UMUC3) was frankly tumorigenic; here, FGFR1 knockdown inhibited tumor growth. Our results indicate that FGFR1 has significant effects on urothelial cell phenotype and may represent a useful therapeutic target in some cases of urothelial carcinoma. [Cancer Res 2009;69(11):4613–20]
WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3
Authors: Gourley Charlie , Paige Adam J.W. , Taylor Karen J. , Ward Carol , Kuske Barbara , Zhang Jieqing , Sun Mingjun , Janczar Szymon , Harrison David J. , Muir Morwenna , Smyth John F. , Gabra Hani 
Published: May 2009

Abstract
The WW domain–containing oxidoreductase (WWOX) gene is located at FRA16D, a common fragile site involved in human cancer. Targeted deletion of Wwox in mice causes increased spontaneous tumor incidence, confirming that WWOX is a bona fide tumor suppressor gene. We show that stable transfection of WWOX into human PEO1 ovarian cancer cells, containing homozygous WWOX deletion, abolishes in vivo tumorigenicity, but this does not correlate with alteration of in vitro growth. Rather, WWOX restoration in PEO1, or WWOX overexpression in SKOV3 ovarian cancer cells, results in reduced attachment and migration on fibronectin, an extracellular matrix component linked to peritoneal metastasis. Conversely, siRNA-mediated knockdown of endogenous WWOX in A2780 ovarian cancer cells increases adhesion to fibronectin. In addition, whereas there is no WWOX-dependent difference in cell death in adherent cells, WWOX-transfected cells in suspension culture display a proapoptotic phenotype. We further show that WWOX expression reduces membranous integrin α3 protein but not integrin α3 mRNA levels, and that adhesion of PEO1 cells to fibronectin is predominantly mediated through integrin α3. We therefore propose that WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix and by inducing apoptosis in detached cells. Consistent with this, the suppression of PEO1 tumorigenicity by WWOX can be partially overcome by implanting these tumor cells in Matrigel. These data suggest a possible role for the loss of WWOX in the peritoneal dissemination of human ovarian cancer cells. [Cancer Res 2009;69(11):4835–42]
Development of Mammary Tumors by Conditional Expression of GLI1
Authors: Fiaschi Marie , Rozell Björn , Bergström Åsa , Toftgård Rune 
Published: May 2009

Abstract
A diverse set of cellular defects, presumably elicited by multiple genetic alterations, underlies cancer development. Aberrant Hedgehog (Hh) signaling has recently been implicated in the development and maintenance of breast cancer. However, evidence conclusively showing that activated Hh signaling can induce mammary tumors is lacking. We now show that transgenic expression of the Hh effector protein GLI1 under the regulation of the mouse mammary tumor virus promoter, expressed in the mouse mammary gland, is associated with the appearance of hyperplastic lesions, defective terminal end buds, and tumor development. The GLI1-induced tumors are histologically heterogeneous and involve the expansion of a population of epithelial cells expressing the progenitor cell markers keratin 6 and Bmi-1. Moreover, tumor cells express genes involved in proliferation, cell survival, and metastasis. GLI1-induced tumors do not fully regress following transgene deinduction, indicating that some tumors develop and are maintained autonomously, independent of sustained transgenic GLI1 expression. The data strongly support a role of Hh/GLI signaling in breast cancer development and suggest that inhibition of this signaling pathway represents a new therapeutic opportunity for limiting tumorigenesis and early tumorigenic progression. [Cancer Res 2009;69(11):4810–7]
Peptidyl-Prolyl Isomerase Pin1 Markedly Enhances the Oncogenic Activity of the Rel Proteins in the Nuclear Factor-κB Family
Authors: Fan Gaofeng , Fan Yongjun , Gupta Nupur , Matsuura Isao , Liu Fang , Zhou Xiao Zhen , Lu Kun Ping , Gélinas Céline 
Published: May 2009

Abstract
The peptidyl-prolyl isomerase Pin1 is frequently up-regulated in human cancers in which Rel/nuclear factor-κB (NF-κB) is constitutively activated, but its role in these cancers remains to be determined, and evidence is still lacking to show that Pin1 contributes to cell transformation by Rel/NF-κB. Rel/NF-κB transcriptional and oncogenic activities are modulated by several posttranslational modifications and coregulatory proteins, and previous studies showed that cytokine treatment induces binding of Pin1 to the RelA subunit of NF-κB, thereby enhancing RelA nuclear localization and stability. Here we show that Pin1 associates with the Rel subunits of NF-κB that are implicated in leukemia/lymphomagenesis and modulates their transcriptional and oncogenic activities. Pin1 markedly enhanced transformation of primary lymphocytes by the human c-Rel protein and also increased cell transformation by the potent viral Rel/NF-κB oncoprotein v-Rel, in contrast to a Pin1 mutant in the WW domain involved in interaction with NF-κB. Pin1 promoted nuclear accumulation of Rel proteins in the absence of activating stimuli. Importantly, inhibition of Pin1 function with the pharmacologic inhibitor juglone or with Pin1-specific shRNA led to cytoplasmic relocalization of endogenous c-Rel in human lymphoma-derived cell lines, markedly interfered with lymphoma cell proliferation, and suppressed endogenous Rel/NF-κB–dependent gene expression. Together, these results show that Pin1 is an important regulator of Rel/NF-κB transforming activity and suggest that Pin1 may be a potential therapeutic target in Rel/NF-κB–dependent leukemia/lymphomas. [Cancer Res 2009;69(11):4589–97]
Genetic Inactivation of ADAMTS15 Metalloprotease in Human Colorectal Cancer
Authors: Viloria Cristina G. , Obaya Alvaro J. , Moncada-Pazos Angela , Llamazares María , Astudillo Aurora , Capellá Gabriel , Cal Santiago , López-Otín Carlos 
Published: May 2009

Abstract
Matrix metalloproteinases have been traditionally linked to cancer dissemination through their ability to degrade most extracellular matrix components, thus facilitating invasion and metastasis of tumor cells. However, recent functional studies have revealed that some metalloproteases, including several members of the ADAMTS family, also exhibit tumor suppressor properties. In particular, ADAMTS1, ADAMTS9, and ADAMTS18 have been found to be epigenetically silenced in malignant tumors of different sources, suggesting that they may function as tumor suppressor genes. Herein, we show that ADAMTS15 is genetically inactivated in colon cancer. We have performed a mutational analysis of the ADAMTS15 gene in human colorectal carcinomas, with the finding of four mutations in 50 primary tumors and 6 colorectal cancer cell lines. Moreover, functional in vitro and in vivo studies using HCT-116 and SW-620 colorectal cancer cells and severe combined immunodeficient mice have revealed that ADAMTS15 restrains tumor growth and invasion. Furthermore, the presence of ADAMTS15 in human colorectal cancer samples showed a negative correlation with the histopathologic differentiation grade of the corresponding tumors. Collectively, these results provide evidence that extracellular proteases, including ADAMTS15, may be targets of inactivating mutations in human cancer and further validate the concept that secreted metalloproteases may show tumor suppressor properties. [Cancer Res 2009;69(11):4926–34]
Crystalline Camptothecin-20(S)-O-Propionate Hydrate:A Novel Anticancer Agent with Strong Activity against 19 Human Tumor Xenografts
Authors: Cao Zhisong , Kozielski Anthony , Liu Xing , Wang Yang , Vardeman Dana , Giovanella Beppino 
Published: May 2009

Abstract
To find a more effective and less toxic chemotherapeutic agent, we have successfully prepared crystalline camptothecin-20(S)-O-propionate hydrate (CZ48) by reacting camptothecin with propionic anhydride using concentrated sulfuric acid as catalyst. The biological effectiveness of this new anticancer agent was evaluated by using xenografts of human cancers in nude mice as the testing models. The extensive treatment of 21 human tumors with various dose levels of CZ48 has shown that this agent is highly effective against many different human tumors tested with a striking lack of toxicity. Of the 21 human tumor lines tested, 9 regressed, 5 were &lt;10% of the control, 3 were &lt;20%, and 2 were &lt;40%. Two tumors did not respond. The total response rate was 90% (19 of 21). No toxicity was observed in mice. The effective doses required to achieve the positive response varied from 100 to 1,000 mg/kg/d depending on the tumors. The maximum tolerated dose was not reached because of the nontoxic nature of the drug in mice. Thus, this compound has a much wider therapeutic index compared with that of the existing anticancer drugs currently in use. [Cancer Res 2009;69(11):4742–9]
Peroxisome Proliferator-Activated Receptor-γ Contributes to the Inhibitory Effects of Embelin on Colon Carcinogenesis
Authors: Dai Yun , Qiao Liang , Chan Kwok Wah , Yang Mo , Ye Jieyu , Ma Juan , Zou Bing , Gu Qing , Wang Jide , Pang Roberta , Lan H.Y. , Wong Benjamin C.Y. 
Published: May 2009

Abstract
Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-γ (PPARγ) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPARγ is required for embelin to exert its effect. A dominant-negative PPARγ was used to antagonize endogenous PPARγ in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-κB (NF-κB) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPARγ+/+ and PPARγ+/− mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPARγ. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPARγ. PPARγ+/− mice were more susceptible to DMH-induced colon carcinogenesis than PPARγ+/+ mice, and embelin significantly reduced the incidence of colon cancer in PPARγ+/+ mice but not in PPARγ+/− mice. Embelin inhibited NF-κB activity in PPARγ+/+ mice but marginally so in PPARγ+/− mice. Thus, reduced expression of PPARγ significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPARγ, indicating that PPARγ is a necessary signaling pathway involved in the antitumor activity of normal organisms. [Cancer Res 2009;69(11):4776–83]
Histone Deacetylase Inhibitors Induce a Very Broad, Pleiotropic Anticancer Drug Resistance Phenotype in Acute Myeloid Leukemia Cells by Modulation of Multiple ABC Transporter Genes
Authors: Hauswald Stefanie , Duque-Afonso Jesus , Wagner Michaela M. , Schertl Florian M. , Lübbert Michael , Peschel Christian , Keller Ulrich , Licht Thomas 
Published: May 2009

Abstract
Purpose: Histone deacetylase inhibitors (HDACi) are being studied in clinical trials with the aim to induce cellular differentiation, growth arrest, and apoptosis of tumor cells. Recent reports suggest that the multidrug resistance-1 (MDR1) gene is regulated by epigenetic mechanisms. To investigate whether additional drug transporters are regulated by HDACi and how this affects cytotoxicity, acute myeloid leukemia (AML) cells were examined.
Experimental Design: AML cells were cultured in the presence of phenylbutyrate, valproate, suberoylanilide hydroxamic acid, or trichostatin A and analyzed for drug transporter expression and function as well as sensitivity to anticancer drugs.
Results: MDR1, breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRP) 7 and 8 were induced in a dose- and time-dependent manner as shown by semiquantitative PCR. The pattern of gene induction was cell line specific. Phenylbutyrate induced P-glycoprotein and BCRP expression and the efflux of drugs as determined with labeled substrates. KG-1a cells treated with phenylbutyrate developed resistance to daunorubicin, mitoxantrone, etoposide, vinblastine, paclitaxel, topotecan, gemcitabine, and 5-fluorouracil; as a result drug-induced apoptosis was impaired. Chromatin immunoprecipitation revealed the hyperacetylation of histone proteins in the promoter regions of MDR1, BCRP, and MRP8 on valproate treatment. Furthermore, an alternative MRP8 promoter was induced by HDACi treatment.
Conclusions: Exposure of AML cells to HDACi induces a drug resistance phenotype broader than the “classic multidrug resistance,” which might negatively affect treatment effectiveness.