bluuebunny/crossref_metadata_2025 huggingface dataset:
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
THE FOUNDATION FOR ADVANCING THE TOYOTA PRODUCTION SYSTEM UTILIZING NEW JIT
Authors: AMASAKA KAKURO
Published: May 2009

The foundation for advancing the Toyota Production System (TPS) is based on efforts to attain simultaneous acheivement of QCD (Quality, Cost and Delivery) through innovation of manufacturing technology utilizing New JIT new management technology principle for manufacturing in the 21st century. This new principle contains hardware and software systems, "TMS, TDS, TPS and Science TQM" as the next generation technical principles to accelerate the optimization (high-linkage) of business process cycles of all the divisions. This in turn is accomplished by having cooperation between on-site "white-collar engineers" and "supervisors and workers" with affiliated and non-affiliated suppliers. The author believes that effectiveness of advancing TPS has been demonstrated as described based on the author's experienced at Toyota.
SOLVING JOINT REPLENISHMENT PROBLEM WITH DETERIORATING ITEMS USING GENETIC ALGORITHM
Authors: LI CHENGYAN , XU XIAOFEI , ZHAN DECHEN
Published: May 2009

Deterioration occurs for most items in the real world, such as decay, spoilage, evaporation, and so on. The deterioration of item may cause extra costs for inventory storage and additional costs from shortage. In this paper, Joint replenishment problem (JRP) model with exponentially distribution deterioration rate was proposed. The objective function of the JRP model was to minimize the setup costs, inventory holding costs and deterioration costs. Genetic algorithm (GA) was used for solving this problem and researches were also made in aspects such as chromosome coding, fitness function, selection, crossover and mutation operations etc. Procedure of adaptive adjusting of genetic parameters was designed to prevent the premature convergence and refine the performance of GA. Numerical examples demonstrate the effectiveness of the model and algorithm presented in this paper, and the total relevant costs are significantly influenced by the varying rate of deterioration.
SOFTWARE FRAMEWORK FOR THE APPROACH: COMPUTER AIDED SAFETY INTEGRATION IN DESIGN PROCESS (CASID)
Authors: HOUSSIN RÉMY , GARDONI MICKAËL
Published: May 2009

Nowadays, safety is often integrated at too late a stage in the design process of complex systems, such as machines or production lines. In most cases, this integration is made on an individual basis without any systematic method. Moreover, there are very few computer-aided software packages that allow the integration of safety aspects into the design process. In this paper, we present propositions of a model working situation using (UML).1 This model is implemented by prototype software called Computer Aided Safety Integration in Design process (CASID). The CASID approach is founded on a database in which all previous data generated by the designer using CASID is stored; furthermore, the software allows communication between designers in order to solve safety problems.
AGILE MODELING AND OPTIMIZATION OF END MILLING
Authors: RAJ K. HANS , SHARMA RAHUL SWARUP , UPADHYAY VIKAS , VERMA ALOK K.
Published: May 2009

The rising demand for precision and quality in manufacturing necessitates that vast amounts of manufacturing knowledge be incorporated in manufacturing systems. Surface finish in end milling depends upon a number of variables such as cutting speed, feed rate, spindle speed, radial depth of cut, etc. The relative effect of these variables on surface roughness and machining time is quite considerable. A complex relationship exists between these process parameters and hence there is a need to develop models which can capture this complex interrelationship and enable fast computation of the average surface roughness and machining time based on process parameters. Neuro Fuzzy (NF) modeling has gained prominence recently on account of its fast reaction times, improved ease of operation and flexibility to respond to change in process parameters. In the present work, initially a Neuro Fuzzy Model is trained with experimental results of end milling. Subsequently, a generic approach is developed for optimization of end milling where the applicability and effectiveness of Neuro Fuzzy Model for function approximation is used to rapidly estimate average surface roughness and machining time in an integrated framework of Hybrid Stochastic Search Technique (HSST) to form a Neuro Fuzzy Hybrid Stochastic Search Technique (NFHSST). The results indicate that the NFHSST heuristic converges to better solutions rapidly as it provides the values of various process parameters for optimizing the objectives in a single run. Thus, NFHSST assists in the improvement of quality by developing multiple sound parts in an agile manner.
Transdifferentiation properties of adipocytes in the adipose organ
Authors: Cinti Saverio
Published: May 2009

Mammals have two types of adipocytes, white and brown, but their anatomy and physiology is different. White adipocytes store lipids, and brown adipocytes burn them to produce heat. Previous descriptions implied their localization in distinct sites, but we demonstrated that they are mixed in many depots, raising the concept of adipose organ. We explain the reason for their cohabitation with the hypothesis of reversible physiological transdifferentiation; they are able to convert one into each other. If needed, the brown component of the organ could increase at the expense of the white component and vice versa. This plasticity is important because the brown phenotype of the organ associates with resistance to obesity and related disorders. Another example of physiological transdifferetiation of adipocytes is offered by the mammary gland; the pregnancy hormonal stimuli seems to trigger a reversible transdifferentiation of adipocytes into milk-secreting epithelial glands. The obese adipose organ is infiltrated by macrophages inducing chronic inflamation that is widely considered as a causative factor for insulin resistance. We showed that the vast majority of macrophages infiltrating the obese organ are arranged around dead adipocytes, forming characteristic crown-like structures. We recently found that visceral fat is more infiltrated than the subcutaneous fat despite a smaller size of visceral adipocytes. This suggests a different susceptibility of visceral and subcutaneous adipocytes to death, raising the concept of smaller critical death size that could be important to explain the key role of visceral fat for the metabolic disorders associated with obesity.
Effect of Vergence on Human Ocular Following Response (OFR)
Authors: Joshi Anand C. , Thurtell Matthew J. , Walker Mark F. , Serra Alessandro , Leigh R. John
Published: May 2009

The human ocular following response (OFR) is a preattentive, short-latency visual-field–holding mechanism, which is enhanced if the moving stimulus is applied in the wake of a saccade. Since most natural gaze shifts incorporate both saccadic and vergence components, we asked whether the OFR was also enhanced during vergence. Ten subjects viewed vertically moving sine-wave gratings on a video monitor at 45 cm that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequency of 0.17, 0.27, or 0.44 cycle/deg. In Fixation/OFR experiments, subjects fixed on a white central dot on the video monitor, which disappeared at the beginning of each trial, just as the sinusoidal grating started moving up or down. We measured the change in eye position in the 70- to 150-ms open-loop interval following stimulus onset. Group mean downward responses were larger (0.14°) and made at shorter latency (85 ms) than upward responses (0.10° and 96 ms). The direction of eye drifts during control trials, when gratings remained stationary, was unrelated to the prior response. During vergence/OFR experiments, subjects switched their fixation point between the white dot at 45 cm and a red spot at 15 cm, cued by the disappearance of one target and appearance of the other. When horizontal vergence velocity exceeded 15°/s, motion of sinusoidal gratings commenced and elicited the vertical OFR. Subjects showed significantly ( P < 0.001) larger OFR when the moving stimulus was presented during convergence (group mean increase of 46%) or divergence (group mean increase of 36%) compared with following fixation. Since gaze shifts between near and far are common during natural activities, we postulate that the increase of OFR during vergence movements reflects enhancement of early cortical motion processing, which serves to stabilize the visual field as the eyes approach their new fixation point.
Impaired Perception of Gravity Leads to Altered Head Direction Signals: What Can We Learn From Vestibular-Deficient Mice?
Authors: Beraneck M. , Lambert F. M.
Published: May 2009

Many mutant mouse strains display pathological behaviors, such as head tilts, head bobbing, or circling and waltzing, strongly suggesting that their vestibular system is impaired. Recently, Yoder and Taube studied head direction signals in tilted mutant mice, which have an impaired gravitation sensitivity in the vestibular periphery. Here we summarize their findings and discuss a caveat related to the general use of mutant mouse strains in systems physiology.
Angiosarcoma of the Retroperitoneum: Report on a Patient Treated with Sunitinib
Authors: Yoo Changhoon , Kim Jeong-Eun , Yoon Shin-Kyo , Kim Song Cheol , Ahn Jin-Hee , Kim Tae Won , Suh Cheolwon , Lee Jae-Lyun
Published: May 2009

A 52 year-old woman presented with an incidentally detected retroperitoneal angiosarcoma and multiple hepatic metastases. After chemotherapy with weekly paclitaxel and doxorubicin, angiosarcoma had progressed rapidly. Because few chemotherapeutic options were available for her, sunitinib (37.5 mg/day, daily) as a salvage regimen was administered. Although sunitinib was interrupted after two weeks due to hematologic abnormalities, some metastatic nodules were regressed. Therefore, sunitinib was recommenced at a reduced dose (25 mg/day, daily). Serial computed tomography scans showed variable response in each tumor, however, sunitinib at least delayed tumor progression, compared to previous chemotherapy. With this case report, we suggest sunitinib may be effective against angiosarcomas. When sunitinib is administered to patients with angiosarcomas, hematologic abnormalities should be monitored frequently as severe hematologic toxicity may be caused either by sunitinib per se or angiosarcoma.
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

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

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

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

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

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

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 <10% of the control, 3 were <20%, and 2 were <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

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

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.
A Single Recombinant Adenovirus Expressing p53 and p21-targeting Artificial microRNAs Efficiently Induces Apoptosis in Human Cancer Cells
Authors: Idogawa Masashi , Sasaki Yasushi , Suzuki Hiromu , Mita Hiroaki , Imai Kohzoh , Shinomura Yasuhisa , Tokino Takashi
Published: May 2009

Purpose: Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. The activation of p53 induces either cell cycle arrest or apoptosis. Cell cycle arrest in response to p53 activation is mediated primarily through the induction of the cyclin-dependent kinase inhibitor p21. Because p21 also has an inhibitory effect on p53-mediated apoptosis, the suppression of p53-induced p21 expression would be expected to result in the preferential induction of apoptosis. However, p21 also has tumor-suppressive properties. In this study, we developed an adenovirus vector that expresses p53 and suppresses p21 simultaneously to enhance p53-mediated apoptosis.

Experimental Design: We constructed a replication-deficient recombinant adenovirus (Ad-p53/miR-p21) that enabled cocistronic expression of the p53 protein and artificial microRNAs that targeted p21, and examined the therapeutic effectiveness of this vector in vitro and in vivo.

Results: The levels of p21 were significantly attenuated following infection with Ad-p53/miR-p21. In colorectal and hepatocellular carcinoma cells, infection with Ad-p53/miR-p21 augmented apoptosis as compared with an adenovirus that expressed p53 alone (Ad-p53/miR-control). Ad-p53/miR-p21 also significantly increased the chemosensitivity of cancer cells to adriamycin (doxorubicin). In a xenograft tumor model in nude mice, tumor volume was significantly decreased following the direct injection of Ad-p53/miR-p21 into the tumor, as compared with the injection of Ad-p53/miR-control.

Conclusion: These results suggest that adenovirus-mediated transduction of p53 and p21-specific microRNAs may be useful for gene therapy of human cancers.
Association of XPD Polymorphisms with Severe Toxicity in Non–Small Cell Lung Cancer Patients in a Chinese Population
Authors: Wu Wenting , Zhang Wei , Qiao Rong , Chen Dan , Wang Huibo , Wang Yi , Zhang Shuyu , Gao Ge , Gu Aiqin , Shen Jie , Qian Ji , Fan Weiwei , Jin Li , Han Baohui , Lu Daru
Published: May 2009

Purpose: Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non–small cell lung cancer patients.

Experimental Design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non–small cell lung cancer patients treated with platinum-based chemotherapy.

Results: The variant homozygotes of XPD p.Arg156Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype “CG” (in the order of p.Arg156Arg-p.Asp312Asn) on the risk of grade 3 or 4 hematologic toxicity.

Conclusions: This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg156Arg polymorphism on severe toxicity variability among platinum-treated non–small cell lung cancer patients.
Low-Intensity Pulsed Ultrasound Accelerates Osteoblast Differentiation and Promotes Bone Formation in an Osteoporosis Rat Model
Authors: Wu Shuliang , Kawahara Yumi , Manabe Tomotaka , Ogawa Kazuyuki , Matsumoto Masaya , Sasaki Akira , Yuge Louis
Published: May 2009

Objective: We examined the effects of low-intensity pulsed ultrasound (LIPUS) on cell differentiation, bone mineralized nodule formation and core-binding factor A1 (Cbfa1) expression in a normal human osteoblast (NHOst) cell line and bone formation in an osteoporosis animal model. Methods: NHOst cells were cultured in vitro in medium with or without LIPUS stimulation. The ultrasound stimulation frequency was 1.0 MHz at an intensity of 30 mW/cm2 for 20 min. Rats were divided into a sham-operated group (Sham) and an ovariectomized group (OVX). The right femur was treated with LIPUS (Sham-LIPUS and OVX-LIPUS) and the left femur was left untreated (Sham-CON and OVX-CON). Results: LIPUS stimulation accelerated bone nodule formation and enhanced alkaline phosphatase activity. The expression levels of Cbfa1 decreased and calcification occurred earlier and more frequently in the LIPUS than in the CON groups. The wet weight of the femur increased in OVX rats with LIPUS stimulation. Morphological images showed an increase in trabecular spongiosa in the OVX-LIPUS group. Conclusion: LIPUS accelerated osteogenesis. Moreover, since LIPUS prevents bone loss, it may be a promising treatment for osteoporosis.
Poly(ADP-Ribose) Polymerase Inhibition Down-Regulates Expression of Metastasis-Related Genes in CT26 Colon Carcinoma Cells
Authors: Li Ming , Threadgill Michael D. , Wang Yalan , Cai Li , Lin Xiao
Published: May 2009

Objectives: The current study was designed to test the hypothesis that inhibition of poly(ADP-ribose) polymerase in colorectal cancer mediates down-regulation of metastasis-related gene expression through the regulation of nuclear factor-κB (NF-κB) activity. Methods: Mouse colon carcinoma cells (CT26) were treated with and without the PARP inhibitor 5-aminoisoquinolin-1(2H)-one hydrochloride (5-AIQ). We investigated adhesion, migration and invasion of differently treated CT26 cells. In addition, the expression levels of PARP, NF-κB, integrin β1, MMP-9 and MMP-2 as well as the activities of NF-κB, MMP-9 and MMP-2 were determined by Western blot, electrophoretic mobility gel shift assay and zymography, respectively. Results: Inhibition ofPARP attenuated the adhesion of CT26 cells to the extracellular matrix and their migration and invasion through Matrigel. In addition, the results of Western blot showed that the expression levels of PARP, NF-κB, integrin β1, MMP-9 and MMP-2 were reduced in 5-AIQ-treated CT26 cells; the activities of NF-κB, MMP-9 and MMP-2 were also suppressed. Conclusions: Inhibition of PARP down-regulates the expression of metastasis-related genes in mouse colon carcinoma cells. This could be, at least in part, through the regulation of NF-κB activity, but the precise mechanisms of action remain to be elucidated.
Association of the c.3972C>T Variant of the Multidrug Resistance-Associated Protein 2 Gene (MRP2/ABCC2) with Susceptibility to Bile Duct Cancer
Authors: Höblinger A. , Grünhage F. , Sauerbruch T. , Lammert F.
Published: May 2009

Background: Multidrug resistance-associated protein 2 (MRP2/ABCC2) is one of the ATP-binding cassette (ABC) transporters expressed on the apical membrane of hepatocytes and cholangiocytes. ABCC2 plays an important role in the biliary clearance of endogenous and exogenous toxic compounds. Recently, the ABCC2 variant c.3972C>T in exon 28 has been shown to be associated with hepatocellular carcinoma risk. Our aim was to assess the role of this ABCC2 variant on cholangiocarcinoma susceptibility. Methods: Prospectively, we recruited 60 cholangiocarcinoma patients and 73 healthy controls of Caucasian origin. The c.3972C>T polymorphism was genotyped using solution-phase hybridization reactions with 5′-nuclease and fluorescence detection (TaqMan assays). Results: Allele frequencies were in Hardy-Weinberg equilibrium (p > 0.05). The c.3972T allele was significantly more frequent in patients with cholangiocarcinoma (39.2%) compared to healthy controls (26.0%, p = 0.022), resulting in an odds ratio (OR) of 1.83 (95% CI = 1.09–3.08). Armitage’s trend test showed a significant association between genotypes and cancer susceptibility (p = 0.026, OR = 1.95). Conclusions: We describe a novel association between the common ABCC2 variant c.3972C>T and cholangiocarcinoma risk. Further studies are warranted to replicate our findings in different populations and to elucidate the mechanisms of this observation.
Impaired Elastic Properties of the Aorta in Fat-Fed, Streptozotocin-Treated Rats
Authors: Sun Hui , Zhong Ming , Miao Ya , Ma Xiao , Gong Hui-Ping , Tan Hong-Wei , Zhang Yun , Zhang Wei
Published: May 2009

Background: Vascular complications associated with diabetes are the major cause for the increased morbidity and mortality in diabetic patients. However, the progression of vascular complications in diabetes is not well understood. We aimed to investigate the biomechanical and biochemical changes associated with vascular dysfunction in diabetic rats. Methods:Male Wistar rats were randomly divided into two groups: normal control (n = 8) and fat-fed, streptozotocin-treated diabetic rats (n = 11). After 16 weeks, Peterson’s modulus of elasticity (Ep) and cross-sectional distensibility (CD) were calculated and compared between the two groups. Aortas were harvested from rats for histopathological and electron-microscopic analysis. Results: Collagenous fibers were scattered in the extracellular matrix and invaded the elastic lamina in the aortas of diabetic rats, suggesting a significant accumulation of collagen in diabetic vessels. Compared with normal rats, diabetic rats showed significantly reduced aortic distensibility (CD: 0.10 ± 0.04 vs. 0.17 ± 0.08 kPa–1, p = 0.033) and an increased aortic stiffness index (Ep: 0.25 ± 0.13 vs. 0.15 ± 0.05 × 106 dyn/cm2, p = 0.045). Ep was positively and CD negatively correlated with glucose and collagen in diabetic rats. Conclusions: In diabetic rats, elastic properties of the aorta are impaired, being closely related to hyperglycemia-induced vascular wall remodeling.
Extent of Intra-Arterial Calcification on Head CT Is Predictive of the Degree of Intracranial Atherosclerosis on Digital Subtraction Angiography
Authors: Kassab Mounzer Y. , Gupta Rishi , Majid Arshad , Farooq Muhammad U. , Giles Brian P. , Johnson Mark D. , Graybeal Dion F. , Rappard George
Published: May 2009

Background: Intracranial intra-arterial calcifications (ICAC) are a common finding on head CT examinations, but their significance is not known. The aim of this study is to determine if a relationship exists between ICAC on head CT and the presence of a high-grade atherosclerotic stenosis on cerebral angiography. Methods: This was a retrospective study of 108 consecutive patients admitted to the stroke service at Parkland Hospital in Dallas, Tex., USA. Each patient had undergone a head CT and catheter-based angiographic study to meet the inclusion criteria. Demographic information was recorded along with CT imaging data in regards to the amount of calcification. Angiographic images were reviewed independently, and a comparison was made to determine if calcification was predictive of finding a high-grade stenosis on angiography. Results: A total of 108 consecutive patients with a mean age of 56 ± 12 years were studied. Of the 540 vessels studied, 65 (12%) were found to have a stenosis of ≥50% on angiography, and 71 (13.1%) were found to have a calcium grade of 3 or 4 on head CT. ICAC appeared to be more common in the anterior circulation compared to the posterior circulation. Patients with grade 3 or 4 calcification of an intracranial vessel on head CT were more likely to have a stenosis of ≥50% on cerebral angiography. Conclusions: The presence of ICAC on head CT appears to correlate with the presence of an underlying intracranial stenosis on angiography. Further study is required to validate these preliminary findings.
Diffusion-Weighted Imaging Showing ‘Pearls’ Predicts Large-Vessel Disease as Stroke Etiology
Authors: Turtzo L. Christine , Gottesman Rebecca F. , Llinas Rafael H.
Published: May 2009

Background: The patterns on diffusion-weighted (DWI) MRI may be predictive of stroke etiology. In this retrospective study, we assessed whether DWI bright lesions termed ‘pearls’ predicted the presence of large-vessel arterial stenosis as the etiology of stroke. Methods: All stroke and transient ischemic attack admissions to an academic hospital over a 2-year period were reviewed. Patients without DWI, with hemorrhagic strokes or with nonvascular disease were excluded. Two vascular neurologists reviewed medical records and classified the probable stroke etiology by modified TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. Another investigator, blinded to the clinical diagnoses, reviewed MRI images only. A ‘pearl’ was defined as a DWI bright lesion 20 mm or less in diameter. A ’string of pearls’ was defined as 3 or more pearls in a line found unilaterally in the anterior circulation. ‘Scattered pearls’ were classified as 3 or more pearls distributed such that no single line could connect them, also found unilaterally in the anterior circulation. Results: Fifty-six percent of the patients with either ‘pearls’ sign were classified as TOAST 1 or 2, with this classification only found in 33% of the patients with other DWI patterns (p = 0.0009). If either ‘pearl’ sign was seen on MRI, a patient was 2.65 times (95% CI = 1.32–5.32) more likely to have either extracranial or intracranial large-vessel stenosis. Conclusions: The presence of either ‘string of pearls’ or ‘scattered pearls’ on MRI was associated with an independently determined mechanism of intracranial or extracranial arterial stenosis. In patients with acute stroke distributions consistent with either of these patterns, additional vascular imaging should be considered.
Perfusion CT Improves Diagnostic Accuracy for Hyperacute Ischemic Stroke in the 3-Hour Window: Study of 100 Patients with Diffusion MRI Confirmation
Authors: Lin Ke , Do Kinh G. , Ong Phat , Shapiro Maksim , Babb James S. , Siller Keith A. , Pramanik Bidyut K.
Published: May 2009

Purpose: Conventional noncontrast CT (NCCT) is insensitive to hyperacute cerebral infarction in the first 3 h. Our aim was to determine if CT perfusion (CTP) can improve diagnostic accuracy over NCCT for patients presenting with stroke symptoms in the 3-hour window. Methods: Consecutive patients presenting to our emergency department with symptoms of ischemic stroke <3 h old and receiving NCCT and CTP as part of their triage evaluation were retrospectively reviewed. Patients with follow-up diffusion-weighted MRI (DWI) <7 days from ictus were included. Two readers rated the NCCT and CTP for evidence of acute infarct and its vascular territory. CTP selectively covered 24 mm of brain centered at the basal ganglia with low relative cerebral blood volume in a region of low cerebral blood flow or elevated time to peak as the operational definition for infarction. A third reader rated all follow-up DWI for acute infarct and its vascular territory as the reference standard. Sensitivity, specificity, and predictive values were calculated. An exact McNemar test and generalized estimating equations from a binary logistic regression model were used to assess the difference in detection rates between modalities. A two-sided p value <0.05 was considered significant. Results: 100 patients were included. Sixty-five (65%) patients had follow-up DWI confirmation of acute infarct. NCCT revealed 17 (26.2%) acute infarcts without false positives. CTP revealed 42 (64.6%) acute infarcts with one false positive. Of the 23 infarcts missed on CTP, 10 (43.5%) were outside the volume of coverage while the remaining 13 (56.5%) were small cortical or lacunar type infarcts (≤15 mm in size). CTP was significantly more sensitive (64.6 vs. 26.2%, p < 0.0001) and accurate (76.0 vs. 52%, p < 0.0001) and had a better negative predictive value (59.6 vs. 42.2%, p = 0.032) than NCCT. Conclusion: In a retrospective cohort of 100 patients with symptoms of hyperacute stroke in the 3-hour window, CTP provided improved sensitivity and accuracy over NCCT.