bluuebunny/crossref_metadata_2025 huggingface dataset:
Electromagnetic Radiation in Accelerator Physics
Authors: Stupakov G.
Published: December 2010

This article reviews some fundamental concepts and presents several recent techniques used for calculation of radiation in various environments. They include properties of longitudinal and transverse formation lengths of radiation, usage of the parabolic equation and the Kirchhoff diffraction integral in radiation, coherent radiation and fluctuations in the beam, and the radiative reaction force resulting from coherent radiation.
G. I. Budker: Brilliant Physicist, Great Scientific Leader
Authors: Skrinsky A. N.
Published: December 2010

In this brief article I present my memories and impressions of academician G. I. Budker (1918–1977), the brilliant physicist and outstanding leader of scientific research.
Energy Recovery Linacs for Light Sources
Authors: Hajima Ryoichi
Published: December 2010

Energy recovery linacs (ERLs), which can generate an electron beam having a high average current and a small-emittance with the complete manipulation of electron beams in the transverse and the longitudinal phase space, are expected to realize future light sources for various photon energies from terahertz to x- and γ-rays. In this paper, we present an overview of the history, current status, and prospects of ERLs for light sources. Research activities on the critical components of the ERLs, such as electron guns and superconducting cavities, are also described.
Electron-Beam-Based Sources of Ultrashort X-ray Pulses
Authors: Zholents Alexander
Published: December 2010

A review of various methods for generation of ultrashort X-ray pulses using relativistic electron beam from conventional accelerators is presented. Both spontaneous and coherent emission of electrons are considered.
Estuarine and Coastal Ocean Carbon Paradox: CO2 Sinks or Sites of Terrestrial Carbon Incineration?
Authors: Cai Wei-Jun
Published: December 2010

Estuaries are a major boundary in the land-ocean interaction zone where organic carbon (OC) and nutrients are being processed, resulting in a high water-to-air carbon dioxide (CO2) flux (∼0.25 Pg C y−1). The continental shelves, however, take up CO2 (∼0.25 Pg C y−1) from the atmosphere, accounting for approximately 17% of open ocean CO2 uptake (1.5 Pg C y−1). It is demonstrated here that CO2 release in estuaries is largely supported by microbial decomposition of highly productive intertidal marsh biomass. It appears that riverine OC, however, would bypass the estuarine zone, because of short river-transit times, and contribute to carbon cycling in the ocean margins and interiors. Low-latitude ocean margins release CO2 because they receive two-thirds of the terrestrial OC. Because of recent CO2 increase in the atmosphere, CO2 releases from low latitudes have become weaker and CO2 uptake by mid- and high-latitude shelves has become stronger, thus leading to more dissolved inorganic carbon export to the ocean.
Observations of CFCs and SF6 as Ocean Tracers
Authors: Fine Rana A.
Published: December 2010

An advantage of using chlorofluorocarbons (CFCs) and sulfur hexafluoride (SF6) as tracers of ocean circulation is that the time-dependent source functions permit calculation of rates for ocean processes. These compounds are also sensitive indicators highlighting interior ocean regions where surface-derived anomalies can be transported on timescales of decades. Significant applications for CFCs have been for the deep limb of the Atlantic meridional overturning circulation, upper ocean ventilation, and biogeochemical rates, including apparent oxygen utilization rates and anthropogenic CO2 inventories. Although CFCs have started to decrease in the atmosphere, SF6 continues to increase. There are benefits to measuring both CFCs and SF6: A large global CFC data set exists; CFCs are still increasing in older waters; SF6 expands estimates of age; and calculations of anthropogenic CO2 inventory are enhanced. Thus, the outlook for using CFCs as tracers for oceanic processes, and in particular in concert with SF6, remains very positive.
Influence of Thickness Variation on the Flapping Performance of Symmetric NACA Airfoils in Plunging Motion
Authors: Zhao Liangyu , Yang Shuxing
Published: December 2010

In order to investigate the impact of airfoil thickness on flapping performance, the unsteady flow fields of a family of airfoils from an NACA0002 airfoil to an NACA0020 airfoil in a pure plunging motion and a series of altered NACA0012 airfoils in a pure plunging motion were simulated using computational fluid dynamics techniques. The “class function/shape function transformation“ parametric method was employed to decide the coordinates of these altered NACA0012 airfoils. Under specified plunging kinematics, it is observed that the increase of an airfoil thickness can reduce the leading edge vortex (LEV) in strength and delay the LEV shedding. The increase of the maximum thickness can enhance the time‐averaged thrust coefficient and the propulsive efficiency without lift reduction. As the maximum thickness location moves towards the leading edge, the airfoil obtains a larger time‐averaged thrust coefficient and a higher propulsive efficiency without changing the lift coefficient.
Liver Transplantation for Hepatitis C and Alcoholic Liver Disease
Authors: Carbone Marco , Neuberger James
Published: December 2010

End-stage liver disease due to hepatitis C (HCV) and cirrhosis from alcohol (ALD) are the commonest indications for liver transplantation in the western countries. Up to one third of HCV-infected transplant candidates have a history of significant alcohol intake prior to transplantation. However, there are few data available about the possible interaction between alcohol and HCV in the post-transplant setting. Patients with both HCV and alcohol are more likely to die on the waiting list than those with ALD and HCV alone. However, after transplantation, non-risk adjusted graft and patient survival of patients with HCV + ALD are comparable to those of patients with HCV cirrhosis or ALD cirrhosis alone. In the short and medium term HCV recurrence after transplant in patients with HCV + ALD cirrhosis does not seem more aggressive than that in patients with HCV cirrhosis alone. A relapse in alcohol consumption in patients with HCV + ALD cirrhosis does not have a major impact on graft survival. The evidence shows that, as is currently practiced, HCV + ALD as an appropriate indication for liver transplantation. However, these data are based on retrospective analyses with relatively short follow-up so the conclusions must be treated with caution.
Labour and Neonatal Outcome in Small for Gestational Age Babies Delivered Beyond 36+0 Weeks: A Retrospective Cohort Study
Authors: Boers K. E. , van der Post J. A. M. , Mol Ben W. J. , van Lith J. M. M. , Scherjon S. A.
Published: December 2010

Objective. Small for gestational age (SGA) is associated with increased neonatal morbidity and mortality. At present, evidence on whether these pregnancies should be managed expectantly or by induction is lacking. To get insight in current policy we analysed data of the National Dutch Perinatal Registry (PRN).Methods. We used data of all nulliparae between 2000 and 2005 with a singleton in cephalic presentation beyond 36+0 weeks, with a birth weight below the 10th percentile. We analysed two groups of pregnancies: (I) with isolated SGA and (II) with both SGA and hypertensive disorders. Onset of labour was related to route of delivery and neonatal outcome.Results. Induction was associated with a higher risk of emergency caesarean section (CS), without improvement in neonatal outcome. For women with isolated SGA the relative risk of emergency CS after induction was 2.3 (95% Confidence Interval [CI] 2.1 to 2.5) and for women with both SGA and hypertensive disorders the relative risk was 2.7 (95% CI 2.3 to 3.1).Conclusion. Induction in pregnancies complicated by SGA at term is associated with a higher risk of instrumental deliveries without improvement of neonatal outcome. Prospective studies are needed to determine the best strategy in suspected IUGR at term.
Adverse Life Events and Depressive Symptoms in African American Youth: The Role of Control-Related Beliefs
Authors: Sanchez Yadira M. , Lambert Sharon F. , Ialongo Nicholas S.
Published: December 2010

The association between experiences of adverse life events and adolescent depressive symptoms has been well documented. However, this association is not consistently observed in urban and low income African American youth. In addition, mechanisms linking life event stress and African American adolescents' depressive symptoms have received little attention. This study examined past year violent and nonviolent life events assessed in 6th grade as predictors of 7th grade depressive symptoms among a community epidemiologically defined sample of 447 (47% girls) urban African American adolescents. Depressive symptoms were assessed twice, at a 1-year interval, and initial depressive symptoms were controlled in the analyses. Control-related beliefs were examined as mediators of the association between life events and depressive symptoms, and gender was examined as a moderator of the association between control-related beliefs and depressive symptoms. Associations among study variables were examined in a series of models, from general to more specific. A model in which nonviolent and violent life events were examined separately and control and contingency beliefs examined as one latent variable was the most informative about the etiology of depressive symptoms in a sample of urban, African American youth. Implications of the findings for preventive interventions and future research are discussed.
Pierce1, a Novel p53 Target Gene Contributing to the Ultraviolet-Induced DNA Damage Response
Authors: Sung Young Hoon , Kim Hye Jin , Devkota Sushil , Roh Jusik , Lee Jaehoon , Rhee Kunsoo , Bahk Young Yil , Lee Han-Woong
Published: December 2010

Retinoblastoma (Rb) and p53 genes are mutated or inactivated in most human cancers and mutually regulate each other. Recently, we reported that expression of diverse genes was altered in Rb-deficient mouse embryonic fibroblasts (MEF). In this study, we found that Pierce1, a novel transcript upregulated in Rb-deficient MEFs, is a transcriptional target of p53. Although Pierce1 promoter did not respond to the ectopic expression of E2F1, it was strongly activated by p53 via 2 cis-elements. Consistently, the expression of Pierce1 was induced by genotoxic stresses that activate p53 but was not detected in p53-deficient MEFs. Pierce1 was posttranslationally stabilized by ultraviolet C (UVC) irradiation, and UVC-activated ATR (ataxia telangiectasia-mutated and Rad3-related) signaling suppressed proteosomal degradation of Pierce1 protein. Furthermore, knockdown of Pierce1 compromised the checkpoint response of wild-type MEFs to UVC irradiation, accompanying the diminished expression of p53 target genes. Together, our data suggest that Pierce1 is an important p53 target gene contributing to normal DNA damage response and may play crucial roles in maintaining genomic integrity against genotoxic stresses, including UVC irradiation. Cancer Res; 70(24); 10454–63. ©2010 AACR.
HIF-2α Enhances β-Catenin/TCF-Driven Transcription by Interacting with β-Catenin
Authors: Choi Hyunsung , Chun Yang-Sook , Kim Tae-You , Park Jong-Wan
Published: December 2010

The tumor-promoting factors β-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1α negatively regulates Wnt/β-catenin signaling by sequestering β-catenin from β-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2α in β-catenin regulation. In this study, it was found that, like HIF-1α, HIF-2α interacts with β-catenin, but at a different site. Furthermore, HIF-2α was found to assemble with β-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2α promote p300 coactivator recruitment by β-catenin. Furthermore, HIF-2α and β-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2α was found to be required for β-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2α and β-catenin. Interestingly, these actions of HIF-2α oppose those of HIF-1α on β-catenin and cell growth, and this suggests that HIF-1α/HIF-2α balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist. Cancer Res; 70(24); 10101–11. ©2010 AACR.
The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
Authors: Liu Manran , Sakamaki Toshiyuki , Casimiro Mathew C. , Willmarth Nicole E. , Quong Andrew A. , Ju Xiaoming , Ojeifo John , Jiao Xuanmao , Yeow Wen-Shuz , Katiyar Sanjay , Shirley L. Andrew , Joyce David , Lisanti Michael P. , Albanese Christopher , Pestell Richard G.
Published: December 2010

The role of mammary epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor stem cell pathways. IκBαSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB–dependent mammary tumorigenesis. Cancer Res; 70(24); 10464–73. ©2010 AACR.
Human Bone Marrow–Derived MSCs Can Home to Orthotopic Breast Cancer Tumors and Promote Bone Metastasis
Authors: Goldstein Robert H. , Reagan Michaela R. , Anderson Kristen , Kaplan David L. , Rosenblatt Michael
Published: December 2010

American women have a nearly 25% lifetime risk of developing breast cancer, with 20% to 40% of these patients developing life-threatening metastases. More than 70% of patients presenting with metastases have skeletal involvement, which signals progression to an incurable stage. Tumor–stroma cell interactions are only superficially understood, specifically regarding the ability of stromal cells to affect metastasis. In vivo models show that exogenously supplied human bone marrow–derived stem cells (hBMSC) migrate to breast cancer tumors, but no reports have shown endogenous hBMSC migration from the bone to primary tumors. Here, we present a model of in vivo hBMSC migration from a physiologic human bone environment to human breast tumors. Furthermore, hBMSCs alter tumor growth and bone metastasis frequency. These may home to certain breast tumors based on tumor-derived TGF-β1. Moreover, at the primary tumor level, interleukin 17B (IL-17B)/IL-17BR signaling may mediate interactions between hBMSCs and breast cancer cells. Cancer Res; 70(24); 10044–50. ©2010 AACR.
Paxillin Predicts Survival and Relapse in Non–Small Cell Lung Cancer by MicroRNA-218 Targeting
Authors: Wu De-Wei , Cheng Ya-Wen , Wang John , Chen Chih-Yi , Lee Huei
Published: December 2010

Paxillin (PXN) gene mutations are associated with lung adenocarcinoma progression and PXN is known to be a target gene of microRNA-218 (miR-218). On this basis, we hypothesized that PXN overexpression via miR-218 suppression may promote tumor progression and metastasis and that PXN may predict survival and relapse in non–small cell lung cancer (NSCLC). Expression of miR-218 and PXN in 124 surgically resected lung tumors were evaluated by real-time PCR and immunohistochemical analysis. The prognostic value of miR-218 and PXN expression on overall survival (OS) and relapse-free survival (RFS) was analyzed by the Kaplan–Meier test and Cox regression analysis. miR-218 expression in lung tumors was negatively associated with PXN expression. Multivariate analyses showed that PXN and miR-218 might independently predict OS and RFS, respectively, in NSCLC. Moreover, patients with low miR-218 combined with PXN-positive had the worst OS and RFS among the 4 combinations. In a cell model, PXN was negatively regulated by miR-218 and cell proliferation, invasion, and soft agar colony formation were enhanced by PXN overexpression induced by miR-218 suppression. Taken together, our findings suggest that PXN overexpression induced by miR-218 suppression is an independent predictor of survival and relapse in NSCLC, highlighting PXN as a potential therapeutic target to improve clinical outcomes in this disease. Cancer Res; 70(24); 10392–401. ©2010 AACR.
Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations
Authors: Okamoto Kunio , Okamoto Isamu , Okamoto Wataru , Tanaka Kaoru , Takezawa Ken , Kuwata Kiyoko , Yamaguchi Haruka , Nishio Kazuto , Nakagawa Kazuhiko
Published: December 2010

The molecular mechanism by which epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non–small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation–positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation–positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI–induced apoptotic death in these cells. Cancer Res; 70(24); 10402–10. ©2010 AACR.
Conditional Deletion of the Focal Adhesion Kinase FAK Alters Remodeling of the Blood–Brain Barrier in Glioma
Authors: Lee Jisook , Borboa Alexandra K. , Chun Hyun Bae , Baird Andrew , Eliceiri Brian P.
Published: December 2010

Gliomas generally infiltrate the surrounding normal brain parenchyma, a process associated with increased vascular permeability (VP) and dysregulation of the blood–brain barrier (BBB). However, the molecular mechanisms underlying glioma-induced VP in the brain remain poorly understood. Using a conditional, endothelium-specific deletion of the focal adhesion kinase (FAK) in the mouse (FAK CKO), we show that FAK is critical for destabilization of the tumor endothelium in tumor-bearing mice, with mutant mice exhibiting a relatively normalized vasculature compared with wild-type mice (FAK WT). Tumor vessels in the FAK CKO mice displayed reduced VP compared with FAK WT mice, resulting in reduced tumor growth. Additionally, FAK CKO mice displayed partial restoration of cell–cell junction proteins in the tumor vessels and astrocyte–endothelium interactions in tumors, revealing an additional role of astrocytes in mediating tumor-induced VP. Together, these results provide genetic evidence that FAK is a mediator of tumor-induced VP in the brain. Our findings may help understand how therapeutics might be used to regulate specific cell-type interactions to restore BBB structure/function in cancer and perhaps other pathologic conditions. Cancer Res; 70(24); 10131–40. ©2010 AACR.
RETRACTED: Loss of Metallothionein Predisposes Mice to Diethylnitrosamine-Induced Hepatocarcinogenesis by Activating NF-κB Target Genes
Authors: Majumder Sarmila , Roy Satavisha , Kaffenberger Thomas , Wang Bo , Costinean Stefan , Frankel Wendy , Bratasz Anna , Kuppusamy Periannan , Hai Tsonwin , Ghoshal Kalpana , Jacob Samson T.
Published: December 2010

Metallothioneins (MT) are potent scavengers of free radicals that are silenced in primary hepatocellular carcinomas (HCC) of human and rodent origin. To examine whether loss of MT promotes hepatocarcinogenesis, male Mt-1 and Mt-2 double knockout (MTKO) and wild-type (WT) mice were exposed to diethylnitrosamine (DEN) and induction of HCC was monitored at 23 and 33 weeks. The size and number of liver tumors, the ratio between liver and body weight, and liver damage were markedly elevated in the MTKO mice at both time points compared with the WT mice. At 23 weeks, MTKO mice developed HCC whereas WT mice developed only preneoplastic nodules suggesting that loss of MT accelerates hepatocarcinogenesis. MTKO tumors also exhibited higher superoxide anion levels. Although NF-κB activity increased in the liver nuclear extracts of both genotypes after DEN exposure, the complex formed in MTKO mice was predominantly p50/65 heterodimer (transcriptional activator) as opposed to p50 homodimer (transcriptional repressor) in WT mice. Phosphorylation of p65 at Ser276 causing its activation was also significantly augmented in DEN-exposed MTKO livers. NF-κB targets that include early growth response genes and proinflammatory cytokines were significantly upregulated in MTKO mice. Concurrently, there was a remarkable increase (∼100-fold) in Pai-1 expression; significant increase in c-Jun, c-Fos, c-Myc, Ets2, and ATF3 expressions; and growth factor signaling that probably contributed to the increased tumor growth in MTKO mice. Taken together, these results demonstrate that MTs protect mice from hepatocarcinogen-induced liver damage and carcinogenesis, underscoring their potential therapeutic application against hepatocellular cancer. Cancer Res; 70(24); 10265–76. ©2010 AACR.
Tip30 Deletion in MMTV-Neu Mice Leads to Enhanced EGFR Signaling and Development of Estrogen Receptor–Positive and Progesterone Receptor–Negative Mammary Tumors
Authors: Zhang Chengliang , Mori Mikito , Gao Shenglan , Li Aimin , Hoshino Isamu , Aupperlee Mark D. , Haslam Sandra Z. , Xiao Hua
Published: December 2010

Estrogen receptor–positive and progesterone receptor–negative (ER+/PR−) breast cancers account for 15% to 25% of all human breast cancers and display more aggressive malignant characteristics than ER+/PR+ cancers. However, the molecular mechanism underlying development of ER+/PR− breast cancers still remains elusive. We show here that Tip30 deletion dramatically accelerated the onset of mammary tumors in the MMTV-Neu mouse model of breast cancer. The mammary tumors arising in Tip30−/−/MMTV-Neu mice were exclusively ER+/PR−. The growth of these ER+/PR− tumors depends not only on estrogen but also on progesterone despite the absence of detectable PR. Tip30 is predominantly expressed in ER+ mammary epithelial cells, and its deletion leads to an increase in the number of phospho-ERα–positive cells in mammary glands and accelerated activation of Akt in MMTV-Neu mice. Moreover, we found that Tip30 regulates the EGFR pathway through controlling endocytic downregulation of EGFR protein level and signaling. Together, these findings suggest a novel mechanism in which loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling, leading to the development of ER+/PR− mammary tumors. Cancer Res; 70(24); 10224–33. ©2010 AACR.
Antagonism of Cytotoxic Chemotherapy in Neuroblastoma Cell Lines by 13-cis-Retinoic Acid Is Mediated by the Antiapoptotic Bcl-2 Family Proteins
Authors: Hadjidaniel Michael D. , Reynolds C. Patrick
Published: December 2010

13-cis-Retinoic acid (13-cis-RA) is given at completion of cytotoxic therapy to control minimal residual disease in neuroblastoma. We investigated the effect of combining 13-cis-RA with cytotoxic agents employed in neuroblastoma therapy using a panel of 6 neuroblastoma cell lines. The effect of 13-cis-RA on the mitochondrial apoptotic pathway was studied by flow cytometry, cytotoxicity by DIMSCAN, and protein expression by immunoblotting. Pretreatment and direct combination of 13-cis-RA with etoposide, topotecan, cisplatin, melphalan, or doxorubicin markedly antagonized the cytotoxicity of those agents in 4 out of 6 tested neuroblastoma cell lines, increasing fractional cell survival by 1 to 3 logs. The inhibitory concentration of drugs (IC99) increased from clinically achievable levels to nonachievable levels, greater than 5-fold (cisplatin) to greater than 7-fold (etoposide). In SMS-KNCR neuroblastoma cells, 13-cis-RA upregulated expression of Bcl-2 and Bcl-xL RNA and protein, and this was associated with protection from etoposide-mediated apoptosis at the mitochondrial level. A small molecule inhibitor of the Bcl-2 family of proteins (ABT-737) restored mitochondrial membrane potential loss and apoptosis in response to cytotoxic agents in 13-cis-RA treated cells. Prior selection for resistance to RA did not diminish the response to cytotoxic treatment. Thus, combining 13-cis-RA with cytotoxic chemotherapy significantly reduced the cytotoxicity for neuroblastoma in vitro, mediated at least in part via the antiapoptotic Bcl-2 family of proteins. Mol Cancer Ther; 9(12); 3164–74. ©2010 AACR.
Phase I Clinical Trial of MPC-6827 (Azixa), a Microtubule Destabilizing Agent, in Patients with Advanced Cancer
Authors: Tsimberidou Apostolia-Maria , Akerley Wallace , Schabel Matthias C. , Hong David S. , Uehara Cynthia , Chhabra Anil , Warren Terri , Mather Gary G. , Evans Brent A. , Woodland Deane P. , Swabb Edward A. , Kurzrock Razelle
Published: December 2010

MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on β-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m2, with subsequent increments of 0.6 mg/m2 until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1–10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m2 (1/6 patients) and at 4.5 mg/m2 (1/7 patients). The MTD was determined to be 3.3 mg/m2 (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m2 once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing. Mol Cancer Ther; 9(12); 3410–9. ©2010 AACR.
Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation
Authors: Rho Jin Kyung , Choi Yun Jung , Jeon Byung-Suk , Choi Su Jin , Cheon Gi Jeong , Woo Sang-Keun , Kim Hye-Ryoun , Kim Cheol Hyeon , Choi Chang-Min , Lee Jae Cheol
Published: December 2010

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) produce an initially dramatic response in lung cancer patients harboring a mutation in the EGFR gene, development of acquired resistance is almost inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. This study investigated whether the addition of silibinin to therapy with gefitinib or erlotinib could overcome T790M-mediated drug resistance considering that silibinin has various antitumor effects, including EGFR modulation. Silibinin selectively reduced the activity of the EGFR family (EGFR, ErbB2, and ErbB3) through the inhibition of receptor dimerization in lung cancer cells with EGFR mutations, but not in those harboring the wild type. In primary and acquired resistant cells with T790M, addition of silibinin enhanced the ability of EGFR-TKIs to downregulate EGFR signals and to inhibit cell growth. Similarly, the combination of silibinin and erlotinib effectively suppressed tumor growth in erlotinib resistance-bearing PC-9 xenografts. The results indicate that the addition of silibinin to EGFR-TKIs is a promising strategy to overcome T790M-mediated drug resistance. Mol Cancer Ther; 9(12); 3233–43. ©2010 AACR.
Genome-Wide mRNA and microRNA Profiling of the NCI 60 Cell-Line Screen and Comparison of FdUMP[10] with Fluorouracil, Floxuridine, and Topoisomerase 1 Poisons
Authors: Gmeiner William H. , Reinhold William C. , Pommier Yves
Published: December 2010

A profile of microRNA (miRNA) and mRNA expression patterns across the NCI-60 cell-line screen was analyzed to identify expression signatures that correlate with sensitivity to FdUMP[10], fluorouracil (5FU), floxuridine (FdU), topotecan, and irinotecan. Genome-wide profile analyses revealed FdUMP[10] resembles FdU most closely and shows dissimilarities with 5FU. FdUMP[10] had the largest dynamic range of any of these drugs across the NCI-60 indicative of cancer cell–specific activity. Genes involved in endocytosis, such as clathrin (CLTC), SNF8, annexin A6 (ANXA6), and amyloid protein-binding 2 (APPBP2) uniquely correlated with sensitivity to FdUMP[10], consistent with a protein-mediated cellular uptake of FdUMP[10]. Genes involved in nucleotide metabolism were enriched for the three fluoropyrimidine drugs, with the expression profile for 5FU correlated to an RNA-mediated cytotoxic mechanism, whereas expression of glycosyltransferases (XYLT2) that use UDP sugars as substrates and the nucleoside diphosphatase and metastasis suppressor NM23 (NME1) were associated with FdUMP[10] sensitivity. Topotecan and irinotecan had significant negative correlations with miR-24, a miRNA with a high aggregate PCT score for topoisomerase 1 (Top1). Our results reveal significant new correlations between FdUMP[10] and Top1 poisons, as well as new information on the unique cytotoxic mechanism and genomic signature of FdUMP[10]. Mol Cancer Ther; 9(12); 3105–14. ©2010 AACR.
Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized 13C Magnetic Resonance Spectroscopy
Authors: Bohndiek Sarah E. , Kettunen Mikko I. , Hu De-en , Witney Timothy H. , Kennedy Brett W.C. , Gallagher Ferdia A. , Brindle Kevin M.
Published: December 2010

Nuclear spin hyperpolarization can dramatically increase the sensitivity of the 13C magnetic resonance experiment, allowing dynamic measurements of the metabolism of hyperpolarized 13C-labeled substrates in vivo. Here, we report a preclinical study of the response of lymphoma tumors to the vascular disrupting agent (VDA), combretastatin-A4-phosphate (CA4P), as detected by measuring changes in tumor metabolism of hyperpolarized [1-13C]pyruvate and [1,4-13C2]fumarate. These measurements were compared with dynamic contrast agent–enhanced magnetic resonance imaging (DCE-MRI) measurements of tumor vascular function and diffusion-weighted MRI (DW-MRI) measurements of the tumor cell necrosis that resulted from subsequent loss of tumor perfusion. The rate constant describing flux of hyperpolarized 13C label between [1-13C]pyruvate and lactate was decreased by 34% within 6 hours of CA4P treatment and remained at this lower level at 24 hours. The rate constant describing production of labeled malate from hyperpolarized [1,4-13C2]fumarate increased 1.6-fold and 2.5-fold at 6 and 24 hours after treatment, respectively, and correlated with the degree of necrosis detected in histologic sections. Although DCE-MRI measurements showed a substantial reduction in perfusion at 6 hours after treatment, which had recovered by 24 hours, DW-MRI showed no change in the apparent diffusion coefficient of tumor water at 6 hours after treatment, although there was a 32% increase at 24 hours (P < 0.02) when regions of extensive necrosis were observed by histology. Measurements of hyperpolarized [1-13C]pyruvate and [1,4-13C2]fumarate metabolism may provide, therefore, a more sustained and sensitive indicator of response to a VDA than DCE-MRI or DW-MRI, respectively. Mol Cancer Ther; 9(12); 3278–88. ©2010 AACR.
Treatment Patterns and Outcomes in Bulky Stage IB2 Cervical Cancer Patients: A Single Institution’s Experience over 14 Years
Authors: Kim Woo Young , Chang Suk-Joon , Chang Ki-Hong , Yoo Seung-Chul , Chun Mison , Ryu Hee-Sug
Published: December 2010

Aim: The aim of this study was to assess various treatment options in stage IB2 cervical cancer patients. Methods: Between January 1995 and May 2007, 63 patients with stage IB2 were treated by radical hysterectomy (n = 28), primary concurrent chemoradiation (CCRT, n = 16) or radiation therapy (RT, n = 19). Disease-free survival (DFS) and overall survival (OS) were compared between these treatment modalities. Results: The 3-year DFS of the surgical approach group was 67.5% compared to 70.3% of the primary RT/CCRT group (p = 0.603). The 5-year OS of all patients was 75.9%. The 5-year OS of the surgical approach group was 81.6% compared to 76.2% of the primary RT/CCRT group (p = 0.578). Twelve (42.8%) of 28 surgically treated patients had high-risk pathologic factors. Out of 20 premenopausal patients who underwent the surgical approach, ovarian preservation was possible in 13 patients without adjuvant CCRT. Of these 13 patients, 7 patients did not experience disease recurrence and continued normal ovarian function. Conclusion: Both radical hysterectomy and primary RT/CCRT are effective treatment options in IB2 cervical cancer. In addition, the surgical approach can be considered for preserving ovarian function in premenopausal IB2 cervical cancer patients.
Sustained-Release Dinoprostone Vaginal Pessary with Concurrent High-Dose Oxytocin Infusion Compared to Sustained-Release Dinoprostone Vaginal Pessary Followed 6 h Later by High-Dose Oxytocin Infusion for Labor Induction in Women at Term with Unfavorable Cervix: A Randomized Controlled Trial
Authors: Güngördük Kemal , Yildirim Gokhan , Güngördük Ozgu , Ark Cemal , Tekirdağ İsmet
Published: December 2010

Objective: To compare the efficacy and safety of sustained-release dinoprostone vaginal pessary and concurrent high-dose oxytocin infusion with sustained-release dinoprostone vaginal pessary followed 6 h later by high-dose oxytocin infusion for cervical ripening and labor induction. Methods: A total of 500 nulliparous or multiparous women with a singleton pregnancy, Bishop score ≤4 and admitted for labor induction. Women were randomly assigned to induction of labor using intravaginal dinoprostone with concurrent high-dose oxytocin (n = 250) or intravaginal dinoprostone pessary followed 6 h later by high-dose oxytocin (n = 250). The primary outcome was the number of vaginal deliveries achieved within 24 h of labor induction. Results: Baseline characteristics of both groups were comparable. Vaginal delivery within 24 h of labor induction was significantly increased with sustained-release dinoprostone followed 6 h later by high-dose oxytocin infusion (92.8 vs. 82.0%, RR 2.82, 95% CI 1.58–5.04). There were more cesarean section deliveries in the dinoprostone with concurrent high-dose oxytocin group (16.8 vs. 6.8%, RR 0.36, 95% CI 0.20–0.65). Maternal outcomes did not differ significantly. An Apgar score of <7 at 5 min was found more often in the dinoprostone with concurrent high-dose oxytocin group (3.6%) in comparison to dinoprostone pessary followed 6 h later by high-dose oxytocin (0.8%), although this was not statistically different (RR 0.21, 95% CI 0.04–1.01). Conclusion: Sustained-release dinoprostone followed 6 h later by high-dose oxytocin infusion appears to be safer and more effective than sustained-release dinoprostone with concurrent high-dose oxytocin infusion in achieving cervical ripening and successful vaginal delivery.
Quantification of Feto-Maternal Hemorrhage: Selection of Techniques for a Resource-Poor Setting
Authors: Agarwal Prashant , Sekhar Das Sudipta , Gupta Ritu , Khetan Dheeraj , Chaudhary Rajendra
Published: December 2010

Background: Though RhD sensitization in RhD-negative mothers is now almost eradicated in the developed world, it continues to be a major health problem in developing nations like India. Inadequate immunoprophylaxis is the main reason. Adequate dose calculation of anti-D Ig is possible through estimation of correct feto-maternal hemorrhage (FMH) volume. In this regard, different methods have been used. Methods: We evaluated three quantitative techniques of estimating FMH: the Kleihauer-Betke test (KBT) and two flow cytometry (FC) techniques, i.e., the indirect immunofluorescence technique (IIFT) and direct immunofluorescence technique (DIFT). Stock solutions of both RhD-positive and D-negative cells were made, and 7 serial dilutions of RhD-positive cord cells in D-negative adult cells were prepared. Result: Both KBT and FC approximated the expected concentration of fetal RhD-positive cells in all mixtures tested. In both methods, an underestimation of fetal RhD-positive cells was observed when their expected concentration was ≧0.75%. Conclusion: Though FC is the most sensitive of all techniques, very few laboratories in developing nations can afford such a costly device, so it will be prudent for them to use KBT as the gold standard due to its rapidity, simplicity and affordability.
A Randomized Comparison of Droperidol, Metoclopramide, Tropisetron, and Ondansetron for the Prevention of Postoperative Nausea and Vomiting
Authors: Ekinci Osman , Malat Ibrahim , Işıtmangil Gülbu , Aydın Neşe
Published: December 2010

Background: Nausea and vomiting are the most common causes of postoperative complications, and they are seen most often after operations performed using general anesthesia and sedation. We designed this study to compare the effects of droperidol, metoclopramide, tropisetron, and ondansetron for the prevention of postoperative nausea and vomiting in patients undergoing gynecologic operations. Methods: One hundred patients were randomly assigned to 1 of 5 groups: group D was given 2.5 mg droperidol; group M, 10 mg metoclopramide; group T, 2.5 mg tropisetron; group O, 4 mg ondansetron 5 min after induction, and group C was the control group and received no prophylactic antiemetic treatment. All patients were observed for sedation and postoperative nausea and vomiting for 48 h. Results: Within 24 h after the operation, severe postoperative nausea and vomiting were seen in 4 patients (20%) in group D, 8 (40%) in group M, 5 (25%) in group T, 3 (15%) in group O, and 12 patients (60%) in the control group. Patients receiving droperidol, tropisetron, and ondansetron had significantly less serious emesis than the control group (p < 0.05). Sedation was seen in 5 patients receiving droperidol (4 patients score 2; and 1 patient score 3) and tropisetron (2 patients score 2; and 3 patients score 3) 15 min after surgery; this was significantly higher than in the control group (p < 0.05). Conclusion: We conclude that metoclopramide is not effective in preventing postoperative nausea and vomiting after gynecologic operations. Droperidol, tropisetron, and ondansetron are effective; however, the sedating effects of droperidol and tropisetron should be considered.
Chlorophyll Breakdown as Seen in Bananas: Sign of Aging and Ripening – A Mini-Review
Authors: Müller Thomas , Kräutler Bernhard
Published: December 2010

The ripening of bananas is seen by a characteristic change of their color from deep green to bright yellow. Likewise, their over-ripening and eventual rotting are accompanied by the appearance of an unappetizing brown. Chlorophyll breakdown is a major contributor to the visual signs of these processes in bananas. Outlined here are the basic structures of chlorophyll catabolites in higher plants, with particular reference to ripening and aging bananas. In these fruits, unique fluorescent chlorophyll catabolites accumulate and give rise to their fascinating blue luminescence.
Specific Localization of Five Phosphatidylcholine Species in the Cochlea by Mass Microscopy
Authors: Takizawa Yoshinori , Mizuta Kunihiro , Hayasaka Takahiro , Nakanishi Hiroshi , Okamura Jun , Mineta Hiroyuki , Setou Mitsutoshi
Published: December 2010

Phosphatidylcholine (PC), a phospholipid, is a basic structural component of cell membranes. PC species exhibit various binding patterns with fatty acids; however, the distributions of PC species have not been studied in the cochlea. In recent years, imaging mass spectrometry has been used as a biomolecular visualization technique in medical and biological sciences. We recently developed a ‘mass microscope’ consisting of a mass spectrometry imager with high spatial resolution equipped with an atmospheric-pressure matrix-assisted laser desorption/ionization and quadrupole ion trap time-of-flight analyzer. In this study, we applied the mass microscope to analyze cochlear tissue sections. The imager allowed visualization of the localization of PC species in each region of the cochlea. The structures of the PC species were determined using tandem mass spectrometry. PC(16:0/18:1) was highly localized in the organ of Corti and the stria vascularis. PC(16:0/18:2) was mainly observed in the spiral ligament. PC(16:0/16:1) was found primarily in the organ of Corti. These distributional differences may be associated with the cellular architecture of these cochlear regions.
Development, Cell Differentiation, Angiogenesis—Microparticles and Their Roles in Angiogenesis
Authors: Shai Ela , Varon David
Published: December 2010

Cells of various types release small membrane vesicles called microparticles (MP) on their activation, as well as during the process of apoptosis. The properties and roles of MP generated in different contexts are diverse and are determined by their parent cell and the pathway of their generation, which affects their content. MP are involved in multiple cellular functions, including immunomodulation, inflammation, coagulation, and intercellular communication. MP are able to deliver molecular signals in the form of lipids, proteins, nucleic acids, or functional transmembrane proteins from the parent cell to distantly located targets. In this review, we summarize some of the current knowledge regarding MP and their functional roles in transfer of proteins, nucleic acids, and signal transduction stimulators between cells of different origins in different settings. We will focus on the ability of MP to mediate angiogenesis-related signals and their effect on cell development. The investigation of MP could elucidate new cellular communication pathways and may lead to better understanding of pathophysiological processes. From a clinical point of view, MP may serve as biomarkers for disease status and may be found useful for developing novel therapeutic strategies targeting angiogenesis-related conditions.
Who Has Higher Readmission Rates for Heart Failure, and Why?
Authors: Joynt Karen E. , Jha Ashish K.
Published: December 2010

Background—

Reducing readmissions for heart failure is an important goal for policymakers. Current national policies financially penalize hospitals with high readmission rates, which may have unintended consequences if these institutions are resource-poor, either financially or clinically.

Methods and Results—

We analyzed national claims data for Medicare patients with heart failure discharged from US hospitals in 2006 to 2007. We used multivariable models to examine hospital characteristics, 30-day all-cause readmission rates, and likelihood of performing in the worst quartile of readmission rates nationally. Among 905 764 discharges in our sample, patients discharged from public hospitals (27.9%) had higher readmission rates than nonprofit hospitals (25.7%,
P
<0.001), as did patients discharged from hospitals in counties with low median income (29.4%) compared with counties with high median income (25.7%,
P
<0.001). Patients discharged from hospitals without cardiac services (27.2%) had higher readmission rates than those from hospitals with full cardiac services (25.1%,
P
<0.001); patients discharged from hospitals in the lowest quartile of nurse staffing (28.5%) had higher readmission rates than those from hospitals in the highest quartile (25.4%,
P
<0.001). Patients discharged from small hospitals (28.4%) had higher readmission rates than those discharged from large hospitals (25.2%,
P
<0.001). These same characteristics identified hospitals that were likely to perform in the worst quartile nationally.

Conclusions—

Given that many poor-performing hospitals also have fewer resources, they may suffer disproportionately from financial penalties for high readmission rates. As we seek to improve care for patients with heart failure, we should ensure that penalties for poor performance do not worsen disparities in quality of care.
On the Use of Geometric Moments to Examine the Continuum of Sudden Stratospheric Warmings
Authors: Hannachi A. , Mitchell D. , Gray L. , Charlton-Perez A.
Published: December 2010

The polar winter stratospheric vortex is a coherent structure that undergoes different types of deformation that can be revealed by the geometric invariant moments. Three moments are used—the aspect ratio, the centroid latitude, and the area of the vortex based on stratospheric data from the 40-yr ECMWF Re-Analysis (ERA-40) project—to study sudden stratospheric warmings. Hierarchical clustering combined with data image visualization techniques is used as well. Using the gap statistic, three optimal clusters are obtained based on the three geometric moments considered here. The 850-K potential vorticity field, as well as the vertical profiles of polar temperature and zonal wind, provides evidence that the clusters represent, respectively, the undisturbed (U), displaced (D), and split (S) states of the polar vortex. This systematic method for identifying and characterizing the state of the polar vortex using objective methods is useful as a tool for analyzing observations and as a test for climate models to simulate the observations. The method correctly identifies all previously identified major warmings and also identifies significant minor warmings where the atmosphere is substantially disturbed but does not quite meet the criteria to qualify as a major stratospheric warming.