bluuebunny/crossref_metadata_2025 huggingface dataset:
Field permeability of the weathered Champlain clay crust
Authors: Lafleur J. , Giroux F. , Huot M.
Published: June 2008

This paper discusses methods for evaluating the coefficient of permeability k of the weathered and fissured Champlain clay crust. This parameter is important because losses due to seepage from fluid-retaining structures are directly porportional to the value of k. The presence of fissures complicates its evaluation, and conventional techniques produce questionable results for two reasons: Clogging of fissures by the smearing of the clay on the walls of test holes during drilling and insertion of a probe leads to an underestimation of k, and conversely, hydraulic fracturing caused by the application of excessive heads leads to an overestimation of k. A new technique is presented that prevents the smearing of the clay by reaming the walls of a prebored auger hole. Falling head and constant head tests were performed with feeding devices using a large range of heads including low values. Results confirm that hydraulic fracturing occurs when a critical value of head is reached. As a result, the use of the low-head reaming permeameter described in this paper appears suitable for evaluating the coefficient of permeability of weathered Champlain clay crust. Key words: permeability, field test, hydraulic fracturing, fissured clay, smearing effect.
Geologic and seismic setting pertinent to dam safety review of Duncan Dam
Authors: Little Tim E. , Imrie Alan S. , Psutka John F.
Published: June 2008

Duncan Dam is a B.C. Hydro facility constructed on the Duncan River in southeastern British Columbia, Canada, between 1965 and 1967. The dam was founded on a complex sequence of more than 380 m of glacial drift and glaciofluvial sediments, some of which are pervious and compressible. Some sandy units are potentially liquefiable, in particular a sand layer (unit 3c) up to 23 m thick. Current B.C. Hydro seismic guidelines for dams require that Duncan Dam should be able to withstand the Maximum Credible Earthquake (MCE) without catastrophic release of the reservoir. This paper describes the geologic and seismic setting of the region around the dam and the selection of seismic ground motion parameters. Probabilistic methods were applied to develop MCE ground motions, which were estimated to consist of a firm ground peak horizontal acceleration of 0.12 g, which could be caused by a M 6.5 earthquake at a distance of about 50 km. Several time histories with characteristics similar to this design earthquake were selected for dynamic soil analyses. Key words : dam safety, embankment dam, liquefaction, sand, seismicity, seismic ground motion.
In situ sampling, density measurements, and testing of foundation soils at Duncan Dam
Authors: Plewes Howard D. , Pillai V. Sitham , Morgan Michael R. , Kilpatrick Brian L.
Published: June 2008

As part of the B.C. Hydro Dam Safety Review of Duncan Dam, a comprehensive two-phased program of field and laboratory investigations was carried out between 1988 and 1992 to evaluate the potential for liquefaction of the foundation soils during an earthquake. The initial screening level phase 1 field investigations comprised basic soil sampling, standard penetration tests, and cone penetration tests to determine the spatial distribution of the foundation soils beneath the dam and to characterize the basic engineering properties of the soil units. A screening study using Seed's liquefaction assessment method indicated that soil unit 3c consisting of uniform fine-grained sand would be susceptible to liquefaction. The phase 2 investigations consisted of detailed and careful soil sampling to obtain high-quality in situ samples of the unit 3c sand for laboratory triaxial and simple shear tests. Samples were obtained using a conventional fixed piston sampler and a specially modified Christensen double core barrel sampler. The samples were frozen to minimize sample disturbance during handling and transport. Ground freezing was also conducted using liquid nitrogen, and the frozen soil was sampled using a CRREL core barrel. Borehole density logging was performed to assess the quality and level of disturbance of the soil samples. This paper discusses the procedures and results of the phases 1 and 2 field investigations. Key words : standard penetration test, cone penetration test, geophysical logging, energy calibration, soil sampling, freezing.
Instability and stabilization of an embankment on the Irbid–Amman Highway in Jordan
Authors: Al-Homoud Azm S. , Tal Ahmad B. , Husein (Malkawi) Abdallah I.
Published: June 2008

This paper includes a summary of a geotechnical investigation of an embankment site at station 47 + 300 along the Irbid–Amman Highway in Jordan. The embankment suffered instability problems. This study includes geological and geotechnical mapping of the study area as well as determination of the engineering properties of the various materials encountered at the site.Stability analysis is carried out for the original embankment to explain the failure mechanism, assess the condition at the time of failure, and evaluate the soil parameters for use in stability analysis of remedial measures. Stability analysis is carried out for remedial works. Recommendations are suggested to stabilize the sliding area and to repair the road traversing this landslide zone. Key words : slope stability, embankment, remediation.
Behaviour of a cemented clay
Authors: Feda Jaroslav
Published: June 2008

A series of 18 triaxial CIUP (undrained isotropically consolidated with pore pressure measurement) tests of fissured cemented Neogene lacustrine clay from northern Bohemia is analyzed, with special reference to the shear strength. The effects of sample disturbance, swelling, and cementation are shown to be the principal factors affecting the shear envelope. During the prepeak stage of testing, destruction of the cementation of some specimens occurs, which is reflected in the wavy form of the stress–strain diagrams. The linear strength envelopes were found to be arranged according to the amount of disturbance (as expressed in the magnitude of swelling). Cemented and uncemented specimens differ when pore-water pressure and stress–strain diagrams are compared. Key words : Miocene clay, undisturbed samples, triaxial test, structural bonds, cementation, sample disturbance.
INTEGRABLE COUPLINGS OF THE (2+1)-DIMENSIONAL Li HIERARCHY AND ITS HAMILTONIAN STRUCTURE AS WELL AS THE MULTI-COMPONENT Li HIERARCHY
Authors: SONG MING , DONG HUANHE , XU XIULI , GAO HUIJIAN
Published: June 2008

A (2+1)-dimensional Li hierarchy is generated from one of the reduced equations of self-dual Yang–Mills equations. With the help of a proper loop algebra, the Hamiltonian structure of its expanding integrable couplings is worked out by using the quadratic-form identity, which is Liouville integrable. Moreover, a corresponding multi-component Li hierarchy is given. The method can be widely applied to other soliton hierarchies.
STATISTICAL DAMAGE DETECTION BASED ON FREQUENCIES OF SENSITIVITY-ENHANCED STRUCTURES
Authors: WANG Z. , AU F. T. K. , CHENG Y. S.
Published: June 2008

A statistical method using frequencies of structures under control is proposed for detecting damage. In the study, feedback control based on independent modal space control is first used to assign the pole of the system under detection intentionally. Then the prescribed characteristic frequencies of the structure under control, which may be more sensitive to damage, are obtained and further employed to constitute a sensitivity-enhanced damage indicator (SEDI). The principle of sensitivity-enhancing feedback control for damage detection of multi-degree-of-freedom systems is elaborated. To overcome the effect of measurement noise on modal frequencies, a hypothesis test involving the t-test that utilizes the SEDI is employed to estimate the occurrence of damage, while a statistical pattern recognition method that uses the feature vectors including the SEDI is employed to locate damage. Based on the perturbation theory, the feature vectors are normalized in order to eliminate the effect of damage extent on damage localization. The proposed method is verified by examples including a three-span continuous beam with a single damaged element and the IASC-ASCE benchmark structure with a single damaged brace. Simulation results show that, by using the frequencies of the structures under control, the proposed damage indicators are more sensitive to damage and are capable of detecting and locating small damage of structures.
CONTROLLED QUANTUM SECURE DIRECT COMMUNICATION WITH QUANTUM ENCRYPTION
Authors: CHEN XIU-BO , WANG TIAN-YIN , DU JIAN-ZHONG , WEN QIAO-YAN , ZHU FU-CHEN
Published: June 2008

Utilizing a partially entangled GHZ state, we propose a novel controlled quantum secure direct communication (QSDC) with quantum encryption. Under the supervision and help of the third side, the sender and the receiver can securely share the private quantum entanglement keys used to encrypt and decrypt the secret message. According to the results of checking the eavesdropping on decoy photons, communicators can decide whether the quantum keys are reused in the next round. Not only will eavesdropping inevitably disturb the states of the decoy photons and be detected, but arbitrary transmission errors can also be corrected.
HOW TO MAKE THE QUANTUM ADIABATIC ALGORITHM FAIL
Authors: FARHI EDWARD , GOLDSTONE JEFFREY , GUTMANN SAM , NAGAJ DANIEL
Published: June 2008

The quantum adiabatic algorithm is a Hamiltonian based quantum algorithm designed to find the minimum of a classical cost function whose domain has size N. We show that poor choices for the Hamiltonian can guarantee that the algorithm will not find the minimum if the run time grows more slowly than [Formula: see text]. These poor choices are nonlocal and wash out any structure in the cost function to be minimized, and the best that can be hoped for is Grover speedup. These failures tell us what not to do when designing quantum adiabatic algorithms.
THE RELATIONS OF ENTANGLEMENT DYNAMICS AND ENERGY DISTRIBUTION
Authors: MAN ZHONG-XIAO , XIA YUN-JIE
Published: June 2008

We study the relations between entanglement dynamics and energy distribution for multipartite systems. We show that if two blocks S and [Formula: see text] of a system have energy exchanges, the entanglement and energy distribution between them are closely related, and have definite relations.
DETERMINISTIC SECURE QUANTUM COMMUNICATION ACHIEVED BY USING QUANTUM SWAPPING
Authors: JIANG HUI-JUAN , CAO WEN-ZHEN , LI CHONG
Published: June 2008

Two new deterministic secure quantum communication protocols are proposed in this paper. In these protocols, utilizing auxilians, no particle is transported between two authorized parties, who guarantee the safety of the protocols.
AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome
Authors: Lashinger Erin S. R. , Steiginga Matthew S. , Hieble J. Paul , Leon Lisa A. , Gardner Scott D. , Nagilla Rakesh , Davenport Elizabeth A. , Hoffman Bryan E. , Laping Nicholas J. , Su Xin
Published: June 2008

The activation of the TRPM8 channel, a member of the large class of TRP ion channels, has been reported to be involved in overactive bladder and painful bladder syndrome, although an endogenous activator has not been identified. In this study, N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}- N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB) was evaluated as a TRPM8 channel blocker and used as a tool to evaluate the effects of this class of ion channel blocker on volume-induced bladder contraction and nociceptive reflex responses to noxious bladder distension in the rat. AMTB inhibits icilin-induced TRPM8 channel activation as measured in a Ca2+ influx assay, with a pIC50 of 6.23. In the anesthetized rat, intravenous administration of AMTB (3 mg/kg) decreased the frequency of volume-induced bladder contractions, without reducing the amplitude of contraction. The nociceptive response was measured by analyzing both visceromotor reflex (VMR) and cardiovascular (pressor) responses to urinary bladder distension (UBD) under 1% isoflurane. AMTB (10 mg/kg) significantly attenuated reflex responses to noxious UBD to 5.42 and 56.51% of the maximal VMR response and pressor response, respectively. The ID50 value on VMR response was 2.42 ± 0.46 mg/kg. These results demonstrate that TRPM8 channel blocker can act on the bladder afferent pathway to attenuate the bladder micturition reflex and nociceptive reflex responses in the rat. Targeting TRPM8 channel may provide a new therapeutic opportunity for overactive bladder and painful bladder syndrome.
Preservation of peritubular capillary endothelial integrity and increasing pericytes may be critical to recovery from postischemic acute kidney injury
Authors: Kwon Osun , Hong Seok-Min , Sutton Timothy A. , Temm Constance J.
Published: June 2008

Decreased renal blood flow following an ischemic insult contributes to a reduction in glomerular filtration. However, little is known about the underlying cellular or subcellular mechanisms mediating reduced renal blood flow in human ischemic acute kidney injury (AKI) or acute renal failure (ARF). To examine renal vascular injury following ischemia, intraoperative graft biopsies were performed after reperfusion in 21 cadaveric renal allografts. Confocal fluorescence microscopy was utilized to examine vascular smooth muscle and endothelial cell integrity as well as peritubular interstitial pericytes in the biopsies. The reperfused, transplanted kidneys exhibited postischemic injury to the renal vasculature, as demonstrated by disorganization/disarray of the actin cytoskeleton in vascular smooth muscle cells and disappearance of von Willebrand factor from vascular endothelial cells. Damage to peritubular capillary endothelial cells was more severe in subjects destined to have sustained ARF than in those with rapid recovery of their graft function. In addition, peritubular pericytes/myofibroblasts were more pronounced in recipients destined to recover than those with sustained ARF. Taken together, these data suggest damage to the renal vasculature occurs after ischemia-reperfusion in human kidneys. Preservation of peritubular capillary endothelial integrity and increasing pericytes may be critical to recovery from postischemic AKI.
Synchronization of Neuronal Responses in Primary Visual Cortex of Monkeys Viewing Natural Images
Authors: Maldonado Pedro , Babul Cecilia , Singer Wolf , Rodriguez Eugenio , Berger Denise , Grün Sonja
Published: June 2008

When inspecting visual scenes, primates perform on average four saccadic eye movements per second, which implies that scene segmentation, feature binding, and identification of image components is accomplished in <200 ms. Thus individual neurons can contribute only a small number of discharges for these complex computations, suggesting that information is encoded not only in the discharge rate but also in the timing of action potentials. While monkeys inspected natural scenes we registered, with multielectrodes from primary visual cortex, the discharges of simultaneously recorded neurons. Relating these signals to eye movements revealed that discharge rates peaked around 90 ms after fixation onset and then decreased to near baseline levels within 200 ms. Unitary event analysis revealed that preceding this increase in firing there was an episode of enhanced response synchronization during which discharges of spatially distributed cells coincided within 5-ms windows significantly more often than predicted by the discharge rates. This episode started 30 ms after fixation onset and ended by the time discharge rates had reached their maximum. When the animals scanned a blank screen a small change in firing rate, but no excess synchronization, was observed. The short latency of the stimulation-related synchronization phenomena suggests a fast-acting mechanism for the coordination of spike timing that may contribute to the basic operations of scene segmentation.
The Role of PPARs in Cancer
Authors: Tachibana Keisuke , Yamasaki Daisuke , Ishimoto Kenji , Doi Takefumi
Published: June 2008

Peroxisome proliferator‐activated receptors (PPARs) are ligand‐activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARαis mainly expressed in the liver, where it activates fatty acid catabolism. PPARαactivators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high‐density lipoprotein cholesterol. PPARδis expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARδactivators have been proposed for the treatment of metabolic disease. PPARγ2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARγis involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth.
The Management of Bilateral Ureteric Injury following Radical Hysterectomy
Authors: Shaw Matthew B. K. , Tomes Mark , Rix David A. , Dorkin Trevor J. , Murthy Lakkur N. S. , Pickard Robert S.
Published: June 2008

Iatrogenic ureteric injury is a well-recognised complication of radical hysterectomy. Bilateral ureteric injuries are rare, but do pose a considerable reconstructive challenge. We searched a prospectively acquired departmental database of ureteric injuries to identify patients with bilateral ureteric injury following radical hysterectomy. Five patients suffered bilateral ureteric injury over a 6-year period. Initial placement of ureteric stents was attempted in all patients. Stents were placed retrogradely into 6 ureters and antegradely into 2 ureters. In 1 patient ureteric stents could not be placed and they underwent primary ureteric reimplantation. In the 4 patients in which stents were placed, 2 were managed with stents alone, 1 required ureteric reimplantation for a persistent ureterovaginal fistula, and 1 developed a recurrent stricture. No patient managed by ureteric stenting suffered deterioration in serum creatinine. We feel that ureteric stenting, when possible, offers a safe primary management of bilateral ureteric injury at radical hysterectomy.
Integrative Genomics IdentifiesRAB23as an Invasion Mediator Gene in Diffuse-Type Gastric Cancer
Authors: Hou Qingsong , Wu Yong Hui , Grabsch Heike , Zhu Yansong , Leong Siew Hong , Ganesan Kumaresan , Cross Debra , Tan Lay Keng , Tao Jiong , Gopalakrishnan Veena , Tang Bor Luen , Kon Oi Lian , Tan Patrick
Published: June 2008

Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining high-resolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration. [Cancer Res 2008;68(12):4623–30]
Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling
Authors: Champion Kristen J. , Guinea Maria , Dammai Vincent , Hsu Tien
Published: June 2008

von Hippel-Lindau (VHL) disease results from germline and somatic mutations in the VHL tumor suppressor gene and is characterized by highly vascularized tumors. VHL mutations lead to stabilization of hypoxia-inducible factor (HIF), which up-regulates proangiogenic factors such as vascular endothelial growth factor (VEGF). This pathway is therefore believed to underlie the hypervascular phenotypes of the VHL tumors. However, recent studies have identified novel VHL functions that are independent of the HIF-VEGF pathway. In addition, a potential role of VHL in the tumor microenvironment, which carries heterozygous VHL mutations in VHL patients, has been overlooked. Here, we report a novel HIF-independent VHL function in the endothelium. VHL knockdown in primary human microvascular endothelial cells caused defective turnover of surface fibroblast growth factor (FGF) receptor, increased extracellular signal-regulated kinase signaling, and ETS1 activation, leading to increased cell motility in response to FGF and three-dimensional cord formation in vitro. HIF-α knockdown in VHL loss-of-function endothelial cells does not impede their elevated in vitro angiogenic activity. Importantly, the elevated angiogenic response to FGF is recapitulated in Vhl-heterozygous mice. Thus, partial loss of function of VHL in endothelium may be a contributing factor in tumor angiogenesis through a HIF-VEGF–independent mechanism. [Cancer Res 2008;68(12):4649–57]
Stromal Transforming Growth Factor-β Signaling Mediates Prostatic Response to Androgen Ablation by Paracrine Wnt Activity
Authors: Placencio Veronica R. , Sharif-Afshar Ali-Reza , Li Xiaohong , Huang Hongxia , Uwamariya Consolate , Neilson Eric G. , Shen Michael M. , Matusik Robert J. , Hayward Simon W. , Bhowmick Neil A.
Published: June 2008

Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-β (TGF-β) occurs after androgen ablation. To determine the role of TGF-β on prostate response to androgen ablation, conditional TGF-β type II receptor knockout mouse models of the epithelia (Tgfbr2NKX3.1KO) and stromal fibroblasts (Tgfbr2fspKO) were used. After castration, the prostates of Tgfbr2NKX3.1KO mice had apoptosis levels similar to those expected for control Tgfbr2floxE2/floxE2 mice. Prostates of Tgfbr2fspKO mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2floxE2/floxE2 prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2floxE2/floxE2 and Tgfbr2fspKO stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2fspKO prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2fspKO-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-β, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival. [Cancer Res 2008;68(12):4709–18]
Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas
Authors: Peinado Héctor , Moreno-Bueno Gema , Hardisson David , Pérez-Gómez Eduardo , Santos Vanesa , Mendiola Marta , de Diego Juan Ignacio , Nistal Manuel , Quintanilla Miguel , Portillo Francisco , Cano Amparo
Published: June 2008

Lysyl oxidase–like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically up-regulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node–negative (N0) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways. [Cancer Res 2008;68(12):4541–50]
Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer
Authors: Zhang Mei , Behbod Fariba , Atkinson Rachel L. , Landis Melissa D. , Kittrell Frances , Edwards David , Medina Daniel , Tsimelzon Anna , Hilsenbeck Susan , Green Jeffrey E. , Michalowska Aleksandra M. , Rosen Jeffrey M.
Published: June 2008

Using a syngeneic p53-null mouse mammary gland tumor model that closely mimics human breast cancer, we have identified, by limiting dilution transplantation and in vitro mammosphere assay, a Lin−CD29HCD24H subpopulation of tumor-initiating cells. Upon subsequent transplantation, this subpopulation generated heterogeneous tumors that displayed properties similar to the primary tumor. Analysis of biomarkers suggests the Lin−CD29HCD24H subpopulation may have arisen from a bipotent mammary progenitor. Differentially expressed genes in the Lin−CD29HCD24H mouse mammary gland tumor-initiating cell population include those involved in DNA damage response and repair, as well as genes involved in epigenetic regulation previously shown to be critical for stem cell self-renewal. These studies provide in vitro and in vivo data that support the cancer stem cell (CSC) hypothesis. Furthermore, this p53-null mouse mammary tumor model may allow us to identify new CSC markers and to test the functional importance of these markers. [Cancer Res 2008;68(12):4674–82]
Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma
Authors: Bennett Kristi L. , Karpenko Matthew , Lin Mau-ting , Claus Rainer , Arab Khelifa , Dyckhoff Gerhard , Plinkert Peter , Herpel Esther , Smiraglia Dominic , Plass Christoph
Published: June 2008

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive cancer. In advanced stages, the patient has poor chances of receiving effective treatment, and survival rates are low. To facilitate timely diagnosis and improve treatment, elucidation of early detection markers is crucial. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable mark. A genome-wide screen using Restriction Landmark Genomic Scanning found a set of genes that are most commonly methylated in head and neck cancers. Five candidate genes: septin 9 (SEPT9), sodium-coupled monocarboxylate transporter 1 (SLC5A8), functional smad-suppressing element on chromosome 18 (FUSSEL18), early B-cell factor 3 (EBF3), and iroquois homeobox 1 (IRX1) were methylated in 27% to 67% of the HNSCC patient samples tested. Furthermore, ∼50% of the methylated tumor samples shared methylation between two of the five genes (most commonly between EBF3 and IRX1), and 15% shared methylation between three of the five genes. Expression analysis revealed candidate gene down-regulation in 25% to 93% of the HNSCC samples, and 5-aza-2′-deoxycytidine treatment was able to restore expression in at least 2 of 5 HNSCC cell lines for all of the genes tested. Overexpression of the three most frequently down-regulated candidates, SLC5A8, IRX1, and EBF3, validated their tumor suppressor potential by growth curve analysis and colony formation assay. Interestingly, all of the candidates identified may be involved in the transforming growth factor β signaling pathway, which is often disrupted in HNSCC. [Cancer Res 2008;68(12):4494–99]
Increased Susceptibility of Breast Cancer Cells to Stress Mediated Inhibition of Protein Synthesis
Authors: Pervin Shehla , Tran An H. , Zekavati Shaghayegh , Fukuto Jon M. , Singh Rajan , Chaudhuri Gautam
Published: June 2008

Protein synthesis is a tightly controlled process, and its deregulation plays an important role in tumorigenesis. Protein synthesis remains poorly understood with very few well-identified validated targets for therapeutic purposes. In this study, we use nitric oxide (NO), which suppresses protein synthesis by inactivating eukaryotic initiation factor 2-α (eIF2-α), to examine the mechanism by which low and high oxidative stress inhibits protein synthesis. In breast cancer cells, low NO stress induced heme-regulated inhibitor (HRI) activation, which facilitated gradual decline in short half-life proteins. High NO stress induced HRI and protein kinase R (PKR) activation, leading to a sharp decline in protein synthesis as accessed by a decline in short and long half-life proteins and dramatic morphologic changes. In contrast, human mammary epithelial (HME) and Ras transfected untransformed HME (MCF-10A1 neo N) cells were less susceptible to NO-induced inhibition of protein synthesis and cytostasis. Our results suggest that NO-induced cytostasis in breast cancer cells was due to PKR activation and increased phosphorylation of eIF2-α, whereas the reduced susceptibility of normal mammary epithelial cells to NO could be due to the inaccessibility of PKR, which is bound to inhibitor p58. [Cancer Res 2008;68(12):4862–74]
Detecting Pathway-Based Gene-Gene and Gene-Environment Interactions in Pancreatic Cancer
Authors: Duell Eric J. , Bracci Paige M. , Moore Jason H. , Burk Robert D. , Kelsey Karl T. , Holly Elizabeth A.
Published: June 2008

Data mining and data reduction methods to detect interactions in epidemiologic data are being developed and tested. In these analyses, multifactor dimensionality reduction, focused interaction testing framework, and traditional logistic regression models were used to identify potential interactions with up to three factors. These techniques were used in a population-based case-control study of pancreatic cancer from the San Francisco Bay Area (308 cases, 964 controls). From 7 biochemical pathways, along with tobacco smoking, 26 polymorphisms in 20 genes were included in these analyses. Combinations of genetic markers and cigarette smoking were identified as potential risk factors for pancreatic cancer, including genes in base excision repair (OGG1), nucleotide excision repair (XPD, XPA, XPC), and double-strand break repair (XRCC3). XPD.751, XPD.312, and cigarette smoking were the best single-factor predictors of pancreatic cancer risk, whereas XRCC3.241*smoking and OGG1.326*XPC.PAT were the best two-factor predictors. There was some evidence for a three-factor combination of OGG1.326*XPD.751*smoking, but the covariate-adjusted relative-risk estimates lacked precision. Multifactor dimensionality reduction and focused interaction testing framework showed little concordance, whereas logistic regression allowed for covariate adjustment and model confirmation. Our data suggest that multiple common alleles from DNA repair pathways in combination with cigarette smoking may increase the risk for pancreatic cancer, and that multiple approaches to data screening and analysis are necessary to identify potentially new risk factor combinations. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1470–9)
Is There a Role for Circulating Tumor Cells in the Management of Breast Cancer?
Authors: Hayes Daniel F. , Smerage Jeffrey
Published: June 2008

Circulating tumor cells (CTC) can be identified and characterized in blood of patients with many solid tumors, particularly breast cancer. Between 10% and 30% of patients with stage I to III breast cancer and 50% to 70% of women with metastatic breast cancer have detectable CTCs. In both cases, presence and elevation of CTCs are associated with worse prognosis. In the metastatic setting, persistent CTC after 3 to 5 weeks of a new therapy seem to indicate lack of activity of that regimen, and an ongoing prospective randomized clinical trial is addressing the relative worth of changing to an alternative treatment rather than waiting for classic clinical and radiologic evidence of progression. Recent technical advances offer the promise of further genotyping and phenotyping for important tumor-associated genes and proteins.
ssDNA-Binding Protein 2 Is Frequently Hypermethylated and Suppresses Cell Growth in Human Prostate Cancer
Authors: Liu Jun-Wei , Nagpal Jatin K. , Sun Wenyue , Lee Juna , Kim Myoung Sook , Ostrow Kimberly L. , Zhou Shaoyu , Jeronimo Carmen , Henrique Rui , Van Criekinge Wim , Moon Chu So , Califano Joseph A. , Trink Barry , Sidransky David
Published: June 2008

Purpose: Prostate cancer is a major cause of cancer death among men and the development of new biomarkers is important to augment current detection approaches.

Experimental Design: We identified hypermethylation of the ssDNA-binding protein 2 (SSBP2) promoter as a potential DNA marker for human prostate cancer based on previous bioinformatics results and pharmacologic unmasking microarray. We then did quantitative methylation-specific PCR in primary prostate cancer tissues to confirm hypermethylation of the SSBP2 promoter, and analyzed its correlation with clinicopathologic data. We further examined SSBP2 expression in primary prostate cancer and studied its role in cell growth.

Results: Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer. Reactivation of SSBP2 expression by the demethylating agent 5-aza-2′-deoxycytidine in prostate cancer cell lines confirmed epigenetic inactivation as one major mechanism of SSBP2 regulation. Moreover, forced expression of SSBP2 inhibited prostate cancer cell proliferation in the colony formation assay and caused cell cycle arrest.

Conclusion: SSBP2 inhibits prostate cancer cell proliferation and seems to represent a novel prostate cancer–specific DNA marker, especially in high stages of human prostate cancer.
Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers
Authors: Jeong Eun Goo , Kim Min Sung , Nam Hyo Kyung , Min Chang Ki , Lee Seok , Chung Yeun Jun , Yoo Nam Jin , Lee Sug Hyung
Published: June 2008

Purpose: The aim of this study was to see whether JAK1, JAK3, and TYK2 genes are altered in human cancers.

Experimental Design: We analyzed 494 tissues from 186 acute adulthood leukemias, 30 multiple myelomas, and 278 common solid cancers, including 90 breast, 47 gastric, 47 colon, 47 lung, and 47 hepatocellular carcinomas by single-strand conformation polymorphism analysis.

Results: Overall, we found six JAK1 mutations (four in acute leukemias, one in a lung carcinoma, and one in a breast carcinoma) and three JAK3 mutations (two in breast carcinomas and one in a gastric carcinoma). Of note, three JAK1 mutations were an identical p.V658F mutation, which is homologous to JAK2 p.V617F mutation. We also found two other JAK1 mutations that occurred at very close sites (p.T782M and p.L783F). We found three of the four leukemias with JAK1 mutations expressed mutated JAK1 at the mRNA level. For JAK3 mutations, one of them was JAK3 p.V715I that is homologous to the JAK1 p.L783F. These recurrent mutations in identical and homologous sites suggest a possibility that alterations of these amino acids might be important for tumor pathogenesis. With respect to the cancer types, T-acute lymphoblastic leukemia (T-ALL) showed the highest incidence of the mutations (3 of 11; 27.3%).

Conclusion: Our data indicate that both JAK1 and JAK3 mutations occur in common human cancers and that JAK1 mutation in T-ALL is a frequent event. The data suggest that some of the JAK1 and JAK3 mutations may to be functional and contributes to cancer development, especially to T-ALL development.
Improved Prediction of Disease Relapse after Radical Prostatectomy through a Panel of Preoperative Blood-Based Biomarkers
Authors: Shariat Shahrokh F. , Karam Jose A. , Walz Jochen , Roehrborn Claus G. , Montorsi Francesco , Margulis Vitaly , Saad Fred , Slawin Kevin M. , Karakiewicz Pierre I.
Published: June 2008

Purpose: The preoperative blood levels of biomarkers may allow accurate identification of patients who are likely to fail radical prostatectomy as a first-line therapy for localized prostate cancer, thereby allowing more efficient delivery of neoadjuvant and adjuvant therapy. The aim of this study was to determine the added value of biomarkers relative to established predictors of biochemical recurrence, such as clinical stage, biopsy Gleason sum, and preoperative prostate-specific antigen.

Experimental Design: The preoperative plasma levels of transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), endoglin, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor were measured with the use of commercially available enzyme immunoassays in 423 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer. Multivariable models were used to explore the gain in the predictive accuracy of the models. This predictive accuracy was quantified by the concordance index statistic and was validated with 200 bootstrap resamples.

Results: In standard multivariable analyses, TGF-β1 (P < 0.001), sIL-6R (P < 0.001), IL-6 (P < 0.001), VCAM-1 (P < 0.001), VEGF (P = 0.008), endoglin (P = 0.002), and uPA (P < 0.001) were associated with biochemical recurrence. The multivariable model containing standard clinical variables alone had an accuracy of 71.6%. The addition of TGF-β1, sIL-6R, IL-6, VCAM-1, VEGF, endoglin, and uPA increased the predictive accuracy by 15% to 86.6% (P < 0.001) and showed excellent calibration.

Conclusions: A nomogram based on these biomarkers improves the accuracy of standard predictive models and could help counsel patients about their risk of biochemical recurrence following radical prostatectomy.
Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cβ inhibitor, in non-small cell lung cancer cells
Authors: Morgillo Floriana , Martinelli Erika , Troiani Teresa , Laus Gianluca , Pepe Stefano , Gridelli Cesare , Ciardiello Fortunato
Published: June 2008

Enzastaurin, an acyclic bisindolymaleimide, is a potent and selective competitive inhibitor of protein kinase Cβ, which has been shown to inhibit cancer cell proliferation and angiogenesis in human cancer cell lines. Gemcitabine and pemetrexed are two cytotoxic drugs that are currently used in non-small cell lung cancer (NSCLC) therapy. In this study, we have investigated whether the addition of enzastaurin to gemcitabine or to pemetrexed is able to increase their antitumor activity to establish an effective schedule of combined treatment. The effects on cancer cell proliferation, cell cycle distribution, intracellular mitogenic and antiapoptotic signaling pathways, and induction of apoptosis were evaluated in three different combination sequences (concomitant treatment, sequential treatment with the cytotoxic drug followed by enzastaurin, or sequential treatment with enzastaurin followed by the cytotoxic drug) in a panel of human NSCLC cell lines. The combination of enzastaurin with either gemcitabine or pemetrexed caused different antiproliferative and proapoptotic effects depending on the treatment schedule. A synergistic antiproliferative and proapoptotic activity was only obtained when chemotherapy was followed by treatment with enzastaurin. These effects were accompanied by the arrest of the surviving cancer cells in the S phase, thus limiting their ability to proceed through the cell cycle, and by a maximum inhibition in the activated, phosphorylated forms of Akt and mitogen-activated protein kinase. In contrast, the concomitant treatments or the sequential treatments, in which enzastaurin was given before chemotherapy, resulted in significant antagonistic effects. [Mol Cancer Ther 2008;7(6):1698–707]
Targeting IL-13Rα2-positive cancer with a novel recombinant immunotoxin composed of a single-chain antibody and mutated Pseudomonas exotoxin
Authors: Kioi Mitomu , Seetharam Saraswathy , Puri Raj K.
Published: June 2008

We have shown previously that high-affinity receptors for interleukin-13 (IL-13Rα2) are overexpressed on a variety of solid cancer cells, diseased fibroblasts, and other cells, and a chimeric fusion protein composed of human IL-13 and mutated Pseudomonas exotoxin (IL-13-PE38) is highly and specifically cytotoxic to these cells in vitro and in vivo. To improve the specificity for the target, we isolated specific antibodies against IL-13Rα2 from human single-chain Fv (scFv) antibody phage library and developed immunotoxin by selecting two high-affinity clones of scFv and fused to PE. The fusion chimeric gene was expressed in Escherichia coli, and highly purified IL-13R-specific immunotoxin, termed anti-IL-13Rα2(scFv)-PE38, was tested for its cytotoxicity. This molecule was highly cytotoxic to U251 glioma and PM-RCC renal cell carcinoma cell lines in vitro. The cytotoxic activity was neutralized by purified extracellular domain of IL-13Rα2 but not by IL-13, indicating that cytotoxic activity is specific. Anti-IL-13Rα2(scFv)-PE38 showed significant antitumor activity in immunodeficient mice with s.c. glioma tumors. Both i.p. and i.t. routes of administration showed antitumor activity in a dose-dependent manner. The maximum tolerated dose of anti-IL-13Rα2(scFv)-PE38 was 200 μg/kg i.p. twice daily for 5 days. These results indicate that anti-IL-13Rα2(scFv)-PE38 is a highly selective therapeutic agent for cancer therapy and should be further tested in animal models of human cancer. [Mol Cancer Ther 2008;7(6):1579–87]
ISG15 as a novel tumor biomarker for drug sensitivity
Authors: Desai Shyamal D. , Wood Laurence M. , Tsai Yu-Chen , Hsieh Tao-Shih , Marks Jeffrey R. , Scott Georgia L. , Giovanella Beppino C. , Liu Leroy F.
Published: June 2008

Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity. [Mol Cancer Ther 2008;7(6):1430–9]
Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies
Authors: Garcia Jorge A. , Danielpour David
Published: June 2008

The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth, and apoptosis. Recently, there has been an enormous increase in our understanding on molecular mechanisms underlying the therapeutics of rapamycin in cancer. Alterations in the pathway regulating mTOR occur in many solid malignancies including prostate, bladder, and kidney cancer; in vitro and in vivo models of prostate and bladder cancer have established the importance of the mTOR pathway in control of cancer progression and metastasis. Temsirolimus (Torisel) and everolimus (RAD-001), two ester analogues of rapamycin, as well as rapamycin itself have clear antitumor activity in in vitro and in vivo models and are under clinical trial investigations for prostate and bladder cancer. Phase II and III trials have already established the clinical efficacy of temsirolimus in renal cancer, and current renal trials are evaluating the combined effects of vascular endothelial growth factor and mTOR inhibition. Ongoing studies in prostate and bladder cancer will soon define the activity and safety profiles of everolimus and temsirolimus. Recent molecular advances have uncovered a startling complexity in the macromolecular function of mTOR complexes, with the identification of new mTOR partners (raptor, rictor, FKBP38, PRAS40, and mSIN1), putative cancer therapeutic/prognostic targets for future clinical trials. [Mol Cancer Ther 2008;7(6):1347–54]