bluuebunny/crossref_metadata_2025 huggingface dataset:
Cultural History, Interdisciplinarity, and Romanticism
Authors: Fay Elizabeth
Published: July 2006

This article examines cultural history in relation to interdisciplinary studies and surveys the issues that interdisciplinarity problematizes. Interdisciplinary work presupposes the disciplines, with their predetermined and generalized objects of study; cultural history, sometimes confused with cultural studies and cultural critique, begins with a question that determines a particular object of study. The very nature of interdisciplinarity is interrogated in order to understand its difficulties and its benefits in relation to cultural history. Examples of one kind of cultural history – that of the bodily histories of sensual culture and gestural culture – are examined in relation to Romantic Studies to point to the potential of cultural history studies.
Comparison of the effect of market crop wastes and chemical soil fertility amendments on insect pests, natural enemies and yield of Brassica oleracea
Authors: Karungi J. , Kyamanywa S. , Ekbom B.
Published: July 2006

Field studies were conducted over three growing seasons during 2 years to assess the relative effect of market crop waste (MCW)‐derived soil fertility amendments and conventional fertiliser (NPK) on tritrophic relations as well as yield performance of white cabbage. A randomised complete block design with four treatments and a control replicated four times was used. Treatments were (a) MCW compost incorporated in the soil, (b) uncomposted MCW incorporated in the soil, (c) uncomposted MCW applied as surface mulch, (d) a conventional chemical fertiliser (NPK) incorporated in the soil and (e) the untreated control. Results indicated that relative to NPK‐amended plants, MCW‐amended cabbage performed better in plant growth parameters as well as yield, despite having sustained aphid and Plutella xylostella infestations that could be as much as double as those in the NPK treatment. Natural enemy occurrence followed the trend of host insect infestations. The average yield performance and net financial benefits from MCW‐compost‐amended plants were three‐fold as that of NPK‐amended plants. Soil analysis results indicated an advantage in soil quality accruing from the MCW amendments. This study, therefore, provides documentation for the utilisation of MCW, previously handled as garbage to be disposed of, as a key component in integrated management of insect pests and depleted soils in crop production in sub‐Saharan Africa and beyond.
Detection and variability of the lethal yellowing group (16Sr IV) phytoplasmas in the Cedusa sp. (Hemiptera: Auchenorrhyncha: Derbidae) in Jamaica
Authors: Brown S.E. , Been B.O. , McLaughlin W.A.
Published: July 2006

Lethal yellowing (LY) group phytoplasma was detected in members of the Cedusa species of Derbids from Jamaica by nested PCR assay employing the rRNA primer pairs P1/P7 and LY16Sf/LY16Sr. A 1400‐bp product was obtained from 13/43 Derbids that were analysed. Restriction fragment length polymorphism analysis of the nested PCR product revealed variations in 6/13 Derbids analysed, suggesting that the planthoppers could be infected with different strains of the LY group phytoplasma. Sequence analysis of the 16S rDNA gene determined that the percentage of similarity of the phytoplasma strains in the Derbids ranged from 97–98% to the phytoplasma strain found in coconuts in Florida (LYFL‐C2) and Jamaica (LYJ‐C8). The phytoplasma strains in the Derbids clustered together with the Jamaican and Florida coconut LY phytoplasma, as well as other characterised strains composing the LY phytoplasma (16Sr IV) group.
A review of the reproductive physiology of rhinoceros species in captivity
Authors: ROTH T. L.
Published: July 2006

Substantial progress in understanding the reproductive physiology of the four rhinoceros species in captivity, White rhinoceros Ceratotherium simum, Black rhinoceros Diceros bicornis, Indian or Greater one‐horned rhinoceros Rhinoceros unicornis and Suma‐tran rhinoceros Dicerorhinus sumatrensis, has been achieved over the last two decades largely owing to advances in endocrine and ultrasound techniques, and improved methods of semen collection. Primarily through the non‐invasive monitoring of hormone metabolites, scientists have studied the reproductive cycle, investigated the effects of season and potential stressors, and diagnosed pregnancy in each species. By employing the powerful tool of ultrasonography, more detailed and accurate information regarding reproductive function has been revealed. Important findings include anovula‐tory cycles, induced ovulation, reproductive tract pathologies, early pregnancy diagnosis and early embryonic loss. Interest in the reproductive physiology of c? rhinoceros has lagged behind that of ♀♀ but in recent years data on sperm and semen characteristics, reproductive glands and hormone production have been collected. While the reproductive physiology of each rhinoceros species is interesting in its own right, perhaps most fascinating is the significant inter‐specific variation in reproductive traits within this taxon.
Operant‐conditioning programme for White rhinoceros, Black rhinoceros and Indian or Greater one‐horned Asian rhinoceros Ceratotherium simum, Diceros bi cornis and Rhinoceros unicornis at Whipsnade Wild Animal Park, Dunstable, UK
Authors: HOLDEN M. D. , GREGORY J. , WATKINS V. , RADFORD L.
Published: July 2006

This paper describes the development of an operant conditioning programme for rhinoceros at Whipsnade Wild Animal Park, Dunstable, UK. The programme was designed to facilitate the treatment of a range of health conditions and to allow husbandry procedures to be carried out without the need of anaesthesia. A successful conditioning programme requires good planning, consistency and precise record keeping. Routine management practices can be now carried out within a safe and largely stress‐free environment for both rhinoceros and animal‐management staff.
Metabolism of carbohydrate in alimentary tract of reindeer in winter
Authors: KOCHAN Tatyana I.
Published: July 2006

The study was conducted on six reindeers in December. It was established that concentration of reducing sugars in the chyme of jejunum increases substantially (6 times in comparison with abomasum), whereas concentration cellulose, on the contrary, decreases (4.5 times). The maximal increase of monosaccharides in the small intestine testifies to formation of metabolic fund of sugars in this part of the alimentary tract due to high degree of polysaccharides hydrolysis of exogenous, as well as endogenous, microbial formation. Obtained data assume that the need of the reindeer for glucose is provided for not only by gluconeogenesis as it was considered before, but also by absorption of monosaccharides from the alimentary tract.
Using molecular and quantitative variation for assessing genetic impacts on Nucella lapillus populations after local extinction and recolonization
Authors: Colson Isabelle , Guerra‐Varela Jorge , Hughes Roger N. , Rolán‐Alvarez Emilio
Published: July 2006

The dogwhelk Nucella lapillus is a predatory marine gastropod living on rocky shores in the North Atlantic. As with many other gastropod species, Nucella was affected by tributyltin (TBT) pollution during the 1970s and 1980s, and local populations underwent extinction. After a partial ban on TBT in the UK in 1987, vacant sites have been recolonized. Levels of genetic diversity and quantitative genetic variation in shell form were compared between recolonized sites and sites that showed continuous population at three localities across the British Isles. Overall, estimates of genetic diversity were only slightly lower in recolonized populations, suggesting that populations have recovered from previous impacts due to the relatively high levels of migration from non‐impacted sites. Molecular and quantitative analyses are broadly concordant and a positive correlation was observed (although not statistically significant) between molecular and quantitative estimates of genetic diversity, indicating the potential usefulness of quantitative methods to complement molecular population genetics analyses.
Low-Frequency Spin Dynamics in a Canted Antiferromagnet
Authors: Kumada Norio , Muraki Koji , Hirayama Yoshiro
Published: July 2006

Resistively detected nuclear spin relaxation measurements in closely separated two-dimensional electron systems reveal strong low-frequency electron-spin fluctuations in the quantum Hall regime. As the temperature is decreased, the spin fluctuations, manifested by a sharp enhancement of the nuclear spin-lattice relaxation rate 1/
T
1
, continue to grow down to the lowest temperature of 66 millikelvin. The observed divergent behavior of 1/
T
1
signals a gapless spin excitation mode and is a hallmark of canted antiferromagnetic order. Our data demonstrate the realization of a two-dimensional system with planar broken symmetry, in which fluctuations do not freeze out when approaching the zero temperature limit.
Response to Comment on "Opposing Effects of Native and Exotic Herbivores on Plant Invasions"
Authors: Parker John D. , Burkepile Deron E. , Hay Mark E.
Published: July 2006

Our investigation found that non-native plants were more susceptible to native generalist herbivores than were native plants. Ricciardi and Ward's finding that non-native plants without native congeners are more susceptible to native herbivores than are non-natives with coexisting native congeners supports our hypothesis that evolutionary naïveté leaves plants at greater risk of attack by newly encountered generalist herbivores.
Intracerebral haemorrhage associated with hourly concentration of ambient particulate matter: case-crossover analysis
Authors: Yamazaki S , Nitta H , Ono M , Green J , Fukuhara S
Published: July 2006

Aims:To examine the association of hourly time lagged concentration of ambient particulate matter and death due to stroke.

Methods:Mortality data for five years (January 1990 to December 1994) were obtained from the Ministry of Health, Labour, and Welfare of Japan. Data were used only if the deceased was 65 years old or older at the time of death, if death was attributed to intracerebral haemorrhage or ischaemic stroke, and if the deceased lived in one of 13 major urban areas. Hourly mean concentrations of PM7, NO2, and photochemical oxidants were measured at monitoring stations in the 13 areas. Time stratified case-crossover analysis was used to examine the data for evidence of triggering stroke mortality.

Results:The 1-hour mean concentration of PM7 measured about 2 hours before death was associated with the risk of death due to intracerebral haemorrhage from April to September (odds ratio = 2.40, 95% CI 1.48 to 3.89, for exposure to PM7 of more than 200 μg/m3(threshold)). The higher risk was independent of the 24-hour mean concentration of PM7. PM7 was not associated with death due to ischaemic stroke.

Conclusions:Transiently high concentrations of PM7 are associated with death due to intracerebral haemorrhage. Air quality standards or guidelines for particulate matter should be based not only on 24-hour mean concentrations, but also on hourly data.
ARMI: A High Level Communication Library for STAPL
Authors: Thomas Nathan , Saunders Steven , Smith Tim , Tanase Gabriel , Rauchwerger Lawrence
Published: July 2006

ARMI is a communication library that provides a framework for expressing fine-grain parallelism and mapping it to a particular machine using shared-memory and message passing library calls. The library is an advanced implementation of the RMI protocol and handles low-level details such as scheduling incoming communication and aggregating outgoing communication to coarsen parallelism. These details can be tuned for different platforms to allow user codes to achieve the highest performance possible without manual modification. ARMI is used by STAPL, our generic parallel library, to provide a portable, user transparent communication layer. We present the basic design as well as the mechanisms used in the current Pthreads/OpenMP, MPI implementations and/or a combination thereof. Performance comparisons between ARMI and explicit use of Pthreads or MPI are given on a variety of machines, including an HP-V2200, Origin 3800, IBM Regatta and IBM RS/6000 SP cluster.
DNA Helicases Required for Homologous Recombination and Repair of Damaged Replication Forks
Authors: Wu Leonard , Hickson Ian D.
Published: July 2006

DNA helicases are found in all kingdoms of life and function in all DNA metabolic processes where the two strands of duplex DNA require to be separated. Here, we review recent developments in our understanding of the roles that helicases play in the intimately linked processes of replication fork repair and homologous recombination, and highlight how the cell has evolved many distinct, and sometimes antagonistic, uses for these enzymes.
Space–Time Separation During Obstacle-Avoidance Learning in Monkeys
Authors: Torres Elizabeth , Andersen Richard
Published: July 2006

Is the movement duration time known before we move? To answer this question, a new experimental paradigm is introduced that for the first time monitors the acquisition of a new motor skill in rhesus monkeys. Straight reaches were interleaved with reaches around physical obstacles that elicited a different path geometry. Curved and longer spatial paths were immediately resolved and consistent over months of training. A new temporal strategy separately evolved over repetitions from multiple to a single velocity peak. We propose that the obstacle-avoidance spatial paths were resolved before motion execution and used as reference in the computation of the new dynamics. Path conservation from the first trial occurred both at the hand and at the joint angle levels, whereas the speed profile dramatically changed over time. The spatial solution required no learning and was anticipated by the spontaneous repositioning of the initial arm posture. The learning was in the temporal domain, involving the adjustment of the speed during the motion's first impulse. Within the movement initiation, the partial distance traveled by the hand up to the first velocity peak was finely tuned under a constant time. For a given space location, the time of the first impulse remained robust to learning, but significantly shifted for different targets and obstacle configurations. Differences in the temporal-related parameters across time provided a clear distinction between learning and automatic behavior.
GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle
Authors: Park Jung-Jun , Berggren Jason R. , Hulver Matthew W. , Houmard Joseph A , Hoffman Eric P.
Published: July 2006

Obesity is associated with insulin resistance in skeletal muscle; accordingly, weight loss dramatically improves insulin action. We sought to identify molecular remodeling of muscle commensurate with weight loss that could explain improvements in insulin action. Muscle from morbidly obese women was studied before and after gastric bypass surgery. Gastric bypass surgery significantly reduced body mass by ∼45% and improved insulin action. We then assessed mRNA profiles using a stringent statistical analysis (statistical concordance with three probe set algorithms), with validation in a cross-sectional study of lean ( n = 8) vs. morbidly obese ( n = 8) muscle. Growth factor receptor-bound protein 14 (GRB14), glycerol-3-phosphate dehydrogenase 1 (GPD1), and growth differentiation factor 8 (GDF8; myostatin) significantly decreased ∼2.4-, 2.2-, and 2.4-fold, respectively, after weight loss (gastric bypass). Increased expression of these transcripts was associated with increased obesity in the cross-sectional group (lean vs. morbidly obese muscle). Each transcript was validated by real-time quantitative RT-PCR assays in both study groups. Using Ingenuity Pathway Analysis, we show that all three transcripts are involved in the same regulatory network including AKT1, IGF1, TNF, PPARG, and INS. These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss. Thus our data provide a possible regulatory pathway involved in the development of insulin resistance in the morbidly obese state, and improvement of insulin resistance with weight loss.
Chronic Administration of Valproic Acid Inhibits Prostate Cancer Cell Growth In vitro and In vivo
Authors: Xia Qinghua , Sung Jennifer , Chowdhury Wasim , Chen Chien-lun , Höti Naseruddin , Shabbeer Shabana , Carducci Michael , Rodriguez Ronald
Published: July 2006

Valproic acid (VPA) is an established drug in the long-term therapy of seizure disorders. Recently, VPA has been associated with anticancer activity, an effect thought to be mediated through the inhibition of cellular histone deacetylase 1. We investigated the effect of various doses of VPA (0, 1.2, and 5.0 mmol/L) administered either acutely or chronically on histone acetylation, p21 gene expression, androgen receptor expression, prostate-specific antigen (PSA) expression, and cell survival and proliferation in prostate cancer cell lines. We also studied the effect of chronic VPA on tumor xenograft growth in vivo. Our results show that acute treatment (3 days) VPA can increase net histone H3 acetylation and up-regulate p21, AR, and cytosolic PSA expression. Interestingly, the effects on AR and PSA are reversed with chronic teatment. In addition, acute VPA reduces cell survival but has no effect on the subsequent proliferation of surviving cells following drug withdrawal. However, when VPA is chronically administered (10-14 days) to prostate cancer cells, even lower doses of VPA result in marked decreases in the net proliferation rate, correlating with increased caspase-2 and caspase-3 activation. These effects are evident in both androgen receptor-positive (LNCaP and C4-2) and androgen receptor-negative (DU145 and PC3) prostate cancer cells. Moreover, chronic VPA treatment results in statistically significant reduction of tumor xenograft growth in vivo. We conclude that acute treatment has nominal effects on prostate cancer cell survival and proliferation, but chronic VPA results in profound decreases in proliferation, independently of androgen regulation. (Cancer Res 2006; 66(14): 7237-44)
Peroxisome Proliferator–Activated Receptor γ as a Molecular Target of Resveratrol-Induced Modulation of Polyamine Metabolism
Authors: Ulrich Sandra , Loitsch Stefan M. , Rau Oliver , von Knethen Andreas , Brüne Bernhard , Schubert-Zsilavecz Manfred , Stein Jürgen M.
Published: July 2006

Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator–activated receptor γ (PPARγ). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPARγ ligand–dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPARγ mutant was transfected in Caco-2 cells to suppress PPARγ-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose- and time-dependent manner (P < 0.001). In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPARγ cells. PPARγ involvement was further confirmed via ligand-dependent activation (P < 0.01) as well as by induction of cytokeratin 20 (P < 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P < 0.05) and HCT-116 (P < 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPARγ coactivator PGC-1α (P < 0.05) as well as SIRT1 (P < 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPARγ can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer. (Cancer Res 2006; 66(14): 7348-54)
Detection of Low Molecular Weight Derivatives of Cyclin E1 Is a Function of Cyclin E1 Protein Levels in Breast Cancer
Authors: Spruck Charles , Sun Dahui , Fiegl Heidi , Marth Christian , Mueller-Holzner Elisabeth , Goebel Georg , Widschwendter Martin , Reed Steven I.
Published: July 2006

Cyclin E1 regulates the initiation of the S phase program in the mammalian cell division cycle. In normal cells, cyclin E1 protein expression is tightly controlled through a combination of transcriptional and proteolytic regulatory processes. However, in many types of human tumor, cyclin E1 expression is frequently dysregulated, including overexpression, nonperiodic expression relative to cell division, and generation of low molecular weight (LMW) derivatives. LMW derivatives of cyclin E1 have been proposed to be generated by the in vivo proteolytic cleavage of the full-length cyclin E1 protein by a yet to be identified tumor-specific protease. Recently, it was suggested that overexpression of full-length or LMW derivatives of cyclin E1 are independent variables associated with poor outcome in patients with breast cancer. However, we have extensively analyzed cyclin E1 protein expression in primary breast tumors and breast tumor-derived cell lines and found that the ability to detect LMW derivatives of cyclin E1 correlates only with the level of cyclin E1 protein. When cyclin E1 levels on Western blots are normalized, LMW derivatives of cyclin E1 were observed at roughly equal levels in all primary breast tumors, breast tumor-derived cell lines, immortalized nontransformed human mammary epithelial cells, and normal breast tissue. Therefore, the detection of LMW derivatives of cyclin E1 is likely a function of cyclin E1 protein levels, and the activity of the proteolytic machinery responsible for their generation is not a tumor-specific property. (Cancer Res 2006; 66(14): 7355-60)
Recombinant Human Insulin-like Growth Factor Binding Protein 3 Inhibits Growth of Human Epidermal Growth Factor Receptor-2–Overexpressing Breast Tumors and Potentiates Herceptin Activity In vivo
Authors: Jerome Lori , Alami Nezha , Belanger Sylvie , Page Viviane , Yu Qingnan , Paterson Jesse , Shiry Laura , Pegram Mark , Leyland-Jones Brian
Published: July 2006

Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18–transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer. (Cancer Res 2006; 66(14): 7245-52)
Generation of Replication-Dependent Double-Strand Breaks by the Novel N2-G-Alkylator S23906-1
Authors: Léonce Stéphane , Kraus-Berthier Laurence , Golsteyn Roy M. , David-Cordonnier Marie-Hélène , Tardy Christelle , Lansiaux Amélie , Poindessous Virginie , Larsen Annette K. , Pierré Alain
Published: July 2006

S23906-1, a new DNA alkylating agent that reacts with the exocyclic 2-NH2 group of guanine residues yielding monofunctional adducts, is currently under clinical evaluation in phase I trials. To investigate the mechanism of action of S23906-1, we compared parental KB-3-1 cells and KB/S23-500 cells that are 15-fold resistant to S23906-1. Cell death induced by 1 μmol/L S23906-1 in KB-3-1 cells was associated with their irreversible arrest in the G2-M phases of the cell cycle followed by apoptosis, whereas a proportion of the resistant KB/S23-500 cells were able to exit from the G2 arrest and divide, leading to a significantly lower rate of apoptosis. The attenuated apoptotic response was associated with decreased Chk2 protein phosphorylation, indicating that the DNA damage signaling pathways are more potently activated in the sensitive cells. However, similar rates of adduct formation and repair were measured in both cell lines. Exposure to S23906-1 induced a higher formation of DNA breaks, measured by the comet assay, in sensitive cells. In agreement, a histone H2AX phosphorylation assay revealed that S23906-1 induced double-strand breaks (DSB) in a dose- and time-dependent manner and that these were more persistent in the parental cells. These DSBs were found mainly in S-phase cells and inhibited by aphidicolin, suggesting that they are DNA replication-mediated DSBs. These results suggest that secondary DNA lesions play an important role in the cytotoxicity of this compound and make histone H2AX phosphorylation an attractive marker for monitoring the efficacy of S23906-1. (Cancer Res 2006; 66(14): 7203-10)
High Levels of Dioxin-Like Potential in Cigarette Smoke Evidenced byIn vitroandIn vivoBiosensing
Authors: Kasai Ayumi , Hiramatsu Nobuhiko , Hayakawa Kunihiro , Yao Jian , Maeda Shuichiro , Kitamura Masanori
Published: July 2006

Cigarette smoke contains low levels of agonists for the aryl hydrocarbon receptor (AhR; also called the dioxin receptor). However, little is understood about the whole potential of cigarette smoke for activating AhR. In this report, we evaluated the total “dioxin-like” activity of cigarette smoke using in vitro and in vivo reporter systems. Cigarette smoke extract (CSE) was prepared from seven cigarette brands (1-20 mg tar content) and subjected to in vitro bioassay based on the xenobiotic-responsive element (XRE) as the sensor and secreted alkaline phosphatase (SEAP) as the reporter. Exposure of reporter cells to CSE triggered activation of XRE in a dose-dependent manner, which was suppressed by functional inhibition of AhR. Direct, brief exposure of the cells to cigarette smoke similarly induced activation of XRE. Using 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) as the standard, the XRE-activating potential (XAP) of individual smoke was evaluated quantitatively. Positive correlation was observed between the tar content and XAP values. The XAP values estimated were extremely high with a range from 18.5 to 51.2 ng 2,3,7,8-TCDD equivalent per cigarette. To further estimate XAP of cigarette smoke in vivo, we generated transgenic reporter mice that secrete SEAP under the control of XRE. After exposure of the mice to smoke, serum levels of SEAP were significantly elevated within 12 hours, peaked at 24 hours, and declined thereafter. These results evidenced for the first time that cigarette smoke has unexpectedly high dioxin-like potential that triggers the AhR-XRE pathway in vitro and in vivo. (Cancer Res 2006; 66(14): 7143-50)
Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas
Authors: Davicioni Elai , Graf Finckenstein Friedrich , Shahbazian Violette , Buckley Jonathan D. , Triche Timothy J. , Anderson Michael J.
Published: July 2006

Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior. (Cancer Res 2006; 66(14): 6936-46)
Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer
Authors: Nakashima Hiroshi , Nakamura Masafumi , Yamaguchi Hiroshi , Yamanaka Naoki , Akiyoshi Takashi , Koga Kenichiro , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao , Katano Mitsuo
Published: July 2006

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-κB (NF-κB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-κB by inflammatory stimuli, including interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-κB. NF-κB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell proliferation. Our data suggest that NF-κB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-κB activation in part through Shh overexpression. (Cancer Res 2006; 66(14): 7041-9)
Gene Expression Profiling of Acute Myeloid Leukemia with Translocation t(8;16)(p11;p13) and MYST3-CREBBP Rearrangement Reveals a Distinctive Signature with a Specific Pattern of HOX Gene Expression
Authors: Camós Mireia , Esteve Jordi , Jares Pedro , Colomer Dolors , Rozman María , Villamor Neus , Costa Dolors , Carrió Ana , Nomdedéu Josep , Montserrat Emili , Campo Elías
Published: July 2006

Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) is an infrequent leukemia subtype with characteristic clinicobiological features. This translocation leads to fusion of MYST3 (MOZ) and CREBBP (CBP) genes, probably resulting in a disturbed transcriptional program of a myelomonocytic precursor. Nonetheless, its gene expression profile is unknown. We have analyzed the gene expression profile of 23 AML patients, including three with molecularly confirmed MYST3-CREBBP fusion gene, using oligonucleotide U133A arrays (Affymetrix). MYST3-CREBBP cases clustered together and clearly differentiated from samples with PML-RARα, RUNX1-RUNX1T1, and CBFβ-MYH11 rearrangements. The relative expression of 46 genes, selected according to their differential expression in the high-density array study, was analyzed by low-density arrays in an additional series of 40 patients, which included 7 MYST3-CREBBP AML cases. Thus, genes such as prolactin (PRL) and proto-oncogene RET were confirmed to be specifically overexpressed in MYST3-CREBBP samples whereas genes such as CCND2, STAT5A, and STAT5B were differentially underexpressed in this AML category. Interestingly, MYST3-CREBBP AML exhibited a characteristic pattern of HOX expression, with up-regulation of HOXA9, HOXA10, and cofactor MEIS1 and marked down-regulation of other homeobox genes. This profile, with overexpression of FLT3, HOXA9, MEIS1, AKR7A2, CHD3, and APBA2, partially resembles that of AML with MLL rearrangement. In summary, this study shows the distinctive gene expression profile of MYST3-CREBBP AML, with overexpression of RET and PRL and a specific pattern of HOX gene expression. (Cancer Res 2006; 66(14): 6947-54)
Cancers as Wounds that Do Not Heal: Differences and Similarities between Renal Regeneration/Repair and Renal Cell Carcinoma
Authors: Riss Joseph , Khanna Chand , Koo Seongjoon , Chandramouli Gadisetti V.R. , Yang Howard H. , Hu Ying , Kleiner David E. , Rosenwald Andreas , Schaefer Carl F. , Ben-Sasson Shmuel A. , Yang Liming , Powell John , Kane David W. , Star Robert A. , Aprelikova Olga , Bauer Kristin , Vasselli James R. , Maranchie Jodi K. , Kohn Kurt W. , Buetow Ken H. , Linehan W. Marston , Weinstein John N. , Lee Maxwell P. , Klausner Richard D. , Barrett J. Carl
Published: July 2006

Cancers have been described as wounds that do not heal, suggesting that the two share common features. By comparing microarray data from a model of renal regeneration and repair (RRR) with reported gene expression in renal cell carcinoma (RCC), we asked whether those two processes do, in fact, share molecular features and regulatory mechanisms. The majority (77%) of the genes expressed in RRR and RCC were concordantly regulated, whereas only 23% were discordant (i.e., changed in opposite directions). The orchestrated processes of regeneration, involving cell proliferation and immune response, were reflected in the concordant genes. The discordant gene signature revealed processes (e.g., morphogenesis and glycolysis) and pathways (e.g., hypoxia-inducible factor and insulin-like growth factor-I) that reflect the intrinsic pathologic nature of RCC. This is the first study that compares gene expression patterns in RCC and RRR. It does so, in particular, with relation to the hypothesis that RCC resembles the wound healing processes seen in RRR. However, careful attention to the genes that are regulated in the discordant direction provides new insights into the critical differences between renal carcinogenesis and wound healing. The observations reported here provide a conceptual framework for further efforts to understand the biology and to develop more effective diagnostic biomarkers and therapeutic strategies for renal tumors and renal ischemia. (Cancer Res 2006; 66(14): 7216-24)
Cancer Immunotherapy by Interleukin-21: Potential Treatment Strategies Evaluated in a Mathematical Model
Authors: Cappuccio Antonio , Elishmereni Moran , Agur Zvia
Published: July 2006

The newly characterized interleukin (IL)-21 plays a central role in the transition from innate immunity to adaptive immunity and shows substantial tumor regression in mice. IL-21 is now developed as a cancer immunotherapeutic drug, but conditions for efficacious therapy, and the conflicting immunostimulatory and immunoinhibitory influence of the cytokine, are yet to be defined. We studied the effects of IL-21 on tumor eradication in a mathematical model focusing on natural killer (NK) cell–mediated and CD8+ T-cell-mediated lysis of tumor cells. Model parameters were estimated using results in tumor-bearing mice treated with IL-21 via cytokine gene therapy (CGT), hydrodynamics-based gene delivery (HGD), or standard interval dosing (SID). Our model accurately retrieved experimental growth dynamics in the nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity. Moreover, in melanoma, simulations of CGT-like dosing regimens, dynamically determined according to tumor mass changes, resulted in efficient disease elimination. In contrast, in fibrosarcoma, such a strategy was not superior to that of fixed dosing regimens, HGD or SID. Our model supports clinical use of IL-21 as a potent stimulator of cellular immunity against cancer, and suggests selecting the immunotherapy strategy according to tumor immunogenicity. Nonimmunogenic tumors, but not highly immunogenic tumors, should be controlled by IL-21 dosing, which depends on tumor mass at the time of administration. This method imitates, yet amplifies, the natural anticancer immune response rather than accelerates only one of the response arms in an unbalanced manner. (Cancer Res 2006; 66(14): 7293-300)
ChIP-chip Comes of Age for Genome-wide Functional Analysis
Authors: Wu Jiejun , Smith Laura T. , Plass Christoph , Huang Tim H-M.
Published: July 2006

In the post-genome era, attention has focused on the functions of genome sequences and how they are regulated. The emerging epigenomic changes and the interactions between cis-acting elements and protein factors may play a central role in gene regulation. To understand the crosstalk between DNA and protein on a genome-wide scale, one emerging technique, called ChIP-chip, takes the strategy of combining chromatin immunoprecipitation with microarray. This new high-throughput strategy helps screen the targets of critical transcription factors and profile the genome-wide distribution of histone modifications, which will enable the feasibility of conducting a large-scale study, such as the Human Epigenome Project. (Cancer Res 2006; 66(14): 6899-902)
Primary Cilium Formation Requires von Hippel-Lindau Gene Function in Renal-Derived Cells
Authors: Lutz Mallory S. , Burk Robert D.
Published: July 2006

Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, occurs in the majority of renal clear cell carcinomas (RCC). VHL's function, regulating the degradation of hypoxia-inducible factor α (HIFα) subunits, explains the angiogenic nature of these tumors, but not tumor initiation. Because the development of renal cysts precedes tumor formation, and because the dysfunction of primary cilium is a common pathogenic mechanism in polycystic kidney diseases, we determined whether kidney-derived VHL− cells required VHL for the generation of cilium. Ectopic expression of VHL in RCC(VHL−) cells induced increased polarization and primary cilium formation. Cilium formation correlated directly with the expression of both wild-type VHL isoforms and a VHL mutant not associated with RCC development, whereas expression of RCC-associated VHL mutants did not support ciliogenesis. Requirement of VHL for ciliogenesis was independent of HIFα abundance. These data indicate separable independent functions for VHL (HIFα degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis. (Cancer Res 2006; 66(14): 6903-07)
p73 or p53 Directly Regulates Human p53 Transcription to Maintain Cell Cycle Checkpoints
Authors: Wang Shulin , El-Deiry Wafik S.
Published: July 2006

Whereas the p53 tumor suppressor protein plays a central role in cellular checkpoints that respond to damage or stress to prevent tumorigenesis, the transcriptional control of the p53 gene has remained unclear. We show that chemotherapeutic agents induce p53 transcription and that p73 or p53 transactivates endogenous p53 expression through direct binding to the p53 promoter. Silencing of p53 or p73 by RNA interference significantly suppresses p53 transcription under physiologic conditions or in response to cellular stress. Mutational analysis of the human p53 promoter localized a p53 DNA-binding site, which confers p53- or p73-dependent p53 promoter activation. Importantly, impaired p53-mediated autoregulation of p53 transcription by inducible-interfering RNA results in aberrant cell cycle regulation and suppression of p53-mediated apoptosis. Thus, a positive feedback loop regulates human p53 expression and involves p73 and p53. Disruption of p53 transcription contributes to defective checkpoint control. (Cancer Res 2006; 66(14): 6982-9)
Bortezomib and Depsipeptide Sensitize Tumors to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand: A Novel Method to Potentiate Natural Killer Cell Tumor Cytotoxicity
Authors: Lundqvist Andreas , Abrams Scott I. , Schrump David S. , Alvarez Gauri , Suffredini Dante , Berg Maria , Childs Richard
Published: July 2006

The proteasome inhibitor, bortezomib, and the histone deacetylase inhibitor, depsipeptide (FK228), up-regulate tumor death receptors. Therefore, we investigated whether pretreatment of malignant cells with these agents would potentiate natural killer (NK)–mediated tumor killing. NK cells isolated from healthy donors and patients with cancer were expanded in vitro and then tested for cytotoxicity against tumor cell lines before and after exposure to bortezomib or depsipeptide. In 11 of 13 (85%) renal cell carcinoma cell lines and in 16 of 37 (43%) other cancer cell lines, exposure to these drugs significantly increased NK cell–mediated tumor lysis compared with untreated tumor controls (P < 0.001). Furthermore, NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against autologous tumor cells when pretreated with either bortezomib or depsipeptide compared with untreated tumors. Tumors sensitized to NK cell cytotoxicity showed a significant increase in surface expression of DR5 [tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)-R2; P < 0.05]; in contrast, surface expression of MHC class I, MIC-A/B, DR4 (TRAIL-R1), and Fas (CD95) did not change. The enhanced susceptibility to NK cell killing was completely abolished by blocking TRAIL on NK cells, and partially abolished by blocking DR5 on tumor cells. These findings show that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate the anticancer effects of adoptively infused NK cells in patients with cancer. (Cancer Res 2006; 66(14): 7317-25)
The G-quadruplex Ligand Telomestatin Inhibits POT1 Binding to Telomeric Sequences In vitro and Induces GFP-POT1 Dissociation from Telomeres in Human Cells
Authors: Gomez Dennis , O'Donohue Marie-Françoise , Wenner Thomas , Douarre Céline , Macadré Jérome , Koebel Pascale , Giraud-Panis Marie-Josèphe , Kaplan Hervé , Kolkes Alain , Shin-ya Kazuo , Riou Jean-François
Published: July 2006

Telomestatin is a potent G-quadruplex ligand that specifically interacts with the 3′ telomeric overhang, leading to its degradation and that induces a delayed senescence and apoptosis of cancer cells. Protection of Telomere 1 (POT1) was recently identified as a specific single-stranded telomere-binding protein involved in telomere capping and T-loop maintenance. We showed here that a telomestatin treatment inhibits POT1 binding to the telomeric overhang in vitro. The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2. Thus, we propose that G-quadruplex stabilization at telomeric G-overhang inactivates POT1 telomeric function, generating a telomere dysfunction in which chromosome ends are no longer properly protected. (Cancer Res 2006; 66(14): 6908-12)
Hypomethylated P4 Promoter Induces Expression of the Insulin-Like Growth Factor-II Gene in Hepatocellular Carcinoma in a Chinese Population
Authors: Tang Shao Hui , Yang Dong Hua , Huang Wei , Zhou Hong Ke , Lu Xiao Hua , Ye Gang
Published: July 2006

Purpose: The expression of human insulin-like growth factor-II (IGF-II) is regulated by the activation of four promoters (P1-P4) acting in a development-dependent, tissue-specific manner. IGF-II overexpression associated with P3 and P4 activation is observed in animal and human hepatocarcinogenesis. We correlated P4 epigenetic alteration with P4 transcript activation and clinicopathologic features.

Experimental Design: We analyzed P4 epigenetic alteration using methylation-specific PCR in 34 hepatocellular carcinoma (HCC) specimens, 34 matched adjacent nontumor specimens, and 8 normal adult liver specimens. The data were correlated with activation of P4 transcription by using reverse transcription-PCR. Epigenetic alteration was compared with patients' clinicopathologic features.

Results: Compared with normal liver tissue, hypomethylation of P4 CpG islands was significantly more frequent in HCC (P = 0.03) and matched tissues (P = 0.047). P4 mRNA levels in HCC with unmethylated alleles were significantly higher than in HCC without unmethylated alleles (P = 0.001); P4 mRNA levels in matched nontumor tissues with unmethylated alleles were significantly higher than in matched nontumor tissues without unmethylated alleles (P = 0.005). P4 hypomethylation in HCC was associated with portal vein tumor embolus (P = 0.017) and poorer tumor differentiation (P = 0.025).

Conclusions: These findings suggest that IGF-II P4 hypomethylation may be an early and frequent event and that it may contribute to P4 transcription expression activation during the transformation of a premalignant liver lesion to HCC. Furthermore, aberrant hypomethylation of P4 CpG islands not only may play an important role during hepatocarcinogenesis but might also be a useful biomarker for poor prognosis of patients with HCC.