bluuebunny/crossref_metadata_2025 huggingface dataset:
DESIGNING WOMEN, CAMEROON
Authors: BARLEY NIGEL
Published: December 2006

The Dowayos are a montagnard people numbering some 15,000 and living in the Poli prefecture of North Cameroon. They speak a language that has been classed as Niger‐Congo. Culturally and linguistically, they subdivide themselves into highland and lowland groups, though the distinction is hard to maintain. Dominated as they are by Muslim Fulani groups, there are two paths to modernity: Islamicization or Christianity—though many young people hold fast to the traditional ancestral cult. Subsistence is based on the cultivation of millet but men hunt and keep cattle. There are specialist (unclean) male smiths and female potters as in other parts of West Africa, but other specialist groups also exist, such as “true cultivators” and “hunters” who have to observe numerous prohibitions.

Groups of brothers tend to herd and live together; and geographical distance is often an approximate measure of kin propinquity. A man's foremost friends will be drawn from among those he was circumcised with, a woman's from the girls who began menstruating in the same year as herself. Chiefs were imposed by the French colonial authorities but traditionally the important people were rich men who could organize expensive festivals. Poorer people could associate themselves with these and so fulfill otherwise impossible ritual obligations. Above all other powers were the chiefs of the rain and the earth who organized the annual cycle and controlled the weather and the crops.
Development NEO Research: A Chronological Outline
Authors: REMO JOHN L.
Published: December 2006

ABSTRACT: Milestones in the historical development of NEO studies are briefly outlined.
Gaspra and Ida: Implications of Spacecraft Reconnaissance for NEO Issues
Authors: CHAPMAN CLARK R.
Published: December 2006

ABSTRACT: The first spacecraft encounters with asteroids were flybys of Gaspra and Ida by Galileo. They emphasize the diversity of asteroid properties and permit us to consider the probable physical nature of near‐Earth objects (NEOs).
Tsunami Produced by the Impacts of Small Asteroids
Authors: HILLS JACK G. , MADER CHARLES L.
Published: December 2006

ABSTRACT: The fragmentation of a small asteroid in the atmosphere greatly increases its cross section for aerodynamic braking, so ground impact damage (craters, earthquakes, and tsunami) from a stone asteroid is nearly negligible if it is less than 200 meters in diameter. A larger one impacts the ground at nearly its velocity at the top of the atmosphere producing considerable impact damage. The protection offered by Earth's atmosphere is insidious in that smaller, more frequent impactors such as Tunguska only produce air blast damage and leave no long‐term scars on the Earth's surface, while objects 2.5 times larger than it, which hit every few thousand years, cause coherent destruction over many thousands of kilometers of coast. Smaller impactors give no qualitative warning of the enormous destruction wrought when an asteroid larger than the threshold diameter of 200 meters hits an ocean. A water wave generated by an impactor has a long range because it is two‐dimensional, so its height falls off inversely with distance from the impact. When the wave strikes a continental shelf, its speed decreases and its height increases to produce tsunamis. The average runup in height between a deep‐water wave and its tsunami is more than an order of magnitude. Tsunamis produce most of the damage from asteroids with diameters between 200 meters and 1 km. An impact anywhere in the Atlantic by an asteroid 400 meters in diameter would devastate the coasts on both sides of the ocean by tsunami over 100 meters high. An asteroid 5 km in diameter hitting in mid Atlantic would produce tsunami that would inundate the entire upper East Coast of the United States to the Appalachian Mountains. Studies of ocean sediments may be used to determine when coastal areas have been hit by tsunamis in the past. Tsunami debris has been found to be associated with the Cretaceous‐Tertiary impact and should be detectable for smaller impacts.
High‐Performance Ultra‐light Nuclear Rockets for Near‐Earth Objects Interaction Missionsa
Authors: POWELL JAMES , MAISE GEORGE , LUDEWIG HANS , TODOSOW MICHAEL
Published: December 2006

ABSTRACT: The performance capabilities and technology features of ultra compact nuclear thermal rockets based on very high power density (30 Megawatts per liter) fuel elements are described. Nuclear rockets appear particularly attractive for carrying out missions to investigate or intercept near‐Earth objects (NEOs) that potentially could impact on the Earth. Many of these NEO threats, whether asteroids or comets, have extremely high closing velocities, i.e., tens of kilometers per second relative to the Earth. Nuclear rockets using hydrogen propellant enable flight velocities 2 to 3 times those achievable with chemical rockets, allowing interaction with a potential NEO threat at a much shorter time, and at much greater range. Two versions of an ultra compact nuclear rocket based on very high heat transfer rates are described: the PBR (Particle Bed Reactor), which has undergone substantial hardware development effort, and MITEE (MIniature ReacTor EnginE) which is a design derivative of the PBR. Nominal performance capabilities for the PBR are: thermal power ≃1000 MW thrust ≃45,000 lbsf, and weight ≃500 kg. For MITEE, nominal capabilities are: thermal power 100 MW; thrust ≃4500 lbsf, and weight ≃50 kg. Development of operational PBR/MITEE systems would enable spacecraft launched from LEO (low‐Earth orbit) to investigate intercept NEO's at a range of ∼100 million kilometers in times of ∼30 days.
Near‐Earth Resources
Authors: GERTSCH RICHARD , REMO JOHN L. , GERTSCH LESLIE SOUR
Published: December 2006

ABSTRACT: The technologies required to detect, track, categorize, and intercept objects in Earth‐impacting orbits can also provide access to their rich storehouse of materials. Mitigation of a clear and present near‐Earth object (NEO) threat to the Earth must provide the greatest assurance of success with the least risk to the planet. In some cases, mining a threatening NEO may become a viable alternative or supplement to a deflection or interception scenario. This converts the NEO threat to a near‐Earth resource. NEOs can supply materials for a wide range of operations both in space and on Earth, as they are thought to contain large amounts of water, carbon, structural metals, industrial feedstocks of many types, and precious metals. This wealth has low overhead for utilization in space; some known NEOs would require lower transportation energy expenditure than lunar resources. Mining a NEO inherently requires, among other things, altering the mass distribution of the body during exposure, removal, and processing of the ore. These processes can be tailored to facilitate deflection of the body from Earth impact by altering its orbital characteristics. The advantage of NEO mining is that it can mitigate the threat — the primary effort — while converting it into resources for space exploration. This additional effort, within an appropriate time scale, allows sequential mitigation of the NEO in a controlled manner while providing the resources contained within the NEO for use either in space or on Earth. Both goals, to be successful, will require maximum utilization of all sources of knowledge. The two most important are an extensive reconnaissance of the target NEO and the long history of terrestrial mining practice. This paper discusses how current mining technology might be adapted to mine NEOs, whether threatening or not. It summarizes our knowledge of NEO composition, physical properties, and mining and processing methods, and points out areas where further research, especially physical testing in space, is vital. The great potential of NEO resources and the successful mitigation of NEO threats will be best realized if their utilization is considered from the earliest planning of Earth‐NEO mitigations.
Amyloid Angiopathy and Blood–Brain Barrier Changes in Alzheimer's Diseasea,b
Authors: WISNIEWSKI HENRYK M. , VORBRODT ANDRZEJ W. , WEGIEL JERZY
Published: December 2006

ABSTRACT: Evidence is accumulating that suggests that increased permeability of the BBB to blood‐borne proteins is favorable for the development of neuropathologic changes such as amyloid angiopathy and formation of amyloid plaques in the AD brain. To study this problem, we applied a quantitative immunocytochemical procedure that enables evaluation of the barrier function of brain microvasculature to endogenous albumin. This procedure was successfully used on scrapie‐infected mice, which represent a unique animal model enabling study of an interrelation between BBB function and deposition of amyloid within vascular wall and neuritic plaques. Biopsy specimens obtained during neurosurgical procedures (tumors and dementia) were also examined. Our observations indicate that (1) the vast majority of brain microvessels in scrapie‐infected mice and in demented individuals show normal features of the BBB; (2) only those microvascular segments directly surrounded by amyloid plaques or representing amyloid angiopathy show increased permeability to endogenous albumin; (3) numerous immunosignals over the amyloid deposits in plaques and in the wall of angiopathic vessels suggest the affinity of extravasated albumin to the amyloid material.
Cerebrovascular Degeneration Is Related to Amyloid‐β Protein Deposition in Alzheimer's Diseasea
Authors: KALARIA RAJESH N.
Published: December 2006

ABSTRACT: Current evidence is not inconsistent with the suggestion that cerebrovascular functions decline during normal aging with pronounced effects in both sporadic and familial Alzheimer's disease (AD). The primary causes of these changes remain unknown. It is possible that amyloid β (Aβ) protein is involved in the degeneration of both the larger penetrating vessels as well as the cerebral capillaries that represent the blood‐brain barrier (BBB). Aβ‐induced endothelial changes could also alter muscular tone, resulting not only in increased expression of vascular amyloid precursor protein (APP) and production of Aβ, but also in oxidative injury. We used immunochemical methods to examine the status of the perfusing cerebral vessels and the microvascular endothelium in relation to deposition of Aβ in AD and non‐AD aging control subjects. Double‐immunostaining with antibodies to vascular markers revealed marked loss of smooth muscle in larger vessels and absence or attenuation of the endothelium in capillary profiles that still appeared to retain their basement membranes. These vascular changes were predominantly restricted to neocortical regions abundant in Aβ deposits. Quantitative studies showed that the microvascular abnormalities were correlated to Aβ deposition rather than neurofibrillary tangles or neuronal numbers. Our studies suggest that Aβ irrespective of its origin within vascular myocytes or brain parenchyma, is responsible not only for cerebral amyloid angiopathy, but also for the degeneration of the cerebral microvasculature, which may profoundly affect brain perfusion and BBB functions.
Misery Perfusion with Preserved Vascular Reactivity in Alzheimer's Disease
Authors: NAGATA KEN , BUCHAN ROBERT J. , YOKOYAMA ERIKO , KONDOH YASUSHI , SATO MIKA , TERASHI HIROO , SATOH YUICHI , WATAHIKI YASUHITO , SENOVA MELIS , HIRATA YUTAKA , HATAZAWA JUN
Published: December 2006

ABSTRACT: To elucidate the hemodynamic pathophysiology underlying Alzheimer's disease (AD), cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction fraction (OEF) were measured with positron emission tomography in 10 patients with probable AD and in 20 age‐matched normal volunteers. By the 15O intravenous bolus injection method, CBF was measured during resting state, CO2 inhalation (hypercapnia) and hyperventilation (hypocapnia), and the vascular reactivity (VR) was estimated by comparing the CBF changes (ΔCBF%/PaCO2 mmHg) in the hyper‐ or hypocapnic to the resting state. By the 15O2 single‐breath method or 15O steady‐state method, CMRO2 and OEF were measured during resting state. Based on 26 regions of interest, local CBF, CMRO2 and OEF were compared statistically between the two groups. As compared with the control group, the mean CBF and CMRO2 decreased to as low as 77.0% and 88.4% of the normal values, respectively, while the mean OEF increased by 12.1% (p < 0.05) in AD patients. These changes were most pronounced in the supramarginal and superior temporal gyri. There was no focal change in VR in the AD group, and no significant difference was seen in VR to either hyper‐ or hypocapnia between AD and control groups. The results may suggest a vascular involvement, possibly at the capillary level, that might cause a relative misery perfusion syndrome accompanied by preserved vascular reactivity in AD.
Breast Cancer Genes: Therapeutic Strategies
Authors: HOLT JEFFREY T.
Published: December 2006

ABSTRACT: Although effective treatments for breast cancer predated the identification of causative molecular defects in humans, it is widely hoped that an understanding and/or manipulation of the key genetic events will lead to even more effective therapies or even cures. Powerful methods of positional cloning and gene identification have identified the breast cancer genes, BRCA1 and BRCA2, which together are responsible for the majority of cases of hereditary breast and ovarian cancer. Although the BRCA1 gene is rarely mutated in sporadic breast or ovarian cancer, levels of BRCA1 mRNA and protein are markedly decreased in the majority of sporadic cases of cancer. This suggests that hereditary and sporadic breast cancer share common genetic themes and that treatments aimed at increasing levels of BRCA1 or BRCA2 may be useful for both hereditary and sporadic cancers. We have demonstrated that gene transfer of wild‐type BRCA1 inhibits the growth of sporadic breast and ovarian cancer cells and suppresses growth of established breast and ovarian tumor models in nude mice. Mutant BRCA1 genes do not inhibit growth or suppress tumor, providing additional evidence that BRCA1 is a tumor‐suppressor gene. Strategies designed to increase BRCA1 expression or development of BRCA1‐mimetic agents may be ultimately useful as therapeutic approaches.
Genetics of Suicide
Authors: ROY ALEC , RYLANDER GUNNAR , SARCHIAPONE MARCO
Published: December 2006

ABSTRACT: Suicidal behavior, like so much else in psychiatry, tends to cluster in families. Clinical studies show that a family history of suicide is associated with a raised risk of both attempts at suicide and completed suicide. Twin studies show that monozygotic twins have a greater concordance for suicidal behavior than dizygotic twins. Adoption studies also suggest that there may be genetic factors in suicide. Most recently, molecular genetic studies report that polymorphisms of the tryptophan hydroxylase gene are associated with suicidal behavior.
Behavioral Treatments of Suicidal Behaviors. Definitional Obfuscation and Treatment Outcomesa
Authors: LINEHAN MARSHA M.
Published: December 2006

Abstract This chapter focuses on a review of randomized clinical trials of both psychosocial and behavioral interventions designed to directly reduce rates of suicide and parasuicidal behavior, including suicide attempts. It begins with an overview of the definitional difficulties in this field and then proceeds to an overview of treatment issues and a comprehensive review of treatment studies aiming to reduce suicidal behavior among suicidal individuals. Twenty studies are discussed. Eighteen studies randomly assigned subjects to the experimental and control condition; the other two studies assigned subjects in an alternating sequential fashion. Analyses showed that four psychosocial intervention studies and one pharmacotherapy study have reported efficacious results when compared to treatments‐as‐usual or placebo controls. From another perspective, when outpatient psychosocial interventions were examined, the strongest predictor of whether the experimental treatment would be more effective than the control was whether high‐risk suicidal individuals were included. Psychosocial interventions appear to be most effective with the more high‐risk individuals.
Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
Authors: Kim Hee-Tae , Kong Gu , DeNardo David , Li Yuxin , Uray Ivan , Pal Sunita , Mohsin Syed , Hilsenbeck Susan G. , Bissonnette Reid , Lamph William W. , Johnson Karen , Brown Powel H.
Published: December 2006

Retinoids have been found to be promising chemopreventive agents that play an important role in regulating cell growth, differentiation, and apoptosis. The action of retinoids is mediated by retinoid receptors (retinoic acid receptors and retinoid X receptors), which are nuclear transcription factors that, when bound to retinoids, regulate gene expression. LGD1069 is a highly selective RXR agonist that has reduced toxicity compared with retinoids. Our previous studies have shown that RXR-selective ligands (or “rexinoids”), including LGD1069, can inhibit the growth of normal and malignant breast cells and can suppress the development of breast cancer in transgenic mice. For the current study, we attempted to identify biomarkers of the chemopreventive effect of the RXR-selective retinoid LGD1069. In these experiments, we used Affymetrix microarrays to identify target genes that were modulated by LGD1069 in normal human breast cells. Affymetrix and dChip analysis identified more than 100 genes that were up-regulated or down-regulated by LGD1069 treatment. We then tested 16 of these genes in validation experiments using quantitative reverse transcription-PCR and Western blotting of independently prepared samples, and found that 15 of 16 genes were modulated in a similar manner in these validation experiments as in the microarray experiments. Genes found to be regulated include known retinoid-regulated genes, growth regulatory genes, transcription factors, and differentiation markers. We then showed that the expression of several of these rexinoid-regulated biomarkers is modulated in vivo in mammary glands from mice treated with LGD1069. These critical growth-regulating proteins will be promising targets of future agents for the prevention and treatment of breast cancer. (Cancer Res 2006; 66(24): 12009-18)
The Tumor Metastasis Suppressor Gene Drg-1 Down-regulates the Expression of Activating Transcription Factor 3 in Prostate Cancer
Authors: Bandyopadhyay Sucharita , Wang Ying , Zhan Rui , Pai Sudha K. , Watabe Misako , Iiizumi Megumi , Furuta Eiji , Mohinta Sonia , Liu Wen , Hirota Shigeru , Hosobe Sadahiro , Tsukada Taisei , Miura Kunio , Takano Yukio , Saito Ken , Commes Therese , Piquemal David , Hai Tsonwin , Watabe Kounosuke
Published: December 2006

The tumor metastasis suppressor gene Drg-1 has been shown to suppress metastasis without affecting tumorigenicity in immunodeficient mouse models of prostate and colon cancer. Expression of Drg-1 has also been found to have a significant inverse correlation with metastasis or invasiveness in various types of human cancer. However, how Drg-1 exerts its metastasis suppressor function remains unknown. In the present study, to elucidate the mechanism of action of the Drg-1 gene, we did a microarray analysis and found that induction of Drg-1 significantly inhibited the expression of activating transcription factor (ATF) 3, a member of the ATF/cyclic AMP–responsive element binding protein family of transcription factors. We also showed that Drg-1 attenuated the endogenous level of ATF3 mRNA and protein in prostate cancer cells, whereas Drg-1 small interfering RNA up-regulated the ATF3 expression. Furthermore, Drg-1 suppressed the promoter activity of the ATF3 gene, indicating that Drg-1 regulates ATF3 expression at the transcriptional level. Our immunohistochemical analysis on prostate cancer specimens revealed that nuclear expression of ATF3 was inversely correlated to Drg-1 expression and positively correlated to metastases. Consistently, we have found that ATF3 overexpression promoted invasiveness of prostate tumor cells in vitro, whereas Drg-1 suppressed the invasive ability of these cells. More importantly, overexpression of ATF3 in prostate cancer cells significantly enhanced spontaneous lung metastasis of these cells without affecting primary tumorigenicity in a severe combined immunodeficient mouse model. Taken together, our results strongly suggest that Drg-1 suppresses metastasis of prostate tumor cells, at least in part, by inhibiting the invasive ability of the cells via down-regulation of the expression of the ATF3 gene. (Cancer Res 2006; 66(24): 11983-90)
A Systematic Assessment of Common Genetic Variation in CYP11A and Risk of Breast Cancer
Authors: Setiawan Veronica Wendy , Cheng Iona , Stram Daniel O. , Giorgi Elena , Pike Malcolm C. , Van Den Berg David , Pooler Loreall , Burtt Noel P. , Le Marchand Loic , Altshuler David , Hirschhorn Joel , Henderson Brian E. , Haiman Christopher A.
Published: December 2006

CYP11A catalyzes the rate-limiting step in the biosynthesis of sex-steroid hormones. In this study, we employed a systematic approach that involved gene resequencing and a haplotype-based analysis to investigate the relationship between common variation in CYP11A and breast cancer risk among African-Americans, Latinas, Japanese-Americans, Native Hawaiians, and Whites in the Multiethnic Cohort Study. Resequencing in a multiethnic panel of 95 advanced breast cancer cases revealed no common missense variant (≥5% frequency). Common haplotype patterns were assessed by genotyping 36 densely spaced single nucleotide polymorphisms (SNPs) spanning 67 kb of the CYP11A locus in a multiethnic panel of subjects (n = 349; 1 SNP/1.86 kb on average). We identified one to two regions of strong linkage disequilibrium in these populations. Twelve tagging SNPs were selected to predict the common haplotypes (≥5% frequency) in these regions with high probability (average Rh2 = 0.94) and were examined in a breast cancer case-control study in the Multiethnic Cohort Study (1,615 cases and 1,962 controls). A global test for differences in risk according to common haplotypes over the locus was statistically significant (P = 0.006), as were associations with haplotypes in each block (block 1 global test, P = 0.008; haplotype 1D, effect per haplotype copy, odds ratios, 1.23; 95% confidence interval, 1.03–1.48) and block 2 (global test, P = 0.016; haplotype 2F odds ratios, 1.52; 95% confidence interval, 1.15–2.01). These haplotypes were most common in Japanese-Americans and Native Hawaiians, followed by Whites then Latinas, and were rare in African-Americans (<5% frequency); the haplotype effects on risk across each group were homogeneous. Based on these findings, CYP11A deserves further consideration as a candidate breast cancer susceptibility gene. (Cancer Res 2006; 66(24): 12019-25)
Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5
Authors: Liu Li , Cao Yichen , Chen Charles , Zhang Xiaomei , McNabola Angela , Wilkie Dean , Wilhelm Scott , Lynch Mark , Carter Christopher
Published: December 2006

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK–independent manner. Consistent with the effects on both MEK/ERK–dependent and MEK/ERK–independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase–mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms). (Cancer Res 2006; 66(24): 11851-8)
Amplification and Overexpression ofCTTN(EMS1) Contribute to the Metastasis of Esophageal Squamous Cell Carcinoma by Promoting Cell Migration and Anoikis Resistance
Authors: Luo Man-Li , Shen Xiao-Ming , Zhang Yu , Wei Fang , Xu Xin , Cai Yan , Zhang Xun , Sun Yun-Tian , Zhan Qi-Min , Wu Min , Wang Ming-Rong
Published: December 2006

Gain of chromosome 11q13 is a common event in esophageal squamous cell carcinoma (ESCC). The cortactin gene (CTTN, also EMS1), located at 11q13, plays a pivotal role in coupling membrane dynamics to cortical actin assembly. This gene has been implicated in the motility of several types of cells. In the present study, we found that the amplification and overexpression of the CTTN gene was associated with lymph node metastasis in ESCC. Functional analysis by small interfering RNA–mediated silencing of CTTN revealed that in addition to the effect on cell migration, CTTN influenced cell invasiveness by anoikis resistance. In vivo assay showed that inhibition of CTTN expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, we showed for the first time that the protective role of CTTN in anoikis resistance was correlated with the activation of the phosphatidylinositol 3-kinase/Akt pathway. Overall, the data suggest that CTTN is an oncogene in the 11q13 amplicon and exerts functions on tumor metastasis in ESCC. (Cancer Res 2006; 66(24): 11690-9)
DNA Methylation Pathway Alterations in an Autochthonous Murine Model of Prostate Cancer
Authors: Morey Shannon R. , Smiraglia Dominic J. , James Smitha R. , Yu Jihnhee , Moser Michael T. , Foster Barbara A. , Karpf Adam R.
Published: December 2006

We examined the DNA methylation pathway in an autochthonous murine prostate cancer model, transgenic adenocarcinoma of mouse prostate (TRAMP). We observed that, compared with strain-matched normal prostates, primary and metastatic TRAMP tumors display increased cytosine DNA methyltransferase (Dnmt) activity, Dnmt1 and Dnmt3b protein expression, and Dnmt1, Dnmt3a, and Dnmt3b mRNA expression. Increased expression of Dnmt genes correlates with increased expression of cyclin A and E2F target genes, implicating increased cell proliferation and Rb inactivation in Dnmt overexpression. We analyzed DNA methylation in TRAMP and found that global levels of 5-methyl-2′-deoxycytidine are unaltered, whereas specific tumors display centromeric repeat hypomethylation. To interrogate locus-specific methylation, we did restriction landmark genomic scanning (RLGS) on normal prostates and primary tumors. In primary tumors, 2.3% of ∼1,200 analyzed loci display aberrant DNA hypermethylation, whereas a considerably smaller number of events show hypomethylation. The pattern of RLGS changes was nonrandom, indicating a coordinated methylation defect. Two specific genes identified by RLGS were studied in detail. Surprisingly, methylation of a downstream exon of p16(INK4a) (p16) was the highest frequency hypermethylation event identified in TRAMP, where it is associated with increased p16 mRNA and protein expression. In contrast, hypermethylation of the 5′ CpG island region of the homeobox gene Irx3 in TRAMP is associated with reduced gene expression. In summary, our data reveal a systemic DNA methylation pathway defect in TRAMP reminiscent of human prostate cancer, supporting the use of this model to investigate the functional role of DNA methylation pathway alterations in prostate cancer development. (Cancer Res 2006; 66(24): 11659-67)
A Specific Role for AKT3 in the Genesis of Ovarian Cancer through Modulation of G2-M Phase Transition
Authors: Cristiano Briony E. , Chan Joanna C. , Hannan Katherine M. , Lundie Nicole A. , Marmy-Conus Nelly J. , Campbell Ian G. , Phillips Wayne A. , Robbie Melissa , Hannan Ross D. , Pearson Richard B.
Published: December 2006

Ovarian cancer is the major cause of death from gynecological malignancy, and there is an urgent need for new therapeutic targets. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been strongly implicated in the genesis of ovarian cancer. However, to identify and evaluate potential targets for therapeutic intervention, it is critical to understand the mechanism by which the PI3K/AKT pathway facilitates ovarian carcinogenesis. Here, we show that AKT3 is highly expressed in 19 of 92 primary ovarian tumors. Strikingly, purified AKT3 exhibited up to 10-fold higher specific activity than AKT1, potentially amplifying the effects of AKT3 overexpression. Consistent with this finding, AKT3 levels in a range of ovarian cancer cell lines correlated with total AKT activity and proliferation rates, implicating AKT3 as a key mediator of ovarian oncogenesis. Specific silencing of AKT3 using short hairpin RNA markedly inhibited proliferation of the two cell lines with highest AKT3 expression and total AKT activity, OVCA429 and DOV13, by slowing G2-M phase transition. These findings are consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers. (Cancer Res 2006; 66(24): 11718-25)
Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies
Authors: Martinive Philippe , Defresne Florence , Bouzin Caroline , Saliez Julie , Lair Florence , Grégoire Vincent , Michiels Carine , Dessy Chantal , Feron Olivier
Published: December 2006

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1α (HIF-1α)–targeting small interfering RNA led us to document that the accumulation of HIF-1α during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1α to resensitize the tumor vasculature to anticancer treatments. (Cancer Res 2006; 66(24): 11736-44)
Anti-Aromatase Activity of Phytochemicals in White Button Mushrooms (Agaricus bisporus)
Authors: Chen Shiuan , Oh Sei-Ryang , Phung Sheryl , Hur Gene , Ye Jing Jing , Kwok Sum Ling , Shrode Gayle E. , Belury Martha , Adams Lynn S. , Williams Dudley
Published: December 2006

White button mushrooms (Agaricus bisporous) are a potential breast cancer chemopreventive agent, as they suppress aromatase activity and estrogen biosynthesis. Therefore, we evaluated the activity of mushroom extracts in the estrogen receptor–positive/aromatase-positive MCF-7aro cell line in vitro and in vivo. Mushroom extract decreased testosterone-induced cell proliferation in MCF-7aro cells but had no effect on MCF-10A, a nontumorigenic cell line. Most potent mushroom chemicals are soluble in ethyl acetate. The major active compounds found in the ethyl acetate fraction are unsaturated fatty acids such as linoleic acid, linolenic acid, and conjugated linoleic acid. The interaction of linoleic acid and conjugated linoleic acid with aromatase mutants expressed in Chinese hamster ovary cells showed that these fatty acids inhibit aromatase with similar potency and that mutations at the active site regions affect its interaction with these two fatty acids. Whereas these results suggest that these two compounds bind to the active site of aromatase, the inhibition kinetic analysis indicates that they are noncompetitive inhibitors with respect to androstenedione. Because only conjugated linoleic acid was found to inhibit the testosterone-dependent proliferation of MCF-7aro cells, the physiologically relevant aromatase inhibitors in mushrooms are most likely conjugated linoleic acid and its derivatives. The in vivo action of mushroom chemicals was shown using nude mice injected with MCF-7aro cells. The studies showed that mushroom extract decreased both tumor cell proliferation and tumor weight with no effect on rate of apoptosis. Therefore, our studies illustrate the anticancer activity in vitro and in vivo of mushroom extract and its major fatty acid constituents. (Cancer Res 2006; 66(24): 12026-34)
Cationic Albumin–Conjugated Pegylated Nanoparticles Allow Gene Delivery into Brain Tumors via Intravenous Administration
Authors: Lu Wei , Sun Qing , Wan Jin , She Zhenjue , Jiang Xin-Guo
Published: December 2006

Patients with malignant gliomas have a poor prognosis because these tumors do not respond well to conventional treatments. Studies of glioma xenografts suggest that they may be amenable to gene therapy with cytotoxic genes, such as the proapoptotic Apo2 ligand/tumor necrosis factor–related apoptosis-inducing ligand (Apo2L/TRAIL). Gene therapy of gliomas ideally employs i.v. given vectors, thus excluding viral vectors as they cannot cross the brain microvascular endothelium or blood-brain barrier. Recently, we reported the synthesis of cationic albumin–conjugated pegylated nanoparticles (CBSA-NP) and showed their accumulation in mouse brain cells upon i.v. administration. In this study, plasmid pORF-hTRAIL (pDNA) was incorporated into CBSA-NP, and the resulting CBSA-NP-hTRAIL was evaluated as a nonviral vector for gene therapy of gliomas. Thirty minutes after transfection of C6 glioma cells, CBSA-NP-hTRAIL was internalized and mostly located in the cytoplasm, whereas NP-hTRAIL was entrapped in the endolysosomal compartment. At 6 and 48 hours after transfection, respectively, released pDNA was present in the nuclei and induced apoptosis. At 30 minutes after i.v. administration of CBSA-NP-hTRAIL to BALB/c mice bearing i.c. C6 gliomas, CBSA-NP-hTRAIL colocalized with glycoproteins in brain and tumor microvasculature and, via absorptive-mediated transcytosis, accumulated in tumor cells. At 24 and 48 hours after i.v. administration of CBSA-NP-hTRAIL, respectively, hTRAIL mRNA and protein were detected in normal brain and tumors. Furthermore, repeated i.v. injections of CBSA-NP-hTRAIL induced apoptosis in vivo and significantly delayed tumor growth. In summary, this study indicates that CBSA-NP-hTRAIL is a promising candidate for noninvasive gene therapy of malignant glioma. (Cancer Res 2006; 66(24): 11878-87)
Mammary-Specific Ron Receptor Overexpression Induces Highly Metastatic Mammary Tumors Associated with β-Catenin Activation
Authors: Zinser Glendon M. , Leonis Mike A. , Toney Kenya , Pathrose Peterson , Thobe Megan , Kader Sarah A. , Peace Belinda E. , Beauman Shirelyn R. , Collins Margaret H. , Waltz Susan E.
Published: December 2006

Activated growth factor receptor tyrosine kinases (RTK) play pivotal roles in a variety of human cancers, including breast cancer. Ron, a member of the Met RTK proto-oncogene family, is overexpressed or constitutively active in 50% of human breast cancers. To define the significance of Ron overexpression and activation in vivo, we generated transgenic mice that overexpress a wild-type or constitutively active Ron receptor in the mammary epithelium. In these animals, Ron expression is significantly elevated in mammary glands and leads to a hyperplastic phenotype by 12 weeks of age. Ron overexpression is sufficient to induce mammary transformation in all transgenic animals and is associated with a high degree of metastasis, with metastatic foci detected in liver and lungs of >86% of all transgenic animals. Furthermore, we show that Ron overexpression leads to receptor phosphorylation and is associated with elevated levels of tyrosine phosphorylated β-catenin and the up-regulation of genes, including cyclin D1 and c-myc, which are associated with poor prognosis in patients with human breast cancers. These studies suggest that Ron overexpression may be a causative factor in breast tumorigenesis and provides a model to dissect the mechanism by which the Ron induces transformation and metastasis. (Cancer Res 2006; 66(24): 11967-74)
Physical Association with WWOX Suppresses c-Jun Transcriptional Activity
Authors: Gaudio Eugenio , Palamarchuk Alexey , Palumbo Tiziana , Trapasso Francesco , Pekarsky Yuri , Croce Carlo M. , Aqeilan Rami I.
Published: December 2006

WWOX is a tumor suppressor that functions as a modular protein partner of transcription factors. WWOX contains two WW domains that mediate protein-protein interactions. In this report, we show that WWOX, via its first WW domain, specifically associates with the proline-rich motif of c-Jun proto-oncogene. Our data show that phosphorylation of c-Jun caused by overexpression of mitogen-activated protein kinase kinase kinase 1 (Mekk1), an upstream activator of c-Jun, enhances the interaction of c-Jun with WWOX. Furthermore, exposure of HaCaT keratinocytes to UVC radiation resulted in the association of endogenous WWOX and c-Jun. The WWOX-c-Jun complexes mainly occur in the cytoplasm. Expression of WWOX attenuates the ability of MEKK1 to increase the activity of a c-Jun-driven activating protein-1 (AP-1)-luciferase reporter plasmid. In contrast, a point mutation in the first WW domain of WWOX has no effect on transactivation of AP-1 when coexpressed with c-Jun protein. Our findings reveal a novel functional cross-talk between c-Jun transcription factor and WWOX tumor suppressor protein. (Cancer Res 2005; 66(24): 11585-9)
Influence of the Multidecadal Atlantic Meridional Overturning Circulation Variability on European Climate
Authors: Pohlmann Holger , Sienz Frank , Latif Mojib
Published: December 2006

The influence of the natural multidecadal variability of the Atlantic meridional overturning circulation (MOC) on European climate is investigated using a simulation with the coupled atmosphere–ocean general circulation model ECHAM5/Max Planck Institute Ocean Model (MPI-OM). The results show that Atlantic MOC fluctuations, which go along with changes in the northward heat transport, in turn affect European climate. Additionally, ensemble predictability experiments with ECHAM5/MPI-OM show that the probability density functions of surface air temperatures in the North Atlantic/European region are affected by the multidecadal variability of the large-scale oceanic circulation. Thus, some useful decadal predictability may exist in the Atlantic/European sector.
Climatology of Upper-Tropospheric Relative Humidity from the Atmospheric Infrared Sounder and Implications for Climate
Authors: Gettelman Andrew , Collins William D. , Fetzer Eric J. , Eldering Annmarie , Irion Fredrick W. , Duffy Phillip B. , Bala Govindasamy
Published: December 2006

Recently available satellite observations from the Atmospheric Infrared Sounder (AIRS) are used to calculate relative humidity in the troposphere. The observations illustrate many scales of variability in the atmosphere from the seasonal overturning Hadley–Walker circulation to high-frequency transient variability associated with baroclinic storms with high vertical resolution. The Asian monsoon circulation has a strong impact on upper-tropospheric humidity, with large humidity gradients to the west of the monsoon. The vertical structure of humidity is generally bimodal, with high humidity in the upper and lower troposphere, and a dry middle troposphere. The highest variances in humidity are seen around the midlatitude tropopause. AIRS data are compared to a simulation from a state-of-the-art climate model. The model does a good job of reproducing the mean humidity distribution but is slightly moister than the observations in the middle and upper troposphere. The model has difficultly reproducing many scales of observed variability, particularly in the Tropics. Differences in humidity imply global differences in the top of atmosphere fluxes of ∼1 W m−2.
The Role of Oceanic Heat Advection in the Evolution of Tropical North and South Atlantic SST Anomalies*
Authors: Foltz Gregory R. , McPhaden Michael J.
Published: December 2006

The role of horizontal oceanic heat advection in the generation of tropical North and South Atlantic sea surface temperature (SST) anomalies is investigated through an analysis of the oceanic mixed layer heat balance. It is found that SST anomalies poleward of 10° are driven primarily by a combination of wind-induced latent heat loss and shortwave radiation. Away from the eastern boundary, horizontal advection damps surface flux–forced SST anomalies due to a combination of mean meridional Ekman currents acting on anomalous meridional SST gradients, and anomalous meridional currents acting on the mean meridional SST gradient. Horizontal advection is likely to have the most significant effect on the interhemispheric SST gradient mode through its impact in the 10°–20° latitude bands of each hemisphere, where the variability in advection is strongest and its negative correlation with the surface heat flux is highest. In addition to the damping effect of horizontal advection in these latitude bands, evidence for coupled wind–SST feedbacks is found, with anomalous equatorward (poleward) SST gradients contributing to enhanced (reduced) westward surface winds and an equatorward propagation of SST anomalies.
Learning What Feelings to Desire: Socialization of Ideal Affect Through Children's Storybooks
Authors: Tsai Jeanne L. , Louie Jennifer Y. , Chen Eva E. , Uchida Yukiko
Published: December 2006

Previous findings suggest that cultural factors influence ideal affect (i.e., the affective states that people ideally want to feel). Three studies tested the hypothesis that cultural differences in ideal affect emerge early in life and are acquired through exposure to storybooks. In Study 1, the authors established that consistent with previous findings, European American preschoolers preferred excited (vs. calm) states more (indexed by activity and smile preferences) and perceived excited (vs. calm) states as happier than Taiwanese Chinese preschoolers. In Study 2, it was observed that similar differences were reflected in the pictures (activities, expressions, and smiles) of best-selling storybooks in the United States and Taiwan. Study 3 found that across cultures, exposure to exciting (vs. calm) storybooks altered children's preferences for excited (vs. calm) activities and their perceptions of happiness. These findings suggest that cultural differences in ideal affect may be due partly to differential exposure to calm and exciting storybooks.
Humanizing the Self: Moderators of the Attribution of Lesser Humanness to Others
Authors: Haslam Nick , Bain Paul
Published: December 2006

Three studies investigated moderators of the tendency to attribute greater humanness to the self than to others, an interpersonal counterpart of outgroup infra-humanization. Study 1 demonstrated that this self-humanizing effect is reduced when the other is the focus of comparison. Study 2 showed that the effect is reduced when the other is individuated. Study 3 indicated that empathy does not moderate self-humanizing: Self-humanizing failed to correlate negatively with dispositional empathy or perspective-taking. Study 3 also indicated that abstract construal moderates the self-humanizing effect using a temporal comparison. Participants rated their future self, but not their past self, as less human than their present self. Studies 1 and 3 also showed that self-humanizing is greater for undesirable traits: People may view their failings as “only human.” All findings were distinct from those attributable to self-enhancement. Self-humanizing may reflect a combination of egocentrism, focalism, abstract representation of others, and motivated processes.
Predicting Preferences for Dating Partners From Past Experiences of Psychological Abuse: Identifying the Psychological Ingredients of Situations
Authors: Zayas Vivian , Shoda Yuichi
Published: December 2006

Are women who have been the victim of psychological abuse in the past more likely to prefer an abusive dating partner in the future? Are men who have been the perpetrator of abuse more likely to prefer a dating partner with high attachment anxiety, a characteristic associated with victims of abuse? The present research used a highly repeated, within-subject, multilevel approach to identify the characteristics of potential dating partners that constitute salient psychological ingredients of situations influencing partner preference. Study 1 found that college-age women who reported more instances of receiving psychological abuse, compared to women who did not, showed a stronger preference for male dating partners who possessed characteristics associated with an abusive personality (e.g., possessiveness). Study 2 found that college-age men who reported more instances of inflicting psychological abuse, compared to men who did not, showed a stronger preference for female dating partners characterized by high attachment anxiety.
Stress on the Dance Floor: The Cortisol Stress Response to Social-Evaluative Threat in Competitive Ballroom Dancers
Authors: Rohleder Nicolas , Beulen Silke E. , Chen Edith , Wolf Jutta M. , Kirschbaum Clemens
Published: December 2006

The social self-preservation theory states that humans have a fundamental motivation to preserve the social self and that threats to the social self perturb biological markers such as cortisol. Five studies were designed to examine the cortisol response to competitive ballroom dancing as a paradigm for real-life social-evaluative threat. Competitive dancing produced substantial increases in cortisol compared to a control day. These increases were not due to the physical strain of dancing and were greater than those found during social-evaluative laboratory stressors. Responses did not habituate across competitions and were mostly elevated under highly focused conditions of threat (couple vs. group competition). These findings support the notion of a social self-preservation system that is physiologically responsive to threats to the social self.