bluuebunny/crossref_metadata_2025 huggingface dataset:
SOCIAL NETWORK CHARACTERISTICS AND NETWORK SATISFACTION OF PEOPLE WITH PSYCHIATRIC DISABILITIES LIVING IN THE COMMUNITY
Authors: YAU SANIA S. W. , LEUNG BONNIE Y. L. , LEUNG SAMUEL S. M.
Published: December 2009

Objectives: To understand the social network characteristics and network satisfaction of people with psychiatric disabilities living in the community in Hong Kong. Method: A modified scale was administered to 251 service users attending 5 Community Mental Health Link (LINK) Services measuring the above variables. Findings: The study suggested that people with psychiatric disabilities living in the community have a small social network. Moreover, network satisfaction is related to network size and physical proximity. The results are discussed in terms of their consistency with overseas findings and the implications for social work practice in network building for people with psychiatric disabilities. Conclusion: The results provided an initial understanding of social network characteristics and network satisfaction of service users receiving LINK service, with particular reference to network size and physical proximity.

目的：探討本地精神病康復者的社交網絡特質及他們對社交網絡的滿意程度。方法： 共251名來自5個「精神健康連網」的服務使用者填寫一份問卷，量度他們的社交網絡特質及對社交網絡的滿意程度。結果： 在社區生活的精神病康復者的社交網絡較小，而他們對社交網絡的滿意程度與其網絡的大小及地域的距離有明顯的關係。研究結果與海外的研究結果一致，爲社會工作實務上提供初步的討論。結論： 研究結果爲探討精神病康復者社交網絡的特質及他們對社交網絡的滿意程度提供初步的了解，更爲研究網絡的大小及地域的距離提供參考。.
SOCIAL WITHDRAWAL OF YOUNG PEOPLE IN HONG KONG: A SOCIAL EXCLUSION PERSPECTIVE
Authors: WONG VICTOR , YING WINNIE
Published: December 2009

In the light of the social exclusion perspective, this paper discusses the indicators and different forms of social withdrawal experienced by young people in Hong Kong. The study examined the case records of 88 service users aged 13–24, and conducted 4 focus group interviews with a team of social workers involved in outreaching and reengaging the socially excluded users. Youth's personal agency exercised in their reaction to life events and crisis in the form of social withdrawal is arguably a complex social process, which is shaped, amongst other factors, by the hegemonic definition of youth trajectories and transitions to adulthood, and equally important by social exclusion at the institutional, cultural and relational levels. It is argued that both the structural and subjective dimensions of social withdrawal and reengagement work deserve critical examination in order not to further reproduce social inequalities and disadvantages.
POWER GAMES IN THE PUB: THE POWER NEGOTIATIONS OF PUB-HOSTESSES AND THEIR IMPLICATIONS
Authors: LEUNG CATHERINE LAI-YEE , PANG ANTHONY WOON-KEI , MAK MAX WAI-CHEE , FUNG ALEX LEI-KEI
Published: December 2009

Pub-hostesses are women who work in pubs whose job is to play drinking games such as ''guessing the dice number'' and ''guessing the number of fingers'' with customers to increase the amount of alcohol sold. Research was conducted by the Hong Kong Baptist University and the Tung Wah Group of Hospitals during summer 2005 to explore the power negotiations between pub-hostesses and society, their employers, and customers. Thirty pub-hostesses were interviewed and 25 pubs observed. Foucault's theory of power relations is used to explain the dynamics observed among the parties. The findings indicate that pub-hostess can only exercise weak resistance to the limitations imposed on them by the various parties, and that to improve their situation, changes at the structural, work, and individual levels are necessary.
BOOK REVIEW: "新移民婦女、中學生與大學生：對當代中國人自我觀念的考察", 賀玉英、陳更新
Authors: 邵 家臻
Published: December 2009

未提供摘要。
Book Review: "青少年病態賭博：預防及治療", 謝永齡
Authors: 陳 德茂
Published: December 2009

未提供摘要。
资本主义社会的女性地位
Authors: 杨罗 观翠 , 余 锦伟
Published: December 2009

香港城市大学社会科学部于一九九五年以问卷的方式，访问了二百三十五名香港女性行政人员，该访问的其中一个主要目的，是探讨这阶层的妇女在家庭及工作单位的处境和地位。本文的目的，是报告是次研究的结果，并藉著有关的研究资料，讨论香港妇女在资本主义社会的地位。本文得到的结论，是不同阶层的妇女在工作岗位及家庭所经验的，并不一定相同。因此，就是在男权主导下的社会，有部份妇女在工作上既可取得高薪厚职，在家中又可取得较高的地位，是不足为奇的。然而，这并不表示，大部份妇女便可凭自己的工作能力，改善其社会地位。资本主义运作复杂，其如何影响妇女的社会地位，仍须进一步研究和分析。

In 1995, the Division of Social Studies in the City University of Hong Kong interviewed 235 women in managerial positions with the aim of exploring their status and roles in the family and workplace. This paper presents the findings of that study. Our main argument is that women from difference social classes have difference experiences in developing their careers and looking after their families. It is possible for some women to achieve a high status at work and, at the same time, enjoy a greater share of power at home in a capitalist society. However, this should not be taken as an indication that the majority of women in Hong Kong could enhance their social status solely through participation in the labour market. There are some structural factors in the capitalist system that require further exploration.
中国特色: 经济市场化与福利社会化
Authors: 莫 邦豪 , 刘 继同
Published: December 2009

经济体制改革令市民对福利之需要与供应发生重大改变。经济市场化引导福利向社会化发展。其原则分实践、理论和哲学三个层次。服务策略是：福利供应范围扩大化；多元化兴办福利事业；倡导自助和社会互助；资金来源多元化；福利供应 “地方化” 和 “社区化” ；培育社会服务市场；建立发展功能的福利制度。福利社会化实质是福利制度之创新，社会化的福利供应是过渡性质的福利，目标是建立含有 “发展取向” 的社会福利制度。

Recent structural economic reforms in China have had an enormous impact on the demand and supply of welfare services. The socialist economy is moving towards a market orientation and, as a result, welfare services need to be socialized. "Socialized welfare" can be understood from practical, theoretical and philosophical perspectives. In terms of service strategies, a mixed economy of welfare is preferred. "Socialized welfare" is in fact a reformed welfare system, the nature of welfare by socialized welfare provided is transitional, the primary objective of which is to build a developmental social welfare system.
住院少年罪犯及其父母对亲职、亲子关系、离院适应问题的看法及差异
Authors: 卢 瑞忠 , 石 丹理
Published: December 2009

未提供摘要。
中国古代儒家思想中的心理健康概念
Authors: 叶 锦成
Published: December 2009

中国古代儒家思想自汉代董仲舒罢绌百家独尊儒术之后成为中国文化中的主流。其中尤以四书：《论语》、《孟子》、《大学》、《中庸》的影响至为深远。本文作者从四书有关心理健康的观念去描述古代儒家对自我价值，社会功能和人际关系的有关概念。儒家思想主张个体在个人，人际关系和道德三个层面达到中庸和调和的境界。要维持群体的和谐，个人的情绪思想，行为和私人空间都要受到抑制。这些儒家文化中独特心理健康概念对于中国文化中从事社会工作及心理健康实务有著重要的启示。
SYNTHESIS, CHARACTERIZATION, AND OPTICAL PROPERTIES OF Y-DOPEDZnONANOPARTICLES
Authors: HAMMAD TALAAT M. , SALEM JAMIL K. , HARRISON ROGER G.
Published: December 2009

Zinc oxide ( ZnO ) and yttrium-doped ZnO nanoparticles with particle size in the nanometer range have been successfully synthesized by the alkali precipitation method. The nanoparticle size and morphology have been investigated by X-ray diffraction (XRD), scanning electron microscope (SEM), and transmission electron microscope (TEM). The average particle size of Y-doped ZnO nanoparticles is about 17–29 nm. The absorption and photoluminescence (PL) spectra of the undoped and doped ZnO nanoparticles were also investigated. The optical band gap of ZnO nanoparticles can be tuned from 3.27 to 3.40 eV with increasing yittrium doping levels from 0 to 5%. The nanoparticles gave two emission peaks, one at around 376 nm and the other at 500 nm.
CONTEXT-AWARENESS AND USER PROFILING IN MOBILE ENVIRONMENTS
Authors: PANAGIOTAKIS SPYROS , KOUTSOPOULOU MARIA , ALONISTIOTI ATHANASSIA
Published: December 2009

The evolution of mobile communication systems to 3G and beyond introduces requirements for flexible, customized, and ubiquitous multimedia service provision to mobile users. One must be able to know at any given time the network status, the user location, the profiles of the various entities (users, terminals, network equipment, services) involved and the policies that are employed within the system. Namely, the system must be able to cope with a large amount of context information. The present paper focuses on location and context awareness in service provisioning and proposes a flexible and innovative model for user profiling. The innovation is based on the enrichment of common user profiling architectures to include location and other contextual attributes, so that enhanced adaptability and personalization can be achieved. For each location and context instance an associated User Profile instance is created and hence, service provisioning is adapted to the User Profile instance that better apply to the current context. The generic model, the structure and the content of this location- and context-sensitive User Profile, along with some related implementation issues, are discussed.
The role of engineering geology in risk-based land contamination management for tomorrow's cities
Authors: Nathanail C. P.
Published: December 2009

Tomorrow's cities will be built, at least in part, on yesterday's industrial, and probably chemically contaminated, land. Successful risk-based management of the contaminated land legacy of past industrial activity is an important component of managing urban land in a way that is potentially sustainable. Engineering geology has an essential role to play in ensuring that both risk assessments and remediation options are applied, appraised and implemented in ground investigations. Engineering geological parameters, such as particle size distribution (PSD) and soil organic matter (SOM), influence the fate and transport of contaminants in the solid, liquid, vapour and dissolved phases. PSD, SOM and other parameters, including calorific value and moisture content, also determine the feasibility of remediation technologies. Therefore, it is vital that engineering geologists play a central role in managing the risks posed by contaminated land.
Climate change: implications for engineering geology practice
Authors: Nathanail J. , Banks V.
Published: December 2009

The key questions addressed in this paper are: What is climate change? What are the impacts on engineering geology practice? Can engineering geologists contribute to mitigation of climate change? What research areas are engineering geologists involved with? Where should the focus for future research be? Following an overview of the papers presented for the ‘Legacy of the Past and Future Climate Change’ session of the 10th Congress of the International Association for Engineering Geology and the Environment, this paper reviews the sources of information and current models of climate change. An overview of some of the potential impacts of climate change on engineering geology practice follows. Attention has been given to areas of active research, the potential impacts on the more routine work of the engineering geologist, and the way in which the engineering geologist can contribute to climate change mitigation and adaptation. It is concluded that current planning guidance addresses climate change more fully than current engineering practice, and it is considered that there are considerable research areas open to engineering geologists with regard to potential impacts of climate change. More specifically, it has been noted that current engineering practice draws heavily on empirical approaches to design, and it is suggested that this approach should be reviewed in the context of climate change. Attention is given to a number of mitigating measures, such as ground source heat pumps, carbon sequestration, the ‘reduce, reuse and recycle’ approach to achieving sustainability and sustainable urban drainage systems (SUDSs).
Presence of high-grade rocks in NW Venezuela of possible Grenvillian affinity
Authors: Grande Sebastián , Urbani Franco
Published: December 2009

High-grade metamorphic rocks – marble, charnockite, meta-anorthosite, metapelite, clinopyroxenite and garnet amphibolite – have been found in northwestern Venezuela. They occur as: (a) xenoliths in the Oligo-Miocene lavas of Cerro Atravesado, Central Falcón; (b) possibly olistoliths in Nuezalito Formation, NW Portuguesa; (c) in Cerro El Guayabo, an elongated east–west oriented hill in the Nirgua Complex, Yaracuy; (d) rounded clasts of marble in the basal conglomerate of Casupal Formation, Falcón; (e) rounded clasts of anorthosite and sillimanite gneiss in a conglomerate of Matatere Formation, Lara; and (f) basement cores extracted from La Vela Gulf, Falcón. These high-grade rocks probably suffered a retrograde metamorphism to amphibolite facies of Palaeozoic age, and an even more retrograde event to the greenschist facies during Early Cenozoic, together with strong shearing and hydrothermal alteration. They indicate the possible existence of an extensive high-grade basement, or a mosaic of such blocks, under northwestern Venezuela, especially below the Falcón petroleum basin. Similar rocks crop out extensively in northern and central Colombia, Mexico, Ecuador and Peru. This is the first time they are described from Venezuela. Their high-grade lithology, pre-Mesozoic positions, and the tectonic evolution of Northern South America allow interpretation of a possible Grenvillian affinity, related to the supercontinents of Rodinia and Pangaea.
In situorigin of the Caribbean: discussion of data
Authors: James Keith H.
Published: December 2009

Compiled and synthesized geological data suggest that the Caribbean Plate consists of dispersed continental basement blocks, wedges of ?Triassic–Jurassic clastic rocks, Jurassic–Late Cretaceous carbonate rocks, volcanic arc rocks, widespread, probably subaerial basalts and serpentinized upper mantle. This points to anin situorigin of the Caribbean Plate as part of Middle America, continuing the geology of the eastern North America margin in a more extensional tectonic setting. Extension increases from the Gulf of Mexico through the Yucatán Basin to the Caribbean.
Metabolic effects of intensive insulin therapy in critically ill patients
Authors: Whyte M. B. , Jackson N. C. , Shojaee-Moradie F. , Treacher D. F. , Beale R. J. , Jones R. H. , Umpleby A. M.
Published: December 2009

Our aim was to investigate the effects of glycemic control and insulin concentration on lipolysis, glucose, and protein metabolism in critically ill medical patients. For our methods, the patients were studied twice. In study 1, blood glucose (BG) concentrations were maintained between 7 and 9 mmol/l with intravenous insulin. After study 1, patients entered one of four protocols for 48 h until study 2: low-insulin high-glucose (LIHG; variable insulin, BG of 7–9 mmol/l), low-insulin low-glucose (LILG; variable insulin of BG 4–6 mmol/l), high-insulin high-glucose [HIHG; insulin (2.0 mU · kg−1·min−1plus insulin requirement from study 1), BG of 7–9 mmol/l], or high-insulin low-glucose [HILG; insulin (2.0 mU·kg−1·min−1plus insulin requirement from study 1), BG of 4–6 mmol/l]. Age-matched healthy control subjects received two-step euglycemic hyperinsulinemic clamps achieving insulin levels similar to the LI and HI groups. In our results, whole body proteolysis was higher in patients in study 1 ( P < 0.006) compared with control subjects at comparable insulin concentrations and was reduced with LI ( P < 0.01) and HI ( P = 0.001) in control subjects but not in patients. Endogenous glucose production rate (Ra), glucose disposal, and lipolysis were not different in all patients in study 1 compared with control subjects at comparable insulin concentrations. Glucose Raand lipolysis did not change in any of the study 2 patient groups. HI increased glucose disposal in the patients (HIHG, P = 0.001; HILG, P = 0.07 vs. study 1), but this was less than in controls receiving HI ( P < 0.03). In conclusion, low-dose intravenous insulin administered to maintain BG between 7–9 mmol/l is sufficient to limit lipolysis and endogenous glucose Raand increase glucose Rd. Neither hyperinsulinemia nor normoglycemia had any protein-sparing effect.
Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury
Authors: Wang Yajing , Lau Wayne Bond , Gao Erhe , Tao Ling , Yuan Yuexing , Li Rong , Wang Xiaoliang , Koch Walter J. , Ma Xin-Liang
Published: December 2009

Adiponectin (APN) has traditionally been viewed as an adipocyte-specific endocrine molecule with cardioprotective effects. Recent studies suggest that APN is also expressed in cardiomyocytes. However, biological significances of this locally produced APN remain completely unknown. The aim of this study was to investigate the pathological and pharmacological significance of cardiac-derived APN in cardiomyocyte pathology. Adult cardiomyocytes from wild-type littermates (WT) or gene-deficient mice were pretreated with vehicle (V) or rosiglitazone (RSG) for 6 h followed by simulated ischemia-reperfusion (SI/R, 3 h/12 h). Compared with WT cardiomyocytes, myocytes from APN knockout (APN-KO) mice sustained greater SI/R injury, evidenced by greater oxidative/nitrative stress, caspase-3 activity, and lactate dehydrogenase (LDH) release ( P < 0.05). Myocytes from adiponectin receptor 1 knockdown (AdipoR1-KD) or AdipoR1-KD/AdipoR2-KO mice had slightly increased SI/R injury, but the difference was not statistically significant. RSG significantly ( P < 0.01) increased APN mRNA and protein expression, upregulated AdipoR1/AdipoR2 expression, reduced SI/R-induced apoptosis, and decreased LDH release in WT cardiomyocytes. However, the anti-oxidative/anti-nitrative and cell protective effects of RSG were completely lost in APN-KO cardiomyocytes ( P > 0.05 vs. vehicle group), although a comparable degree of AdipoR1/AdipoR2 upregulation was observed. The upregulatory effect of RSG on APN mRNA and protein expression was significantly potentiated in AdipoR1-KD/AdipoR2-KO cardiomyocytes. However, the cellular protective effects of RSG were significantly blunted, although not completely lost, in these cells. These results demonstrated that cardiomyocyte APN is biologically active in protecting cells against SI/R injury. Moreover, this locally produced APN achieves its protective effect primarily through paracrine/autocrine activation of APN receptors.
Regulation of the Putative TRPV1t Salt Taste Receptor by Phosphatidylinositol 4, 5-Bisphosphate
Authors: Lyall Vijay , Phan Tam-Hao T. , Ren ZuoJun , Mummalaneni Shobha , Melone Pamela , Mahavadi Sunila , Murthy Karnam S. , DeSimone John A.
Published: December 2009

Regulation of the putative amiloride and benzamil (Bz)-insensitive TRPV1t salt taste receptor by phosphatidylinositol 4,5-bisphosphate (PIP2) was studied by monitoring chorda tympani (CT) taste nerve responses to 0.1 M NaCl solutions containing Bz (5 × 10−6 M; a specific ENaC blocker) and resiniferatoxin (RTX; 0–10 × 10−6 M; a specific TRPV1 agonist) in Sprague-Dawley rats and in wildtype (WT) and TRPV1 knockout (KO) mice. In rats and WT mice, RTX elicited a biphasic effect on the NaCl + Bz CT response, increasing the CT response between 0.25 × 10−6 and 1 × 10−6 M. At concentrations >1 × 10−6 M, RTX inhibited the CT response. An increase in PIP2 by topical lingual application of U73122 (a phospholipase C blocker) or diC8-PIP2 (a short chain synthetic PIP2) inhibited the control NaCl + Bz CT response and decreased its sensitivity to RTX. A decrease in PIP2 by topical lingual application of phenylarsine oxide (a phosphoinositide 4 kinase blocker) enhanced the control NaCl + Bz CT response, increased its sensitivity to RTX stimulation, and inhibited the desensitization of the CT response at RTX concentrations >1 × 10−6 M. The ENaC-dependent NaCl CT responses were not altered by changes in PIP2. An increase in PIP2 enhanced CT responses to sweet (0.3 M sucrose) and bitter (0.01 M quinine) stimuli. RTX produced the same increase in the Bz-insensitive Na+response when present in salt solutions containing 0.1 M NaCl + Bz, 0.1 M monosodium glutamate + Bz, 0.1 M NaCl + Bz + 0.005 M SC45647, or 0.1 M NaCl + Bz + 0.01 M quinine. No effect of RTX was observed on CT responses in WT mice and rats in the presence of the TRPV1 blocker N-(3-methoxyphenyl)-4-chlorocinnamide (1 × 10−6 M) or in TRPV1 KO mice. We conclude that PIP2 is a common intracellular effector for sweet, bitter, umami, and TRPV1t-dependent salt taste, although in the last case, PIP2 seems to directly regulate the taste receptor protein itself, i.e., the TRPV1 ion channel or its taste receptor variant, TRPV1t.
Temperature Modulation of Slow and Fast Cortical Rhythms
Authors: Reig R. , Mattia M. , Compte A. , Belmonte C. , Sanchez-Vives M. V.
Published: December 2009

In the local cortical network, spontaneous emergent activity self-organizes in rhythmic patterns. These rhythms include a slow one (<1 Hz), consisting in alternation of up and down states, and also faster rhythms (10–80 Hz) generated during up states. Varying the temperature in the bath between 26 and 41°C resulted in a strong modulation of the emergent network activity. Up states became shorter for warmer temperatures and longer with cooling, whereas down states were shortest at physiological (36–37°C) temperature. The firing rate during up states was robustly modulated by temperature, increasing with higher temperatures. The sparse firing rate during down states hardly varied with temperature, thus resulting in a progressive merging of up and down states for temperatures around 30°C. Below 30°C and down to 26°C the firing lost rhythmicity, becoming progressively continuous. The slope of the down-to-up transitions, which reflects the speed of recruitment of the local network, was progressively steeper for higher temperatures, whereas wave-propagation speed exhibited only a moderate increase. Fast rhythms were particularly sensitive to temperature. Broadband high-frequency fluctuations in the local field potential were maximal for recordings at 36–38°C. Overall, we found that maintaining cortical slices at physiological temperature is critical for the generated activity to be analogous to that in vivo. We also demonstrate that changes in activity with temperature were not secondary to oxygenation changes. Temperature variation sets the in vitro cortical network at different functional regimes, allowing the exploration of network activity generation and control mechanisms.
EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity
Authors: Darrah Rebecca , McKone Edward , O'Connor Clare , Rodgers Christine , Genatossio Alan , McNamara Sharon , Gibson Ronald , Stuart Elborn J. , Ennis Madeleine , Gallagher Charles G. , Kalsheker Noor , Aitken Moira , Wiese Dawn , Dunn John , Smith Paul , Pace Rhonda , Londono Douglas , Goddard Katrina A. B. , Knowles Michael R. , Drumm Mitchell L.
Published: December 2009

Airway inflammation and pulmonary disease are heterogeneous phenotypes in cystic fibrosis (CF) patients, even among patients with the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Endothelin, a proinflammatory peptide and smooth muscle agonist, is increased in CF airways, potentially contributing to the pulmonary phenotype. Four cohorts of CF patients were screened for variants in endothelin pathway genes to determine whether any of these variants associated with pulmonary function. An initial cohort of 808 CF patients homozygous for the common CF mutation, ΔF508, showed significant association for polymorphisms in the endothelin receptor A gene, EDNRA ( P = 0.04), but not in the related endothelin genes ( EDN1, EDN2, EDN3, or EDNRB) or NOS1, NOS2A, or NOS3. Variants within EDNRA were examined in three additional cohorts of CF patients, 238 patients from Seattle, WA, 303 from Ireland and the U.K., and 228 from Cleveland, OH, for a total of 1,577 CF patients. The three additional groups each demonstrated a significant association between EDNRA 3′-untranslated region (UTR) variant rs5335 and pulmonary function ( P = 0.002). At the molecular level, single nucleotide primer extension assays suggest that the effect of the variants is quantitative. EDNRA mRNA levels from cultured primary tracheal smooth muscle cells are greater for the allele that appears to be deleterious to lung function than for the protective allele, suggesting a mechanism by which increased receptor function is harmful to the CF airway. Finally, cell proliferation studies using human airway smooth muscle cells demonstrated that cells homozygous for the deleterious allele proliferate at a faster rate than those homozygous for the protective allele.
A Kirk Type Characterization of Completeness for Partial Metric Spaces
Authors: Romaguera Salvador
Published: December 2009

We extend the celebrated result of W. A. Kirk that a metric space "Equation missing" is complete if and only if every Caristi self-mapping for "Equation missing" has a fixed point, to partial metric spaces.
Identification and Analyses in Optical Light of Gamma‐Ray Sources with Astronomical Archival Plates
Authors: Hudec René , Klíma Miloš
Published: December 2009

The ESA INTEGRAL satellite (International Gamma Ray Laboratory) launched in October 2002 continues to deliver valuable data about the gamma‐ray sky. Nearly 450 gamma‐ray sources have been detected so far mainly by the IBIS onboard instrument, and others are expected in the future. The first 3.5 years of INTEGRAL public and Core Program data have revealed more than 400 sources and this number is expected to increase to more than 500 in the future (Bird et al. 2007). Alternative method to identify and to analyze INTEGRAL gamma‐ray sources using optical light and astronomical archival plates is described, together with additional results from analyses of high‐energy sources in these databases.
Elimination of Human Lung Cancer Stem Cells through Targeting of the Stem Cell Factor–c-kit Autocrine Signaling Loop
Authors: Levina Vera , Marrangoni Adele , Wang Tingting , Parikh Simul , Su Yunyun , Herberman Ronald , Lokshin Anna , Gorelik Elieser
Published: December 2009

Cancer stem cells (CSC) are thought to be responsible for tumor initiation and tumor regeneration after chemotherapy. Previously, we showed that chemotherapy of non–small cell lung cancer (NSCLC) cells lines can select for outgrowth of highly tumorigenic and metastatic CSCs. The high malignancy of lung CSCs was associated with an efficient cytokine network. In this study, we provide evidence that blocking stem cell factor (SCF)–c-kit signaling is sufficient to inhibit CSC proliferation and survival promoted by chemotherapy. CSCs were isolated from NSCLC cell lines as tumor spheres under CSC-selective conditions and their stem properties were confirmed. In contrast to other tumor cells, CSCs expressed c-kit receptors and produced SCF. Proliferation of CSCs was inhibited by SCF-neutralizing antibodies or by imatinib (Gleevec), an inhibitor of c-kit. Although cisplatin treatment eliminated the majority of tumor cells, it did not eliminate CSCs, whereas imatinib or anti-SCF antibody destroyed CSCs. Significantly, combining cisplatin with imatinib or anti-SCF antibody prevented the growth of both tumor cell subpopulations. Our findings reveal an important role for the SCF–c-kit signaling axis in self-renewal and proliferation of lung CSCs, and they suggest that SCF–c-kit signaling blockade could improve the antitumor efficacy of chemotherapy of human NSCLC. Cancer Res; 70(1); 338–46
AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity
Authors: Chresta Christine M. , Davies Barry R. , Hickson Ian , Harding Tom , Cosulich Sabina , Critchlow Susan E. , Vincent John P. , Ellston Rebecca , Jones Darren , Sini Patrizia , James Dominic , Howard Zoe , Dudley Phillippa , Hughes Gareth , Smith Lisa , Maguire Sharon , Hummersone Marc , Malagu Karine , Menear Keith , Jenkins Richard , Jacobsen Matt , Smith Graeme C.M. , Guichard Sylvie , Pass Martin
Published: December 2009

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (∼1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 μmol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials. Cancer Res; 70(1); 288–98
Elevation of Receptor Tyrosine Kinase EphA2 Mediates Resistance to Trastuzumab Therapy
Authors: Zhuang Guanglei , Brantley-Sieders Dana M. , Vaught David , Yu Jian , Xie Lu , Wells Sam , Jackson Dowdy , Muraoka-Cook Rebecca , Arteaga Carlos , Chen Jin
Published: December 2009

One arising challenge in the treatment of breast cancer is the development of therapeutic resistance to trastuzumab, an antibody targeting the human epidermal growth factor receptor-2 (HER2), which is frequently amplified in breast cancers. In this study, we provide evidence that elevated level of the receptor tyrosine kinase Eph receptor A2 (EphA2) is an important contributor to trastuzumab resistance. In a screen of a large cohort of human breast cancers, we found that EphA2 overexpression correlated with a decrease in disease-free and overall survival of HER2-overexpressing patients. Trastuzumab-resistant cell lines overexpressed EphA2, whereas inhibiting EphA2 restored sensitivity to trastuzumab treatment in vivo. Notably, trastuzumab treatment could promote EphA2 phosphorylation by activating Src kinase, leading in turn to an amplification of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signaling in resistant cells. Our findings offer mechanistic insights into the basis for trastuzumab resistance and rationalize strategies to target EphA2 as a tactic to reverse trastuzumab resistance. Cancer Res; 70(1); 299–308.
Receptor Channel TRPC6 Is a Key Mediator of Notch-Driven Glioblastoma Growth and Invasiveness
Authors: Chigurupati Srinivasulu , Venkataraman Rajarajeswari , Barrera Daniel , Naganathan Anusha , Madan Meenu , Paul Leena , Pattisapu Jogi V. , Kyriazis George A. , Sugaya Kiminobu , Bushnev Sergey , Lathia Justin D. , Rich Jeremy N. , Chan Sic L.
Published: December 2009

Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in primary samples and cell lines derived from GBM. TRPC6 is required for the development of the aggressive phenotype because knockdown of TRPC6 expression inhibits glioma growth, invasion, and angiogenesis. Functionally, TRPC6 causes a sustained elevation of intracellular calcium that is coupled to the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Pharmacologic inhibition of the calcineurin-NFAT pathway substantially reduces the development of the malignant GBM phenotypes under hypoxia. Clinically, expression of TRPC6 was elevated in GBM specimens in comparison with normal tissues. Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM in vitro and in vivo and that TRPC6 may be a promising therapeutic target in the treatment of human GBM. Cancer Res; 70(1); 418–27
VentX, a Novel Lymphoid-Enhancing Factor/T-Cell Factor–Associated Transcription Repressor, Is a Putative Tumor Suppressor
Authors: Gao Hong , Le Yi , Wu Xiaoming , Silberstein Leslie E. , Giese Roger W. , Zhu Zhenglun
Published: December 2009

Lymphoid-enhancing factor/T-cell factors (LEF1/TCF) are a high-mobility group of transcriptional factors that play essential roles in cell fate determination during early embryogenesis and ontogenesis. Aberrant activations of LEF1/TCF-mediated transcription have been implicated in a variety of malignancies. Our recent studies on vertebrate embryogenesis identified Xom, a homeobox protein of the bone morphogenetic protein 4 pathway, as a novel LEF/TCF-associated transcriptional modulator. Here, we report that VentX, a human Xom homologue, is a LEF/TCF-associated inhibitor of canonical Wnt/β-catenin signaling and a negative regulator of cell proliferation. VentX is predominately expressed in hematopoietic cells, and its expression is significantly downregulated in chronic lymphocytic leukemia. Altered expression of VentX is associated with corresponding changes of LEF/TCF target oncogenes such as cyclin D1, suggesting a potential role of VentX in the clinical behavior of hematopoietic malignancies. Cancer Res; 70(1); 202–11
Alternative Splicing of the Cyclin D1 Proto-Oncogene Is Regulated by the RNA-Binding Protein Sam68
Authors: Paronetto Maria Paola , Cappellari Manuela , Busà Roberta , Pedrotti Simona , Vitali Roberta , Comstock Clay , Hyslop Terry , Knudsen Karen E. , Sette Claudio
Published: December 2009

Human cyclin D1 is expressed as two isoforms derived by alternate RNA splicing, termed D1a and D1b, which differ for the inclusion of intron 4 in the D1b mRNA. Both isoforms are frequently upregulated in human cancers, but cyclin D1b displays relatively higher oncogenic potential. The splicing factors that regulate alternative splicing of cyclin D1b remain unknown despite the likelihood that they contribute to cyclin D1 oncogenicity. In this study, we report that Sam68, an RNA-binding protein frequently overexpressed in prostate cancer cells, enhances splicing of cyclin D1b and supports its expression in prostate cancer cells. Chromatin immunoprecipitation and RNA coimmunoprecipitation experiments showed that Sam68 is recruited to the human CCND1 gene encoding cyclin D1 and that it binds to cyclin D1 mRNA. Transient overexpression and RNAi knockdown experiments indicated that Sam68 acts to enhance endogenous expression of cyclin D1b. Minigene reporter assays showed that Sam68 directly affected alternative splicing of CCND1 message, with a preference for the A870 allele that is known to favor cyclin D1b splicing. Sam68 interacted with the proximal region of intron 4, and its binding correlated inversely with recruitment of the spliceosomal component U1-70K. Sam68-mediated splicing was modulated by signal transduction pathways that elicit phosphorylation of Sam68 and regulate its affinity for CCND1 intron 4. Notably, Sam68 expression positively correlates with levels of cyclin D1b, but not D1a, in human prostate carcinomas. Our results identify Sam68 as the first splicing factor to affect CCND1 alternative splicing in prostate cancer cells, and suggest that increased levels of Sam68 may stimulate cyclin D1b expression in human prostate cancers. Cancer Res; 70(1); 229–39
Genetically Engineered Salmonella typhimurium as an Imageable Therapeutic Probe for Cancer
Authors: Nguyen Vu H. , Kim Hyung-Seok , Ha Jung-Min , Hong Yeongjin , Choy Hyon E. , Min Jung-Joon
Published: December 2009

Tumor-targeting bacteria have been studied in terms of their ability to visualize the infection pathway (through imaging probes) or to carry therapeutic molecules to tumors. To integrate these monitoring and therapeutic functions, we engineered attenuated Salmonella typhimurium defective in guanosine 5′-diphosphate-3′-diphosphate synthesis to carry cytotoxic proteins (cytolysin A) and express reporter genes. We successfully visualized the therapeutic process with these engineered bacteria in mice and found that they often mediated complete tumor (CT-26) eradication on cytotoxic gene induction. Furthermore, treatment with the engineered bacteria markedly suppressed metastatic tumor growth. Cancer Res; 70(1); 18–23
Inhibitor of Differentiation 1 Contributes to Head and Neck Squamous Cell Carcinoma Survival via the NF-κB/Survivin and Phosphoinositide 3-Kinase/Akt Signaling Pathways
Authors: Lin Jizhen , Guan Zhong , Wang Chuan , Feng Ling , Zheng Yiqing , Caicedo Emiro , Bearth Ellalane , Peng Jie-Ren , Gaffney Patrick , Ondrey Frank G.
Published: December 2009

Purpose: A key issue in cancer is apoptosis resistance. However, little is known about the transcription factors that contribute to cellular survival of head and neck squamous cell carcinoma (HNSCC).

Experimental Design: Three batches (54, 64, and 38) of HNSCC specimens were used for cellular and molecular analyses to determine the major molecular signaling pathways for cellular survival in HNSCC. Animal models (cell culture and xenografts) were used to verify the importance of apoptosis resistance in HNSCC.

Results: Inhibitor of differentiation (Id) family member, Id1, was significantly upregulated in clinical HNSCC specimens and acted to protect keratinocytes from apoptosis. Transfection of HNSCC cells with Id1 in vitro induced the phosphorylation of Akt (p-Akt) via phosphoinositide 3-kinase and increased the expression of survivin via NF-κB. Blockage of both pathways by specific inhibitors (LY294002 and IκBαM, respectively) abrogated Id1-induced cell survival of keratinocytes. In vivo studies showed that increased expression of Id1 allowed nontumorigenic keratinocytes (Rhek-1A) to become tumorigenic in nude mice by increased expression of survival genes such as p-Akt and survivin. More importantly, short interfering RNA for Id1 significantly reduced HNSCC tumor volume of HNSCC in xenograft studies. Analysis of clinical data verified the importance of the Id1 downstream molecule, survivin, in the prognosis of HNSCC patients.

Conclusions: The above data, taken together, suggest that Id1 and its downstream effectors are potential targets for treatment of HNSCC because of their contribution to apoptosis resistance. Clin Cancer Res; 16(1); 77–87
The Role of the Akt/mTOR Pathway in Tobacco Carcinogen–Induced Lung Tumorigenesis
Authors: Memmott Regan M. , Dennis Phillip A.
Published: December 2009

Lung cancer is the leading cause of cancer-related death in the United States, and 85 to 90% of lung cancer cases are associated with tobacco use. Tobacco components promote lung tumorigenesis through genotoxic effects, as well as through biochemical modulation of signaling pathways such as the Akt/mammalian target of rapamycin (mTOR) pathway that regulates cell proliferation and survival. This review will describe cell surface receptors and other upstream components required for tobacco carcinogen–induced activation of Akt and mTOR. Preclinical studies show that inhibitors of the Akt/mTOR pathway inhibit tumor formation in mouse models of carcinogen-induced lung tumorigenesis. Some of these inhibitors will be highlighted, and their clinical potential for the treatment and prevention of lung cancer will be discussed. Clin Cancer Res; 16(1); 4–10
Chromosome 8p Deletions and 8q Gains are Associated with Tumor Progression and Poor Prognosis in Prostate Cancer
Authors: El Gammal Alexander T. , Brüchmann Michael , Zustin Jozef , Isbarn Hendrik , Hellwinkel Olaf J.C. , Köllermann Jens , Sauter Guido , Simon Ronald , Wilczak Waldemar , Schwarz Jörg , Bokemeyer Carsten , Brümmendorf Tim H. , Izbicki Jakob R. , Yekebas Emre , Fisch Margit , Huland Hartwig , Graefen Markus , Schlomm Thorsten
Published: December 2009

Purpose: Deletions of 8p and gains of 8q belong to the most frequent cytogenetic alterations in prostate cancer. The target genes of these alterations and their biological significance are unknown.

Experimental Design: To determine the relationship between chromosome 8 changes, and prostate cancer phenotype and prognosis, a set of 1.954 fully annotated prostate cancers were analyzed in a tissue microarray format by fluorescence in situ hybridization.

Results: Both 8p deletions and 8q gains increased in number during different stages of prostate cancer progression. 8p deletions/8q gains were found in 26.1%/4.8% of 1,239 pT2 cancers, 38.5%/9.8% of 379 pT3a cancers, 43.5%/8.9% of 237 pT3b cancers, 40.7%/14.8% of 27 pT4 cancers, 39.1%/34.8% of 23 nodal metastases, 51.9%/33.3% of 27 bone metastases, and 45.5%/59.9% of 22 hormone refractory cancers (P < 0.0001 each). Both 8p deletions and 8q gains were also significantly associated with high Gleason grade and with each other (P < 0.0001 each). In primary tumors, 8p deletions were seen in only 27.3% of 1,882 cancers without 8q gain but in 57.4% of 122 tumors with 8q gain (P < 0.0001). Among cancers treated with radical prostatectomy, 8p deletions (P = 0.003) and 8q gains (P = 0.02) were associated with biochemical tumor recurrence. However, multivariate analysis (including prostate-specific antigen, pT/pN stage, Gleason score, and surgical margin status) did not reveal any statistically independent effect of 8p or 8q alterations on biochemical tumor recurrence.

Conclusions: 8p deletions and 8q gains are relatively rare in early stage prostate cancer but often develop during tumor progression. The prognostic effect does not seem to be strong enough to warrant clinical application. Clin Cancer Res; 16(1); 56–64
Single Nucleotide Polymorphisms of Gemcitabine Metabolic Genes and Pancreatic Cancer Survival and Drug Toxicity
Authors: Okazaki Taro , Javle Milind , Tanaka Motofumi , Abbruzzese James L. , Li Donghui
Published: December 2009

Purpose: To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2′,2′-difluoro 2′-deoxycytidine (gemcitabine)–based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer.

Experimental Design: We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis.

Results: None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P < 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity.

Conclusions: These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer. Clin Cancer Res; 16(1); 320–29
Expression Signature Developed from a Complex Series of Mouse Models Accurately Predicts Human Breast Cancer Survival
Authors: He Mei , Mangiameli David P. , Kachala Stefan , Hunter Kent , Gillespie John , Bian Xiaopeng , Shen H.-C. Jennifer , Libutti Steven K.
Published: December 2009

Purpose: The capability of microarray platform to interrogate thousands of genes has led to the development of molecular diagnostic tools for cancer patients. Although large-scale comparative studies on clinical samples are often limited by the access of human tissues, expression profiling databases of various human cancer types are publicly available for researchers. Given that mouse models have been instrumental to our current understanding of cancer progression, we aimed to test the hypothesis that novel gene signatures possessing predictability in clinical outcome can be derived by coupling genomic analyses in mouse models of cancer with publicly available human cancer data sets.

Experimental Design: We established a complex series of syngeneic metastatic animal models using a murine breast cancer cell line. Tumor RNA was hybridized on Affymetrix MouseGenome-430A2.0 GeneChips. With the use of Venn logic, gene signatures that represent metastatic competency were derived and tested against publicly available human breast and lung cancer data sets.

Results: Survival analyses showed that the spontaneous metastasis gene signature was significantly associated with metastasis-free and overall survival (P < 0.0005). Consequently, the six-gene model was determined and showed statistical predictability in predicting survival in breast cancer patients. In addition, the model was able to stratify poor from good prognosis for lung cancer patients in most data sets analyzed.

Conclusions: Together, our data support that novel gene signature derived from mouse models of cancer can be used for predicting human cancer outcome. Our approaches set precedence that similar strategies may be used to decipher novel gene signatures for clinical utility. Clin Cancer Res; 16(1); 249–59
Phase 1b Study of Motesanib, an Oral Angiogenesis Inhibitor, in Combination with Carboplatin/Paclitaxel and/or Panitumumab for the Treatment of Advanced Non–Small Cell Lung Cancer
Authors: Blumenschein George R. , Reckamp Karen , Stephenson G. Joe , O'Rourke Timothy , Gladish Gregory , McGreivy Jesse , Sun Yu-Nien , Ye Yining , Parson Mandy , Sandler Alan
Published: December 2009

Purpose: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti–epidermal growth factor receptor monoclonal antibody panitumumab in advanced non–small cell lung cancer (NSCLC).

Experimental Design: Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line).

Results: Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively.

Conclusions: Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC. Clin Cancer Res; 16(1); 279–90