bluuebunny/crossref_metadata_2025 huggingface dataset:
The Global Health Situation in the 21st Century: Aspects from the Global Forum on Health Research and the World Health Organization in Geneva1
Authors: Currat Louis J.
Published: March 2009

The objective of this paper is, in a first part, to give an overview of the main health problems in the world today and of their main causes. Then an attempt is made to compare the financial and human resourced available today to solve these problems with the resources which would be needed if we are to achieve the Health Millennium Development Goals by 2015. Given the fact that the available resources are limited, the question is then raised as to the selection of the strategies which would contribute the most to an improvement of the health situation in the world. To conclude on a positive note, a few examples are then given of great achievements in the health field over the past 50 years, but attention is drawn to the tremendous challenges remaining if the health MDGs are to be reached by 2015, particularly in Africa.
Faith and Health: Leadership Aligning Assets to Transform Communities
Authors: Kiser Miriam , Jones Deborah L. , Gunderdon Gary R.
Published: March 2009

Beginning in 1992, the Interfaith Health Programme (IHP) has worked nationally and internationally as a catalyst to foster both partnerships and the capacity to align the strengths of the faith community with those of the health sector. Key to this role is identifying and developing relationships with strategic leaders and structures with whom the IHP can advance the learning and practice of community scale health improvement. Two programmes represent this role and the contributions being made to understand the strengths of the faith community in creating healthy whole communities. This paper describes the background of the IHP and two programmes, the African Religious Health Assets Programme and the Institute for Public Health and Faith Collaborations. Both demonstrate the potential impact of innovations in interdisciplinary conceptual frameworks that undergird leadership action needed to close the widening gaps of the burden of unnecessary disease and suffering.
The new Quest for Healing: when Therapy and Spirituality Intermingle*
Authors: Ugeux Bernard
Published: March 2009

For some decades one has noted an increased interest in spirituality outside the traditional religions of the West, viz. the three monotheisms. New spiritual quests often develop on the fringes of the churches, and sometimes even as a reaction to the churches' vision of what it means to be human. In this regard, those interested in spirituality often see their spiritual search as something linked to a general care for wellbeing or health, and reproach Christianity for being too disembodied. The association of the spiritual with the therapeutical leads to a certain permeability between the spiritual and therapeutical in terms of the claims each makes. It also leads to the creation of new alternative proposals. This porousness runs the risk of bringing confusion to everything, and using the spiritual and religious to serve therapeutic needs.

However, the way in which the claims of the spiritual and therapeutical realms evolve presents a challenge to Christianity. This can be put in terms of, ‘What place does Christianity attribute to the body, affectivity, pleasure, and legitimate personal development?’ Some individuals and groups in the Christian churches, rather than trying to justify existing approaches, propose more “incarnated” ones that will respond to the new audience in a Christian way. From a theological, pastoral and missiological viewpoint, Christian communities are thus intended to become communities of healing and reconciliation, although not at any price. If Christian spirituality also has to favour the empowering and development of a person — for Christ has assumed everything of humanity, except sin — one should not reduce salvation to healing or ignore the paschal mystery as a way of avoiding the element of pain that this mystery contains. In short, Christianity is invited to do a work of inculturation that not only keeps in mind contemporary developments but also is accompanied by an authentic interdisciplinary discernment.
Of Lions and Rabbits: the Role of the Church in Reconciliation in South Africa*
Authors: Maluleke Tinyiko Sam
Published: March 2009

This essay uses an old African fable about lions and rabbits in order to launch, illustrate, probe and explore the role of the churches in the complex South African process of reconciliation since the end of apartheid, and the election, thirteen years ago, of Nelson Mandela as the first democratic president of the Republic of South Africa. It is argued that both the challenges encountered and the solutions sought in the search for reconciliation have been and remain far from simple. Nor has the role of the churches been simple and straightforward. The author thematically traces the complex role of the church in the equally complex processes that have catapulted South Africa from tyranny to democracy. He argues that the question of reconciliation has always been on the agenda of the South African church. Sometimes this has been overtly present, sometimes covertly, sometimes directly and sometimes indirectly. Even when reconciliation was absent in the discourse and proxy of the church, it was nevertheless present through its absence.
Beyond the Text: Revisiting Jacques Dupuis‘ Theology of Religions
Authors: Sydnor Jon Paul
Published: March 2009

Jacques Dupuis (1923–2004) was a Belgian Jesuit and one of the Roman Catholic Church's leading theologians of religion. Dupuu‘ magnum opus remains “Toward a Christian Theology of Religious Pluralism”. In that work Dupuis attempts to reconcile the particularity of Jesus with the universality of the divine Logos. In order to do so, he utilizes the classical logos ensarkos/logos asarkos distinction. Although he is the Son of God and represents the sacrament of God's salvific will, Jesus Christ is limited by time and space, and cannot exhaust the mystery of God. The surplus of mystery, as well as God's universal intention to save are carried by the logos asarkos, or Holy Spirit, who is also the Spirit of Christ. The Holy Spirit points to and culminates in the ‘Christ‐event’ but is not limited to it, because the Holy Spirit is found in all that is agapic in the world religions.

Dupuis' controversial theology of religions has been much discussed in its theoretical aspect. However, it has been largely neglected in its practical, evaluative aspect. This essay will attempt to answer two related questions. First, how helpful is Dupuis' theology of religions if applied to a certain religion (in this case, Islam)? Second, what can we learn from the successes and failures of application? The questions are important. The theology of religions exists as a discipline in order to assist Christians in their interactions with and inevitable evaluations of other faiths. Therefore, the success or failure of an applied theology of religions is one of the main determinants of its value.

The essay will conclude that the application of Dupuis' theology of religions reveals several problems. Chief among them are an excessive irenicism and a flawed hermeneutic of religions. Nevertheless, these flaws are rectifiable and Fr Dupuis has made a magisterial, invaluable, and perhaps permanent contribution to the discipline.
Theses on Christian Self‐Understanding and Religious Plurality
Authors: Franz Andreas
Published: March 2009

On the one hand, Christians have hem commissioned to work for peace, justice and the preservation of creation. On the other hand, the identity of Christians is firmly rooted in Christ's “Great Commission”. Can one reconcile these two commissions in a religiously pluralistic world?

In the last few decades our world has become increasingly religious. All world religions have experienced spiritual awakenings, and at times significant ones. Now, more than ever, the different faiths and ideologies have direct encounters.

Christian representatives have repeatedly suggested interfaith dialogue as the key to dealing with other religions. This approach has its merits but also holds certain dangers. Dialogue undoubtedly occupies an important place in interpersonal encounters but is it also an appropriate means for the implementation of the Great Commission? The author believes it is so only in a very limited sense.

In the following theses, the author will therefore introduce an additional key that is a non‐negotiable component of the Christian identity, viz. witness. For Christians, this key is the bearing of witness to how they know and have personally experienced God working. It also has its merits and dangers. This is why a clearly defined field has to be allocated to each key.

In what follows, the author will distinguish between two God‐given mandates. All humans, whether Christians or non‐Christians, have the mandate to “work the garden and take care of it”. This is impossible without human co‐operation and common ethical values. For this first mandate, dialogue is a helpful means.

In addition, Christians have a Christ‐given second mandate to proclaim the gospel to all people(s) by means of witness (martyria). Two prerequisites for carrying out this mandate are mutual respect and freedom (of choice). Otherwise, d could well mean martyrdom as exemplified by Jesus.

The following theses aim to introduce this complementary key into the discussion and stake out its scope.
Why do They do it? Lessons on Missionary Mobilization And Motivation From Indian Indigenous Missionaries
Authors: Fox Frampton F.
Published: March 2009

Non — Western mission agencies provide lessons for the global mission community in how to motivate and recruit cross‐cultural missionaries. India, ad the largest non‐ Western producer of cross‐cultural missionaries, has a mobilization story that needs to be given voice. Survey research was done among a sample of indigenous Indian missionaries from one well‐respected, inter‐denominational organization. Candidates were found to be most influenced toward missions during their youth years, and by a variety of mostly para‐church factors. Key among these were the influence of missionaries, specific scriptures which had spoken to the young people, and the mentoring of them by mission agency personnel Often, this influence was felt in the spiritual context of youth camps and prayer gatherings. Notably, the role of local churches and Bible schools in motivating people toward mission careers was nominal Corrective suggestions are made for the local churches and theological institutions.
Struggle and Reconciliation: Some Reflections on Ecumenism in Chile1
Authors: Gros Jeffrey
Published: March 2009

To engage in ecumenism and common witness is always a challenge when one church predominates in a society. In the case of many Latin American countries, the Catholic Church is both historically and demographically dominant, and often has a history of special relations with the states. Protestants, on the other hand, come mostly from evangelical and Pentecostal traditions with little ecumenical history or motivation. This article outlines some of the 20th century history of the churches in Chile against the background of the reception of Vatican II, and especially its leadership on religious freedom and ecumenism. Social and political events in Chile, as well as the particular demography and history of its Christianity, make this a unique context for ecumenical development. Some of these factors and the churches' responses are outlined as resources for global Christian reflection on mission, unity and society.
Conversion to Coloniality: Avoiding the Colonization of Method1
Authors: Heaney Robert S.
Published: March 2009

Caution should be exercised when any defence of mission tends towards a universalizing of a theologically ideal definition of conversion. Such a defence may theologically justify mission against the charge of colonizing minds, while resulting in the colonizing of method. Bruin Stanley assumes that the perspective of converts can he mentally occupied by the scholar, who can then simultaneously speak for the converted and justify mission incursion. In response, this article argues for the importance of the category of “coloniality”. First, the theological significance of coloniality is demonstrated in relation to context, critical awareness and liberative purpose. Second, three methodological characteristics are identified. Particularism is the acknowledgement that understandings of conversion are affected by the existential as well as theological tradition. Subject‐positioning results in a scepticism towards universalized definitions and attempts to bermeneutically occupy the perspective of others. Consequently, transformation in the form of theological decolonization is sought.
Whose Kingdom? Which Context? Ecumenical and Contextual Theology in the World Alliance of YMCAS
Authors: Fretheim Kjetil
Published: March 2009

Considering the mission statements of the World Alliance of YMCAs, this article discusses how contextual ecumenical theology can and should be done. The main part of the article is an interpretative analysis of the international YMCA movement, and the way ecumenical theology is done in this context. The analysis shows how the ecumenical theology of the World Alliance of YMCAs seems to be based on the reaffirmation of the Paris Basis, the unity of the movement, its non‐doctrinal, non‐ecclesiastical and non‐political character, and the priority given to the various member movements' different contexts. In the last section, I reflect on how contextual ecumenical theology should be done. I argue that ecumenical theology must welcome and include in its reflections a wide range of expressions of faith, and that ecumenical minimalism seems like a promising starting point for such endeavours. However, ecumenical theology in a globalized world needs also to be a contextual theology, and must consider the realities of a wide range of contexts in its ongoing reflections. A contextual ecumenical theology cannot only include voices from a number of denominations; it intuit also be conscious of a number of contexts, and their differences, challenges, hopes and despairs. Ecumenical minimalism must, therefore, be combined with contextual maximalism.
Paradigm Shift in Theological Education in Southern and Central Africa and its Relevance to Ministerial Formation
Authors: Amanze James Nathaniel
Published: March 2009

Theological education is of crucial importance in the mission of the Church in Southern and Central Africa. This paper discusses the changes that have taken place in theological education in post‐independence Africa. The author argues that theological education during the colonial period was Euro‐centric. As a result, it did not respond adequately to the pressing problems faced by the African people such as colonial oppression, poverty, patriarchy and others. However, the situation has changed dramatically in modern times. Theological educators have realized the significance and importance of context in theological education. They are, thus, seriously taking into account the political, social, economic and religious context in which the African people live today. This has led to the creation of different theologies that are in line with modern and post‐modern challenges facing the African people thereby making the church both relevant and necessary.
Methods and Reliability of Tissue Doppler Imaging for Assessment of Left Ventricular Radial Wall Motion in Horses
Authors: Schwarzwald C.C. , Schober K.E. , Bonagura J.D.
Published: March 2009

Background:Noninvasive assessment of left ventricular (LV) function is incompletely studied in horses.

Objectives:The goals of this study were to investigate the feasibility, techniques, and reliability of tissue Doppler imaging (TDI) for characterization of LV radial wall motion in healthy horses.

Animals:Three Standardbreds, 3 Thoroughbreds; age 8–14 years; body weight 517–606 kg.

Methods:Repeated echocardiographic examinations were performed by 2 observers in unsedated horses using TDI. Test reliability was determined by estimating measurement variability, within‐day interobserver variability, and between‐day interobserver and intraobserver variability of all echocardiographic variables. Variability was expressed as coefficient of variation (CV) and the absolute value below which the difference between 2 measurements will lie with 95% probability.

Results:Assessment of LV radial wall motion by TDI was feasible in all horses. Measurement variabilities were very low (CV < 5%) to low (CV 5–15%) for most variables. Within‐day interobserver variability as well as between‐day interobserver and intraobserver variabilities were low to moderate (CV 16–25%) for most variables. All pulsed‐wave TDI variables of systolic LV function showed very low to low variability, whereas some of the variables of LV diastolic and LA function showed moderate to high (CV > 25%) variability. Pulsed‐wave TDI variables appeared more reliable than color TDI variables.

Conclusions and Clinical Importance:Measurement of TDI indices of LV function is feasible and reliable in adult Standardbred and Thoroughbred horses. The clinical relevance of LV function assessment by TDI remains to be determined.
Lack of Detectable Equine Herpesviruses 1 and 2 in Paraffin‐Embedded Specimens of Equine Sarcoidosis
Authors: White S.D. , Foley J.E. , Spiegel I.B. , Ihrke P.J.
Published: March 2009

Background: Equine sarcoidosis is a rare, multisystemic, noncaseating, granulomatous and lymphoplasmacytic disease of unknown etiology. A recent report described a horse with granulomatous skin disease displaying histologic, electron microscopic, and polymerase chain reaction (PCR) findings consistent with equine herpesvirus 2 (EHV‐2).

Objective: To investigate the presence of EHV‐2 and equine herpesvirus 1 (EHV‐1) in 8 horses with sarcoidosis.

Animals: Eight horses with sarcoidosis, reported previously.

Methods: Retrospective study. PCR assays of the tissues were performed to detect DNA associated with EHV‐1 and EHV‐2. For both herpesviruses the target was their respective glycoprotein B gene. Positive controls consisted of DNA from viral cultures of culturettes from naturally occurring respiratory infections of EHV‐1 and EHV‐2.

Results: The PCR analyses for both equine herpesviruses' DNA were negative in all 8 horses.

Conclusion: The failure to detect DNA from EHV‐1 and EHV‐2 in paraffin‐embedded skin of these 8 horses does not discount EHV‐1 or EHV‐2 as causing some cases of ES, but lends support to the presumably multifactorial etiologic nature of the disease.
Intersection theory on Shimura surfaces
Authors: Howard Benjamin
Published: March 2009

Kudla has proposed a general program to relate arithmetic intersection multiplicities of special cycles on Shimura varieties to Fourier coefficients of Eisenstein series. The lowest dimensional case, in which one intersects two codimension one cycles on the integral model of a Shimura curve, has been completed by Kudla, Rapoport and Yang. In the present paper we prove results in a higher dimensional setting. On the integral model of a Shimura surface we consider the intersection of a Shimura curve with a codimension two cycle of complex multiplication points, and relate the intersection to certain cycle classes constructed by Kudla, Rapoport and Yang. As a corollary we deduce that our intersection multiplicities appear as Fourier coefficients of a Hilbert modular form of half-integral weight.
Singularities on normal varieties
Authors: de Fernex Tommaso , Hacon Christopher D.
Published: March 2009

In this paper we generalize the definitions of singularities of pairs and multiplier ideal sheaves to pairs on arbitrary normal varieties, without any assumption on the variety being ℚ-Gorenstein or the pair being log ℚ-Gorenstein. The main features of the theory extend to this setting in a natural way.
TWO PERMANENTS IN THE UNIVERSAL ENVELOPING ALGEBRAS OF THE SYMPLECTIC LIE ALGEBRAS
Authors: ITOH MINORU
Published: March 2009

This paper presents new generators for the center of the universal enveloping algebra of the symplectic Lie algebra. These generators are expressed in terms of the column-permanent and it is easy to calculate their eigenvalues on irreducible representations. We can regard these generators as the counterpart of central elements of the universal enveloping algebra of the orthogonal Lie algebra given in terms of the column-determinant by Wachi. The earliest prototype of all these central elements is the Capelli determinants in the universal enveloping algebra of the general linear Lie algebra.
RECOGNIZING TEXTILE STRUCTURES BY FINITE TYPE KNOT INVARIANTS
Authors: GRISHANOV S. A. , MESHKOV V. R. , VASSILIEV V. A.
Published: March 2009

Typical examples of textile structures are separated by finite type invariants of knots in non-trivial (in particular, non-orientable) manifolds. A new series of such invariants is described.
TORUS KNOTS ARE FOURIER-(1,1,2) KNOTS
Authors: HOSTE JIM
Published: March 2009

Every torus knot can be represented as a Fourier-(1,1,2) knot which is the simplest possible Fourier representation for such a knot. This answers a question of Kauffman and confirms the conjecture made by Boocher, Daigle, Hoste and Zheng.

In particular, the torus knot Tp,q can be parameterized as [Formula: see text]
POLYNOMIAL COCYCLES OF ALEXANDER QUANDLES AND APPLICATIONS
Authors: AMEUR KHEIRA , SAITO MASAHICO
Published: March 2009

Cocycles are constructed by polynomial expressions for Alexander quandles. As applications, non-triviality of some quandle homology groups are proved, and quandle cocycle invariants of knots are studied. In particular, for an infinite family of quandles, the non-triviality of quandle homology groups is proved for all odd dimensions.
THE ROAD LESS INTENDED: INTEGRATING ENTREPRENEURIAL COGNITION AND RISK IN ENTREPRENEURSHIP EDUCATION
Authors: BARBOSA SAULO D. , KICKUL JILL , SMITH BRETT R.
Published: March 2009

In this paper, we review recent developments in the fields of cognitive theory and risk in order to highlight generally overlooked dilemmas in entrepreneurship education. Such dilemmas concern the amount of planning necessary to succeed in creating a new business and the extent to which educators should boost students' intentions and self perceptions. We suggest that integrating research on entrepreneurial cognition and risk provides a theoretical perspective that enables the identification of these dilemmas and guides practice in a more effective and balanced way. We introduce two modes of thinking — analysis and intuition — and succinctly layout their implications in terms of risk throughout the different phases of the entrepreneurial process, including the development of entrepreneurial intentions and the passage to action. We then present an entrepreneurship education program conceived to develop both kinds of thinking and to minimize risks by providing students a knowledge-resource base that can enable them to critically examine their projects and then proceed down the road of transforming intentions into action if so desired. In presenting such a program, we show how a sequence of entrepreneurship education experiences may help to develop both the analytic and intuitive skills necessary to succeed in the different aspects of the entrepreneurial process.
A UNIQUENESS CONDITION FOR NONLINEAR CONVECTION-DIFFUSION EQUATIONS WITH DISCONTINUOUS COEFFICIENTS
Authors: DIEHL STEFAN
Published: March 2009

The paper focuses on the uniqueness issue for scalar convection-diffusion equations where both the convective flux and diffusion functions have a spatial discontinuity. An interface entropy condition is proposed at such a spatial discontinuity. It implies the Kružkov-type entropy condition presented by Karlsen et al. in 2003. They proved uniqueness when the convective flux function satisfies an additional "crossing condition". The crossing condition becomes redundant with the entropy condition proposed here. Thereby, more general flux functions are allowed. Another advantage of the entropy condition is its simple geometrical interpretation, which facilitates the construction of stationary solutions.
Lipoprotein lipase: from gene to obesity
Authors: Wang Hong , Eckel Robert H.
Published: March 2009

Lipoprotein lipase (LPL) is a multifunctional enzyme produced by many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins (VLDL). LPL-catalyzed reaction products, fatty acids, and monoacylglycerol are in part taken up by the tissues locally and processed differentially; e.g., they are stored as neutral lipids in adipose tissue, oxidized, or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels in a tissue-specific manner. Nutrient states and hormonal levels all have divergent effects on the regulation of LPL, and a variety of proteins that interact with LPL to regulate its tissue-specific activity have also been identified. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. Mice with LPL deletion in skeletal muscle have reduced TG accumulation and increased insulin action on glucose transport in muscle. Ultimately, this leads to increased lipid partitioning to other tissues, insulin resistance, and obesity. Mice with LPL deletion in the heart develop hypertriglyceridemia and cardiac dysfunction. The fact that the heart depends increasingly on glucose implies that free fatty acids are not a sufficient fuel for optimal cardiac function. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation.
Human ZNF312b Promotes the Progression of Gastric Cancer by Transcriptional Activation of the K-ras Gene
Authors: Song In-Sung , Oh Nang Su , Kim Hyun-Taek , Ha Ga-Hee , Jeong So-Young , Kim Jeong-Min , Kim Dong-Il , Yoo Hyang-Sook , Kim Cheol-Hee , Kim Nam-Soon
Published: March 2009

Gastric cancer ranks second among the most common causes of cancer deaths worldwide. Recent studies reported target molecules that are candidates for new therapeutic interventions; however, their molecular mechanism has not been clearly defined. In this study, we found that ZNF312b plays a role in tumor progression and metastasis in gastric cancer via transcriptional activation of the K-ras oncogene. ZNF312b seems to be specifically overexpressed in gastric cancer tissues and cell lines. The overexpression of ZNF312b induces cancer-like phenotypes, including accelerated proliferation and increased tumor masses in nude mice, which are completely reversed by its knockdown in gastric cancer cell lines, implying direct involvement in gastric tumor progression. From analyses using deletion mutants of ZNF312b and K-ras promoter-driven luciferase reporters, we found that it translocates into the nucleus via the proline-rich domain of its COOH terminus to activate transcription of the K-ras gene, resulting in an enhancement of the extracellular signal-regulated kinase signaling pathway that governs cell proliferation. Taken together, these results suggest that ZNF312b contributes to the promotion of gastric cancer by triggering K-ras oncogene expression. The current study is the first to report that ZNF312b, a novel transcription factor, was associated with tumorigenicity of gastric cancer. This might be a valuable target that could provide new insight into the development of new therapeutic modalities for patients with gastric cancer. [Cancer Res 2009;69(7):3131–9]
Caveolin-1 Regulates the Antagonistic Pleiotropic Properties of Cellular Senescence through a Novel Mdm2/p53-Mediated Pathway
Authors: Bartholomew Janine N. , Volonte Daniela , Galbiati Ferruccio
Published: March 2009

We show that caveolin-1 is a novel binding protein for Mdm2. After oxidative stress, caveolin-1 sequesters Mdm2 away from p53, leading to stabilization of p53 and up-regulation of p21Waf1/Cip1 in human fibroblasts. Expression of a peptide corresponding to the Mdm2 binding domain of caveolin-1 is sufficient to up-regulate p53 and p21Waf1/Cip1 protein expression and induce premature senescence. Oxidative stress–induced activation of the p53/p21Waf1/Cip1 pathway and induction of premature senescence are compromised in caveolin-1 null mouse embryonic fibroblasts (MEF). We also show that reintroduction of caveolin-1 in oncogenic Ras (RasG12V)–transformed fibroblasts, which express residual levels of caveolin-1, is sufficient to promote cellular senescence. Moreover, caveolin-1 expression in MEFs is required for senescent fibroblast-induced stimulation of cell growth and tumorigenesis of both RasG12V-transformed fibroblasts and MDA-MB-231 breast cancer epithelial cells both in vitro and in vivo. Thus, our results propose caveolin-1 as a key mediator of the antagonistic pleiotropic properties of cellular senescence. [Cancer Res 2009;69(7):2878–86]
In vivo Imaging of Cutaneous T-Cell Lymphoma Migration to the Skin
Authors: Hoeller Christoph , Richardson Stephen K. , Ng Lai Guan , Valero Teresa , Wysocka Maria , Rook Alain H. , Weninger Wolfgang
Published: March 2009

Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of malignant CD4+ T cells in the skin. Although the expression of adhesion molecules and chemokine receptors on CTCL cells has been studied extensively on ex vivo isolated cells, very little is known about the dynamics and mechanisms of CTCL trafficking in vivo. However, detailed knowledge of the molecular cues mediating CTCL migration may be used to interfere with their homing to the skin. We made use of real-time intravital epifluorescence video and two-photon microscopy to visualize malignant T cells from Sezary syndrome (SS), a leukemic variant of CTCL, in dermal microvessels in mouse ear skin. We found that SS cells rolled along dermal venules in a P-selectin– and E-selectin–dependent manner at ratios similar to CD4+ memory T cells from normal donors. We furthermore show that the chemokine CCL17/TARC, but not CCL27/CTACK, was sufficient to induce the arrest of SS cells in the microvasculature. However, a combination of both chemokines was required to induce extravasation of SS cells. Together, our experiments delineate the molecular adhesion cascade operant in SS cell homing to the skin in vivo. [Cancer Res 2009;69(7):2704–8]
Hyperactivation of the Insulin-like Growth Factor Receptor I Signaling Pathway Is an Essential Event for Cisplatin Resistance of Ovarian Cancer Cells
Authors: Eckstein Niels , Servan Kati , Hildebrandt Barbara , Pölitz Anne , Jonquières Georg von , Wolf-Kümmeth Sybille , Napierski Inge , Hamacher Alexandra , Kassack Matthias U. , Budczies Jan , Beier Manfred , Dietel Manfred , Royer-Pokora Brigitte , Denkert Carsten , Royer Hans-Dieter
Published: March 2009

Platinum plays a central role in the therapy of ovarian cancer, and the emergence of platinum resistance is a major obstacle for clinical management of the disease. We treated A2780 ovarian cancer cells by weekly cycles of cisplatin over a period of 6 months and unveiled that enhanced insulin-like growth factor I receptor (IGF-IR) expression and autocrine IGF-I are associated with hyperactivation of the IGF-IR and phosphatidylinositol-3-OH kinase (PI3K) pathways in cisplatin-resistant cells. IGF-IR expression levels increased during treatment cycles and correlated with cisplatin resistance. Purified IGF-I induced cisplatin resistance in diverse ovarian cancer cell lines, and small molecule inhibitors proved that IGF-IR and PI3K are essential for cisplatin resistance. Similar results were obtained with BG-1 ovarian cancer cells. Cytogenetic and array comparative genomic hybridization analyses revealed selection and de novo formation of chromosomal alterations during resistance development. An analysis of gene expression profiles of primary ovarian carcinomas identified the regulatory subunit PIK3R2 of PI3-kinase as a significant negative prognosis factor for ovarian cancer. We conclude that targeting the IGF-IR and the PI3K pathways is a promising new strategy to treat cisplatin-resistant ovarian carcinomas. [Cancer Res 2009;69(7):2996–3003]
Association of LETM1 and MRPL36 Contributes to the Regulation of Mitochondrial ATP Production and Necrotic Cell Death
Authors: Piao Longzhen , Li Yuwen , Kim Soung Jung , Byun Hee Sun , Huang Song Mei , Hwang Soon-Kyung , Yang Keum-Jin , Park Kyeong Ah , Won Minho , Hong Janghee , Hur Gang Min , Seok Jeong Ho , Shong Minho , Cho Myung-Haing , Brazil Derek P. , Hemmings Brian A. , Park Jongsun
Published: March 2009

Leucine zipper/EF hand–containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis. [Cancer Res 2009;69(8):3397–404]
Depletion of Guanine Nucleotides Leads to the Mdm2-Dependent Proteasomal Degradation of Nucleostemin
Authors: Huang Min , Itahana Koji , Zhang Yanping , Mitchell Beverly S.
Published: March 2009

Nucleostemin is a positive regulator of cell proliferation and is highly expressed in a variety of stem cells, tumors, and tumor cell lines. The protein shuttles between the nucleolus and the nucleus in a GTP-dependent fashion. Selective depletion of intracellular guanine nucleotides by AVN-944, an inhibitor of the de novo purine synthetic enzyme, IMP dehydrogenase, leads to the rapid disappearance of nucleostemin protein in tumor cell lines, an effect that does not occur with two other nucleolar proteins, nucleophosmin or nucleolin. Endogenous nucleostemin protein is completely stabilized by MG132, an inhibitor of the 26S proteasome, as are the levels of expressed enhanced green fluorescent protein–tagged nucleostemin, both wild-type protein and protein containing mutations at the G1 GTP binding site. Nutlin-3a, a small molecule that disrupts the binding of the E3 ubiquitin ligase, Mdm2, to p53, stabilizes nucleostemin protein in the face of guanine nucleotide depletion, as does siRNA-mediated knockdown of Mdm2 expression and overexpression of a dominant-negative form of Mdm2. Neither Doxorubicin nor Actinomycin D, which cause the release of nucleostemin from the nucleolus, results in nucleostemin degradation. We conclude that nucleostemin is a target for Mdm2-mediated ubiquitination and degradation when not bound to GTP. Because this effect does not occur with other chemotherapeutic agents, the induction of nucleostemin protein degradation in tumor cells by IMP dehydrogenase inhibition or by other small molecules that disrupt GTP binding may offer a new approach to the treatment of certain neoplastic diseases. [Cancer Res 2009;69(7):3004–12]
Androgen-Induced Coactivator ANCCA Mediates Specific Androgen Receptor Signaling in Prostate Cancer
Authors: Zou June X. , Guo Linlang , Revenko Alexey S. , Tepper Clifford G. , Gemo Abigael T. , Kung Hsing-Jien , Chen Hong-Wu
Published: March 2009

Androgen receptor (AR) plays a pivotal role in prostate cancer, primarily by regulating different gene expression programs elicited by androgen, which is important for cancer cell proliferation, survival, and differentiation. It is believed that the transcriptional function of AR is mediated largely by distinct nuclear coregulators. We report here the identification of ANCCA (also known as ATAD2), a new member of the AAA+ ATPase family proteins, as a novel AR coactivator. ANCCA interacts directly with AR and enhances its transcriptional activity, and is required for androgen-stimulated expression of a specific subgroup of genes including IGF1R, IRS-2, SGK1, and survivin. Upon androgen stimulation, ANCCA together with AR is recruited to the specific AR target genes. Suppression of ANCCA expression strongly inhibited the proliferation of androgen-responsive or androgen-independent, AR-positive prostate cancer cells and caused a significant increase of cellular apoptosis. Strikingly, the ANCCA gene itself, located at chromosome 8q24, is highly induced by androgen in androgen-dependent prostate cancer cells and xenograft tumors. Although ANCCA is hardly detected in normal human prostate tissue, high levels of ANCCA are found in hormone-independent prostate cancer cell lines, xenograft tumor, and a subset of prostate cancers with high Gleason scores. Together, these findings suggest that ANCCA plays an important role in prostate cancer by mediating specific AR functions in cancer cell survival and proliferation. The possession of ATPase and bromodomain by ANCCA makes it an attractive target for the development of therapeutics for the disease. [Cancer Res 2009;69(8):3339–46]
Association between Chronic Atrophic Gastritis and Serum Antibodies to 15 Helicobacter pylori Proteins Measured by Multiplex Serology
Authors: Gao Lei , Weck Melanie N. , Michel Angelika , Pawlita Michael , Brenner Hermann
Published: March 2009

Infection with Helicobacter pylori is a major risk factor for chronic atrophic gastritis (CAG), a precursor lesion of intestinal gastric cancer. The pathogenicity of the bacterium is thought to play an important role in determining the extent and severity of clinical outcome. We aimed to assess the associations between CAG and the serostatus of antibodies to 15 H. pylori proteins. The analyses were based on 534 cases with serologically defined CAG and 1,068 age-matched and sex-matched controls participating in a population-based study conducted in Saarland, Germany among 9,953 men and women ages 50 to 74 years. A newly developed H. pylori multiplex serology method was used to detect antibodies specific to 15 H. pylori antigens. Significant associations were observed between seropositivity for all 15 specific antibodies and the presence of CAG. Exclusion of severe cases, who might have lost the infection in the course of CAG progression, substantially increased the observed associations. In H. pylori–seropositive subjects, cytotoxin-associated gene A (CagA), vacuolating toxin (VacA), helicobacter cysteine-rich protein C (HcpC), and the chaperonin GroEL were identified as independent virulence factors for CAG with adjusted odds ratios (95% confidence interval) of 3.52 (2.01–6.10), 3.19 (1.44–7.05), 4.03 (1.53–10.65), and 2.65 (1.06–6.62), respectively; the simultaneous presence of all four independent virulence factors was associated with an 18-fold risk of CAG. In conclusion, HcpC and GroEL were identified as new independent virulence factors, and in combination with the established virulence factors, CagA and VacA, were strongly associated with CAG. [Cancer Res 2009;69(7):2973–80]
Telomere Length in Peripheral Blood Predicts Survival in Clear Cell Renal Cell Carcinoma
Authors: Svenson Ulrika , Ljungberg Börje , Roos Göran
Published: March 2009

Telomeres are repetitive structures located at chromosome ends. Previous studies have indicated that blood cell telomeres may serve as a biomarker for cancer risk. In addition, we recently reported that blood telomere length predicted survival in patients with breast cancer. In the present study, we examined whether blood telomere length may act as a predictor for survival in newly diagnosed patients with clear cell renal cell carcinoma. Furthermore, we analyzed telomere length in tumor samples and corresponding kidney cortex. Relative telomere length (RTL) was measured on extracted DNA using real-time PCR. Interestingly, and in line with our previous findings in breast cancer, patients with the longest blood telomeres (fourth quartile) had a significantly worse prognosis compared with patients with shorter blood RTL (P = 0.005). A highly significant association was found between long blood telomeres and a poor outcome in patients with nonmetastatic disease (P < 0.001), whereas patients with distant metastases had a poor survival regardless of blood RTL (P = 0.432). No correlations were found between blood RTL and various clinical variables, such as erythrocyte sedimentation rate, hemoglobin, and thrombocyte count. Multivariate Cox regression analysis verified long blood RTL as an independent negative prognostic marker. In contrast, telomere length in kidney cortex and tumor tissue did not predict survival. In conclusion, our results indicate that blood RTL may predict kidney cancer survival, with implications for future treatment strategies. [Cancer Res 2009;69(7):2896–901]
Genome-Wide Impact of Androgen Receptor Trapped clone-27 Loss on Androgen-Regulated Transcription in Prostate Cancer Cells
Authors: Nwachukwu Jerome C. , Mita Paolo , Ruoff Rachel , Ha Susan , Wang Qianben , Huang S. Joseph , Taneja Samir S. , Brown Myles , Gerald William L. , Garabedian Michael J. , Logan Susan K.
Published: March 2009

The androgen receptor (AR) directs diverse biological processes through interaction with coregulators such as AR trapped clone-27 (ART-27). Our results show that ART-27 is recruited to AR-binding sites by chromatin immunoprecipitation analysis. In addition, the effect of ART-27 on genome-wide transcription was examined. The studies indicate that loss of ART-27 enhances expression of many androgen-regulated genes, suggesting that ART-27 inhibits gene expression. Surprisingly, classes of genes that are up-regulated upon ART-27 depletion include regulators of DNA damage checkpoint and cell cycle progression, suggesting that ART-27 functions to keep expression levels of these genes low. Consistent with this idea, stable reduction of ART-27 by short-hairpin RNA enhances LNCaP cell proliferation compared with control cells. The effect of ART-27 loss was also examined in response to the antiandrogen bicalutamide. Unexpectedly, cells treated with ART-27 siRNA no longer exhibited gene repression in response to bicalutamide. To examine ART-27 loss in prostate cancer progression, immunohistochemistry was conducted on a tissue array containing samples from primary tumors of individuals who were clinically followed and later shown to have either recurrent or nonrecurrent disease. Comparison of ART-27 and AR staining indicated that nuclear ART-27 expression was lost in the majority of AR-positive recurrent prostate cancers. Our studies show that reduction of ART-27 protein levels in prostate cancer may facilitate antiandrogen-resistant disease. [Cancer Res 2009;69(7):3140–7]
Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines
Authors: Pignon Jean-Christophe , Koopmansch Benjamin , Nolens Gregory , Delacroix Laurence , Waltregny David , Winkler Rosita
Published: March 2009

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR and ERBB2 expression in PCa cells. In steroid-depleted medium (SDM), EGFR protein was less abundant in androgen-sensitive LNCaP than in androgen ablation–resistant 22Rv1 cells, whereas transcript levels were similar. Dihydrotestosterone (DHT) treatment increased both EGFR mRNA and protein levels and stimulated RNA polymerase II recruitment to the EGFR gene promoter, whereas it decreased ERBB2 transcript and protein levels in LNCaP cells. DHT altered neither EGFR or ERBB2 levels nor the abundance of prostate-specific antigen (PSA), TMEPA1, or TMPRSS2 mRNAs in 22Rv1 cells, which express the full-length and a shorter AR isoform deleted from the COOH-terminal domain (ARΔCTD). The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full-length or both AR isoforms. Silencing of both isoforms strongly reduced PSA, TMEPA1, and TMPRSS2 transcript levels. Inhibition of both AR isoforms did not affect EGFR and ERBB2 transcript levels but decreased EGFR and increased ERBB2 protein levels. Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and ARΔCTD. A further decrease was obtained with PKI166, an EGFR/ERBB2 kinase inhibitor. Overall, we showed that ARΔCTD is responsible for constitutive EGFR expression and ERBB2 repression in 22Rv1 cells and that ARΔCTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth. [Cancer Res 2009;69(7):2941–9]
In situ Expression of Tumor Antigens by Messenger RNA–Electroporated Dendritic Cells in Lymph Nodes of Melanoma Patients
Authors: Schuurhuis Danita H. , Verdijk Pauline , Schreibelt Gerty , Aarntzen Erik H.J.G. , Scharenborg Nicole , de Boer Annemiek , van de Rakt Mandy W.M.M. , Kerkhoff Marieke , Gerritsen Marie-Jeanne P. , Eijckeler Femke , Bonenkamp Johannes J. , Blokx Willeke , van Krieken J. Han , Boerman Otto C. , Oyen Wim J.G. , Punt Cornelis J.A. , Figdor Carl G. , Adema Gosse J. , de Vries I. Jolanda M.
Published: March 2009

Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) for cancer immunotherapy has been proved efficient and clinically safe. It obviates prior knowledge of CTL and Th epitopes in the antigen and leads to the presentation of multiple epitopes for several HLA alleles. Here we studied the migration capacity and the antigen expression of mRNA-electroporated DC (mRNA-DC) in lymph nodes after vaccination in melanoma patients. DC were electroporated with mRNA encoding gp100 or tyrosinase, labeled with indium-111 and superparamagnetic iron oxide particles, and injected intranodally in melanoma patients 24 to 48 hours before scheduled dissection of regional lymph nodes. Immunohistochemical analysis of the lymph nodes after surgery revealed that mRNA-DC migrated from the injection site into the T-cell areas of the same and subsequent lymph nodes, where they expressed the antigen encoded by the electroporated mRNA. Furthermore, vaccine-related CD8+ T-cell responses could be detected in 7 of 11 patients vaccinated with mRNA-DC. Together these data show that mature DC electroporated with mRNA encoding TAA migrate and express antigens in the lymph nodes and induce specific immune responses. [Cancer Res 2009;69(7):2927–34]