bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non–small-cell lung, pancreatic, colon, and breast tumors
Authors: Buck Elizabeth , Eyzaguirre Alexandra , Brown Eric , Petti Filippo , McCormack Siobhan , Haley John D. , Iwata Kenneth K. , Gibson Neil W. , Griffin Graeme
Published: November 2006

The receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated by EGFR is the phosphatidylinositol 3′-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin (mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the sensitivity of non–small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is dependent on inhibition of the phosphatidylinositol 3′-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention. Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived from a variety of tissue types (non–small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance response to erlotinib. [Mol Cancer Ther 2006;5(11):2676–84]
Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine
Authors: Estève Marie-Anne , Carré Manon , Bourgarel-Rey Véronique , Kruczynski Anna , Raspaglio Giuseppina , Ferlini Cristiano , Braguer Diane
Published: November 2006

Vinflunine, a new microtubule-targeting drug, has a marked antitumor activity in vitro and in vivo. Here, we studied the mechanisms mediating resistance to vinflunine. We investigated the response to vinflunine of ovarian cancer cells initially selected as paclitaxel-resistant cells (A2780-TC1 cells). By comparison with A2780-wild-type (wt) cells, we showed that A2780-TC1 cells were highly resistant to vinflunine, with resistance factors reaching 800 and 1,830 for IC50 and IC70, respectively. We showed that P-glycoprotein minimally participated in this cell resistance. The examination of tubulin composition revealed increased levels of acetylated α-tubulin, βII-tubulin, and βIII-tubulin in A2780-TC1 cells before vinflunine treatment. As a consequence, vinflunine unequally affected microtubule network organization and function in A2780-wt and A2780-TC1 cells. Whereas the drug depolymerized microtubules and induced a mitotic block in A2780-wt cells, it did not depolymerize microtubules and induced a G2 block in A2780-TC1 cells. Elsewhere, the mitochondrial protein Bcl-2 was down-regulated in A2780-TC1 cells. This down-regulation was related to resistance, as A2780-TC1 cells stably transfected with a Bcl-2 construct recovered a partial sensitivity to vinflunine. Lastly, we confirmed the role played by Bcl-2 by showing that the mitochondrial membrane potential was only disrupted by vinflunine in cells expressing Bcl-2. Altogether, our results indicate that modifications acquired during treatment (i.e., paclitaxel) have significant consequences on cell response to the following drug (i.e., vinflunine). Especially, this study shows that a specific pool of tubulin subtypes and a down-regulation of Bcl-2 are associated with resistance of ovarian cancer cells to vinflunine. [Mol Cancer Ther 2006;5(11):2824–33]
Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells
Authors: Cianchi Fabio , Cortesini Camillo , Magnelli Lucia , Fanti Elena , Papucci Laura , Schiavone Nicola , Messerini Luca , Vannacci Alfredo , Capaccioli Sergio , Perna Federico , Lulli Matteo , Fabbroni Valentina , Perigli Giuliano , Bechi Paolo , Masini Emanuela
Published: November 2006

Cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) are key enzymes involved in arachidonic acid metabolism. Their products, prostaglandins and leukotrienes, are involved in colorectal tumor development. We aimed at evaluating whether combined blocking of the COX-2 and 5-LOX pathways might have additive antitumor effects in colorectal cancer. The expression/activity of COX-2 and 5-LOX were assessed in 24 human colorectal cancer specimens. The effects of the COX-2 inhibitor celecoxib and the 5-LOX inhibitor MK886 on prostaglandin E2 and cysteinyl leukotriene production, tumor cell proliferation, cell apoptosis, and Bcl-2/Bax expression were evaluated in the Caco-2 and HT29 colon cancer cells. We also investigated the effect of the enzymatic inhibition on mitochondrial membrane depolarization, one of the most important mechanisms involved in ceramide-induced apoptosis. Up-regulation of the COX-2 and 5-LOX pathways was found in the tumor tissue in comparison with normal colon mucosa. Inhibition of either COX-2 or 5-LOX alone resulted in activation of the other pathway in colon cancer cells. Combined treatment with 10 μmol/L celecoxib and MK886 could prevent this activation and had additive effects on inhibiting tumor cell proliferation, inducing cell apoptosis, decreasing Bcl-2 expression, increasing Bax expression, and determining mitochondrial depolarization in comparison with treatment with either inhibitor alone. The administration of the ceramide synthase inhibitor fumonisin B1 could prevent some of these antineoplastic effects. In conclusion, our study showed that inhibition of 5-LOX by MK886 could augment the antitumor activity of celecoxib in human colorectal cancer. [Mol Cancer Ther 2006;5(11):2716–26]
Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs
Authors: Roudier Emilie , Mistafa Oras , Stenius Ulla
Published: November 2006

Cholesterol-lowering statins have been shown to have anticancer effects in different models and sensitize human tumor cells to cytostatic drugs. We have investigated the effect of statins on Akt/protein kinase B signaling and the sensitizing effect of cytostatic drugs. It was found that insulin– and cytostatic drug–induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H1299 cells in an mTOR-dependent manner. Statins also induced mTOR-dependent phosphorylation of insulin receptor substrate 1. In p53 wild-type cells (HepG2 and A549), pretreatment with statins did not sensitize cells to etoposide in concentrations which induced p53 stabilization. In line with our previous data, statins were found to attenuate the etoposide-induced p53 response. However, silencing p53 by RNA interference rescued the sensitizing effect. We also show that in a p53-deficient cell line (H1299), pretreatment with atorvastatin sensitized cells to etoposide, doxorubicin, and 5-fluorouracil and increased the level of apoptosis. Taken together, these data suggest that a mTOR-dependent, statin-induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs. However, this effect can be counteracted in p53 competent cells by the ability of statins to destabilize p53. [Mol Cancer Ther 2006;5(11):2706–15]
Absorption and subcellular localization of lycopene in human prostate cancer cells
Authors: Liu Ang , Pajkovic Natasa , Pang Yan , Zhu Dongwei , Calamini Barbara , Mesecar Andrew L. , van Breemen Richard B.
Published: November 2006

Lycopene, the red pigment of the tomato, is under investigation for the chemoprevention of prostate cancer. Because dietary lycopene has been reported to concentrate in the human prostate, its uptake and subcellular localization were investigated in the controlled environment of cell culture using the human prostate cancer cell lines LNCaP, PC-3, and DU145. After 24 hours of incubation with 1.48 μmol/L lycopene, LNCaP cells accumulated 126.6 pmol lycopene/million cells, which was 2.5 times higher than PC-3 cells and 4.5 times higher than DU145 cells. Among these cell lines, only LNCaP cells express prostate-specific antigen and fully functional androgen receptor. Levels of prostate-specific antigen secreted into the incubation medium by LNCaP cells were reduced 55% as a result of lycopene treatment at 1.48 μmol/L. The binding of lycopene to the ligand-binding domain of the human androgen receptor was carried out, but lycopene was not found to be a ligand for this receptor. Next, subcellular fractionation of LNCaP cells exposed to lycopene was carried out using centrifugation and followed by liquid chromatography-tandem mass spectrometry quantitative analysis to determine the specific cellular locations of lycopene. The majority of lycopene (55%) was localized to the nuclear membranes, followed by 26% in nuclear matrix, and then 19% in microsomes. No lycopene was detected in the cytosol. These data suggest that the rapid uptake of lycopene by LNCaP cells might be facilitated by a receptor or binding protein and that lycopene is stored selectively in the nucleus of LNCaP cells. [Mol Cancer Ther 2006;5(11):2879–85]
The Second Intifada and the "Day of Wrath": Safar al-Hawālī and his anti-Semitic reading of Biblical Prophecy
Authors: Reichmuth Stefan
Published: November 2006

Few months after the outbreak of the al-Aqsa Intifada, Safar al-Hawālī, one of the most prominent and controversial Islamic scholars of Saudi Arabia, published his book Yawm al-gadab, "The Day of Wrath", which has enjoyed a wide readership both for its Arabic and English versions in the internet. Engaging with the current wave of Christian and Jewish apocalyptical literature, he challenges the widespread view that the biblical prophecies predict the final victory of the Israel over its neighbours. The book claims that, quite to the contrary, they can be read as indications of the violent end of that state and its allies. The article analyses Safar al-Hawālī's unusually close reading of the Bible which even transfers the biblical promises of return to the Palestinians. His fierce accusations against Israel and the U.S.A., which are orchestrated with extensive quotes from the biblical Prophets, testify to a new stage of the sacralisation of political language in the Middle East.
Some Early Jewish and Christian Exegetical Problems and the Dynamics of Monotheism
Authors: Kister Menahem
Published: November 2006

The thesis of this article is that a Jewish theological formula or an interpretation of biblical passages which, in one period, successfully served one side of a polemic, became, in a later period and in another context, a springboard for an adversary's attack, or an insidious internal theological problem. The author attempts to illuminate the inner dynamics of Judaism as a monotheistic religion, and to observe the potential of inherent theological tensions in Judaism of the Second Temple period and rabbinic Judaism for the emergence of Christian and Gnostic theological concepts and interpretations which were in conflict with the Jewish ones.
Writing the History of African Christianity: Reflections of an Editor
Authors: Maxwell David
Published: November 2006

This article reviews the literature on African Christian Studies from the 1990s onwards and suggests new directions for research. The field has drawn great impetus from a series of historical/anthropological debates over conversion and the relative significance of missionary imperial hegemony and African agency. But there is a great need for work on twentieth-century missionaries and their contribution to colonial science. And there are too few studies of African leaders within mission churches, particularly in the era of decolonisation. Research on Pentecostalism has flourished but needs to be historicised. New areas for research are: African Christian diaspora and its impact on host communities; the impact of development and human rights agendas on the church; the effects of the AIDS pandemic. As the African Church becomes a more prominent part of World Christianity, scholars need to assess how African moral sensibilities are recasting the theology and politics of the historic mission churches.
On the Waxing and Waning of Working Memory: Action Orientation Moderates the Impact of Demanding Relationship Primes on Working Memory Capacity
Authors: Jostmann Nils B. , Koole Sander L.
Published: November 2006

The present research examined how actionversus state-oriented individuals (Kuhl & Beckmann, 1994) utilize their working memory capacity under varying situational demands. Participants visualized either a demanding or an accepting person, after which their working memory capacity was assessed. Among action-oriented participants, visualizing a demanding person led to greater operation spans (Study 1) and superior memory for intention-related information (Study 2) than visualizing an accepting person. State-oriented participants displayed the opposite pattern, such that visualizing an accepting person led to greater operation spans (Study 1) and superior memory for intentions (Study 2) than visualizing a demanding person. These findings indicate that action versus state orientation moderates the impact of situational demands on working memory capacity.
Fertility Cycle Patterns in Motives for Sexual Behavior
Authors: Sheldon Melanie Skaggs , Cooper M. Lynne , Geary David C. , Hoard Mary , DeSoto M. Catherine
Published: November 2006

Three studies examined the relationship between fertility, as indexed by day in cycle or salivary estradiol levels, and reported motives for sexual intercourse. Data from university and community samples in both cross-sectional and repeated-measures designs showed that sex-for-intimacy motives are endorsed significantly less by women who are relatively more fertile or show higher salivary estrogen levels. Sex for enhancement, self-affirmation, and partner approval also declined, although the data were less consistent. The remaining motives (coping and power) showed no consistent patterns across fertility status. Results suggest that sexual motives are rooted partly in woman's biology and are discussed in terms of plausible evolutionary mechanisms that might promote female “choosiness” at midcycle.
‘The Voice of Mahmūd’
Authors: Sarkar Nilanjan
Published: November 2006

This article is an initial attempt to study the ‘internal dynamics’ of the Fatāwā-i Jahāndārī, a ‘Mirrors for Princes’ text written in the mid-fourteenth century by Ziya Barani, an ex-courtier, resident in Delhi. It focuses on the author's use of the ‘voice’ of Mahmud of Ghazni and, through examples from the text, tries to understand possible meanings that it may have en-gendered for the narrative and the reader. As such, the article is both a methodological and empirical exercise.
The Impact of Group Size and Social Presence on Small-Group Communication
Authors: Lowry Paul Benjamin , Roberts Tom L. , Romano Nicholas C. , Cheney Paul D. , Hightower Ross T.
Published: November 2006

This study evaluates the impact of varying group size and social presence on small-group communication. It compares key communication factors—faceto-face (FtF) without computer-mediated communication (CMC) support, FtF with CMC support, and virtual with CMC support—on two different small group sizes (3 and 6). Results indicate that smaller groups establish and maintain higher levels of communication quality, and FtF with CMC support groups have higher levels of communication quality than virtual with CMC support groups; however, no significant difference between traditional FtF groups and virtual groups with CMC support was found. Also, CMC minimized the impact of increased group size. Process losses that a larger FtF group might ordinarily experience can be reduced through the use of CMC. These results should help project managers plan for and deal with the difficulty of communication between project group members in virtual environments.
Are All Distributed Teams the Same? Differentiating Between Temporary and Ongoing Distributed Teams
Authors: Saunders Carol Stoak , Ahuja Manju K.
Published: November 2006

Distributed teams, sometimes called virtual teams, are becoming increasingly prevalent as businesses bring geographically dispersed members together to achieve a common goal. A framework for understanding geographically distributed teams based on their time span is yet to be developed. The authors believe that theory building in this area has centered on temporary teams and propose that many distributed teams have ongoing and recurring tasks. Using attention focus and the shadow of the future models, this article presents a framework for understanding the differences between temporary and ongoing distributed teams' structure, processes, and outcomes, suggesting that ongoing distributed teams must tackle more process and structural issues than temporary teams and that findings of virtual teams research thus far may not always apply here. The model also implies that ongoing distributed teams are more difficult to manage and experience greater variance in well-being outcome levels, whereas in temporary teams, members are more focused on task-related (production) outcomes.
Bursting Bubbles
Authors: Arend Richard J.
Published: November 2006

This article explains that the Internet bubble was a unique and unfortunately missed opportunity for strategic management academia to vastly increase the field's perceived legitimacy. This author challenges strategic management scholars to acknowledge this failure, understand it, and reconsider their responsibilitiesto the public and to the field.
Astute Foresight or Wishful Thinking?
Authors: Schwarz Gavin M. , Kerr Steve , Mowday Richard T. , Starbuck William H. , Tung Rosalie L. , Von Glinow Mary Ann
Published: November 2006

This essay discusses the relevance of visions to individual learning and management education. Five past presidents of the Academy of Management review their vision making experiences and contemplate the pros and cons of management prophecy. Unlike prescriptive pieces that treat visions as a positive, linear force, the presidents' critical, reflective experiences raise questions about the extent to which visions create learning opportunities.
When the President Comes to Town
Authors: Barrett Andrew W. , Peake Jeffrey S.
Published: November 2006

Domestic travel has become a common practice for modern presidents. Many claim local media cover these presidential trips more extensively and positively than the national media, yet no one has examined the validity of this assumption. We begin this examination with a study of local and national newspaper coverage of President George W. Bush’s 2001 domestic travel. Our findings confirm that the local press covers presidential domestic trips both more comprehensively and favorably than the national press. We also analyze variations in local newspaper coverage of presidential visits, finding that the most important factor influencing both the amount and tone of such coverage is the level of presidential support within a community. Other factors discovered to affect either the amount or tone of local coverage include the availability of adversarial sources, whether a newspaper has a Democratic editorial bent, and whether a visit occurred after the 9/11 terrorist attacks.
Calculation of specific surface area of foam metals using dodecahedron model
Authors: Duan D. L. , Zhang R. L. , Ding X. J. , Li S.
Published: November 2006

A pentagonal dodecahedron model of metal foam with open cells was considered for calculation of specific surface area of the high porosity metals. According to the pentagonal dodecahedron model the authors calculate the specific surface area of nickel foam samples with the cell size of ∼200 μm and find it approximate agreement with the results obtained by other methods, and the specific surface area of metal foams is correlated with cell size and the width of cell wall.
Macrotexture and microtexture evolution in cold rolled non-oriented electrical steel sheets during annealing
Authors: Hu Y. , Randle V. , Irons T.
Published: November 2006

Texture evolution in cold rolled non-oriented electrical steel sheets during annealing has been investigated using both electron backscatter diffraction (EBSD) microtexture and macrotexture sampling strategies. The comparison between macrotexture and microtexture pole figures showed that a reliable orientation distribution is obtained if a sampling strategy which acquires data from a sufficiently large number of grains, i.e. using a step size of the order of the grain size, is used. On the other hand, step sizes much smaller than the grain size must be used to generate an orientation map which reveals the microstructure morphology. The texture measurements showed that deformed bands in cold rolled sheets have strong orientations of {100}<011>, {111}<011>, {211}<011> and {311}<011>, i.e. on the α fibre. During annealing at 800°C, recrystallisation occurred. The deformed bands in which the rolling direction was far away from <110> were consumed initially during recrystallisation. In contrast, the α fibres remained to be consumed last. Grain growth occurred after annealing at 900°C.
Use of EBSD to characterise high temperature oxides formed on low alloy and stainless steels
Authors: Higginson R. L. , Jepson M. A. E. , West G. D.
Published: November 2006

Exposure of steel to high temperatures in air leads to the formation of an oxide scale, the composition and structure of which depends sensitively on the oxidation conditions and the alloying elements contained within the steel. In this paper, the oxide scale structures formed on low alloy and stainless steels are characterised using electron backscatter diffraction (EBSD). In low alloy steels, this crystallographic information obtained using EBSD enables both the phases within the scale (i.e. haematite, magnetite and wüstite) and orientation relationships between them to be established. This showed that both strong preferred growth within the phase layers and orientational relationships between phase layers, can occur depending on the composition and oxidation conditions. For the scales on stainless steels, the technique enabled the two crystallographic structures, corundum and spinel to be isolated. These structures can be easily differentiated using the EBSD data alone, but the individual phases within them can only be distinguished using the chemical data, collected simultaneously with the EBSD data, because of their crystallographic similarity. This technique revealed two discrete phases for each structure within the oxide scales. For the spinel structure, this consisted of a predominantly chromium and iron containing layer beside the substrate below a coarse grained phase composed of nickel and iron. Meanwhile, an iron rich (haematite) layer at the upper scale surface and a thin chromium rich phase that exists within the fine grained lower scale both possessed the corundum structure.
Solidification defects in directionally solidified nickel base superalloys: Problem solving using electron backscattered diffraction
Authors: Shollock B. A.
Published: November 2006

The production of high quality turbine blades from nickel base superalloys poses a challenging problem for the aeroengine and power generation industries. The occurrence of defects in the final single crystal component has become more common with the increasing complexity of the components in the aerospace sector and the increasing size of the blades in industrial gas turbines. In parallel, alloy development has improved the operating capabilities of these parts, but these new generation alloys have encountered more casting difficulties. The defects that occur are normally identified by metallographic and X-ray diffraction techniques. These approaches are limited by the subjectivity of determining subtle changes in contrast and by the averaging over the relatively large sampling volumes of the X-ray beam. Electron backscattered diffraction (EBSD) provides a direct approach for identifying the nature of the defects formed in these castings. This paper will present an EBSD driven assessment of problems encountered in directional solidification of nickel base superalloys: the formation of stray grains in seeded single crystals and the effect of alloy composition on the evolution of orientation. The origins of these defects will be considered with respect to classical grain growth theory.
Myths and Lessons from the Adult/Pediatric Interface in Acute Lymphoblastic Leukemia
Authors: Sallan Stephen E.
Published: November 2006

The development of effective therapy for children with acute lymphoblastic leukemia (ALL) is one of the great successes of clinical oncology, with long-term survival achieved in over 80% of patients. However, cure rates for adults with ALL remain relatively low, with only 40% of patients cured. With an age-unrestricted, biology-based approach, we anticipate a better understanding about why these outcome differences exist, and think that by extending successful pediatric clinical programs to include adult patients with ALL, we can directly compare uniformly treated adults and children in terms of response to therapy, toxicity and underlying biology.
The Biology of Acute Promyelocytic Leukemia and Its Impact on Diagnosis and Treatment
Authors: Lo-Coco Francesco , Ammatuna Emanuele
Published: November 2006

Several genetic and phenotypic characteristics of acute promyelocytic leukemia (APL) blasts provide relevant targets and the rationale for tailored treatment. These include the PML/RARα fusion and the transcription co-repressor complex recruited at the promoter of target genes by the hybrid protein, the intense and homogeneous expression of the CD33 antigen, absence of multidrug resistance–related phenotype, and a frequently mutated and constitutively activated FLT3 receptor. Such genotypic and phenotypic features are targeted by agents currently in use in front-line therapy or at relapse (i.e., retinoids, arsenic trioxide, anthracyclines and anti-CD33 monoclonal antibodies), and by novel agents that may find a place in future treatments such as histone deacetylase and FLT3 inhibitors. The unique PML/RARα aberration serves as a molecular marker for rapid diagnosis and prediction of response to ATRA-and ATO-containing therapies. Methods for prompt and low-cost detection of this genetic abnormality, such as the analysis of PML nuclear staining, are extremely useful in clinical practice and could be adopted in countries with limited resources as a surrogate for rapid genetic diagnosis. Finally, PML/RARα monitoring through sensitive RT-PCR can be regarded as an integrating part of the overall treatment strategy in this disease, whereby the treatment type and intensity are modulated in patients at different risk of relapse according to RT-PCR status during follow-up. Because recent clinical studies suggest that most APL patients receiving intensive chemotherapy may be over-treated, longitudinal and stringent RT-PCR monitoring is becoming increasingly important to test the extent to which chemotherapy can be minimized in those presenting with low-risk disease.
Controversies in Treatment of AML: Case-based Discussion
Authors: Stock Wendy
Published: November 2006

Treatment of acute myeloid leukemia (AML) in older adults remains a tremendous challenge. Standard approaches to treatment have resulted in progression-free survival in only a small minority of patients with AML over the age of 60. Elucidation of the molecular genetic events that contribute to the pathogenesis of AML in older patients are providing insights into mechanisms of resistance. This knowledge is also providing new opportunities to begin to refine and direct novel therapies for these heterogeneous diseases. In this case-based review, prognostic factors for treatment outcome in older adults will be covered along with discussion of a risk-based approach to potential therapeutic options, ranging from palliative care to novel therapies and reduced-intensity allogenenic transplant.
Treatment of the 5q– Syndrome
Authors: Fenaux Pierre , Kelaidi Charikleia
Published: November 2006

Defined by isolated del 5q and no excess of marrow blasts, the “5q– syndrome” is a specific type of myelodysplastic syndrome (MDS) with particular characteristics, including severe anemia, frequent thrombocytosis, typical dysmegakaryopoiesis and favorable outcome. Its pathogenesis remains uncertain, in particular the role of inactivation of gene(s) situated in 5q. It should be differentiated from other MDS with del 5q having an excess of marrow blasts and/or additional cytogenetic abnormalities, which carry a poor prognosis.

Until the advent of lenalidomide, repeated RBC transfusions were generally the only treatment of the 5q– syndrome, which was resistant to other therapeutic approaches. Lenalidomide can lead to RBC transfusion independence in at least two thirds of cases of the 5q– syndrome, two thirds of those responses persisting after 2 years of treatment. Importantly, not only reversal of anemia but also frequent complete pathological and cytogenetic responses are obtained. Grade 3 or 4 neutropenia and thrombocytopenia, especially during the first 6 to 8 weeks of treatment, are the major side effect of lenalidomide, justifying close monitoring of blood counts and regular patient visits.

Preliminary results suggest that lenalidomide is also very active in MDS with del 5q other than the 5q–syndrome. Although its mechanism of action remains uncertain, lenalidomide appears to target specifically the del 5q clone. By doing this, lenalidomide may have an effect on disease course and survival, which is currently being assessed in clinical trials.
Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders
Authors: Levine Ross L. , Wernig Gerlinde
Published: November 2006

The identification of JAK2V617F mutations in polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) represents an important advance in our understanding of these myeloproliferative disorders (MPD). Most, if not all, patients with PV and a significant number of patients with ET and MF are JAK2V617F positive, and the mutation likely arises in the hematopoietic stem cell compartment. JAK2V617F is a constitutively active tyrosine kinase that is able to activate JAK-STAT signaling most efficiently when co-expressed with the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte colony-stimulating factor receptor (GCSFR). Data from murine models supports the central role of JAK2V617F in the pathogenesis of MPD, as expression of JAK2V617F in a bone marrow transplantation assay results in polycythemia and myelofibrosis in recipient mice. Activation of JAK-STAT signaling by JAK2V617F in some, but not all MPD patients with ET and MF led to the identification of the constitutively active MPLW515L allele in ET and MF. Small molecule inhibitors of JAK-STAT signaling are currently being developed, which offer potential for molecularly targeted therapy for patients with PV, ET, and MF. Despite these advances, many questions remain regarding the role of a single disease allele in three phenotypically distinct MPD, the potential clinical efficacy of JAK2 inhibitors, and the identity of oncogenic alleles in JAK2V617F/MPLW515-negative MPD.
An Update on Therapy of Primary Central Nervous System Lymphoma
Authors: DeAngelis Lisa M. , Iwamoto Fabio M.
Published: November 2006

The most important advance in primary central nervous system (CNS) lymphoma treatment has been the convincing data that high-dose methotrexate-based chemotherapy regimens improve survival compared to historical controls treated with radiotherapy alone. However, the optimal treatment approach is still unclear and therapy can be associated with long-term neurotoxicity. Current research focuses on maximizing survival while minimizing neurologic sequelae.
New Advances in Iron Chelation Therapy
Authors: Cohen Alan R.
Published: November 2006

The emergence of new chelators is likely to have a major impact on the treatment of thalassemia major, sickle cell disease and other hematologic disorders for which regular red cell transfusions are required either to correct severe anemia or to prevent major complications of the underlying disease. In comparison with deferoxamine, which requires prolonged parenteral infusion to achieve negative iron balance, orally active chelators offer the promise of easier administration and better compliance. Moreover, the availability of more than one iron chelator opens up the possibility of combination therapy to target iron in specific organs and to enhance overall iron excretion. Long-term studies, employing new technologies to measure tissue iron, are required to determine whether the new chelators will be as safe and effective as deferoxamine in maintaining control of iron stores and preventing iron-induced cardiac disease, the major complication of transfusional iron overload.
Perioperative Evaluation of Bleeding Diathesis
Authors: Leung Lawrence L.K.
Published: November 2006

The differential diagnosis of a long APTT with a normal prothrombin time can be due to either a clotting factor deficiency or the presence of an inhibitor, which can be distinguished by using a plasma-mixing study. The various clotting factor deficiency states are reviewed. Clinical bleeding following cardiac bypass surgery due to acquired factor V and thrombin antibodies is also reviewed.
Transfusion-Related Acute Lung Injury: An Update
Authors: Triulzi Darrell J.
Published: November 2006

Transfusion-associated acute lung injury (TRALI) has emerged as a leading cause of transfusion-related morbidity and mortality. TRALI is characterized by acute non-cardiogenic pulmonary edema and respiratory compromise in the setting of transfusion. The study of TRALI has been hampered by inadequate case definitions and an incomplete understanding of the pathologic mechanisms. Recent consensus conferences took an important first step by providing a framework for case definition. Recent advances in the understanding of the pathogenesis of TRALI have also occurred. TRALI has been primarily attributed to donor leukocyte antibodies that are thought to interact with recipient neutrophils, resulting in activation and aggregation in pulmonary capillaries, release of local biologic response modifiers causing capillary leak, and lung injury. An alternate mechanism termed the “two hit” or “neutrophil priming” hypothesis postulates that a pathway to neutrophil activation and aggregation can occur without leukocyte antibodies. A first event such as sepsis or trauma can induce pulmonary endothelial activation, release of cytokines, and priming of neutrophils. A subsequent second event such as exposure to lipids, cytokines or antibodies in a blood component would then cause activation of adherent neutrophils and a release of bioreactive molecules leading to lung injury. There are limited clinical and animal studies to support the “two hit” model. These proposed mechanisms are not mutually exclusive in that donor leukocyte antibody can be pathogenic in both models and have implications for new strategies to prevent TRALI.
Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome–positive leukemia
Authors: Carpenter Paul A. , Snyder David S. , Flowers Mary E. D. , Sanders Jean E. , Gooley Theodore A. , Martin Paul J. , Appelbaum Frederick R. , Radich Jerald P.
Published: November 2006

Relapse occurs frequently after allogeneic hematopoietic cell transplantation (HCT) for treatment of high-risk Philadelphia chromosome–positive (Ph+) leukemia. Administration of imatinib early after HCT might provide an effective approach for preventing recurrent Ph+ leukemia, but the feasibility of this approach has not been systematically tested. Twenty-two patients, 15 with Ph+ acute lymphoblastic leukemia and 7 with high-risk chronic myelogenous leukemia, were enrolled in a prospective study and given imatinib from the time of engraftment until 365 days after HCT. Before day 90, adults (n = 19) tolerated a median average daily imatinib dose of 400 mg/d (range, 200-500 mg/d), and children (n = 3) tolerated 265 mg/m2/d (range, 200-290 mg/m2/d). The most common adverse events related to imatinib administration were grade 1-3 nausea, emesis, and serum transaminase elevations. We conclude that imatinib can be safely administered early after myeloablative allogeneic HCT at a dose intensity comparable to that used in primary therapy.
Mouse models of IgG- and IgM-mediated hemolysis
Authors: Schirmer David A. , Song Shuh-Chyung , Baliff Jeffrey P. , Harbers Stephanie O. , Clynes Raphael A. , Krop-Watorek Anna , Halverson Gregory R. , Czerwinski Marcin , Spitalnik Steven L.
Published: November 2006

Well-characterized mouse models of alloimmune antibody-mediated hemolysis would provide a valuable approach for gaining greater insight into the pathophysiology of hemolytic transfusion reactions. To this end, mouse red blood cells (mRBCs) from human glycophorin A transgenic (hGPA-Tg) donor mice were transfused into non-Tg recipients that had been passively immunized with IgG or IgM hGPA-specific monoclonal antibodies (mAbs). In this novel murine “blood group system,” mRBCs from hGPA-Tg mice are “antigen positive” and mRBCs from non-Tg mice are “antigen negative.” Passive immunization of non-Tg mice with the IgG1 10F7 and IgG3 NaM10-2H12 anti-hGPA mAbs each induced rapid clearance of incompatible transfused hGPA-Tg-mRBCs in a dose-response manner. Using various knockout mice as transfusion recipients, both the complement system and activating Fcγ receptors were found to be important in the clearance of incompatible mRBCs by each of these IgG mAbs. In addition, the IgM E4 anti-hGPA mAb induced complement-dependent intravascular hemolysis of transfused incompatible hGPA-Tg-mRBCs accompanied by gross hemoglobinuria. These initial studies validate the relevance of these new mouse models for addressing important questions in the field of transfusion medicine.
Gene expression patterns that predict sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer cell lines and human lung tumors
Authors: Balko Justin M , Potti Anil , Saunders Christopher , Stromberg Arnold , Haura Eric B , Black Esther P
Published: November 2006

Background

Increased focus surrounds identifying patients with advanced non-small cell lung cancer (NSCLC) who will benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). EGFR mutation, gene copy number, coexpression of ErbB proteins and ligands, and epithelial to mesenchymal transition markers all correlate with EGFR TKI sensitivity, and while prediction of sensitivity using any one of the markers does identify responders, individual markers do not encompass all potential responders due to high levels of inter-patient and inter-tumor variability. We hypothesized that a multivariate predictor of EGFR TKI sensitivity based on gene expression data would offer a clinically useful method of accounting for the increased variability inherent in predicting response to EGFR TKI and for elucidation of mechanisms of aberrant EGFR signalling. Furthermore, we anticipated that this methodology would result in improved predictions compared to single parameters alone bothin vitroandin vivo.

Results

Gene expression data derived from cell lines that demonstrate differential sensitivity to EGFR TKI, such as erlotinib, were used to generate models fora prioriprediction of response. The gene expression signature of EGFR TKI sensitivity displays significant biological relevance in lung cancer biology in that pertinent signalling molecules and downstream effector molecules are present in the signature. Diagonal linear discriminant analysis using this gene signature was highly effective in classifying out-of-sample cancer cell lines by sensitivity to EGFR inhibition, and was more accurate than classifying by mutational status alone. Using the same predictor, we classified human lung adenocarcinomas and captured the majority of tumors with high levels of EGFR activation as well as those harbouring activating mutations in the kinase domain. We have demonstrated that predictive models of EGFR TKI sensitivity can classify both out-of-sample cell lines and lung adenocarcinomas.

Conclusion

These data suggest that multivariate predictors of response to EGFR TKI have potential for clinical use and likely provide a robust and accurate predictor of EGFR TKI sensitivity that is not achieved with single biomarkers or clinical characteristics in non-small cell lung cancers.
Possible criteria for inpatient psychiatric admissions: which patients are transferred from emergency services to inpatient psychiatric treatment?
Authors: Ziegenbein Marc , Anreis Christoph , Brüggen Bernhard , Ohlmeier Martin , Kropp Stefan
Published: November 2006

Background

Patients with psychiatric problems often seek help and assistance in hospital emergency departments. An important task of emergency room staff is to decide whether such patients need to be admitted or whether they can be treated on an outpatient basis.

Methods

Psychiatric treatments given in the Central Interdisciplinary Emergency Department (CED) at the Medical University of Hannover (MHH) in 2002 were analysed.

Results

Of a total of 2632 patients seeking psychiatric help, 51.4% were admitted for inpatient treatment. Patients with dementia syndromes were admitted more frequently than patients with other psychiatric diseases. Suicidality was often the reason for admission. Accompanied patients were less likely to be hospitalised, unless a care-order was in force. Restraining measures and acute medication also had an impact on the rate of admissions.

Conclusion

The results may help psychiatrists in the emergency department to make a more effective decision regarding inpatient admission in the interest of the individual patient.
Effects of in vitro fertilization and embryo culture on TRP53 and Bax expression in B6 mouse embryos
Authors: Chandrakanthan Vashe , Li Aiqing , Chami Omar , O'Neill Christopher
Published: November 2006

In the mouse, embryo culture results in a characteristic phenotype of retarded embryo preimplantation development and reduced numbers of cells within embryos. The expression of TRP53 is central to the regulation of the cell's capacity to proliferate and survive. In this study we found that Trp53 mRNA is expressed throughout the preimplantation stage of development. Levels of TRP53 protein expression were low during the cleavage stages and increased at the morula and blastocyst stages in B6 embryos collected from the reproductive tract. Embryos collected at the zygote stage and cultured for 96 h also showed low levels of TRP53 expression at precompaction stages. There were higher levels of TRP53 in cultured morula and the level in cultured blastocysts was clearly increased above blastocysts collected directly from the uterus. Immunolocalization of TRP53 showed that its increased expression in cultured blastocysts corresponded with a marked accumulation of TRP53 within the nuclei of embryonic cells. This pattern of expression was enhanced in embryos produced by in vitro fertilization and subjected to culture. The TRP53 was transcriptionally active since culture also induced increased expression of Bax, yet this did not occur in embryos lacking Trp53 (Trp53-/-). The rate of development of Trp53-/- zygotes to the blastocyst stage was not different to wildtype controls when embryos were cultured in groups of ten but was significantly faster when cultured individually. The results show that zygote culture resulted in the accumulation of transcription activity of TRP53 in the resulting blastocysts. This accounts for the adverse effects of culture of embryos individually, but does not appear to be the sole cause of the retarded preimplantation stage growth phenotype associated with culture in vitro.
Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment
Authors: Lewis Anne M , Varghese Sheelu , Xu Hui , Alexander H Richard
Published: November 2006

The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFα, and TGFβ. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.