bluuebunny/crossref_metadata_2025_split 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

AbstractThe 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

AbstractVinflunine, 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

Abstract
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

Abstract
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

Abstract
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

AbstractFew 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

AbstractThe 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

AbstractThis 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.
Myths and Lessons from the Adult/Pediatric Interface in Acute Lymphoblastic Leukemia
Authors: Sallan Stephen E. 
Published: November 2006

Abstract
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

AbstractSeveral 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

AbstractTreatment 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

AbstractDefined 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

Abstract
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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractTransfusion-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.