bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Mammalian Target of Rapamycin Inhibitor Rapamycin and HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Has Synergistic Activity in Multiple Myeloma
Authors: Francis Lanie K. , Alsayed Yazan , Leleu Xavier , Jia Xiaoying , Singha Ujjal K. , Anderson Judith , Timm Michael , Ngo Hai , Lu Ganwei , Huston Alissa , Ehrlich Lori A. , Dimmock Elizabeth , Lentzsch Suzanne , Hideshima Teru , Roodman G. David , Anderson Kenneth C. , Ghobrial Irene M. 
Published: November 2006

Abstract
Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells.
Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination.
Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment.
Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.
The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity
Authors: Mirzoeva Olga K. , Kawaguchi Tomohiro , Pieper Russell O. 
Published: November 2006

AbstractThe chemotherapeutic agent temozolomide produces O6-methylguanine (O6MG) in DNA, which triggers futile DNA mismatch repair, DNA double-strand breaks (DSB), G2 arrest, and ultimately cell death. Because the protein complex consisting of Mre11/Rad50/Nbs1 (MRN complex) plays a key role in DNA damage detection and signaling, we asked if this complex also played a role in the cellular response to temozolomide. Temozolomide exposure triggered the assembly of MRN complex into chromatin-associated nuclear foci. MRN foci formed significantly earlier than γ-H2AX and 53BP1 foci that assembled in response to temozolomide-induced DNA DSBs. MRN foci formation was suppressed in cells that incurred lower levels of temozolomide-induced O6MG lesions and/or had decreased mismatch repair capabilities, suggesting that the MRN foci formed not in response to temozolomide-induced DSB but rather in response to mismatch repair processing of mispaired temozolomide-induced O6MG lesions. Consistent with this idea, the MRN foci colocalized with those of proliferating cell nuclear antigen (a component of the mismatch repair complex), and the MRN complex component Nbs1 coimmunoprecipitated with the mismatch repair protein Mlh1 specifically in response to temozolomide treatment. Furthermore, small inhibitory RNA–mediated suppression of Mre11 levels decreased temozolomide-induced G2 arrest and cytotoxicity in a manner comparable to that achieved by suppression of mismatch repair. These data show that temozolomide-induced O6MG lesions, acted upon by the mismatch repair system, drive formation of the MRN complex foci and the interaction of this complex with the mismatch repair machinery. The MRN complex in turn contributes to the control of temozolomide-induced G2 arrest and cytotoxicity, and as such is an additional determining factor in glioma sensitivity to DNA methylating chemotherapeutic drugs such as temozolomide. [Mol Cancer Ther 2006;5(11):2757–66]
Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model
Authors: Rahman KM Wahidur , Sarkar Fazlul H. , Banerjee Sanjeev , Wang Zhiwei , Liao Dezhong J. , Hong Xin , Sarkar Nurul H. 
Published: November 2006

AbstractSeveral lines of experimental evidence have suggested that chemokine receptor CXCR4, a metastasis-promoting molecule, may play important roles in breast cancer bone metastasis. There is emerging evidence linking CXCR4 to matrix metalloproteinases (MMP) as well as their regulator nuclear factor-κB (NF-κB), a key transcription factor, which is known to activate metastasis-promoting molecules for many types of malignancies, including breast cancer. A recent study also showed that promoter region of CXCR4 has several NF-κB-binding sites, suggesting that there may be a cross-talk between CXCR4 and NF-κB. We have shown previously that indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica, can inhibit NF-κB in breast cancer cells. However, there are no reports in the literature showing any effect of I3C on CXCR4 expression in vitro and in vivo. We therefore examined whether I3C could inhibit bone metastasis of breast cancer by inhibiting CXCR4 and MMP-9 expression mediated via the inhibition of the NF-κB signaling pathway. Here, we have modified the severe combined immunodeficient (SCID)-human mouse model of experimental bone metastasis for use with the MDA-MB-231 breast cancer cell line. In this animal model, we found that I3C significantly inhibited MDA-MB-231 bone tumor growth, and our results were correlated with the down-regulation of NF-κB. Moreover, we found that I3C significantly inhibited the expression of multiple genes involved in the control of metastasis and invasion in vitro and in vivo, especially the expression of CXCR4 and MMP-9 along with pro-MMP-9, with concomitant decrease in Bcl-2 and increase in the proapoptotic protein Bax. From these results, we conclude that the CXCR4/NF-κB pathway is critical during I3C-induced inhibition of experimental breast cancer bone metastasis. These results also suggest that I3C could be a promising agent for the prevention and/or treatment of breast cancer bone metastasis in the future. [Mol Cancer Ther 2006;5(11):2747–56]
Gallium-induced cell death in lymphoma: role of transferrin receptor cycling, involvement of Bax and the mitochondria, and effects of proteasome inhibition
Authors: Chitambar Christopher R. , Wereley Janine P. , Matsuyama Shigemi 
Published: November 2006

Abstract
Gallium nitrate is a metallodrug with clinical efficacy in non-Hodgkin's lymphoma. Its mechanisms of antineoplastic action are not fully understood. In the present study, we investigated the roles of transferrin receptor (TfR) targeting and apoptotic pathways in gallium-induced cell death. Although DoHH2 lymphoma cells displayed a 3-fold lower number of TfRs than CCRF-CEM lymphoma cells, they were 3- to 4-fold more sensitive to gallium nitrate. Despite a lower TfR expression, DoHH2 cells had greater TfR cycling and iron and gallium uptake than CCRF-CEM cells. In other lymphoma cell lines, TfR levels per se did not correlate with gallium sensitivity. Cells incubated with gallium nitrate showed morphologic changes of apoptosis, which were decreased by the caspase inhibitor Z-VAD-FMK and by a Bax-inhibitory peptide. Cells exposed to gallium nitrate released cytochrome c from mitochondria and displayed a dose-dependent increase in caspase-3 activity. An increase in active Bax levels without accompanying changes in Bcl-2 or Bcl-XL was seen in cells incubated with gallium nitrate. The endogenous expression of antiapoptotic Bcl-2 was greater in DoHH2 cells than in CCRF-CEM cells, suggesting that endogenous Bcl-2 levels do not correlate with cell sensitivity to gallium nitrate. Gallium-induced apoptosis was enhanced by the proteasome inhibitor bortezomib. Our results suggest that TfR function rather than TfR number is important in gallium targeting to cells and that apoptosis is triggered by gallium through the mitochondrial pathway by activating proapoptotic Bax. Our studies also suggest that the antineoplastic activity of combination gallium nitrate and bortezomib warrants further investigation. [Mol Cancer Ther 2006;5(11):2834–43]
Frequent overexpression of aurora B kinase, a novel drug target, in non–small cell lung carcinoma patients
Authors: Vischioni Barbara , Oudejans Joost J. , Vos Wim , Rodriguez Jose A. , Giaccone Giuseppe 
Published: November 2006

Abstract
The serine/threonine protein kinase aurora B, a key regulator of mitosis, is emerging as a novel drug target for cancer treatment. Aurora B overexpression has been previously documented by immunohistochemistry in several types of human tumors. We assessed aurora B expression in a series of 160 non–small cell lung cancer (NSCLC) samples (60% stage I, 21% stage II, 11% stage III, and 8% stage IV). In addition, we determined the expression of survivin and p16, two molecules also involved in cell cycle control. Aurora B was expressed selectively in tumor cells compared with normal epithelium. Aurora B expression was significantly correlated with expression of survivin in the nucleus (P &lt; 0.0001), but not with expression of p16 (P = 0.134). High aurora B expression levels were significantly associated with older age (P = 0.012), male sex (P = 0.013), squamous cell carcinoma histology (P = 0.001), poor tumor differentiation grade (P = 0.007), and lymph node invasion (P = 0.037), in the subset of radically resected patients in our series. In addition, aurora B expression predicted shorter survival for the patients with adenocarcinoma histology, at both univariate (P = 0.020) and multivariate (P = 0.012) analysis. Survivin expression levels were neither associated with patient clinicopathologic characteristics nor with survival. However, expression of survivin in the nucleus was preferentially detected in stage I and II than in stage III and IV (P = 0.007) in the overall series of NSCLC samples. Taken together, our results suggest that aurora B may represent a valid target in NSCLC. [Mol Cancer Ther 2006;5(11):2905–13]
Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4
Authors: Thomson Peter , Naylor Matthew A. , Everett Steven A. , Stratford Michael R.L. , Lewis Gemma , Hill Sally , Patel Kantilal B. , Wardman Peter , Davis Peter D. 
Published: November 2006

Abstract
Nitrothienylprop-2-yl ether formation on the 3′-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized following model kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promising new lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gem-dimethyl α-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drug release. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the α-carbon. Cellular and supersomal studies showed that this α-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug. [Mol Cancer Ther 2006;5(11):2886–94]
Spiritual Surrender: From Companionship to Hierarchy in the History of Bektashism
Authors: Doja Albert 
Published: November 2006

AbstractThe system of beliefs and practices related to Bektashism seems to have corresponded to a kind of liberation theology, whereas the structure of Bektashi groups corresponded more or less to the type of religious organization conventionally known as charismatic groups. It becomes understandable therefore that their spiritual tendency could at times connect with and meet social, cultural and national perspectives. In turn, when members of the previously persecuted religious minority will acquire a degree of religious and political respectability within society at large, the doctrines of heterodoxy and liberation theology fade into the background. In the end, the heirs of the heterodox promoters of spiritual reform and social movement turn into followers and faithful defenders of a legitimate authority. They become the spokespeople for an institutionalized orthodoxy whose support is sought by the political regime.
Lord, remember David: G.H. Wilson and the message of the Psalter
Authors: Mitchell David C. 
Published: November 2006

AbstractFollowing the recent death of G.H. Wilson, this article offers an appraisal of Wilson's views past and present, restates the case for an eschatologico-messianic programme in the Psalms, replies to Wilson's recent remarks on the author's own work, and points out the strengths and weaknesses of Wilson's final views.
Antiochus IV Epiphanes and the Ptolemaic Triad: The Three Uprooted Horns in Dan 7:8, 20 and 24 Reconsidered
Authors: Blasius Andreas 
Published: November 2006

AbstractThis article deals with the enigmatic prediction and explanation in Dan 7:8, 20 and 24 concerning the three out of ten horns of the fourth beast that were "uprooted" in front of the eleventh, little horn widely identified with Antiochus IV. Analysing the verses from a historical point of view like the text's first exegete Porphyry in the late third c. C.E. and modifying his thesis as it has been proposed by E. Bickermann the author presents and discusses the evidence for the rule of a Ptolemaic triad at the time of Antiochus' IV reign, still questioned by some scholars, which should be seen as the model for Daniel's visionary report. This identification set on firmer ground allows to critically question the wide range of other interpretations and to confirm the strong parallel in processing certain historical facts in Dan 7 and 11 in yet another special aspect. The relationship between Seleucids and Ptolemies in its final stage witnessed by the author of Daniel, the 6th Syrian War, characterizes Antiochus' total victory over the hated enemy "of the South" as the climax of the Seleucid's foreign success—and glory.
Bona fides: a requirement for the acquisition of ownership by means of specificatio
Authors: Kraft Christina 
Published: November 2006

AbstractThere are good reasons why bona fides should be seen as a requirement for the acquisition of ownership through specificatio. Firstly, the specificator produces something new, a res aliqua, and is therefore given the right to incorporate the product in his property by occupatio. Secondly, if the specificator knew he was working with foreign raw material, and therefore knew that by his performance he was depriving the owner of the material of his property, the specificator would commit a furtum. A res nova, the origin of which is chained with a furtum, can never be res habilis.
When balancing the respective interests of the specificator on the one hand and the owner of the material on the other hand, one finds that accepting bona fides of the specificator as a requirement for his acquisition of ownership is convenient to ensure both legal certainty and the free movement of goods.
The concept of mutuum cum stipulatione
Authors: Gröschler Peter 
Published: November 2006

AbstractRoman documents of loan mostly follow the form of the so-called mutuum cum stipulatione. The informal loan contract (mutuum) is supplemented by a stipulatio in which the borrower faithfully promises the repayment of the loan. This combined contract was probably meant to include interest to the documented loan capital in a legally valid way. This was achieved by using a stipulatio which was structured in an abstract way. Unlike the mutuum abstract stipulations were valid whether the loan capital had been paid to the borrower or not. Actually, the archive of the Sulpicii suggests that in the documents mutuum and stipulatio existed independently of each other. Contrary to prevailing opinion, this combined model, probably representing the initial concept of mutuum cum stipulatione, was also supported by Roman jurisprudence, most likely by Ulpian. Consequently, the contractus re et verbis, which often led legal historians to assume interpolations, has to be regarded as a category of classical Roman law.
Immune Hemolytic Anemia—Selected Topics
Authors: Hoffman Philip C. 
Published: November 2006

Abstract
Autoimmune hemolytic anemia (AIHA) is most often idiopathic. However, in recent years, AIHA has been noted with increased incidence in patients receiving purine nucleoside analogues for hematologic malignancies; it has also been described as a complication of blood transfusion in patients who have also had alloimmunization. As the technology of hematopoietic stem cell transplantation has become more widespread, immune hemolysis in the recipients of ABO-mismatched products has become better recognized. The syndrome is caused by passenger lymphocytes transferred from the donor, and although transient, can be quite severe. A similar syndrome has been observed in recipients of solid organ transplants when there is ABO-incompatibility between donor and recipient.
Venous thromboembolism is a little-recognized, though likely common, complication of autoimmune hemolytic anemia (AIHA), and may in some instances be related to coexistent antiphospholipid antibodies. While AIHA is a well-documented complication of malignant lymphoproliferative disorders, lymphoproliferative disorders may also paradoxically appear as a consequence of AIHA.
A number of newer options are available for treatment of AIHA in patients refractory to corticosteroids and splenectomy. Newer immunosuppressives such as mycophenolate may have a role in such cases. Considerable experience has been accumulating in the last few years with monoclonal antibody therapy, specifically rituximab, in difficult AIHA cases; it appears to be a safe and effective option.
Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia
Authors: Mrózek Krzysztof , Bloomfield Clara D. 
Published: November 2006

Abstract
Pretreatment clinical features and prognosis of patients with acute myeloid leukemia (AML) are strongly influenced by acquired genetic alterations in leukemic cells, which include microscopically detectable chromosome aberrations and, increasingly, submicroscopic gene mutations and changes in gene expression. Cytogenetic findings separate AML patients into three broad prognostic categories: favorable, intermediate and adverse. The cytogenetic-risk classifications differ somewhat for younger adult patients and those aged 60 years or older. In many instances, patients with specific cytogenetic findings, e.g., those with a normal karyotype or those with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [collectively referred to as core-binding factor (CBF) AML] can be further subdivided into prognostic categories based on the presence or absence of particular gene mutations or changes in gene expression. Importantly, many of these molecular genetic alterations constitute potential targets for risk-adapted therapies. In this article, we briefly review major cytogenetic prognostic categories and discuss molecular genetic findings of prognostic significance in two of the largest cytogenetic groups of patients with AML, namely AML with a normal karyotype and CBF AML.
New Prognostic Markers in CLL
Authors: Montserrat Emili 
Published: November 2006

Abstract
The individual prognosis of patients with chronic lymphocytic leukemia (CLL) is extremely variable. Although clinical stages remain the basis for assessing prognosis in CLL, a number of biological markers, particularly serum markers, cytogenetic abnormalities, IgVH mutations, CD38 and ZAP-70 expression in leukemic cells offer important, independent prognostic information. Before being incorporated into daily practice, however, these markers require standardization and validation in large, prospective trials. Meanwhile, treatment of patients with CLL not included in clinical studies should be decided on the basis of classical NCI/CLL Working Group criteria. An important area of research in CLL prognostication is the identification of markers useful for predicting response to therapy and its duration. Among them, del(17p), reflecting P53 abnormalities, is particularly important. Also relevant is del(11q), which points to ATM defects. There is also some correlation between IgVH mutational status, ZAP-70 and CD38 expression and response to therapy and its duration, although these relationships need further investigation. Finally, there is increasing evidence that response to therapy, particularly in those cases in which minimal residual disease is eradicated, is associated with longer survival.
The Role of Immunomodulation in the Management of Factor VIII Inhibitors
Authors: Lillicrap David 
Published: November 2006

AbstractApproximately 25% of persons with hemophilia A will have their treatment complicated by the development of anti-FVIII inhibitory antibodies. This adverse event requires the use of alternative hemostatic agents to treat bleeding and the consideration of a protocol to generate immunological tolerance to FVIII. The pathogenetic factors contributing to FVIII inhibitor generation include both patient- and concentrate-related characteristics. The FVIII genotype contributes to this risk as do other, less well defined, immunogenetic factors. The role of the type of FVIII concentrate as a precipitant for inhibitor generation appears to be less influential. Immunomodulatory management of FVIII inhibitors requires sustained and repeated exposure to FVIII through a variety of intravenous immune tolerance induction (ITI) protocols. Certain pre-ITI characteristics predict for the likelihood of success, most especially the pre-ITI anti-FVIII inhibitor titer. Currently, two major areas of debate remain unresolved with relation to the optimal form of ITI schedule. The best FVIII dose to generate FVIII tolerance is under investigation in an international prospective trial, while the issue of whether von Willebrand factor–containing concentrates may provide more powerful tolerizing effects remains open for further discussion. With a variety of ITI protocols, success rates of approximately 80% have been achieved with good-risk patients. In those that fail initial attempts at ITI, additional treatments using agents such rituximab are now being explored with further evidence of success in 60–80% of these salvage patients. Finally, several pre-clinical studies of innovative approaches to achieving FVIII tolerance suggest that combinations of immunomodulatory therapy may be of benefit in the future.