bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Targeted Nanoparticles for Imaging and Treatment of Brain Tumors
Authors: Reddy G. Ramachandra , Bhojani Mahaveer S. , McConville Patrick , Moody Jonathan , Moffat Bradford A. , Hall Daniel E. , Kim Gwangseong , Koo Yong-Eun L. , Woolliscroft Michael J. , Sugai James V. , Johnson Timothy D. , Philbert Martin A. , Kopelman Raoul , Rehemtulla Alnawaz , Ross Brian D.
Published: November 2006

Purpose: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index.

Experimental Design: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents.

Results: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin.

Conclusions: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.
NPI-0052 Enhances Tumoricidal Response to Conventional Cancer Therapy in a Colon Cancer Model
Authors: Cusack James C. , Liu Rong , Xia Lijun , Chao Ta-Hsiang , Pien Christine , Niu Wei , Palombella Vito J. , Neuteboom Saskia T.C. , Palladino Michael A.
Published: November 2006

Purpose: In the current study, we examine the effects of a novel proteasome inhibitor, NPI-0052 (salinosporamide A), on proteasome function and nuclear factor-κB activation and evaluate its ability to enhance treatment response in colon cancer xenografts when administered orally.

Experimental Design: The effects of treatment on nuclear factor-κB activation, cell cycle regulation, and apoptosis were determined. The pharmacodynamic effect of NPI-0052 on 20S proteasome function was assayed in vivo following oral and i.v. drug administration and compared with treatment with bortezomib. The effect of combined treatment with chemotherapy was determined in a colon cancer xenograft model.

Results: We found that NPI-0052 is a potent, well-tolerated proteasome inhibitor that has pharmacodynamic properties distinct from bortezomib in that it achieves significantly higher and more sustained levels of proteasome inhibition. When combined with chemotherapy, NPI-0052 increases apoptosis and shifts cells toward G2 cell cycle arrest. When added to chemotherapy in vivo [using combinations of 5-fluorouracil (5-FU), CPT-11, Avastin (bevacizumab), leucovorin, and oxaliplatin], NPI-0052 significantly improved the tumoricidal response and resulted in a 1.8-fold increased response to CPT-11, 5-FU, and leucovorin triple-drug combination (P = 0.0002, t test), a 1.5-fold increased response to the oxaliplatin, 5-FU, and leucovorin triple-drug combination (P = 0.013, t test), and a 2.3-fold greater response to the CPT-11, 5-FU, leucovorin, and Avastin regimen (P = 0.00057).

Conclusions: The high level of proteasome inhibition achieved by NPI-0052 is well tolerated and significantly improves the tumoricidal response to multidrug treatment in a colon cancer xenograft model. Further evaluation of this novel proteasome inhibitor in clinical trials is indicated.
Computed Tomography–Diagnosed Emphysema, Not Airway Obstruction, Is Associated with the Prognostic Outcome of Early-Stage Lung Cancer
Authors: Ueda Kazuhiro , Jinbo Mitsutaka , Li Tao-Sheng , Yagi Takaharu , Suga Kazuyoshi , Hamano Kimikazu
Published: November 2006

Purpose: Because both emphysema and lung cancer can arise from biological damage caused by cigarette smoking, we investigated if the development of emphysema is associated with the clinical features of smoker's lung cancer.

Experimental Design: The subjects were a consecutive series of 100 smokers who underwent lobectomy with hilar and mediastinal dissection for clinical stage I non–small cell lung cancer. We studied the relationship between the presence or absence of emphysema at the onset of the lung cancer and clinicopathologic features. Emphysema was diagnosed by measuring the low-attenuation area using computed tomography densitometry.

Results: There were no differences in clinicopathologic variables, including the degree of smoking exposure between the patients with (n = 58) and those without (n = 42) emphysema, although male gender and airflow limitation were predominant in the patients with emphysema. The presence of emphysema, but neither male gender nor airflow limitation, adversely affected both overall and disease-specific survival. According to Cox regression analysis, emphysema was an independent prognosticator among age, gender, degree of smoking exposure, tumor size, nodal status, histologic subtype, histologic grade, and microvessel invasion. These results were stabilized by a bootstrap sampling model.

Conclusions: Computed tomography–diagnosed emphysema, but not airway obstruction, is associated with poor prognosis in smokers with early-stage lung cancer. Thus, routine computed tomography densitometry in smokers with lung cancer should be mandatory.
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

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

The 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

Several 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

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

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 < 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

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

The 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

Following 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

This 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

There 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

Roman 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.
Self-Conscious Emotions and Depression: Rumination Explains Why Shame But Not Guilt is Maladaptive
Authors: Orth Ulrich , Berking Matthias , Burkhardt Simone
Published: November 2006

Feelings of shame and guilt are factors associated with depression. However, studies simultaneously investigating shame and guilt suggest that only shame has a strong unique effect, although it is not yet clear which psychological processes cause shame and not shame-free guilt to be related to depression. The authors hypothesized that shame, in contrast to guilt, elicits rumination, which then leads to depression. Therefore, in this study we investigated event-related shame and guilt, eventrelated rumination, and depression among 149 mothers and fathers following family breakup due to marital separation. Data were analyzed using latent variable modeling. The results confirm that shame but not guilt has a strong unique effect on depression. Moreover, the results show that the effect of shame is substantially mediated by rumination. The results are discussed against the background of self-discrepancies and self-esteem.
Meeting Satisfaction for Technology-Supported Groups
Authors: Briggs Robert O. , Reinig Bruce A. , de Vreede Gert-Jan
Published: November 2006

Research shows that people who feel dissatisfied with a technology-supported meeting may discontinue use of such technology, even if it provides demonstrable benefits. It is therefore important to derive theoretical understandings of the satisfaction phenomenon. This article validates an instrument that measures the constructs of a goal-attainment model of meeting satisfaction. It then tests the model among 237 working professionals in 19 groups in the field. Results support the propositions that satisfaction with meeting process and satisfaction with meeting outcome are both a function of an individual's perceived net goal attainment with respect to the meeting. The results also support a proposed link between satisfaction with meeting outcome and satisfaction with meeting process. The authors discuss the implications of these findings for research and practice.
Why is Organization Theory so Ignorant? The Neglect of Total Institutions
Authors: Clegg Stewart R.
Published: November 2006

Organization theory has, on the whole, failed to adequately address the role that organizations have played in some of the crimes of humanity. The tools to do so have long been available to the discipline, in work by scholars such as Goffman on total institutions, Foucault on disciplinary mechanisms, and Bauman on the Holocaust. The article retrieves the work of these scholars to raise some important questions left begging by much contemporary scholarship.
Random thoughts on non-random misorientation distributions
Authors: Wright S. I.
Published: November 2006

Automated electron backscatter diffraction (EBSD) or orientation imaging microscopy (OIM) has become a common analytical tool for the statistical characterisation of grain boundaries in polycrystalline materials. However, as such studies have become more tractable with the advances in EBSD technology some critical complexities of grain boundary analysis have been neglected. This includes the multidimensionality of grain boundaries, correlated versus uncorrelated misorientation distributions, OIM scanning artefacts specifically critical to boundary analysis. The present work describes some of these shortfalls as well as approaches for mitigating problems in grain boundary analysis via EBSD.
High resolution mapping of strains and rotations using electron backscatter diffraction
Authors: Wilkinson A. J. , Meaden G. , Dingley D. J.
Published: November 2006

The angular resolution of electron backscatter diffraction (EBSD) measurements can be significantly improved using an analysis based on determination of small shifts in features from one pattern to the next using cross-correlation functions. Using pattern shift measurements at many regions of the pattern, errors in the best fit strain and rotation tensors can be reduced. The authors show that elements of the strain tensor and small misorientations can be measured to ± 10−4 and ±0·006° for rotations. We apply the technique to two quite different materials systems. First, we determine the elastic strain distribution near the interface in a cross-sectioned SiGe epilayer, Si substrate semiconductor heterostructure. The plane stress boundary conditions at the sample surface are used to separate every term in the strain tensor. Second, the applicability to structural materials is illustrated by determining the lattice curvature caused by dislocations within the plastic zone associated with the wake and tip of a fatigue crack in a Ni based superalloy. The lattice curvatures are used to calculate the geometrically necessary dislocation content in the plastic zone.
Characterisation of microstructure and thermal stability of rapidly solidified Al–8·5Fe–1·3V–1·7Si alloy during prolonged exposure at 625°C
Authors: Solis-Ramos E. , Jones H. , Rainforth W. M.
Published: November 2006

Al–8·5Fe–1·3V–1·7Si (wt-%) alloy consolidated and rolled into sheet from pulverised planar flow cast material has been subjected to exposure times up to 575 h at 625°C. Both as received and exposed samples were investigated to reveal the effect of the exposure on microstructural stability, including dispersoid size. Microstructural characterisation was performed by a combination of X-ray diffraction, differential thermal analysis, and scanning and transmission electron microscopy. The results showed the presence of coarse plate shaped Al13Fe4 particles after 2 h at 625°C and additional polyhedral shaped Al13(Fe,V)3Si particles were observed evenly distributed within the matrix after exposure at 625°C for 290 h. Even after 575 h at 625°C, the silicide phase in the material retained the same bcc structure as in the as received condition but with a slightly increased lattice parameter. The experimentally determined coarsening rates of silicides in the material were a factor of 2 to 3 lower than predictions based on control by volume diffusion of V in the α-Al matrix.
Immune Hemolytic Anemia—Selected Topics
Authors: Hoffman Philip C.
Published: November 2006

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

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

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

Approximately 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.
New Anticoagulants
Authors: Bauer Kenneth A.
Published: November 2006

Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. New anticoagulants have been developed that target a single coagulation factor and have predictable dose-response relationships. These include direct thrombin inhibitors and factor Xa inhibitors. Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia (HIT). Bivalirudin is a parenteral direct thrombin inhibitor that is licensed for patients undergoing percutaneous coronary interventions and for those with HIT who require percutaneous coronary interventions. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, showed efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. However, due to nonhematologic safety concerns, it did not receive FDA approval in the US. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux demonstrated efficacy compared to low-molecular-weight heparin in randomized clinical trials and is FDA approved for the prevention and treatment of venous thromboembolism. The OASIS 5 trial in non-ST-segment elevation acute coronary syndromes recently demonstrated that the fondaparinux dose approved for prophylaxis of deep venous thrombosis is as efficacious with respect to ischemic outcomes as therapeutic doses of enoxaparin; fondaparinux, however, was associated with a substantial reduction in major bleeding at 9 days and mortality at 1 and 6 months. A number of oral direct factor Xa inhibitors as well as other oral direct thrombin inhibitors are in clinical development for the prevention and treatment of thrombosis; the current status of these anticoagulants is reviewed along with the challenges faced in designing pivotal clinical trials of these agents in comparison to existing anticoagulants.
Thrombosis in Infants and Children
Authors: Schneppenheim Reinhard , Greiner Jeanette
Published: November 2006

During the last decade much progress has been made toward better understanding of the underlying reasons causing thromboembolism in children. A considerable number of acquired and hereditary thrombotic risk factors have been identified which may also have an impact on therapeutic decisions and prognosis concerning outcome and the risk of a second event. However, indications for therapeutic interventions, such as thrombolysis and prophylactic anticoagulation with respect to the different clinical conditions and their combination with other risk factors, are not yet well defined. The following article describes the causes, clinical presentation and management of thrombosis in neonates, infants and older children, focusing on the clinically most relevant conditions.
A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus–associated lymphoid malignancies
Authors: Perrine Susan P. , Hermine Olivier , Small Trudy , Suarez Felipe , O'Reilly Richard , Boulad Farid , Fingeroth Joyce , Askin Melissa , Levy Arthur , Mentzer Steven J. , Di Nicola Massimo , Gianni Alessandro M. , Klein Christoph , Horwitz Steven , Faller Douglas V.
Published: November 2006

Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV+ lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV+ lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV+ lymphoid malignancies which are refractory to other regimens.
TACI regulates IgA production by APRIL in collaboration with HSPG
Authors: Sakurai Daisuke , Hase Hidenori , Kanno Yumiko , Kojima Hidefumi , Okumura Ko , Kobata Tetsuji
Published: November 2006

Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is a member of the tumor necrosis factor (TNF) receptor family that serves as a receptor for B-cell activating factor of the TNF family (BAFF) and as a proliferation-inducing ligand (APRIL). Although TACI is reported to function as a positive or negative regulator for B-cell responses, its roles remain elusive. Experiments using TACI siRNA into B cells indicated that TACI positively regulated APRIL-induced IgA production in collaboration with heparan sulfate proteoglycans (HSPG). Furthermore, TACI negatively regulated BAFF-induced B-cell proliferation and production of IgA and IgG. In addition, B cells treated with heparitinase to denature HSPG showed that HSPG is essential for APRIL-induced B-cell responses such as B-cell proliferation, IgG and IgA production, induction of activation-induced cytidine deaminase (AID), and noncanonical NF-κB2. In contrast, phosphorylation of physiological AID kinase, protein kinase A (PKA), was dependent on TACI. Importantly, coligation of TACI and HSPG by specific antibodies, but not by TACI or HSPG ligation itself, could induce the phosphorylation of PKA and IgA production instead of APRIL. Our findings indicate that simultaneous binding of TACI and HSPG on B cells with APRIL is crucial for IgA production.
The effect of the Thanksgiving Holiday on weight gain
Authors: Hull Holly R , Radley Duncan , Dinger Mary K , Fields David A
Published: November 2006

Background

More people than ever are considered obese and the resulting health problems are evident. These facts highlight the need for identification of critical time periods for weight gain. Therefore the purpose was to assess potential changes that occur in body weight during the Thanksgiving holiday break in college students.

Methods

94 college students (23.0 ± 4.6 yrs, 72.1 ± 14.0 kg, 172.6 ± 9.3 cm, 24.0 ± 3.9 kg/m2) reported to the human body composition laboratory at the University of Oklahoma following a 6-hour fast with testing occurring prior to, and immediately following the Thanksgiving holiday break (13 ± 3 days). Body weight (BW) was assessed using a balance beam scale while participants were dressed in minimal clothing. Paired t-tests were used to assess changes in BW pre and post Thanksgiving holiday with additional analysis by gender, body mass index (BMI), and class standing (i.e. undergraduate vs. graduate).

Results

Overall, a significant (P < 0.05) increase in BW was found between pre (72.1 kg) and post (72.6 kg) Thanksgiving holiday. When stratified by gender and class standing a significant (P < 0.05) increase in body weight was observed between the pre and post Thanksgiving holiday in males (0.6 kg), females (0.4 kg) and graduate students (0.8 kg). When participants were classified by BMI as normal or as overweight/obese, a significant 1.0 kg BW gain was found (P < 0.05) in the overweight/obese (≥25 kg/m2) group compared to a non significant 0.2 kg gain in the normal group (<25 kg/m2).

Conclusion

These data indicate that participants in our study gained a significant amount of BW (0.5 kg) during the Thanksgiving holiday. While an increase in BW of half a kilogram may not be cause for alarm, the increase could have potential long-term health consequences if participants retained this weight gain throughout the college year. Additionally, because the overweight/obese participants gained the greatest amount of BW, this group may be at increased risk for weight gain and further obesity development during the holiday season.
A rapidly evolving secretome builds and patterns a sea shell
Authors: Jackson Daniel J , McDougall Carmel , Green Kathryn , Simpson Fiona , Wörheide Gert , Degnan Bernard M
Published: November 2006

Background

Instructions to fabricate mineralized structures with distinct nanoscale architectures, such as seashells and coral and vertebrate skeletons, are encoded in the genomes of a wide variety of animals. In mollusks, the mantle is responsible for the extracellular production of the shell, directing the ordered biomineralization of CaCO3 and the deposition of architectural and color patterns. The evolutionary origins of the ability to synthesize calcified structures across various metazoan taxa remain obscure, with only a small number of protein families identified from molluskan shells. The recent sequencing of a wide range of metazoan genomes coupled with the analysis of gene expression in non-model animals has allowed us to investigate the evolution and process of biomineralization in gastropod mollusks.

Results

Here we show that over 25% of the genes expressed in the mantle of the vetigastropod Haliotis asinina encode secreted proteins, indicating that hundreds of proteins are likely to be contributing to shell fabrication and patterning. Almost 85% of the secretome encodes novel proteins; remarkably, only 19% of these have identifiable homologues in the full genome of the patellogastropod Lottia scutum. The spatial expression profiles of mantle genes that belong to the secretome is restricted to discrete mantle zones, with each zone responsible for the fabrication of one of the structural layers of the shell. Patterned expression of a subset of genes along the length of the mantle is indicative of roles in shell ornamentation. For example, Has-sometsuke maps precisely to pigmentation patterns in the shell, providing the first case of a gene product to be involved in molluskan shell pigmentation. We also describe the expression of two novel genes involved in nacre (mother of pearl) deposition.

Conclusion

The unexpected complexity and evolvability of this secretome and the modular design of the molluskan mantle enables diversification of shell strength and design, and as such must contribute to the variety of adaptive architectures and colors found in mollusk shells. The composition of this novel mantle-specific secretome suggests that there are significant molecular differences in the ways in which gastropods synthesize their shells.
Is Crystal Growth under Low Supersaturations Influenced by a Tendency to a Minimum of the Surface‐Free Energy?
Authors: NANEV CHRISTO N.
Published: November 2006

Abstract:  The long‐standing problem of face morphology is discussed. Special emphasis is put on macroscopically flat faces, whose growth, under low supersaturations, is driven by dislocations possessing some screw component. The most general case, where the crystal face is pierced by more than one screw dislocation, is considered.
If performed under sufficiently low supersaturation, the growth leads to the formation of the face morphology corresponding to the minimum of the surface‐free energy. The thermodynamic driving force for face flattening is the difference in the surface‐free energy of the vicinal faces of the hillocks (emanating from screw dislocations) and that of a singular face, which can truncate the valley between the growth hillocks. The hillock slope gives the quantitative relation between energetics and kinetics. The result of the considerations is that the lower the supersaturation, the more important is the role of the surface‐free energy in face flattening. Another factor, particularly under sufficiently low supersaturations, is the effective increase in the local supersaturation at the valley separating two growth hillocks. The reason is that the dislocation strain energy vanishes there. (This is most evident when two dislocations of opposite sign are considered.) Besides, the valley floors are concave regions on the crystal surface, where the building blocks are bound more strongly. Thus, the kinetic reason for face flattening is the relative preference for incorporation of atoms, arriving from the ambient phase, at the valley floor. Note that accelerated step annihilation in the valley floor should be a universal factor, which favors face flattening under any supersaturation. The amount of flattening in the growth situation is determined by the interplay between supersaturation and thermodynamics.