bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local radiotherapy as a complement to incomplete transcatheter arterial chemoembolization in locally advanced hepatocellular carcinoma
Authors: Shim Su Jung , Seong Jinsil , Han Kwang Hyub , Chon Chae Yoon , Suh Chang Ok , Lee Jong Tae 
Published: September 2005

Abstract: Purpose: In order to determine the effect of additional radiotherapy (RT) after an incomplete transcatheter arterial chemoembolization (TACE) in an unresectable hepatocellular carcinoma (HCC), the treatment results of patients receiving TACE plus RT were analyzed and compared with those treated with TACE alone.Materials and methods: One hundred and five patients with an unresectable HCC were treated with TACE from January 1992 to December 2002. In 73 of these patients, the TACE was incomplete. Among them, TACE was repeatedly performed in 35 patients (TACE group), and the remaining 38 patients were also treated with local RT (TACERT group). The patients were either in stage III or IVa, Eastern Cooperative Oncology Group 2 or less, and Child–Pugh class A or B. The average frequency of TACE prior to RT was 2 and the RT was started within 7–10 days after the TACE.Results: The 2‐year survival rate was significantly higher in the TACERT than in the TACE group (36.8 % vs. 14.3%, P=0.001). According to the tumor size, the 2‐year survival rates in the TACERT and TACE groups were 63% vs. 42% in 5–7 cm (P=0.22), 50% vs. 0% in 8–10 cm (P=0.03), and 17% vs. 0% in larger than 10 cm (P=0.0002) respectively.Conclusion: There was a significantly improved survival rate in the TACERT group of unresectable HCC patients than in the TACE group, particularly in case of tumors ≥8 cm in diameter. Therefore, RT in addition to TACE is strongly recommended for patients with an unresectable HCC.
Altered protein expression and protein nitration pattern during d‐galactosamine‐induced cell death in human hepatocytes: a proteomic analysis
Authors: Rodríguez‐Ariza Antonio , López‐Sánchez Laura M. , González Raul , Corrales Fernando J. , López Pedro , Bernardos Angel , Muntané Jordi 
Published: September 2005

Abstract: Background/Aims: Hepatic injury by d‐galactosamine (d‐GalN) is a suitable experimental model of hepatocellular injury. The induction of oxidative and nitrosative stress participates during d‐GalN‐induced cell death in cultured rat hepatocytes. This study aimed to identify protein expression changes during the induction of apoptosis and necrosis by d‐GalN in cultured human hepatocytes.Methods: A proteomic approach was used to identify the proteins involved and those altered by tyrosine nitration. A high dose of d‐GalN (40 mM) was used to induce apoptosis and necrosis in primary culture of human hepatocytes. Cellular lysates prepared at different times after addition of d‐GalN were separated by two‐dimensional electrophoresis. Gel spots with an altered expression and those matching nitrotyrosine‐immunopositive proteins were excised and analyzed by mass spectrometry.Results: d‐GalN treatment upregulated microsomal cytochrome b5, fatty acid binding protein and manganese superoxide dismutase, and enhanced annexin degradation. d‐GalN increased tyrosine nitration of four cytosolic (Hsc70, Hsp70, annexin A4 and carbonyl reductase) and three mitochondrial (glycine amidinotransferase, ATP synthase β chain, and thiosulfate sulfurtransferase) proteins in human hepatocytes.Conclusions: The results provide evidences that oxidative stress and nitric oxide‐derived reactive oxygen intermediates induce specific alterations in protein expression that may be critical for the induction of apoptosis and necrosis by d‐GalN in cultured human hepatocytes.
Developing an administrative plan for transfusion medicine—a global perspective
Authors: Sullivan Patrick 
Published: September 2005

Throughout the world blood services aim to provide a life‐saving service by ensuring an adequate supply of safe blood. However, across the world blood services are at very different levels of development. Consequently, the actions taken in one country or region would not be appropriate in another. This paper aims to identify how suitable solutions can be developed to match the different prevailing circumstances of an individual country or region.In trying to do this it is important to look at the whole of the supply chain within a blood service and identify the part where a change could make the biggest impact.Four key areas are identified that are integral to this. These are the donor, testing of blood, hemovigilance, and overall management arrangements. Whilst the first two have largely been addressed in highly developed countries, there is still much work that could be done in these areas in developing countries. In particular, a move to voluntary nonremunerated donors worldwide would significantly improve overall safety.Hemovigilance systems are identified as a powerful tool to influence policy development, yet these are largely under developed throughout the world.In order to make high impact and sustainable changes it is important that those in the blood industry across the world work together to improve education and training, to share experience of best practice, and to move to develop agreed standards in transfusion medicine.It is imperative that developed countries recognize the importance of working with developing countries if the safety of the global blood supply is to be maintained and improved.
The lifetime of galactic bars: central mass concentrations and gravity torques
Authors: Bournaud F. , Combes F. , Semelin B. 
Published: September 2005

Abstract
Bars in gas-rich spiral galaxies are short-lived. They drive gas inflows through their gravity torques, and at the same time self-regulate their strength. Their robustness has been subject of debate, as it was thought that only the resulting central mass concentrations (CMCs) were weakening bars, and only relatively rare massive CMCs were able to completely destroy them. Through numerical simulations including gas dynamics, we find that with the gas parameters of normal spiral galaxies, the CMC is not sufficient to fully dissolve the bar. But another overlooked mechanism, the transfer of angular momentum from the infalling gas to the stellar bar, can also strongly weaken the bar. In addition, we show that gravity torques are correctly reproduced in simulations, and conclude that bars are transient features, with lifetime of 1–2 Gyr in typical Sb-Sc galaxies, because of the combined effects of CMCs and gravity torques, while most existing works had focussed on the CMC effects alone.
Acid-Induced Activation of the Urease Promoters Is Mediated Directly by the ArsRS Two-Component System of
Helicobacter pylori
Authors: Pflock Michael , Kennard Simone , Delany Isabel , Scarlato Vincenzo , Beier Dagmar 
Published: September 2005

ABSTRACT

The nickel-containing enzyme urease is an essential colonization factor of the human gastric pathogen
Helicobacter pylori
which enables the bacteria to survive the low-pH conditions of the stomach. Transcription of the urease genes is positively controlled in response to increasing concentrations of nickel ions and acidic pH. Here we demonstrate that acid-induced transcription of the urease genes is mediated directly by the ArsRS two-component system. Footprint analyses identify binding sites of the phosphorylated ArsR response regulator within the
ureA
and
ureI
promoters. Furthermore, deletion of a distal upstream ArsR binding site of the
ureA
promoter demonstrates its role in acid-dependent activation of the promoter. In addition, acid-induced transcription of the
ureA
gene is unaltered in a
nikR
mutant, providing evidence that pH-responsive regulation and nickel-responsive regulation of the
ureA
promoter are mediated by independent mechanisms involving the ArsR response regulator and the NikR protein.
Working Mechanism of Immunoglobulin A1 (IgA1) Protease: Cleavage of IgA1 Antibody toNeisseria meningitidisPorA Requires De Novo Synthesis of IgA1 Protease
Authors: Vidarsson Gestur , Overbeeke Natasja , Stemerding Annette M. , van den Dobbelsteen Germie , van Ulsen Peter , van der Ley Peter , Kilian Mogens , van de Winkel Jan G. J. 
Published: September 2005

ABSTRACTNeisseria meningitidissecretes a protease that specifically cleaves the hinge region of immunoglobulin A1 (IgA1), releasing the effector (Fc) domain of IgA1 from the antigen binding (Fab) determinants. Theoretically, the remaining Fab fragments can block pathogen receptors or toxins and still provide protection. Here, we describe binding of V-gene-matched human IgA1 and IgA2 to PorA of strain H44/76. On live meningococci, efficient cleavage of IgA1, but not cleavage of IgA2, was observed, and up to ∼80% of the IgA1 Fc tails were lost from the meningococcal surface within 30 min. No cleavage of IgA1 was found on an isogenic H44/76 strain lacking IgA1 protease. Furthermore, our data indicate that PorA-bound IgA1 is masked by the serogroup B polysaccharide capsule, rendering the IgA1 less accessible to degradation by secreted IgA1 protease present in the bacterial surroundings. Experiments with protein synthesis inhibitors showed that de novo production of IgA1 protease was responsible for cleavage of PorA-bound IgA1 on encapsulated bacteria. Finally, our data suggest that cleavage of IgA1 by IgA1 protease releases a significant proportion of Fab fragments from the bacterium, probably as a result of their reduced avidity compared to that of whole antibodies.
Bacillus anthracisEdema Toxin InhibitsStaphylococcus aureusEnterotoxin B Effects In Vitro: a Potential Protein Therapeutic?
Authors: Krakauer Teresa , Little Stephen F. , Stiles Bradley G. 
Published: September 2005

ABSTRACTVarious in vitro effects of staphylococcal enterotoxin B (SEB) on human peripheral blood mononuclear cells were mitigated byBacillus anthracisedema toxin. In particular, levels of some SEB-induced cytokines (tumor necrosis factor alpha, gamma interferon) and chemokines (monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β) were significantly diminished or even nonexistent, depending upon the timing of edema toxin administration. Overall, these results suggest a novel use ofB. anthracisedema toxin against a bacterial superantigen.
The Cyclin-dependent Kinase Inhibitor CYC202 (R-Roscovitine) Inhibits Retinoblastoma Protein Phosphorylation, Causes Loss of Cyclin D1, and Activates the Mitogen-activated Protein Kinase Pathway
Authors: Whittaker Steven R. , Walton Mike I. , Garrett Michelle D. , Workman Paul 
Published: September 2005

AbstractDeregulation of the cell cycle commonly occurs during tumorigenesis, resulting in unrestricted cell proliferation and independence from mitogens. Cyclin-dependent kinase inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells. CYC202 (R-roscovitine) is a potent inhibitor of CDK2/cyclin E that is undergoing clinical trials. Drugs selected to act on a particular molecular target may exert additional or alternative effects in intact cells. We therefore studied the molecular pharmacology of CYC202 in human colon cancer cells. Treatment of HT29 and KM12 colon carcinoma cell lines with CYC202 decreased both retinoblastoma protein phosphorylation and total retinoblastoma protein. In addition, an increase in the phosphorylation of extracellular signal-regulated kinases 1/2 was observed. As a result, downstream activation of the mitogen-activated protein kinase pathway occurred, as demonstrated by an increase in ELK-1 phosphorylation and in c-FOS expression. Use of mitogen-activated protein kinase kinases 1/2 inhibitors showed that the CYC202-induced extracellular signal-regulated kinases 1/2 phosphorylation was mitogen-activated protein kinase kinases 1/2 dependent but did not contribute to the cell cycle effects of the drug, which included a reduction of cells in G1, inhibition of bromodeoxyuridine incorporation during S-phase, and a moderate increase in G2-M phase. Despite activation of the mitogen-activated protein kinase pathway, cyclin D1 protein levels were decreased by CYC202, an effect that occurred simultaneously with loss of retinoblastoma protein phosphorylation and inhibition of cell cycle progression. The reduced expression of cyclin D1 protein was independent of the p38SAPK and phosphatidylinositol 3-kinase pathways, which are known regulators of cyclin D1 protein. Interestingly, CYC202 caused a clear reduction in cyclins D1, A, and B1 mRNA, whereas c-FOS mRNA increased by 2-fold. This was accompanied by a loss of RNA polymerase II phosphorylation and total RNA polymerase II protein, suggesting that CYC202 was inhibiting transcription, possibly via inhibition of CDK7 and CDK9 complexes. It can be concluded that although CYC202 can act as a CDK2 inhibitor, it also has the potential to inhibit CDK4 and CDK1 activities in cancer cells through the down-regulation of the corresponding cyclin partners. This provides a possible mechanism by which CYC202 can cause a reduction in retinoblastoma protein phosphorylation at multiple sites and cell cycle arrest in G1, S, and G2-M phases. In addition to providing useful insights into the molecular pharmacology of CYC202 in human cancer cells, the results also suggest potential pharmacodynamic end points for use in clinical trials with the drug.
The Adrenal Androgen Androstenediol Is Present in Prostate Cancer Tissue after Androgen Deprivation Therapy and Activates Mutated Androgen Receptor
Authors: Mizokami Atsushi , Koh Eitetsu , Fujita Hiroshi , Maeda Yuji , Egawa Masayuki , Koshida Kiyoshi , Honma Seijiro , Keller Evan T. , Namiki Mikio 
Published: September 2005

Abstract
Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR’s association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.
neu Antigen-Negative Variants Can Be Generated after neu-Specific Antibody Therapy in neu Transgenic Mice
Authors: Knutson Keith L. , Almand Bond , Dang Yushe , Disis Mary L. 
Published: September 2005

Abstract
Prolonged administration of HER-2/neu-specific monoclonal antibody therapy is now widely used for the treatment of HER-2/neu-overexpressing tumors in advanced-stage breast cancer patients. Monoclonal antibody therapy has the potential to promote reduced tumor expression of HER-2/neu by receptor down-modulation and/or the generation of antigen-negative variants. Loss of antigen by either mechanism could potentially impact subsequent therapeutic strategies targeting HER-2/neu. In this study, the effects of chronic neu-specific monoclonal antibody therapy on tumor growth and neu protein expression were examined in a murine model of neu-overexpressing breast cancer. Treatment of neu-overexpressing tumors with neu-specific antibody, in vitro or in vivo, resulted in significant tumor growth inhibition. When neu antibody was used to treat neu-overexpressing tumor cells both in vitro and in vivo in tumor-bearing mice, neu receptor expression was not diminished after cessation of therapy. However, in the setting of clinically undetectable disease in a fraction of animals, antigen-negative variants were generated. An understanding of the effects of monoclonal antibodies on target antigen expression is critical for the future design and testing of novel HER-2/neu-targeted therapies administered in combination with or after HER-2/neu-specific monoclonal antibody therapy.
Differential Gene Expression in Metastasizing Cells Shed from Kidney Tumors
Authors: Bockhorn Maximilian , Roberge Sylvie , Sousa Cristina , Jain Rakesh K. , Munn Lance L. 
Published: September 2005

Abstract
We developed a novel orthotopic mouse tumor model of renal cell carcinoma to collect and characterize cells spontaneously shed from SN12C (renal cell carcinoma) and SN12L1 (high metastatic variant of SN12C) tumors grown in kidneys of severe combined immunodeficient mice. Viability of the shed cell population was greater for SN12L1 tumors (25%) compared with SN12C tumors (11%, P &lt; 0.05). Gene array analysis of 23 genes involved in metastasis showed that CD44, α3 integrin, and caveolin were down-regulated in the shed tumor cells compared with their primary counterparts, and blocking α3 integrin or CD44 function inhibited attachment and migration of both cell lines. These results suggest that cohesion of the cells within the primary tumor mediated by CD44 and α3 integrins hinders metastasis and that shedding is a passive process not necessarily mediated by cell migration in these tumors. Furthermore, resistance to apoptosis may enhance metastasis in the higher metastatic tumor.
Prolonged Culture of Vaccine-Primed Lymphocytes Results in Decreased Antitumor Killing and Change in Cytokine Secretion
Authors: Sussman Jeffrey J. , Parihar Robin , Winstead Karen , Finkelman Fred D. 
Published: September 2005

AbstractAdoptive transfer of effector T cells has been used successfully to eliminate metastases in animal models. Because antitumor activity depends on the number of effector cells transferred, some human trials have used in vitro-repetitive activation and expansion techniques to increase cell number. We hypothesized that the prolonged culture period might contribute to the lack of human trial success by decreasing the potency of the effector T cells. Lymph nodes draining a progressively growing murine melanoma tumor transduced to secrete granulocyte/macrophage colony-stimulating factor were harvested and activated in vitro with anti-CD3 monoclonal antibody followed by expansion in IL-2 for a total of 5 days in culture. Some lymphocytes were reactivated and further expanded for a total of 9 days in culture. In vivo activity of the effector T cells was measured by the reduction in lung metastases and is shown to be dose dependent. The prolonged culture period resulted in nearly 3-fold more T cells but at least 8-fold less antitumor activity. This was accompanied by decreased secretion of the proinflammatory cytokine, IFN-γ, and increased secretion of the anti-inflammatory cytokine, IL-10. Thus, although increased cell number is important to maximize the effectiveness of adoptive immunotherapy, some culture conditions may actually be counterproductive in that decreases in cell potency can outweigh the benefits of increased cell numbers. The T-cell cytokine secretion pattern predicts decreased effector cell function and may explain the decreased antitumor effect.
In Vitroandin VivoCytotoxic Activities of Recombinant Immunotoxin 8H9(Fv)-PE38 against Breast Cancer, Osteosarcoma, and Neuroblastoma
Authors: Onda Masanori , Wang Qing-cheng , Guo Hong-fen , Cheung Nai-Kong V. , Pastan Ira 
Published: September 2005

AbstractThe 8H9 monoclonal antibody (MAb) is highly reactive with a cell surface glycoprotein expressed on human breast cancers, childhood sarcomas, and neuroblastomas but is not reactive with the cell surface of normal human tissues. This specific reactivity suggests that MAb 8H9 may be useful for targeted cancer therapy. To explore this possibility, we generated two recombinant immunotoxins (ITs) using the single-chain Fv (scFv) of MAb 8H9. Initially the 8H9(scFv) cDNA was fused to a DNA encoding a 38-kDa truncated form of Pseudomonas exotoxin (PE38) to generate the IT 8H9(scFv)-PE38. The fusion gene was expressed in Escherichia coli, and the IT was purified to near homogeneity from inclusion bodies. The purified IT showed specific cytotoxicity on nine different cancer cell lines derived from breast cancer, osteosarcoma, and neuroblastomas, known to react with MAb 8H9. The cytotoxic activity was inhibited by MAb 8H9, showing the cytotoxic activity is specific. The antitumor activity of 8H9(scFv)-PE38 was evaluated in severe combined immunodeficient mice bearing MCF-7 breast cancers or OHS-M1 osteosarcomas. The IT showed a specific dose-dependent antitumor activity at 0.075 and 0.15 mg/kg. Next, a more stable disulfide-linked IT, 8H9(dsFv)-PE38, was constructed. It was produced in high yield (16%) and showed cytotoxic and antitumor activities similar to those of 8H9(scFv)-PE38. 8H9(dsFv)-PE38 was given to two cynomolgus monkeys at doses of 0.1 and 0.2 mg/kg i.v. QOD × 3 and was well tolerated. This shows that a dose that causes significant tumor regressions in mice is well tolerated by monkeys. These results make 8H9(dsFv)-PE38 a candidate for further development as a therapeutic agent for breast cancers, osteosarcomas, and neuroblastomas.