bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transendothelial Migration of Myeloma Cells Is Increased by Tumor Necrosis Factor (TNF)-α
via
TNF Receptor 2 and Autocrine Up-Regulation of MCP-1
Authors: Jöhrer Karin , Janke Katrin , Krugmann Jens , Fiegl Michael , Greil Richard 
Published: September 2005

Abstract
The proinflammatory cytokine tumor necrosis factor (TNF)-α has been shown to facilitate leukocyte transendothelial migration. In multiple myeloma, TNF-α is an important factor in the promotion of growth and survival of the malignant cells. Studies have shown that enhanced TNF-α levels in myeloma patients correlated with aggressive disease. Therefore, we investigated the effect of recombinant human TNF-α on the migrational behavior of myeloma cells across the physiological barrier of the major disease compartment, i.e., human bone marrow endothelial cells. In the presence of TNF-α, we observed significantly increased migration both in established myeloma cell lines and in plasma cells from myeloma patients. Expression of TNF-receptor 2 (TNF-R2) but not TNF-receptor 1 (TNF-R1) was detected in myeloma cell lines. Myeloma cells of patients also showed expression of TNF-R2 but not TNF-R1. The effect of TNF-α could not be explained by altered expression of adhesion molecules or metalloproteases. Instead, we found an up-regulation of monocyte chemoattractant protein (MCP)-1 and confirmed that myeloma cells express the relevant receptor C-C chemokine receptor 2. Preincubation of myeloma cells with recombinant human MCP-1 also enhanced cell migration, and this effect, as well as the effect of TNF-α, was abolished by treatment with anti-MCP-1 antibody. In contrast, migration of myeloma cells in the direction of an MCP-1 gradient, i.e., chemotaxis, could not be observed in the cell lines investigated. Additionally, the mRNA level of TNF-α was up-regulated by the cytokine treatment, which points to an autocrine loop augmenting and/or stabilizing the TNF-α–MCP-1 pathway. In summary, our data clearly support additional investigations using anti-MCP-1 antibodies in myeloma progression.
Infection with Oncolytic Herpes Simplex Virus-1 Induces Apoptosis in Neighboring Human Cancer Cells
Authors: Stanziale Stephen F. , Petrowsky Henrik , Adusumilli Prasad S. , Ben-Porat Leah , Gonen Mithat , Fong Yuman 
Published: September 2005

AbstractPurpose: The antitumor efficacy of a herpes simplex virus (HSV)-1 oncolytic virus depends on the cytotoxic effect of the virus, but also on viral replication and spread within the tumor. Apoptosis is considered a defense mechanism of infected cells that minimizes the spread of viral progeny by limiting cellular production of virus. We sought to determine whether oncolytic HSV-1 infection induces apoptosis in neighboring, uninfected cells and whether manipulation of apoptosis can increase viral replication and cytotoxicity.Experimental Design: NV1066 is an oncolytic HSV-1 mutant that contains the marker gene for enhanced green fluorescent protein. OCUM human gastric cancer cells were infected with NV1066 in vitro and inspected for apoptosis by Hoechst and terminal deoxynucleotidyltransferase-mediated nick end labeling staining and for infection by expression of green fluorescence.Results: A significant increase in apoptosis was seen in cells infected by NV1066. More interestingly, a significant percentage (10%) of uninfected cells also proceeded to apoptosis. After NV1066 infection, cells were also treated with N-acetylcysteine (NAC), an inhibitor of apoptosis. By day 4 after infection, 2.7× more NV1066 was produced in cells exposed to NAC than in those not exposed to NV1066 (P = 0.04). NAC also increased tumor kill when administered with virus.Conclusions: These data suggest that NV1066 induces apoptosis in uninfected cocultured cells, potentially hindering propagation of viral progeny and concomitant tumor kill. Inhibition of apoptosis may improve the efficacy of oncolytic HSV-1 therapy.
A Pooled Analysis of Eastern Cooperative Oncology Group and Intergroup Trials of Adjuvant High-Dose Interferon for Melanoma
Authors: Kirkwood John M. , Manola Judith , Ibrahim Joseph , Sondak Vernon , Ernstoff Marc S. , Rao Uma 
Published: September 2005

Abstract
Purpose: Nearly 2000 patients with stage IIB and III melanoma have participated in four multicenter, randomized trials, conducted by the Eastern Cooperative Oncology Group and the Intergroup, investigating adjuvant high-dose IFN-α 2b therapy. The objectives of this study were to update the analyses of each individual trial and to analyze prognostic factors and treatment effects based on pooled data.
Experimental Design: Survival and disease status were updated to April 2001. Analysis of prognostic factors using optimized statistical models was based on data from patients in E1684, E1690, E1694, and E2696. Analysis of treatment effects versus observation (Obs) was based on data from 713 patients randomized to high-dose IFN-α 2b (HDI) or Obs in Trials E1684 and E1690.
Results: Updated analysis of E1684, E1690, and E1694 confirmed their original conclusions, now at median follow-up intervals of 2.1–12.6 years. Based on two-sided univariate log-rank analysis of pooled data from E1684 and E1690 (median follow-up, 7.2 years), relapse-free survival (RFS)—but not overall survival (OS)—was significantly prolonged (two-sided log-rank P value = 0.006) for patients treated with HDI versus Obs. Among all patients, prognostic factors that significantly negatively impacted RFS and OS included ulceration, recurrent disease at entry, enrollment in E1684, and age &gt; 49 years. Multivariate statistical models adjusting for these factors confirmed the statistically significant RFS benefit of HDI versus Obs but did not demonstrate a significant OS benefit in the pooled populations.
Conclusions: In patients with high-risk resected melanoma, HDI is effective adjuvant therapy with strong evidence for improved RFS and evidence for moderate improvement in OS based on two prospective randomized studies but not the pooled analysis. Analyses of predictors of relapse and response are now needed to improve the therapeutic value of this modality.
Schedule-Dependent Cytotoxic Interaction between Epidoxorubicin and Gemcitabine in Human Bladder Cancer Cells
in Vitro
Authors: Zoli Wainer , Ricotti Luca , Tesei Anna , Ulivi Paola , Campani Anna Gasperi , Fabbri Francesco , Gunelli Roberta , Frassineti Giovanni Luca , Amadori Dino 
Published: September 2005

Abstract
Purpose: The aim of the study was to evaluate the activity of epidoxorubicin (EPI) and gemcitabine (GEM) and to define the most effective schedule in human bladder cancer cells.
Experimental Design: The study was performed on HT1376 and MCR cell lines. Cells were exposed for 1 and 24 h to drugs used in different schemes. Cytotoxic activity was evaluated by the sulforhodamine B assay, potential clinical activity was estimated by relative antitumor activity, and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were assessed by flow cytometry; BAX, BCL-2, and P53 expression was evaluated by Western blot; and DNA damage was assessed using the alkaline Comet assay.
Results: EPI and GEM produced a cytotoxic effect in both cell lines, with 50% inhibitory concentration and relative antitumor activity values suggestive of a high clinical activity. Simultaneous treatment with EPI and GEM and the sequence GEM→EPI caused an antagonistic interaction (combination index &gt; 1) after both 1- and 24-h treatments. Conversely, the inverse sequence, EPI→GEM, produced a synergistic interaction that was more pronounced in MCR cells than in HT1376 cells. The increase in DNA-damaged cells from 10% to 20% after single-drug exposure to 40–60% at the end of EPI→GEM treatment may explain the synergistic interaction produced by the anthracycline-antimetabolite sequence.
Conclusions: Our findings show that the efficacy of the EPI and GEM combination is highly schedule dependent and indicate that the most active scheme is EPI followed by GEM, which is currently being validated in an ongoing intravesical Phase I-II clinical protocol.
In Vitro
and
in Vivo
Characterization of Doxorubicin and Vincristine Coencapsulated within Liposomes through Use of Transition Metal Ion Complexation and pH Gradient Loading
Authors: Abraham Sheela A. , McKenzie Cheryl , Masin Dana , Ng Rebecca , Harasym Troy O. , Mayer Lawrence D. , Bally Marcel B. 
Published: September 2005

Abstract
Purpose: There is an opportunity to augment the therapeutic potential of drug combinations through use of drug delivery technology. This report summarizes data obtained using a novel liposomal formulation with coencapsulated doxorubicin and vincristine. The rationale for selecting these drugs is due in part to the fact that liposomal formulations of doxorubicin and vincristine are being separately evaluated as components of drug combinations.
Experimental Design: Doxorubicin and vincristine were coencapsulated into liposomes using two distinct methods of drug loading. A manganese-based drug loading procedure, which relies on drug complexation with a transition metal, was used to encapsulate doxorubicin. Subsequently the ionophore A23187 was added to induce formation of a pH gradient, which promoted vincristine encapsulation.
Results: Plasma elimination studies in mice indicated that the drug:drug ratio before injection [4:1 doxorubicin:vincristine (wt:wt ratio)] changed to 20:1 at the 24-h time point, indicative of more rapid release of vincristine from the liposomes than doxorubicin. Efficacy studies completed in MDA MB-435/LCC6 tumor-bearing mice suggested that at the maximum tolerated dose, the coencapsulated formulation was therapeutically no better than liposomal vincristine. This result was explained in part by in vitro cytotoxicity studies evaluating doxorubicin and vincristine combinations analyzed using the Chou and Talalay median effect principle. These data clearly indicated that simultaneous addition of vincristine and doxorubicin resulted in pronounced antagonism.
Conclusion: These results emphasize that in vitro drug combination screens can be used to predict whether a coformulated drug combination will act in an antagonistic or synergistic manner.
T-Cell Activation Marker Expression on Tumor-Infiltrating Lymphocytes As Prognostic Factor in Cutaneous Malignant Melanoma
Authors: Ladányi Andrea , Somlai Beáta , Gilde Katalin , Fejös Zsuzsanna , Gaudi István , Tímár József 
Published: September 2005

AbstractThe central role of T cells in antitumor immunity is well established. However, tumor progression, often seen in the presence of substantial lymphocytic infiltration, suggests that these T cells are not capable of mounting an effective immune response to control tumor growth. Evidence has accumulated that T lymphocytes infiltrating human neoplasms are functionally defective, incompletely activated, or anergic. Therefore, when characterizing the immune competent cells within lymphoid infiltrates of tumors, it is important to assess their activation state. We investigated the expression of two T-cell activation markers, interleukin 2 receptor α (CD25) and OX40 (CD134), by immunohistochemistry in primary cutaneous melanoma samples of 76 patients and analyzed it in relation to tumor stage and tumor progression (&gt;5 years follow-up), as well as to patients’ survival. We found that the degree of infiltration by CD25+ and intratumoral OX40+ lymphocytes showed a tendency to decrease in thicker melanomas. The frequency of samples with high numbers of peritumoral CD25+ and OX40+ cells was significantly lower (P = 0.0009 and P = 0.0087, respectively) in melanomas developing distant visceral metastases, compared with nonmetastatic or lymph node metastatic tumors. For both activation markers studied, high peritumoral densities were associated with longer survival by univariate analysis (P = 0.0028 and P = 0.0255 for CD25 and OX40, respectively), whereas peritumoral OX40+ lymphocyte infiltration had an impact on survival also in multivariate analysis (P = 0.035). The results suggest that the presence of lymphocytes expressing the T-cell activation markers CD25 or OX40 shows correlation with tumor progression as well as with patients’ survival in cutaneous malignant melanoma.
Quantification of Plasma β-Catenin mRNA in Colorectal Cancer and Adenoma Patients
Authors: Wong Sze Chuen Cesar , Lo Siu Fong Elena , Cheung Moon Tong , Ng Kai On Enders , Tse Chun Wah , Lai Bo San Paul , Lee King Chung , Lo Y. M. Dennis 
Published: September 2005

Abstract
Purpose: Colorectal cancer is an important cause of cancer deaths. Here, we focused our investigation on the β-catenin gene which is implicated in colorectal carcinogenesis and tested whether β-catenin mRNA is detectable in the plasma of colorectal carcinoma and adenoma patients using quantitative reverse transcriptase-PCR.
Experimental Design: Plasma β-catenin mRNA was measured from 58 colorectal carcinoma patients, 49 colorectal adenoma patients, and 43 apparently normal subjects using intron-spanning primers and Taqman probes. Five clinicopathological parameters were studied and correlated with plasma β-catenin mRNA concentration. Additionally, 19 colorectal carcinoma patients after tumor removal were also recruited for plasma β-catenin mRNA measurement to further demonstrate the clinical usefulness of this test.
Results: β-catenin mRNA was detected with median concentrations of 8737 (range: 1480–933,100), 1218 (range: 541–2,254) and 291 (range: 0–1,366) copies/ml plasma in colorectal carcinoma, colorectal adenoma, and apparently normal subjects, respectively. Statistical analysis demonstrated that plasma β-catenin mRNA concentration was correlated to tumor stage but not sex, age, lymph node status, and degree in differentiation. Moreover, plasma β-catenin mRNA concentration decreased significantly after tumor removal in 16 of 19 (84%) colorectal carcinoma patients.
Conclusions: We conclude that plasma β-catenin mRNA may potentially serve as a marker for colorectal cancer.
Overexpressed Decorin in Pancreatic Cancer
Authors: Köninger Jörg , Giese Nathalia A. , di Mola Fabio Francesco , Berberat Pascal , Giese Thomas , Esposito Irene , Bachem Max G. , Büchler Markus W. , Friess Helmut 
Published: September 2005

Abstract
Purpose: The aim of this study was to investigate the expression and significance of decorin in pancreatic cancer.
Experimental Design: Decorin expression in normal pancreas and excised tumors was examined by real-time quantitative PCR, Western blot analysis, and immunohistochemistry. Reverse transcription-PCR was used to analyze cultures of pancreatic cancer and stellate cells. Growth-inhibitory effects of decorin in vitro were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, Western blot, and fluorescence-activated cell-sorting analysis.
Results: Pancreatic cancer was characterized by striking overexpression of decorin mRNA in tumor tissues (9-fold by real-time quantitative PCR; 44 patients versus 18 healthy donors; P &lt; 0.01). Strong decorin immunostaining was observed in the extracellular matrix of pancreatic cancer tissue, whereas tumor cells were devoid of decorin. Double staining for anti-smooth muscle actin and decorin and reverse transcription-PCR analysis of primary cultures revealed pancreatic stellate cells as the putative source of decorin. Human recombinant decorin was able to suppress growth of pancreatic cancer cells in vitro through p21mediated G1-S block of the cell cycle. However, in contrast to the previously described chemotherapy-potentiating capacity of decorin, this proteoglycan attenuated the cytostatic action of carboplatin and gemcitabine toward pancreatic cancer cells.
Conclusions: Decorin might exert an antiproliferative effect toward pancreatic cancer cells, thus playing a role in a host stromal reaction aimed at sequestering and inhibiting growing malignant cells. However, in clinical settings, the importance of collagen-associated decorin as a moderate antitumor modality would be undermined by its ability to attenuate the efficiency of chemotherapeutics. Considering the general failure of adjuvant therapies in pancreatic cancer, the role of decorin in this process warrants further investigation.
The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer
Authors: Kaelin William G. 
Published: September 2005

Abstract
The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in &gt;50% of sporadic clear cell renal cell carcinomas. Germ-line VHL mutations give rise to VHL disease, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas) and renal cell carcinomas. In this setting, VHL inactivation gives rise to premalignant renal cysts. Additional genetic alterations are presumably required for conversion of these cysts to renal cell carcinomas. Restoration of VHL function in VHL−/− renal cell carcinomas is sufficient to inhibit tumorigenesis in vivo. On the basis of these and other data, VHL appears to be a critical gatekeeper with respect to the development of renal cell carcinoma. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL, accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor α. We have demonstrated that inhibition of HIF is necessary and sufficient for tumor suppression by pVHL in renal cell carcinoma nude mouse xenograft assays. This provides a rationale for treating VHL−/− renal cell carcinoma with inhibitors of HIF or its downstream targets. Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth.
Moving Cellular Structure of Fog Echoes Obtained with a Millimeter-Wave Scanning Doppler Radar at Kushiro, Japan
Authors: Uematsu Akihisa , Hashiguchi Hiroyuki , Teshiba Michihiro , Tanaka Hisamichi , Hirashima Koichi , Fukao Shoichiro 
Published: September 2005

Abstract
Observations of fogs with a millimeter-wave scanning Doppler radar were conducted at Kushiro in Hokkaido, Japan, in the summer seasons of 1999 and 2000. Three typical types of plan position indicator (PPI) displays were observed: cellular echoes with high radar reflectivity factors (∼−10 dBZ), uniformly distributed echoes with high reflectivities (∼−10 dBZ), and uniformly distributed echoes with low reflectivities (∼−30 dBZ). The authors focused on advection fog with cellular echoes observed on 5 August 1999 and 31 July 2000. Echoes showed structures of cells with a reflectivity of −10 dBZ and with intervals of about 1 km. This echo pattern moved northward (i.e., from the sea to the land). There was a vertical shear of the horizontal wind at a height around 200 m in both cases, and structures of each cell were upright above the shear line and were leaning below it. The direction and the speed of the echo pattern in both PPI and range–height indicator (RHI) displays agreed well with that of the horizontal wind at heights above the shear (200 m). In the echo cells, existence of drizzle drops is implied.
On the Fire Nature of a Subtropical Maritime Island in East Asia: Taiwan
Authors: Yen Ming-Cheng , Chen Tsing-Chang 
Published: September 2005

Abstract
Active wild fires over continental landmasses occur in the warm, dry summer. In contrast, in a study by Yen and Chen it was observed that the fire occurrence in Taiwan exhibits an annual variation with a peak in the cool, dry winter. Analysis of the fire-disaster reports released recently by the National Fire Administration of Taiwan shows that fire-related house damage, property loss, and human casualties, overall, exhibit annual variations in concert with the annual variation in the fire-occurrence frequency. The fire-disaster statistics support Yen and Chen’s observation of the annual variation of the fire-occurrence frequency on a subtropical maritime island.
Family Burden During Exacerbation of Schizophrenia: Quantification and Determinants of Additional Costs
Authors: Lauber Christoph , Keller Christian , Eichenberger Adrian , Rössler Wulf 
Published: September 2005

Background/aims: Family members of people with schizophrenia are heavily burdened. Thus, we aimed at quantifying the amount of additional efforts during the two weeks before hospitalisation of acute exacerbating psychosis compared to the time before. Methods: By means of the semi-structured ‘Interview for Measuring the Burden on the Family' we interviewed relatives of people with schizophrenia. To quantify additional burden we asked how much time a person who would take over the additional burden has to afford. Subscales of different sources of burden and total scales were correlated. Results: An additional 8.9 hours per day would have to be spent in favour of the patient, which results in additional costs of C= 3,115– C= 4,984 (ca. £2,100–3,400) for two weeks. The main sources of additional burden are quantity, quality and nature of contacts to the affected. This includes the frequency of contact to the affected, the whereabouts and symptoms of the affected, as well as the social contacts of the relatives. Conclusions: Our results clarify the quantitative aspect of care provided by relatives of people with schizophrenia. Apart from the practical and emotional help to relatives the development of a diversified network of community psychiatry services, e.g. day and night hospitals, as well as crisis accommodations should be established.
Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment
Authors: Wang Lei , Yang Linda , Filippi Marie-Dominique , Williams David A. , Zheng Yi 
Published: September 2005

AbstractRho family GTPases are key signal transducers in cell regulation. Although a body of literature has implicated the Rho family members Rac1 and Rac2 in multiple hematopoietic-cell functions, the role of Cdc42 in hematopoiesis remains unclear. Here we have examined the hematopoietic properties and the hematopoietic stem/progenitor cell (HSP) functions of gene-targeted mice carrying null alleles of cdc42gap, a negative regulator of Cdc42. The Cdc42GAP-/- fetal liver and bone marrow cells showed a 3-fold increase in Cdc42 activity but normal Rac and RhoA activities, indicating that Cdc42GAP knockout resulted in a gain of Cdc42 activity in the hematopoietic tissues. Cdc42GAP-/- mice were anemic. The cellularity of fetal liver and bone marrow, the number and composition percentage of HSPs, and the erythroid blast-forming unit and colony-forming unit (BFU-E/CFU-E) activities were significantly reduced in the homozygous mice. The decrease in HSP number was associated with increased apoptosis of the Cdc42GAP-/- HSPs and the activation of JNK-mediated apoptotic machinery. Moreover, homozygous HSPs showed impaired cortical F-actin assembly, deficiency in adhesion and migration, and defective engraftment. These results provide evidence that Cdc42 activity is important for erythropoiesis and for multiple HSP functions, including survival, adhesion, and engraftment.