bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixed Lineage Leukemia–Rearranged Childhood Pro-B and CD10-Negative Pre-B Acute Lymphoblastic Leukemia Constitute a Distinct Clinical Entity
Authors: Attarbaschi Andishe , Mann Georg , König Margit , Steiner Manuel , Strehl Sabine , Schreiberhuber Anita , Schneider Björn , Meyer Claus , Marschalek Rolf , Borkhardt Arndt , Pickl Winfried F. , Lion Thomas , Gadner Helmut , Haas Oskar A. , Dworzak Michael N. ,   on behalf of the Austrian Berlin-Frankfurt-Münster Cooperative Study Group
Published: May 2006

Abstract
Purpose:Mixed lineage leukemia (MLL) abnormalities occur in ∼50% of childhood pro-B acute lymphoblastic leukemia (ALL). However, the incidence and type of MLL rearrangements have not been determined in common ALL (cALL) and CD10+ or CD10− pre-B ALL.
Experimental Design: To address this question, we analyzed 29 patients with pro-B ALL, 11 patients with CD10− pre-B ALL, 23 pre-B, and 26 cALL patients with CD10 on 20% to 80%, as well as 136 pre-B and 143 cALL patients with CD10 ≥80% of blasts. They were all enrolled in four Austrian ALL multicenter trials. Conventional cytogenetics were done to detect 11q23 abnormalities and in parallel the potential involvement of the MLL gene was evaluated with a split apart fluorescence in situ hybridization probe set.
Results: We found that 15 of 29 pro-B ALL, 7 of 11 CD10− pre-B ALL, and 1 of 2 French-American-British classification L1 mature B-cell leukemia cases had a MLL rearrangement. However, no 11q23/MLL translocation was identified among the CD10+ pre-B and cALL patients. MLL-rearranged pro-B and CD10− pre-B ALL cases had similar clinical and immunophenotypic (coexpression of CDw65 and CD15) features at initial diagnosis.
Conclusions: The striking similarities between the two CD10− ALL subsets imply that CD10− pre-B ALL variants may represent pro-B ALL cases that maintained the propensity to rearrange and express their immunoglobulin heavy chain rather than actual pre-B ALL forms transformed at this later stage of B-cell differentiation. However, direct experimental data are needed to confirm this observation.
Effective Treatment of Pancreatic Cancer Xenografts with a Conditionally Replicating Virus Derived from Type 2 Herpes Simplex Virus
Authors: Fu Xinping , Tao Lihua , Li Min , Fisher William E. , Zhang Xiaoliu 
Published: May 2006

Abstract
Purpose: Pancreatic cancer is a devastating disease that is almost universally fatal because of the lack of effective treatments. We recently constructed a novel oncolytic virus (FusOn-H2) from the type 2 herpes simplex virus. Because the replication potential of FusOn-H2 depends on the activation of the Ras signaling pathway, we evaluated its antitumor effect against pancreatic cancer, which often harbors K-ras gene mutations.
Experimental Design: Human pancreatic cancer xenografts were established in nude mice either s.c. or orthotopically (n = 8/group). FusOn-H2 was injected either directly (s.c. tumors) or by the i.v. or i.p. route (orthotopic tumors). Tumor volume, weight, and survival time were recorded for each animal. Statistical analyses were done by Student's t test.
Results: A single intratumor injection of FusOn-H2 completely eradicated s.c. pancreatic cancers in all animals. Systemic injection of the oncolytic virus produced clear antitumor effects but did not abolish tumors in any animal. The most striking antitumor effect was seen when the virus was given i.p. Delivery of FusOn-H2 by this route completely eradicated established orthotopic tumors in 75% of the animals and completely prevented local metastases.
Conclusions: FusOn-H2 has potent activity against human pancreatic cancer xenografts and may be a promising candidate for investigative virotherapy of this malignancy.
Epidermal Growth Factor Receptor Messenger RNA Expression, Gene Dosage, and Gefitinib Sensitivity in Non–Small Cell Lung Cancer
Authors: Dziadziuszko Rafal , Witta Samir E. , Cappuzzo Federico , Park Seongjin , Tanaka Koji , Danenberg Peter V. , Barón Anna E. , Crino Lucio , Franklin Wilbur A. , Bunn Paul A. , Varella-Garcia Marileila , Danenberg Kathleen D. , Hirsch Fred R. 
Published: May 2006

Abstract
Purpose: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non–small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression].
Experimental Design: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens.
Results: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (&gt;5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P &lt; 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35).
Conclusion: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.
United States Food and Drug Administration Approval Summary: Bortezomib for the Treatment of Progressive Multiple Myeloma after One Prior Therapy
Authors: Kane Robert C. , Farrell Ann T. , Sridhara Rajeshwari , Pazdur Richard 
Published: May 2006

Abstract
Purpose: On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomib's efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomib's regulatory development are summarized here.
Experimental Design and Results: Following a preplanned interim analysis of time to disease progression (the primary end point), an independent data-monitoring committee advised the sponsor to halt the study and offer bortezomib to all dexamethasone-treated study patients. Time to progression was significantly prolonged in the bortezomib treatment arm (median, 6.2 months) compared with the dexamethasone arm (median, 3.5 months; log-rank test, P &lt; 0.0001; hazard ratio, 0.55; 95% confidence interval, 0.44-0.69). Analysis of overall survival done on the interim database (with 20% of events) showed the superiority of bortezomib for patients (log-rank test, P &lt; 0.05; hazard ratio, 0.57; 95% confidence interval, 0.40-0.81). Using criteria from the European Group for Blood and Marrow Transplantation, the response rate (complete plus partial response) with bortezomib was also superior to dexamethasone (38% versus 18%; P &lt; 0.0001). Adverse events on the bortezomib arm were similar to those previously observed in phase 2 studies; some notable adverse events included asthenia, peripheral neuropathy, thrombocytopenia, and neutropenia.
Conclusions: The U.S. FDA had earlier (May 2003) granted bortezomib accelerated approval for the treatment of patients with MM progressing after two prior therapies. The results of the phase 3 trial and the FDA analysis of the data, along with the sponsor's completion of other postmarketing commitments, confirm bortezomib's benefit and support regular approval.
Effect of cA2 Anti–Tumor Necrosis Factor-α Antibody Therapy on Hematopoiesis of Patients with Myelodysplastic Syndromes
Authors: Boula Anna , Voulgarelis Michael , Giannouli Stavroula , Katrinakis George , Psyllaki Maria , Pontikoglou Charalambos , Markidou Fotini , Eliopoulos George D. , Papadaki Helen A. 
Published: May 2006

AbstractPurpose: Tumor necrosis factor α (TNF-α) plays a prominent role in the pathophysiology of myelodysplastic syndromes (MDS). The aim of this study was to explore the biological and immunoregulatory effect of the treatment with the anti–tumor necrosis factor-α monoclonal antibody cA2 on bone marrow (BM) progenitor/precursor and stromal cells and lymphocyte subsets, as well as the clinical response in MDS patients.Experimental Design: Ten low-intermediate risk MDS patients received i.v. cA2 (3 mg/kg) at weeks 0, 2, 6, and 12. The number, survival, and clonogenic potential of BM progenitor/precursor cells, the hematopoiesis-supporting capacity of BM stromal cells, and the lymphocyte activation status were investigated in the patients at baseline and following treatment using flow cytometry, clonogenic assays, and long-term BM cultures (LTBMC). Clinical response was evaluated according to standardized criteria.Results: cA2 administration reduced the proportion of apoptotic and Fas+ cells in the CD34+ cell compartment (P = 0.0215 and P = 0.0344, respectively) and increased the clonogenic potential of BM mononuclear and CD34+ cells (P = 0.0399 and P = 0.0304, respectively) compared with baseline. The antibody reduced tumor necrosis factor-α levels in LTBMC supernatants (P = 0.0043) and significantly improved the hematopoiesis-supporting capacity of LTBMC adherent cells. The proportion of activated peripheral blood and BM T-lymphocytes decreased significantly after treatment, suggesting an immunomodulatory effect of cA2. Two patients displayed minor hematologic responses whereas the remaining patients displayed stable disease with no disease progression.Conclusions: The encouraging biological insights from cA2 administration may be useful in conducting further clinical trials using cA2 for selected MDS patients, particularly those with evidence of immune-mediated inhibition of hematopoiesis.
Transforming growth factor-β1 regulates macrophage migration via RhoA
Authors: Kim Jun-Sub , Kim Jae-Gyu , Moon Mi-Young , Jeon Chan-Young , Won Ha-Young , Kim Hee-Jun , Jeon Yee-Jin , Seo Ji-Yeon , Kim Jong-Il , Kim Jaebong , Lee Jae-Yong , Kim Pyeung-Hyeun , Park Jae-Bong 
Published: May 2006

AbstractBrief treatment with transforming growth factor (TGF)–β1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-β1 was markedly inhibited by 10 μg/mL Tat-C3 exoenzyme. TGF-β1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)–1α in the initial period, and these effects also were inhibited by 10 μg/mL Tat-C3 and a dominant-negative (DN)–RhoA (N19RhoA). Cycloheximide, actinomycin D, and antibodies against MIP-1α and monocyte chemoattractant protein-1 (MCP-1) abolished the stimulation of cell migration by TGF-β1. These findings suggest that migration of these cells is regulated directly and indirectly via the expression of chemokines such as MIP-1α and MCP-1 mediated by RhoA in response to TGF-β1. TGF-β1 activated RhoA in the initial period, and thereafter inactivated them, suggesting that the inactivation of RhoA may be the cause of the reduced cell migration in response to TGF-β1 at later times. We therefore attempted to elucidate the molecular mechanism of the inactivation of RhoA by TGF-β1. First, TGF-β1 phosphorylated RhoA via protein kinase A, leading to inactivation of RhoA. Second, wild-type p190 Rho GTPase activating protein (p190RhoGAP) reduced and DN-p190RhoGAP reversed the reduction of cell migration induced by TGF-β, suggesting that it inactivated RhoA via p190 Rho GAP.
The epitope recognized by rituximab
Authors: Binder Mascha , Otto Florian , Mertelsmann Roland , Veelken Hendrik , Trepel Martin 
Published: May 2006

AbstractRituximab is a monoclonal antibody widely used in the treatment of malignant lymphoma and autoimmunity. Its epitope within the B-cell antigen CD20 is largely unknown. We used phage display libraries to select peptides binding to rituximab. Enriched peptides showed 2 sequence patterns: one motif (CALMIANSC) is related to (170)ANPS(173) within CD20, while another motif (WEWTI) may mimic the CD20 segment (182)YCYSI(185). Phages displaying either motif specifically bound rituximab. Binding to rituximab by the CD20 peptides ANPS and YCYSI was weak when used separately and enhanced when both peptides were linked. Recombinant CD20 extracellular loop proteins blocked binding of the selected CWWEWTIGC phage to rituximab, suggesting that CWWEWTIGC mimics the epitope. Blocking capacity was strongly reduced upon mutation of the CD20 strings ANPS or YCYSI. We conclude that rituximab binds a discontinuous epitope in CD20, comprised of (170)ANPS(173) and (182)YCYSI(185), with both strings brought in steric proximity by a disulfide bridge between C(167) and C(183).
Analysis of fibrinogen variants at γ387Ile shows that the side chain of γ387 and the tertiary structure of the γC-terminal tail are important not only for assembly and secretion of fibrinogen but also for lateral aggregation of protofibrils and XIIIa-catalyzed γ-γ dimer formation
Authors: Kani Satomi , Terasawa Fumiko , Yamauchi Kazuyoshi , Tozuka Minoru , Okumura Nobuo 
Published: May 2006

AbstractTo examine the role of fibrinogen γ-chain residue 387Ile in the assembly and secretion of this multichain protein, we synthesized a series of variants with substitution at γ387 by Arg, Leu, Met, Ala, or Asp. Only the variant γ387Asp showed impaired synthesis in the cells and very low secretion into the medium. In addition, we performed thrombin-catalyzed fibrin polymerization and factor (F) XIIIa-catalyzed cross-linking of the γ-chain for 4 variants. The degree of lateral aggregation of protofibrils into fibrin fibers was slightly reduced for γ387Arg and Ala, and moderately reduced for γ387Leu and Met. Although the FXIIIa-catalyzed cross-linking for all of the variants was slower than that for γ387Ile, that of γ387Arg was much more markedly impaired than that of the others. In summary, our studies demonstrated that the specific residue at γ387 or the conformation of γ388-411 residues, but not the length of the γC tail, is critical for fibrinogen assembly and subsequent secretion. Moreover, this residue or the conformation is also important for not only the lateral aggregation of fibrin polymers but also the FXIIIa-catalyzed cross-linking of the γ-chain. Interestingly, our results clearly indicate that the conformations critical for these 2 functions are different from each other.
The development and validation of the Virtual Tissue Matrix, a software application that facilitates the review of tissue microarrays on line
Authors: Conway Catherine M , O'Shea Deirdre , O'Brien Sallyann , Lawler Darragh K , Dodrill Graham D , O'Grady Anthony , Barrett Helen , Gulmann Christian , O'Driscoll Lorraine , Gallagher William M , Kay Elaine W , O'Shea Daniel G 
Published: May 2006

Abstract

Background
The Tissue Microarray (TMA) facilitates high-throughput analysis of hundreds of tissue specimens simultaneously. However, bottlenecks in the storage and manipulation of the data generated from TMA reviews have become apparent. A number of software applications have been developed to assist in image and data management; however no solution currently facilitates the easy online review, scoring and subsequent storage of images and data associated with TMA experimentation.

Results
This paper describes the design, development and validation of the Virtual Tissue Matrix (VTM). Through an intuitive HTML driven user interface, the VTM provides digital/virtual slide based images of each TMA core and a means to record observations on each TMA spot. Data generated from a TMA review is stored in an associated relational database, which facilitates the use of flexible scoring forms. The system allows multiple users to record their interpretation of each TMA spot for any parameters assessed. Images generated for the VTM were captured using a standard background lighting intensity and corrective algorithms were applied to each image to eliminate any background lighting hue inconsistencies or vignetting.
Validation of the VTM involved examination of inter-and intra-observer variability between microscope and digital TMA reviews. Six bladder TMAs were immunohistochemically stained for E-Cadherin, β-Catenin and PhosphoMet and were assessed by two reviewers for the amount of core and tumour present, the amount and intensity of membrane, cytoplasmic and nuclear staining.

Conclusion
Results show that digital VTM images are representative of the original tissue viewed with a microscope. There were equivalent levels of inter-and intra-observer agreement for five out of the eight parameters assessed. Results also suggest that digital reviews may correct potential problems experienced when reviewing TMAs using a microscope, for example, removal of background lighting variance and tint, and potential disorientation of the reviewer, which may have resulted in the discrepancies evident in the remaining three parameters.
Characterization of human malignant mesothelioma cell lines orthotopically implanted in the pleural cavity of immunodeficient mice for their ability to grow and form metastasis
Authors: Martarelli Daniele , Catalano Alfonso , Procopio Antonio , Orecchia Sara , Libener Roberta , Santoni Giorgio 
Published: May 2006

Abstract

Background
Malignant pleural mesothelioma (MPM) is a tumor known to be resistant to conventional therapies. Thus, an in vivo model can represent an important tool for assessing the efficacy of novel approaches in the treatment of MPM.
Presently, human MPM cells have been grown orthotopically in mice upon transplantation of tumor masses or tumor cell suspensions following surgery. In these models however, surgery can interfere with the tumor growth and the early stages of tumor development cannot be easily explored. Finally, results may not be so accurate due to implantation of potentially different tumor samples in different experimental groups.
Our work aimed at establishing a nude mouse model xenotransplanted with human MPM cell lines in which tumor progression exhibits some features of the human disease.

Methods
Three distinct human MPM cell lines previously established from MPM patients displaying two different phenotypes, biphasic (MM-B1 and IST-Mes3) and epithelioid (IST-Mes2), were directly injected into the pleural cavity of nude mice. At different times, mice were sacrificed for autopsy, tumor nodules were counted and then removed for histology. Presence of metastases in visceral organs was also monitored.

Results
IST-Mes2 cells were unable to grow in nude mice. MM-B1 and IST-Mes3 cells were capable of growing in nude mice and formed tumor nodules in the pleura. Post-mortem examination showed that MPM cells progressively colonized the parietal and visceral pleura, the diaphragm, the mediastinum and, lastly the lung parenchyma. No pneumo-thorax was evidenced in the mice. Pleural effusions as well as lymph node metastases were observed only at later times.

Conclusion
This model mimics the progression of human malignant mesothelioma and it is easy to perform and reproducible; therefore it can be useful to study human MPM biology and evaluate the efficacy of novel therapies.
Analysis of folylpoly-γ-glutamate synthetase gene expression in human B-precursor ALL and T-lineage ALL cells
Authors: Leclerc Guy J , Leclerc Gilles M , Kinser Ting Ting Hsieh , Barredo Julio C 
Published: May 2006

AbstractBackgroundExpression of folylpoly-γ-glutamate synthetase (FPGS) gene is two- to three-fold higher in B-precursor ALL (Bp- ALL) than in T-lineage ALL (T-ALL) and correlates with intracellular accumulation of methotrexate (MTX) polyglutamates and lymphoblast sensitivity to MTX. In this report, we investigated the molecular regulatory mechanisms directing FPGS gene expression in Bp-ALL and T-ALL cells.MethodsTo determine FPGS transcription rate in Bp-ALL and T-ALL we used nuclear run-on assays. 5'-RACE was used to uncover potential regulatory regions involved in the lineage differences. We developed a luciferase reporter gene assay to investigate FPGS promoter/enhancer activity. To further characterize the FPGS proximal promoter, we determined the role of the putative transcription binding sites NFY and E-box on FPGS expression using luciferase reporter gene assays with substitution mutants and EMSA.ResultsFPGS transcription initiation rate was 1.6-fold higher in NALM6vs. CCRF-CEM cells indicating that differences in transcription rate led to the observed lineage differences in FPGS expression between Bp-ALL and T-ALL blasts. Two major transcripts encoding the mitochondrial/cytosolic and cytosolic isoforms were detected in Bp-ALL (NALM6 and REH) whereas in T-ALL (CCRF-CEM) cells only the mitochondrial/cytosolic transcript was detected. In all DNA fragments examined for promoter/enhancer activity, we measured significantly lower luciferase activity in NALM6vs. CCRF-CEM cells, suggesting the need for additional yet unidentified regulatory elements in Bp-ALL. Finally, we determined that the putative transcription factor binding site NFY, but not E-box, plays a role in FPGS transcription in both Bp- and T-lineage.ConclusionWe demonstrated that the minimal FPGS promoter region previously described in CCRF-CEM is not sufficient to effectively drive FPGS transcription in NALM6 cells, suggesting that different regulatory elements are required for FPGS gene expression in Bp-cells. Our data indicate that the control of FPGS expression in human hematopoietic cells is complex and involves lineage-specific differences in regulatory elements, transcription initiation rates, and mRNA processing. Understanding the lineage-specific mechanisms of FPGS expression should lead to improved therapeutic strategies aimed at overcoming MTX resistance or inducing apoptosis in leukemic cells.