bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter Clinical Trial of Bortezomib in Relapsed/Refractory Waldenstrom's Macroglobulinemia: Results of WMCTG Trial 03-248
Authors: Treon Steven P. , Hunter Zachary R. , Matous Jeffrey , Joyce Robin M. , Mannion Brian , Advani Ranjana , Cook David , Songer Joseph , Hill John , Kaden Bruce R. , Sharon David , Steiss Ronald , Leleu Xavier , Branagan Andrew R. , Badros Ashraf 
Published: June 2007

Abstract
Purpose: Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM.
Experimental Design: In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease.
Results: Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P &lt; 0.0001). The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of 1.4 months. The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months. The most common grade III/IV toxicities occurring in ≥5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.
Conclusions: The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.
DNA Copy Number Gains at Loci of Growth Factors and Their Receptors in Salivary Gland Adenoid Cystic Carcinoma
Authors: Vékony Hedy , Ylstra Bauke , Wilting Saskia M. , Meijer Gerrit A. , van de Wiel Mark A. , Leemans C. René , van der Waal Isaäc , Bloemena Elisabeth 
Published: June 2007

Abstract
Purpose: Adenoid cystic carcinoma (ACC) is a malignant salivary gland tumor with a high mortality rate due to late, distant metastases. This study aimed at unraveling common genetic abnormalities associated with ACC. Additionally, chromosomal changes were correlated with patient characteristics and survival.
Experimental Design: Microarray-based comparative genomic hybridization was done to a series of 18 paraffin-embedded primary ACCs using a genome-wide scanning BAC array.
Results: A total of 238 aberrations were detected, representing more gains than losses (205 versus 33, respectively). Most frequent gains (&gt;60%) were observed at 9q33.3-q34.3, 11q13.3, 11q23.3, 19p13.3-p13.11, 19q12-q13.43, 21q22.3, and 22q13.33. These loci harbor numerous growth factor [fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF)] and growth factors receptor (FGFR3 and PDGFRβ) genes. Gains at the FGF(R) regions occurred significantly more frequently in the recurred/metastasized ACCs compared with indolent ACCs. Furthermore, patients with 17 or more chromosomal aberrations had a significantly less favorable outcome than patients with fewer chromosomal aberrations (log-rank = 5.2; P = 0.02).
Conclusions: Frequent DNA copy number gains at loci of growth factors and their receptors suggest their involvement in ACC initiation and progression. Additionally, the presence of FGFR3 and PDGFRβ in increased chromosomal regions suggests a possible role for autocrine stimulation in ACC tumorigenesis.
Molecular Characterization of Inflammatory Genes in Sentinel and Nonsentinel Nodes in Melanoma
Authors: Torisu-Itakura Hitoe , Lee Jonathan H. , Scheri Randall P. , Huynh Young , Ye Xing , Essner Richard , Morton Donald L. 
Published: June 2007

AbstractPurpose: Identification of regional node metastasis is important for accurate staging and optimal treatment of early melanoma. We hypothesize that the nodal profile of immunoregulatory cytokines can confirm the identity of the first tumor-draining regional node, i.e., the sentinel node (SN) and indicate its tumor status.Experimental Design: RNA was extracted from freshly dissected and preserved nodal tissue of 13 tumor-negative SNs, 10 tumor-positive SNs (micrometastases &lt;2 mm), and 11 tumor-negative non-SNs (NSN). RNA was converted into cDNA and then amplified by PCR. Expression of 96 cytokines and chemokines was assessed using cDNA microarray and compared by using hierarchical clustering.Results: Fifty-seven genes were expressed at significantly (P &lt; 0.05) different levels in SNs and NSNs (4 genes had higher expression, and 53 genes had lower expression in SNs). Expression levels of interleukin-13 (IL-13), leptin, lymphotoxin β receptor (LTbR), and macrophage inflammatory protein 1b (MIP1b) were significantly higher (P &lt; 0.04, P &lt; 0.01, P &lt; 0.05, and P &lt; 0.01, respectively), and expression level of IL-11Ra was lower (P &lt; 0.03) for tumor-positive as compared with tumor-negative SN. Receiver-operator characteristics curve analyses showed that the area under the curve (AUC) for IL-13, leptin, LTbR, MIP1b, and IL-11Ra was 0.79, 0.83, 0.75, 0.81, and 0.77, respectively. The AUC for the five genes in combination was 0.973, suggesting high concordance of gene-expression profiles with SN staging.Conclusions: SNs have a different immunoregulatory cytokine profile than NSNs. The cytokine profile of tumor-positive SNs; increased expression of IL-13, leptin, LTbR, and MIP1b and decreased expression of IL-11Ra, may provide clues to the local tumor lymph node interaction seen in the earliest steps of melanoma metastasis.
Strong Time Dependence of the 76-Gene Prognostic Signature for Node-Negative Breast Cancer Patients in the TRANSBIG Multicenter Independent Validation Series
Authors: Desmedt Christine , Piette Fanny , Loi Sherene , Wang Yixin , Lallemand Françoise , Haibe-Kains Benjamin , Viale Giuseppe , Delorenzi Mauro , Zhang Yi , d'Assignies Mahasti Saghatchian , Bergh Jonas , Lidereau Rosette , Ellis Paul , Harris Adrian L. , Klijn Jan G.M. , Foekens John A. , Cardoso Fatima , Piccart Martine J. , Buyse Marc , Sotiriou Christos ,   on behalf of the TRANSBIG Consortium
Published: June 2007

Abstract
Purpose: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node–negative (N−) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment.
Experimental Design: Gene expression profiling of frozen samples from 198 N− systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online.
Results: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively.
Conclusion: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.
The Mammalian Target of Rapamycin Signaling Pathway: Twists and Turns in the Road to Cancer Therapy
Authors: Abraham Robert T. , Gibbons James J. 
Published: June 2007

Abstract
The immunosuppressive drug rapamycin played a key role in the functional characterization of mammalian target of rapamycin (mTOR), an unusual protein kinase that coordinates growth factor and nutrient availability with cell growth and proliferation. Several rapamycin-related compounds are now in various stages of clinical development as anticancer agents. This article highlights recent advances in our understanding of the mTOR signaling pathway and the implications of these findings for the clinical application of mTOR inhibitors in cancer patients.
Methylation ofCASP8, DCR2, andHIN-1in Neuroblastoma Is Associated with Poor Outcome
Authors: Yang Qiwei , Kiernan Colleen M. , Tian Yufeng , Salwen Helen R. , Chlenski Alexandre , Brumback Babette A. , London Wendy B. , Cohn Susan L. 
Published: June 2007

AbstractPurpose: Epigenetic aberrations have been shown to play an important role in the pathogenesis of most cancers. To investigate the clinical significance of epigenetic changes in neuroblastoma, we evaluated the relationship between clinicopathologic variables and the pattern of gene methylation in neuroblastoma cell lines and tumors.Experimental Design: Methylation-specific PCR was used to evaluate the gene methylation status of 19 genes in 14 neuroblastoma cell lines and 8 genes in 70 primary neuroblastoma tumors. Associations between gene methylation, established prognostic factors, and outcome were evaluated. Log-rank tests were used to identify the number of methylated genes that was most predictive of overall survival.Results: Epigenetic changes were detected in the neuroblastoma cell lines and primary tumors, although the pattern of methylation varied. Eight of the 19 genes analyzed were methylated in &gt;70% of the cell lines. Epigenetic changes of four genes were detected in only small numbers of cell lines. None of the cell lines had methylation of the other seven genes analyzed. In primary neuroblastoma tumors, high-risk disease and poor outcome were associated with methylation of DCR2, CASP8, and HIN-1 individually. Although methylation of the other five individual genes was not predictive of poor outcome, a trend toward decreased survival was seen in patients with a methylation phenotype, defined as ≥4 methylated genes (P = 0.055).Conclusion: Our study indicates that clinically aggressive neuroblastoma tumors have aberrant methylation of multiple genes and provides a rationale for exploring treatment strategies that include demethylating agents.
Schedule-Dependent Cytotoxic Synergism of Pemetrexed and Erlotinib in Human Non–Small Cell Lung Cancer Cells
Authors: Li Tianhong , Ling Yi-He , Goldman I. David , Perez-Soler Roman 
Published: June 2007

AbstractPurpose: This study was undertaken to select the optimal combination schedule of erlotinib and pemetrexed for the treatment of relapsed non–small cell lung cancer (NSCLC) using a panel of human NSCLC lines.Experimental Design: Human NSCLC cell lines, with variable expression of the known molecular determinants of erlotinib sensitivity, were exposed to pemetrexed and erlotinib using different schedules. Antitumor effect was measured by growth inhibition by cell count and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis by flow cytometry, and expression of cell cycle mediators by immunoblots. The cytotoxic interaction between pemetrexed and erlotinib (i.e., synergistic, additive, or antagonistic) was determined by median effect analysis.Results: When cells were exposed to concurrent pemetrexed and erlotinib or sequential pemetrexed followed by erlotinib, cytotoxic synergism was observed in both erlotinib-sensitive and erlotinib-resistant human NSCLC cell lines. This was independent of the mutation status of epidermal growth factor receptor or K-Ras genes. Synergism was associated with a combination of cell cycle effects from both agents. In contrast, exposure of cells to erlotinib followed by pemetrexed was mostly antagonistic in erlotinib-sensitive cells and additive at best in erlotinib-resistant cells. Antagonism was associated with erlotinib-induced G1-phase blockade of erlotinib-sensitive cells, which protects cells from pemetrexed cytotoxicity. Pemetrexed induced an epidermal growth factor receptor–mediated activation of the phosphatidylinositol 3-kinase/AKT pathway, which was inhibited by erlotinib and a specific phosphatidylinositol 3-kinase inhibitor, LY294002.Conclusions: The combination of pemetrexed and erlotinib is synergistic in NSCLC in vitro if exposure to erlotinib before pemetrexed is avoided, particularly in tumors that are sensitive to erlotinib. Based on these findings, a randomized phase II study comparing the progression-free survival between an intermittent combination of erlotinib and pemetrexed (experimental arm) and pemetrexed alone (control arm) in patients with relapsing NSCLC has been initiated.
Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibitionin vivo
Authors: Yip-Schneider Michele T. , Wu Huangbing , Ralstin Matthew , Yiannoutsos Constantin , Crooks Peter A. , Neelakantan Sundar , Noble Stephen , Nakshatri Harikrishna , Sweeney Christopher J. , Schmidt C. Max 
Published: June 2007

AbstractThe design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-κB (NF-κB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-κB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P &lt; 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/COX-2 levels or activity in any of the treatment groups. NF-κB DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents. [Mol Cancer Ther 2007;6(6):1736–44]
The Earliest Homo Sapiens (Sapiens): Biological, Chronological and Taxonomic Perspectives
Authors: Tillier Anne-marie 
Published: June 2007

AbstractOver the last twenty years the debate over the origin of modern Man has broadened, the supporters of a theory of regional diversification of Homo sapiens being often opposed by those holding to the single source theory (the ‘Out of Africa’ model). At the same time, the idea of Homo neanderthalensis as a separate species was being resurrected, supported by bone classification typology and drawing on arguments derived from palaeogenetic analyses, which buttressed the case for the existence of distinct species and for privileging an African origin for modern humans. The prospects offered by palaeogenetic research to find answers for the questions concerning the relationship between modern humans and Neanderthals throw up numerous questions and all the obstacles have not yet been removed. Palaeoanthropology, from its point of view, casts major doubt on the thesis according to which man has always evolved in the same direction.
Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences
Authors: Fredriksen Agnete Brunsvik , Bogen Bjarne 
Published: June 2007

AbstractV regions of monoclonal Ig express an exquisite B-cell tumor–specific antigen called idiotype (Id). Id is a weak antigen and it is important to improve immunogenicity of Id vaccines. Chemokine receptors are expressed on antigen-presenting cells (APCs) and are promising targets for Id vaccines. Here we compare monomeric and dimeric forms of MIP-1α and RANTES that target Id to APCs in a mouse B lymphoma (A20) and a multiple myeloma model (MOPC315). MIP-1α was more potent than RANTES. The dimeric proteins were more potent than monomeric equivalents in short-term assays. When delivered in vivo by intramuscular injection of plasmids followed by electroporation, dimeric proteins efficiently primed APCs in draining lymph nodes for activation and proliferation of Id-specific CD4+ T cells. Good anti-Id antibody responses were obtained, and mice immunized only once were 60% to 80% protected in both tumor models. CD8+ T cells contributed to the protection. Antibody responses and tumor protection were reduced when the human Ig hinge = CH3 dimerization motif was replaced with syngeneic mouse counterparts, indicating that tumor-protective responses were dependent on xenogeneic sequences. The results suggest that bivalency and foreign sequences combine to increase the efficiency of chemokine-Id DNA vaccines.
Critical role of FLT3 ligand in IL-7 receptor–independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors
Authors: Sitnicka Ewa , Buza-Vidas Natalija , Ahlenius Henrik , Cilio Corrado M. , Gekas Christos , Nygren Jens M. , Månsson Robert , Cheng Min , Jensen Christina T. , Svensson Marcus , Leandersson Karin , Agace William W. , Sigvardsson Mikael , Jacobsen Sten Eirik W. 
Published: June 2007

AbstractThe molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)–deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor α (IL-7Rα) signaling. Fl−/−Il-7r−/− mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Rα–independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Rα, in regulation of the earliest lineage-negative (Lin−) Lin−SCA1+KIT+ (LSK) FLT3hi lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge
Authors: Kowalska M. Anna , Mahmud Shawn A. , Lambert Michele P. , Poncz Mortimer , Slungaard Arne 
Published: June 2007

AbstractPharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4−/−) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C–deficient (PC+/−) mice. Transgenic mice overexpressing human PF4 (hPF4+) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC+/− mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4+ and PC+/−/hPF4+ mice had improved survival. Further, infusion of hPF4+ platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting.
The cooperative activity between the carboxyl-terminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow
Authors: Zhang Ping , Pan Weilan , Rux Ann H. , Sachais Bruce S. , Zheng X. Long 
Published: June 2007

Abstract
ADAMTS13 cleaves von Willebrand factor (VWF) between Tyr1605 and Met1606 residues at the central A2 subunit. The amino-terminus of ADAMTS13 protease appears to be sufficient to bind and cleave VWF under static and denatured condition. However, the role of the carboxyl-terminus of ADAMTS13 in substrate recognition remains controversial. Present study demonstrates that ADAMTS13 cleaves VWF in a rotation speed– and protease concentration–dependent manner on a mini vortexer. Removal of the CUB domains (delCUB) or truncation after the spacer domain (MDTCS) significantly impairs its ability to cleave VWF under the same condition. ADAMTS13 and delCUB (but not MDTCS) bind VWF under flow with dissociation constants (KD) of about 50 nM and about 274 nM, respectively. The isolated CUB domains are neither sufficient to bind VWF detectably nor capable of inhibiting proteolytic cleavage of VWF by ADAMTS13 under flow. Addition of the TSP1 5-8 (T5-8CUB) or TSP1 2-8 repeats (T2-8CUB) to the CUB domains restores the binding affinity toward VWF and the inhibitory effect on cleavage of VWF by ADAMTS13 under flow. These data demonstrate directly and quantitatively that the cooperative activity between the middle carboxyl-terminal TSP1 repeats and the distal carboxyl-terminal CUB domains may be crucial for recognition and cleavage of VWF under flow.
The twisted pharynx phenotype in C. elegans
Authors: Axäng Claes , Rauthan Manish , Hall David H , Pilon Marc 
Published: June 2007

Abstract

Background
The pharynx of C. elegans is an epithelial tube whose development has been compared to that of the embryonic heart and the kidney and hence serves as an interesting model for organ development. Several C. elegans mutants have been reported to exhibit a twisted pharynx phenotype but no careful studies have been made to directly address this phenomenon. In this study, the twisting mutants dig-1, mig-4, mnm-4 and unc-61 are examined in detail and the nature of the twist is investigated.

Results
We find that the twisting phenotype worsens throughout larval development, that in most mutants the pharynx retains its twist when dissected away from the worm body, and that double mutants between mnm-4 and mutants with thickened pharyngeal domains (pha-2 and sma-1) have less twisting in these regions. We also describe the ultrastructure of pharyngeal tendinous organs that connect the pharyngeal basal lamina to that of the body wall, and show that these are pulled into a spiral orientation by twisted pharynges. Within twisted pharynges, actin filaments also show twisting and are longer than in controls. In a mini screen of adhesionmolecule mutants, we also identified one more twisting pharynx mutant, sax-7.

Conclusion
Defects in pharyngeal cytoskeleton length or its anchor points to the extracellular matrix are proposed as the actual source of the twisting force. The twisted pharynx is a useful and easy-to-score phenotype for genes required in extracellular adhesion or organ attachment, and perhaps forgenes required for cytoskeleton regulation.