bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL–Expressing Hematopoietic Progenitors in a Mouse Model
Authors: Kometani Kohei , Aoki Misayo , Kawamata Shin , Shinozuka Yoriko , Era Takumi , Taniwaki Masafumi , Hattori Masakazu , Minato Nagahiro
Published: October 2006

SPA-1 is a negative regulator of Rap1 signal in hematopoietic cells, and SPA-1-deficient mice develop myeloproliferative disorders (MPD) of long latency. In the present study, we showed that the MPDs in SPA-1−/− mice were associated with the increased hematopoietic stem cells expressing LFA-1 in bone marrow and their premature mobilization to spleen with extensive extramedullary hematopoiesis, resembling human chronic myelogenous leukemia (CML). We further showed that human BCR-ABL oncogene caused a partial down-regulation of endogenous SPA-1 gene expression in mouse hematopoietic progenitor cells (HPC) and immature hematopoietic cell lines. Although both BCR-ABL-transduced wild-type (wt) and SPA-1−/− HPC rapidly developed CML-like MPD when transferred to severe combined immunodeficient mice, the latter recipients showed significantly increased proportions of BCR-ABL+ Lin− c-Kit+ cells compared with the former ones. Serial transfer experiments revealed that spleen cells of secondary recipients of BCR-ABL+ wt HPC failed to transfer MPD to tertiary recipients due to a progressive reduction of BCR-ABL+ Lin− c-Kit+ cells. In contrast, SPA-1−/− BCR-ABL+ Lin− c-Kit+ cells were sustained at high level in secondary recipients, and their spleen cells could transfer MPD to tertiary recipients, a part of which rapidly developed blast crisis. Present results suggest that endogenous SPA-1 plays a significant role in regulating expansion and/or survival of BCR-ABL+ leukemic progenitors albeit partial repression by BCR-ABL and that Rap1 signal may represent a new molecular target for controlling leukemic progenitors in CML. (Cancer Res 2006; 66(20): 9967-76)
EBV Latent Membrane Protein 1 Up-regulates Hypoxia-Inducible Factor 1α through Siah1-Mediated Down-regulation of Prolyl Hydroxylases 1 and 3 in Nasopharyngeal Epithelial Cells
Authors: Kondo Satoru , Seo So Young , Yoshizaki Tomokazu , Wakisaka Naohiro , Furukawa Mitsuru , Joab Irene , Jang Kyung Lib , Pagano Joseph S.
Published: October 2006

Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit α. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1α and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1α activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1α for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1α complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1α and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1. (Cancer Res 2006; 66(20): 9870-7)
Characterization of the Nuclear Import Pathways of Galectin-3
Authors: Nakahara Susumu , Oka Natsuo , Wang Yi , Hogan Victor , Inohara Hidenori , Raz Avraham
Published: October 2006

Galectin-3 (Gal-3), a pleiotropic β-galactoside–binding protein, was shown to be involved in several nuclear-dependent functions, including up-regulation of transcriptional factors, RNA processing, and cell cycle regulation. Gal-3 compartmentalization in the nucleus versus the cytoplasm affects, in part, the malignant phenotype of various cancers. However, to date, the mechanism by which Gal-3 translocates into the nucleus remains debatable. Thus, we have constructed and expressed a variety of fusion proteins containing deletion mutants of Gal-3 fused with monomers, dimers, and trimers of enhanced green fluorescent protein and searched for the Gal-3 sequence motifs essential for its nuclear localization in vivo. In addition, a digitonin-permeabilized, cell-free transport in vitro assay was used to directly examine the mechanism of Gal-3 nuclear import. Partial deletions of the COOH-terminal region (114-250) of the human Gal-3 significantly decreases its nuclear translocation, whereas a peptide (1-115) was transported to the nuclei. The in vitro nuclear import assay revealed that there are at least two independent nuclear pathways for shuttling Gal-3 into the nucleus: a passive diffusion and an active transport. This is the first article providing direct evidence for the nuclear import mechanisms of Gal-3 and suggests that Gal-3 nuclear translocation is governed by dual pathways, whereas the cytoplasmic/nuclear distribution may be regulated by multiple processes, including cytoplasmic anchorage, nuclear retention, and or nuclear export. These results may lead to the development of a therapeutic modality aiming at abrogating Gal-3 translocation into the nucleus and thus hampering its activity during cancer progression and metastasis. (Cancer Res 2006; 66(20): 9995-10006)
Common Variants in RB1 Gene and Risk of Invasive Ovarian Cancer
Authors: Song Honglin , Ramus Susan J. , Shadforth Danielle , Quaye Lydia , Kjaer Susanne Kruger , DiCioccio Richard A. , Dunning Alison M. , Hogdall Estrid , Hogdall Claus , Whittemore Alice S. , McGuire Valerie , Lesueur Fabienne , Easton Douglas F. , Jacobs Ian J. , Ponder Bruce A.J. , Gayther Simon A. , Pharoah Paul D.P.
Published: October 2006

Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P8df = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5′-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action. (Cancer Res 2006; 66(20): 10220-6)
Phosphorylation of the Menin Tumor Suppressor Protein on Serine 543 and Serine 583
Authors: MacConaill Laura E. , Hughes Christina M. , Rozenblatt-Rosen Orit , Nannepaga Suraj , Meyerson Matthew
Published: October 2006

Multiple endocrine neoplasia type 1 (MEN-1) is a heritable syndrome typified by tumors in multiple endocrine organs, including the pituitary, parathyroids, and pancreatic islets. MEN-1 is attributable to mutations in the MEN1 tumor-suppressor gene that encodes the menin protein. Recent studies have implicated menin in transcriptional regulation and in covalent histone modification; however, little is known about modifications of the menin protein. Here, we report that menin is subject to phosphorylation on serine residues, including Ser543 and Ser583. Phosphorylation-defective mutants of either or both of these residues retain the associated histone methyltransferase activity of menin, as well as binding to the trithorax complex members Ash2L, Rbbp5, and MLL2 and to RNA polymerase II. Chromatin immunoprecipitation experiments reveal that binding of menin to the Hoxc8 locus is not affected by phosphorylation on Ser543 or Ser583. (Mol Cancer Res 2006;4(10):793–801)
PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme
Authors: Gallia Gary L. , Rand Vikki , Siu I-Mei , Eberhart Charles G. , James C. David , Marie Suely K.N. , Oba-Shinjo Sueli M. , Carlotti Carlos G. , Caballero Otavia L. , Simpson Andrew J.G. , Brock Malcolm V. , Massion Pierre P. , Carson Benjamin S. , Riggins Gregory J.
Published: October 2006

The phosphatidylinositol 3-kinases (PI3K) are a family of enzymes that relay important cellular growth control signals. Recently, a large-scale mutational analysis of eight PI3K and eight PI3K-like genes revealed somatic mutations in PIK3CA, which encodes the p110α catalytic subunit of class IA PI3K, in several types of cancer, including glioblastoma multiforme. In that report, 4 of 15 (27%) glioblastomas contained potentially oncogenic PIK3CA mutations. Subsequent studies, however, showed a significantly lower mutation rate ranging from 0% to 7%. Given this disparity and to address the relation of patient age to mutation frequency, we examined 10 exons of PIK3CA in 73 glioblastoma samples by PCR amplification followed by direct DNA sequencing. Overall, PIK3CA mutations were found in 11 (15%) samples, including several novel mutations. PIK3CA mutations were distributed in all sample types, with 18%, 9%, and 13% of primary tumors, xenografts, and cell lines containing mutations, respectively. Of the primary tumors, PIK3CA mutations were identified in 21% and 17% of pediatric and adult samples, respectively. No evidence of PIK3CA gene amplification was detected by quantitative real-time PCR in any of the samples. This study confirms that PIK3CA mutations occur in a significant number of human glioblastomas, further indicating that therapeutic targeting of this pathway in glioblastomas is of value. Moreover, this is the first study showing PIK3CA mutations in pediatric glioblastomas, thus providing a molecular target in this important pediatric malignancy. (Mol Cancer Res 2006;4(10):709–14)
Cellular Functions of γ-Secretase-Related Proteins
Authors: Haffner Christof , Haass Christian
Published: October 2006

Amyloid-β peptide (Aβ) is generated by γ-secretase, a membrane protein complex with an unusual aspartyl protease activity consisting of the four components presenilin, nicastrin, APH-1 and PEN-2. Presenilin is considered the catalytic subunit of this complex since it represents the prototype of the new family of intramembrane-cleaving GxGD-type aspartyl proteases. Recently, five novel members of this family and a nicastrin-like protein were identified. Whereas one of the GxGD-type proteins was shown to be identical with signal peptide peptidase (SPP), the function of the others, now called SPP-like proteins (SPPLs), is not known. We therefore analyzed SPPL2b and SPPL3 and demonstrated that they localize to different subcellular compartments suggesting nonredundant functions. This was supported by different phenotypes obtained in knockdown studies in zebrafish embryos. In addition, these phenotypes could be phenocopied by ectopic expression of putative active site mutants, providing strong evidence for a proteolytic function of SPPL2b and SPPL3. We also identified and characterized the nicastrin-like protein nicalin which, together with the 130-kDa protein NOMO (Nodal modulator), forms a membrane protein complex different from γ-secretase. We found that during zebrafish embryogenesis this complex is involved in the patterning of the axial mesendoderm, a process controlled by the Nodal signaling pathway.
γ-Secretase Modulation with Aβ42-Lowering Nonsteroidal Anti-Inflammatory Drugs and Derived Compounds
Authors: Czirr Eva , Weggen Sascha
Published: October 2006

The amyloid-β (Aβ) peptides and specifically the highly amyloidogenic isoform Aβ42 appear to be key agents in the pathogenesis of familial and sporadic forms of Alzheimer’s disease (AD). The final step in the generation of Aβ from the amyloid precursor protein is catalyzed by the multiprotein complex γ-secretase, which constitutes a prime drug target for prevention and therapy of the disease. However, highly potent γ-secretase inhibitors that block formation of all Aβ peptides have provoked troubling side effects in preclinical animal models of AD. This toxicity can be readily explained by the promiscuous substrate specificity of γ-secretase and its essential role in the NOTCH signaling pathway. For that reason and because of the crucial role of Aβ42 in the pathogenesis of the disease, selective inhibition of Aβ42 production would seem to be a more promising alternative to complete inhibition of γ-secretase activity. This theoretical concept has edged much closer to clinical reality with the surprising finding that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, and derived compounds display preferential Aβ42-lowering activity. In contrast to γ-secretase inhibitors, these γ-secretase modulators effectively suppress Aβ42 production while sparing processing of NOTCH and other γ-secretase substrates. Although not fully resolved on the molecular level, the mechanism of action of Aβ42-lowering NSAIDs is independent of cyclooxygenase inhibition and most likely involves direct interaction with components of the γ-secretase complex or its substrates. Current efforts to improve the pharmacological shortcomings of available γ-secretase modulators will hopefully lead to the development of clinically useful Aβ42-lowering compounds in the near future.
Growth Hormone Receptor Antagonists
Authors: van der Lely A.J. , Kopchick John J.
Published: October 2006

The currently available long-acting somatostatin analogs normalize serum growth hormone (GH) levels and insulin-like growth factor-I levels in approximately 60% of patients with acromegaly. The recently introduced GH receptor antagonist, pegvisomant, is able to normalize insulin-like growth factor-I levels in virtually all acromegalic subjects. Although no correlation between increased GH concentrations and tumor size has been found, long-term safety studies are still in progress. Also, pegvisomant monotherapy is administered once daily and is very costly. Combined treatment of a somatostatin analog with pegvisomant appears to be an effective and rational approach.
Portal Blood Flow Regulates Volume Recovery of the Rat Liver after Partial Hepatectomy: Molecular Evaluation
Authors: Nobuoka T. , Mizuguchi T. , Oshima H. , Shibata T. , Kimura Y. , Mitaka T. , Katsuramaki T. , Hirata K.
Published: October 2006

Background/Aim: Liver regeneration is a finely tuned process that is closely regulated by multiple cell cycle steps. Although the portal blood flow affects liver regeneration, the molecular mechanism by which the blood flow regulates gene expression and liver function is largely unknown. The aim of this study was to investigate the molecular effect of portal blood flow on hepatocyte proliferation and gene regulation during liver regeneration. Materials and Methods: We developed a simple surgical rat model to investigate the relation between portal blood flow and liver regeneration by partially ligating the portal trunk with 8-0 Proline sutures under microscopy to reduce the blood flow by 40%. We investigated recovery of liver volume, DNA synthesis, and gene expression associated with cell cycle regulators, comparing partially hepatectomized (PH) rats without (PH group; n = 30) and with partial portal ligation (PHPL group; n = 30) for 7 days after the operation. Results: The hepatic tissue blood flow and the recovery ratio between liver weight and body weight in the PHPL group were significantly lower than in the PH group after hepatectomy. The peak 5-bromo-2′-deoxyuridine labeling index in the PHPL group was delayed and weak compared with the PH group. The expression of CT-1 and cyclin D, E, and B mRNAs indicated that the liver regeneration in the PHPL group was delayed and weak. In addition, there was reciprocal expression of C/EBPα and C/EBPβ mRNAs, an observation supported by their nuclear protein levels. Furthermore, the cytochrome P-450 protein level in the PHPL group was higher than that in the PH group 1 day after hepatectomy. Conclusion: The portal blood flow regulates the activity of liver regeneration and the gene expression associated with cell cycle regulators, while the functions are maintained.
Religion in Contemporary Society: Eroded by Human Well-being, Supported by Cultural Diversity
Authors: Pettersson Thorleif
Published: October 2006

Most versions of secularization theory expect advanced modernity to weaken religion. In contrast, this chapter argues that two different dimensions of contemporary society affect religion in opposite ways. Rising levels of human security and well-being are assumed to drive towards religious decline, while growing cultural diversity is assumed to push towards religious growth. These two hypotheses are simultaneously investigated, using world wide data for 50 000 respondents from 37 countries with a predominantly Christian heritage. As dependent variables, two dimensions of religious involvement which relate to two core aspects of secularization theory are analyzed: church-oriented religious involvement and preferences for a religious impact on politics. The findings from three different analytical strategies demonstrate that each of the two religious orientations is positively related to the cultural diversity, and also that each of them is negatively related to human security and well-being. Furthermore, the results also indicate that the religious changes which took place between 1981 and 1999/2000 are negatively related to human well-being and security, and positively to cultural diversity. Thus, a set of comprehensive analyses of one and the same set of world wide data indicate that human security and cultural diversity affect religious involvement in opposite ways. It seems too simplistic, therefore, to view modernization as a universal cause of religious decline.
A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation
Authors: Sather Susan , Kenyon Karla D. , Lefkowitz Jerry B. , Liang Xiayuan , Varnum Brian C. , Henson Peter M. , Graham Douglas K.
Published: October 2006

Membrane-bound receptors generate soluble ligand-binding domains either by proteolytic cleavage of the extracellular domain or alternative mRNA splicing yielding a secreted protein. Mertk (Mer) is in a receptor tyrosine kinase family with Axl and Tyro-3, and all 3 receptors share the Gas6 ligand. Mer regulates macrophage activation, promotes apoptotic cell engulfment, and supports platelet aggregation and clot stability in vivo. We have found that the membrane-bound Mer protein is cleaved in the extracellular domain via a metalloproteinase. The cleavage results in the production of a soluble Mer protein released in a constitutive manner from cultured cells. Significant amounts of the soluble Mer protein were also detected in human plasma, suggesting its physiologic relevance. Cleavage of Mer was enhanced by treatment with LPS and PMA and was specifically inhibited by a tumor necrosis factor α-converting enzyme metalloproteinase inhibitor. As a decoy receptor for Gas6, soluble Mer prevented Gas6-mediated stimulation of membrane-bound Mer. The inhibition of Gas6 activity by soluble Mer led to defective macrophage-mediated engulfment of apoptotic cells. Furthermore, soluble Mer decreased platelet aggregation in vitro and prevented fatal collagen/epinephrine-induced thromboembolism in mice, suggesting a potential therapeutic use for soluble Mer in the treatment of clotting disorders.
Kaposi sarcoma herpesvirus–encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells
Authors: Lagos Dimitrios , Trotter Matthew W. B. , Vart Richard J. , Wang Hsei-Wei , Matthews Nick C. , Hansen Amy , Flore Ornella , Gotch Frances , Boshoff Chris
Published: October 2006

Kaposi sarcoma–associated herpesvirus (KSHV) is etiologically linked to Kaposi sarcoma (KS), a tumor genetically akin to lymphatic endothelial cells (LECs). We obtained the immune transcriptional signature of KS and used KSHV-infected LECs (KLECs) as an in vitro model to determine the effects of KSHV on transcription and expression of genes involved in immunity. The antigen presentation, interferon (IFN) response, and cytokine transcriptomes of KLECs resemble those of KS. Transcription of genes involved in class I presentation is increased in KS and after infection of LECs, but MHC-I and ICAM-1 surface expression are down-regulated in KLECs. Inhibition of IFN induction of MHC-I transcription indicates that KSHV regulates MHC-I transcription. We show that MHC-I transcription is regulated by the KSHV-encoded viral FLICE inhibitory protein (vFLIP) and by viral IFN regulatory factor 1 (vIRF1). vFLIP up-regulates MHC-I and ICAM-1 through activation of NF-κB and stimulates T-cell proliferation, revealing a mechanism to prevent uncontrolled viral dissemination. In contrast, vIRF1 inhibits basal and IFN- and vFLIP-induced MHC-I transcription and surface expression through its interaction with the transcriptional coactivator p300, contributing to immune evasion. We propose that regulation of MHC-I by vFLIP and vIRF1 plays a crucial role in the host-pathogen equilibrium.
Expression analysis of primary mouse megakaryocyte differentiation and its application in identifying stage-specific molecular markers and a novel transcriptional target of NF-E2
Authors: Chen Zhao , Hu Michael , Shivdasani Ramesh A.
Published: October 2006

Megakaryocyte (MK) differentiation is well described in morphologic terms but its molecular counterparts and the basis for platelet release are incompletely understood. We profiled mRNA expression in populations of primary mouse MKs representing successive differentiation stages. Genes associated with DNA replication are highly expressed in young MKs, in parallel with endomitosis. Intermediate stages are characterized by disproportionate expression of genes associated with the cytoskeleton, cell migration, and G-protein signaling, whereas terminally mature MKs accumulate hemostatic factors, including many membrane proteins. We used these expression profiles to extract a reliable panel of molecular markers for MKs of early, intermediate, or advanced differentiation and establish the value of this marker panel using mouse models of defective thrombopoiesis resulting from absence of GATA1, NF-E2, or tubulin β1. Computational analysis of the promoters of late-expressed MK genes identified new candidate targets for NF-E2, a critical transcriptional regulator of platelet release. One such gene encodes the kinase adaptor protein LIMS1/PINCH1, which is highly expressed in MKs and platelets and significantly reduced in NF-E2–deficient cells. Transactivation studies and chromatin immunoprecipitation implicate Lims1 as a direct target of NF-E2 regulation. Attribution of stage-specific genes, in combination with various applications, thus constitutes a powerful way to study MK differentiation and platelet biogenesis.
Allergens induce enhanced bronchoconstriction and leukotriene production in C5 deficient mice
Authors: McKinley Laura , Kim Jiyoun , Bolgos Gerald L , Siddiqui Javed , Remick Daniel G
Published: October 2006

Background

Previous genetic analysis has shown that a deletion in the complement component 5 gene-coding region renders mice more susceptible to allergen-induced airway hyperresponsiveness (AHR) due to reduced IL-12 production. We investigated the role of complement in a murine model of asthma-like pulmonary inflammation.

Methods

In order to evaluate the role of complement B10 mice either sufficient or deficient in C5 were studied. Both groups of mice immunized and challenged with a house dust extract (HDE) containing high levels of cockroach allergens. Airways hyper-reactivity was determined with whole-body plesthysmography. Bronchoalveolar lavage (BAL) was performed to determine pulmonary cellular recruitment and measure inflammatory mediators. Lung homogenates were assayed for mediators and plasma levels of IgE determined. Pulmonary histology was also evaluated.

Results

C5-deficient mice showed enhanced AHR to methylcholine challenge, 474% and 91% increase above baseline Penh in C5-deficient and C5-sufficient mice respectively, p < 0.001. IL-12 levels in the lung homogenate (LH) were only slightly reduced and BAL IL-12 was comparable in C5-sufficient and C5-deficient mice. However, C5-deficient mice had significantly higher cysteinyl-leukotriene levels in the BAL fluid, 1913 +/- 246 pg/ml in C5d and 756 +/- 232 pg/ml in C5-sufficient, p = 0.003.

Conclusion

These data demonstrate that C5-deficient mice show enhanced AHR due to increased production of cysteinyl-leukotrienes.
NBA-Palm: prediction of palmitoylation site implemented in Naïve Bayes algorithm
Authors: Xue Yu , Chen Hu , Jin Changjiang , Sun Zhirong , Yao Xuebiao
Published: October 2006

Background

Protein palmitoylation, an essential and reversible post-translational modification (PTM), has been implicated in cellular dynamics and plasticity. Although numerous experimental studies have been performed to explore the molecular mechanisms underlying palmitoylation processes, the intrinsic feature of substrate specificity has remained elusive. Thus, computational approaches for palmitoylation prediction are much desirable for further experimental design.

Results

In this work, we present NBA-Palm, a novel computational method based on Naïve Bayes algorithm for prediction of palmitoylation site. The training data is curated from scientific literature (PubMed) and includes 245 palmitoylated sites from 105 distinct proteins after redundancy elimination. The proper window length for a potential palmitoylated peptide is optimized as six. To evaluate the prediction performance of NBA-Palm, 3-fold cross-validation, 8-fold cross-validation and Jack-Knife validation have been carried out. Prediction accuracies reach 85.79% for 3-fold cross-validation, 86.72% for 8-fold cross-validation and 86.74% for Jack-Knife validation. Two more algorithms, RBF network and support vector machine (SVM), also have been employed and compared with NBA-Palm.

Conclusion

Taken together, our analyses demonstrate that NBA-Palm is a useful computational program that provides insights for further experimentation. The accuracy of NBA-Palm is comparable with our previously described tool CSS-Palm. The NBA-Palm is freely accessible from: http://www.bioinfo.tsinghua.edu.cn/NBA-Palm.
Quality of Life for Women Diagnosed With Breast Carcinoma in Situ
Authors: Claus Elizabeth B. , Petruzella Stacey , Carter Darryl , Kasl Stanislav
Published: October 2006

Purpose

Limited data exist on long-term quality of life (QOL) for women diagnosed with breast carcinoma in situ (BCIS).

Participants and Methods

The data are on 795 BCIS participants diagnosed among female residents of Connecticut from September 15, 1994 to March 14, 1998, and 702 controls frequency-matched to the case participants by 5-year age intervals and geography. These women were participants in a large, population-based case/control study and subsequent follow-up study. Telephone interviews at follow-up were used to collect data on QOL at 5 years from initial diagnosis or contact, using the Medical Outcomes Study, Center for Epidemiologic Studies-Depression, and CAGE (Cut down, Annoyed, Guilty, Eye-opener) alcohol consumption scales. QOL outcomes were compared by case/control status and by case treatment group: lumpectomy, lumpectomy with adjuvant radiation therapy, and mastectomy.

Results

At 5 years after diagnosis, women diagnosed with BCIS report levels of physical, emotional, and mental health functioning similar with those reported in a general healthy female population. Case participants and controls did not differ in reported levels of limitations due to physical health problems, bodily pain, social functioning, or overall physical functioning. Case participants who underwent lumpectomy with radiation reported lower levels of emotional functioning, general health perceptions, vitality, sexual interest, and overall mental health, as well as more depressive symptoms than did control subjects; although, the clinical significance of these statistical differences appears to be limited.

Conclusion

At 5 years after treatment, women diagnosed with BCIS report good physical and emotional functioning relative to control populations.
Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines
Authors: Lenz Heinz-Josef , Van Cutsem Eric , Khambata-Ford Shirin , Mayer Robert J. , Gold Philip , Stella Philip , Mirtsching Barry , Cohn Allen L. , Pippas Andrew W. , Azarnia Nozar , Tsuchihashi Zenta , Mauro David J. , Rowinsky Eric K.
Published: October 2006

Purpose

This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.

Patients and Methods

Patients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed.

Results

The response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03).

Conclusion

Cetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.
Randomized Phase II Trial of Pemetrexed Combined With Either Cisplatin or Carboplatin in Untreated Extensive-Stage Small-Cell Lung Cancer
Authors: Socinski Mark A. , Weissman Charles , Hart Lowell L. , Beck J. Thaddeus , Choksi Janak K. , Hanson John P. , Prager Diane , Monberg Matthew J. , Ye Zhishen , Obasaju Coleman K.
Published: October 2006

Purpose

Given the activity and tolerability of pemetrexed/platinum combinations in non–small-cell lung cancer, and the success of novel therapeutic strategies employed in recent extensive-stage small-cell lung cancer (ES-SCLC) trials, a randomized phase II trial was initiated to evaluate the use of cisplatin or carboplatin plus pemetrexed in previously untreated ES-SCLC.

Patients and Methods

Patients were randomly assigned to receive pemetrexed 500 mg/m2plus cisplatin 75 mg/m2or pemetrexed plus carboplatin area under the concentration curve 5. Treatment was administered once every 21 days for a maximum of six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis.

Results

Between December 19, 2002, and May 17, 2004, 78 patients were enrolled onto this multicenter trial. Median age was 63 years (range, 46 to 82 years) for cisplatin/pemetrexed and 66 years (range, 47 to 75 years) for carboplatin/pemetrexed. Median survival time (MST) for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% CI, 20.6% to 51.7%). The MST for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39.0% and a response rate of 39.5% (95% CI, 24.0 to 56.6). Median time to progression for cisplatin/pemetrexed was 4.9 months and for carboplatin/pemetrexed was 4.5 months. Median dose-intensity (actual/planned dose) was 98.94% for cisplatin and 99.95% for pemetrexed in the cisplatin/pemetrexed group and 93.21% for carboplatin and 98.50% for pemetrexed in the carboplatin/pemetrexed group. Grade 3/4 hematologic toxicities included neutropenia (15.8% v 20.0%) and thrombocytopenia (13.2% v 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively.

Conclusion

Pemetrexed/platinum doublets had activity and appeared to be well-tolerated in first-line ES-SCLC.
The Supratonsillar Approach to the Inferior Cerebellar Peduncle: Anatomy, Surgical Technique, and Clinical Application to Cavernous Malformations
Authors: Lawton Michael T. , Quiñones-Hinojosa Alfredo , Jun Peter
Published: October 2006

OBJECTIVE:

To introduce the supratonsillar approach, an approach that traverses the tonsillobiventral fissure in a trajectory over the cerebellar tonsil to the inferior cere-bellar peduncle, and to demonstrate the utility of this approach for resecting peduncular cavernous malformations.

METHODS:

Anatomy of the cerebellar tonsil and surrounding fissures, arteries, and veins are reviewed using cadaveric brain specimens. The surgical approach uses the three-quarter prone position, a suboccipital craniotomy, and wide splitting of the tonsillobiventral fissure.

RESULTS:

Of our experience with 171 patients with cavernous malformations, six patients had lesions in the inferior cerebellar peduncle that were resected using the supratonsillar approach. All cavernous malformations were removed completely and no patients experienced surgical complications or new deficits. @@CONCLUSION:@@ The supratonsillar approach differs from the transvermian and telove-lar approaches to the fourth ventricle, with a more superolateral trajectory that leads instead to the inferior cerebellar peduncle. By splitting the tonsillobiventral fissure and mobilizing the tonsil inferomedially, the point of access to the lesion is deepened and transgression of normal cerebellar tissue is minimized. This elegant approach is ideally suited to the removal of cavernous malformations.
Frameless Stereotactic Cannulation Of The Foramen Ovale For Ablative Treatment Of Trigeminal Neuralgia
Authors: Bale Reto J. , Laimer Ilse , Martin Arno , Schlager Andreas , Mayr Christoph , Rieger Michael , Czermak Benedikt V. , Kovacs Peter , Widmann Gerlig
Published: October 2006

OBJECTIVE:

Ablative neurosurgical treatment of trigeminal neuralgia, including percutaneous radiofrequency thermocoagulation, requires cannulation of the foramen ovale. To maximize patient security and cannulation success, a frameless stereotactic system was evaluated in a phantom study, a cadaveric study, and a preliminary clinical trial.

METHODS:

Frameless stereotaxy using an optical navigation system, an aiming device, and a noninvasive vacuum mouthpiece-based registration and patient fixation technique was used for the targeting of a test body based on 1-, 3-, and 5-mm axial computed tomographic slices and of the foramen ovale in three cadavers and 15 patients based on 3-mm axial computed tomographic slices.

RESULTS:

The mean normal (x/y) localization accuracy/standard deviation (n = 360) was 1.31/0.67 mm (1-mm slices), 1.38/0.65 mm (3-mm slices), and 1.84/0.96 mm (5-mm slices). Significantly better results were achieved with 1- and 3-mm slices when compared with 5-mm slices (P < 0.001). The foramen ovale (3 × 6 mm) was successfully cannulated at the first attempt in all cadavers and patients, which indicates clinical localization accuracies better than 1.5 mm in the anteroposterior and 3 mm in the medial-lateral directions.

CONCLUSION:

Based on the noninvasive Vogele-Bale-Hohner vacuum mouthpiece, there is no need for invasive head clamp fixation. Imaging, real laboratory simulation, and the actual surgical intervention can be separated in time and location. The presented data suggest that frameless stereotaxy is a predictable and reproducible procedure, which may enhance patient security and cannulation success independent of the surgeon's experience.
Submandibular-Infratemporal Interpositional Carotid Artery Bypass for Cranial Base Tumors and Giant Aneurysms
Authors: Couldwell William T. , Liu James K. , Amini Amin , Kan Peter
Published: October 2006

OBJECTIVE:

Cerebral revascularization is an important strategy in the surgical management of some complex cranial base tumors and unclippable aneurysms. A high-flow bypass may be necessary in planned carotid occlusion or sacrifice. The cervical-to-supraclinoid internal carotid artery bypass or cervical carotid-to-middle cerebral artery bypass are useful procedures to bypass lesions at the base of the cranium. We describe technical modifications of the submandibular-infratemporal interpositional saphenous vein (or radial artery) graft bypass technique specifically designed to avoid removal of the zygoma.

METHODS:

The saphenous vein or radial artery interpositional graft is tunneled through a burr hole created in the floor of the middle fossa via a submandibular-infratemporal route avoiding removal of zygoma and attachments of the masseter or temporalis muscles.

RESULTS:

The technique is demonstrated in one patient with removal of a malignant cavernous sinus tumor and in another patient with an unclippable giant carotid bifurcation aneurysm.

CONCLUSION:

The advantages of this approach include preservation of the facial anatomy and creation of a short and safe route for passage of the saphenous vein or radial artery graft.
Intratumoral Hydrogen Peroxide Injection During Meningioma Resection
Authors: Lichtenbaum Roger , de Souza Atos Alves , Jafar Jafar J.
Published: October 2006

OBJECTIVE:

Meningiomas, although histologically benign, pose a particular challenge to the neurosurgeon because of their extensive and exuberant vascularity. They often bleed extensively during resection until separated from their blood supply. There are a wide variety of hemostatic agents available to the neurosur-geon. Most of these means of hemostasis involve some sort of chemical, electrical, or compressive action. Although anecdotally known to be useful, the use of hydrogen peroxide as an intracranial hemostatic agent in meningioma surgery has not been formally reported. We report a technique of meningioma resection that uses intratumoral hydrogen peroxide injection, reducing the potential for blood loss and shortening resection times.

METHODS:

Seventy-five patients underwent resection of a meningioma using the direct intratumoral H2O2 injection technique. The locations of these meningiomas included convexity and cranial-based lesions. None of the patients underwent preoperative endovascular embolization.

RESULTS:

The use of this technique greatly facilitated the removal of these tumors. No evidence of air embolism occurred during Doppler surveillance and no other significant side effects attributable to H2O2 application were observed. @@CONCLUSION:@@ We demonstrate a previously unreported technique of meningi-oma resection that uses direct intratumoral hydrogen peroxide injection, potentially reducing blood loss, shortening resection times, and obviating the need for preoperative embolization.
Recanalization of Obstructed Cerebrospinal Fluid Ventricular Catheters Using Ultrasonic Cavitation
Authors: Ginsberg Howard J. , Drake James M. , Peterson Thomas M. , Cobbold Richard S.C.
Published: October 2006

OBJECTIVE:

Fifty percent of implanted cerebrospinal fluid (CSF) shunts fail within 2 years, primarily because of obstruction of the proximal catheter. Percutaneous techniques to reduce the morbidity of shunt revision are being developed. The authors describe the development of a device that uses ultrasonic cavitation to unblock ventricular catheters.

METHODS:

In collaboration with Cybersonics, Inc. (Erie, PA), we designed, built, and tested a system that produces low-frequency ultrasound (20–28 kHz). Extensional ultrasonic waves are transmitted along a tapered wire (final diameter, approximately 0.8 mm) to the tip, where cavitation is produced in a highly localized region. An in vitro model of sheep choroid plexus occluding typical ventricular catheters was developed. The device was safety tested in vivo in rat and pig brains by introducing the device into shunt catheters inserted during simulated shunt surgery. A clinical safety trial using the device to attempt to remove blocked and adherent ventricular catheters has commenced. RESULTS: In the sheep choroid plexus model, at least 90% of the occluded holes were unblocked in a few minutes, restoring normal flow. There was no adverse effect of the device within shunt catheters inserted into live animal brains. Four patients have undergone treatment with the device at open CSF shunt surgery without adverse effect, and the device seems effective at unblocking and freeing the occluded catheters.

CONCLUSION:

Ultrasonic cavitation produced at the end of a fine wire that is introduced percutaneously into a CSF shunt promises to be a useful technique for minimally invasive proximal ventricular CSF shunt catheter revision.
Treatment of Giant and Large Internal Carotid Artery Aneurysms With a High-Flow Replacement Bypass Using the Excimer Laser-Assisted Nonocclusive Anastomosis Technique
Authors: van Doormaal Tristan P.C. , Zwan Albert van der , Verweij Bon H. , Langer David J. , Tulleken Cornelis A.F.
Published: October 2006

OBJECTIVE:

To define the clinical value of the high-flow replacement bypass using the excimer laser-assisted nonocclusive anastomosis technique in the treatment of patients with a noncoilable, nonclippable giant or large intracranial aneurysm of the internal carotid artery (ICA).

METHODS:

We studied 34 patients with a giant intracranial aneurysm of the ICA proximal to its bifurcation who were treated with an extracranial-intercranial high-flow replacement bypass in our hospital between 1999 and 2004. We retrospectively collected data for patient characteristics, operative aspects, complications, and functional health scores using the modified Rankin scale. Long-term data were updated by questionnaire and telephone survey. Mean long-term follow-up period was 3.3 years (range, 0.6-5.6 yr).

RESULTS:

We were able to construct a patent bypass in 33 out of 34 patients (97%). In six patients (17%), we needed two bypass attempts. In one patient (3%), the bypass was technically impossible. After bypass construction, we occluded the ICA during or after surgery in 32 patients (94%), causing aneurysm thrombosis in all of these patients. A fatal complication occurred in two patients (6%) before we could occlude the ICA. A nonfatal complication occurred in seven patients (21%). In the long term, 25 patients (74%) had a favorable outcome and 27 patients (79%) were independent (modified Rankin scale, <3).

CONCLUSION:

This study shows that the excimer laser-assisted nonocclusive anastomosis high-flow replacement bypass, which provides maximum brain protection because of its nonocclusive character, is a reliable and effective method to treat these otherwise untreatable patients.
Therapy of Brain Arteriovenous Malformations: Multimodality Treatment from a Balanced Standpoint
Authors: Richling Bernd , Killer Monika , Al-Schameri Abdul R. , Ritter Lutz , Agic Rada , Krenn Michael
Published: October 2006

THE THREE THERAPEUTIC modalities for arteriovenous malformation (AVM) treatment (surgery, embolization, and radiotherapy) developed in the past years with specific tools, each tool with its own qualities. Soon after the implementation of embolization for treatment of AVMs, this technique was used in combination with microsurgery; since the development of radiosurgery, treatment algorithms combining embolization with surgery and eventual subsequent radiosurgery, embolization with radiosurgery, or surgery with subsequent radiosurgery have been reported. These different combinations have been in use under the term multimodality treatment for many years, but the algorithms regarding the combination of tools, which tool has priority, and how the risk levels of each tool are assessed shows great variability among institutions. Centers with a surgical background see embolization as a technique to increase surgical feasibility and radiosurgery as a tool to complete subtotal AVM excision. Institutions with an endovascular background embolize AVMs with the aim of maximal occlusion rates and view surgery or radiosurgery as a technique to be used if the goal of total endovascular occlusion cannot be achieved. Radiosurgeons receive patients after incomplete embolization or surgical extirpation or a combination of both.
Stickleback sperm saved by salt in ovarian fluid
Authors: Elofsson Helena , Van Look Katrien J. W. , Sundell Kristina , Sundh Henrik , Borg Bertil
Published: October 2006

Sperm of the three-spined stickleback Gasterosteus aculeatusdisplay a prolonged motility in the presence of ovarian fluid. The ovarian fluid prolongs sperm motility in freshwater from approximately 1 min to several hours, a trait that possibly gives the stickleback its unusual ability to spawn in waters of all salinities. The aim of the study was to look for factor(s) within the ovarian fluid responsible for prolonging sperm motility as well as to investigate the possible biological importance of the ovarian fluid under natural conditions. To that end, we measured the ionic content(Na+, Cl-, Ca2+ and K+) of the ovarian fluid and prepared ionic artificial ovarian fluids. We also prepared a mannitol solution with the same osmolality as the ovarian fluid in order to distinguish between the ionic and osmotic effect. We found that the ionic artificial fluids were equally effective as the natural ovarian fluid in prolonging sperm motility and survival over a range of concentrations, whereas the mannitol solution was far less effective. By insertion of natural ovarian fluid or ovarian fluid from which macromolecules had been removed by ultra filtration in nests it was found that macromolecules help by retaining ions. We also found that ovarian fluid in water, at concentrations as low as 0.75 and 1.56%, prolonged sperm motility and that the concentration of ions(Na+) present in the nest 15 min after spawning corresponded to at least 3% ovarian fluid. Previous fertilisation experiments have shown that it takes at least 15 min for stickleback sperm to fertilise all eggs in a batch. This indicates that the role of ovarian fluid in prolonging the sperm motility is biologically relevant and that the effect is exerted by the fluid's ionic content.