bluuebunny/crossref_metadata_2025 huggingface dataset:
Mammalian Target of Rapamycin Inhibitors as Possible Adjuvant Therapy for Microscopic Residual Disease in Head and Neck Squamous Cell Cancer
Authors: Nathan Cherie-Ann O. , Amirghahari Nazanin , Rong Xiaohua , Giordano Tony , Sibley Don , Nordberg Mary , Glass Jonathan , Agarwal Anshul , Caldito Gloria
Published: March 2007

Molecular therapeutics identifies an aberration in tumors to select patients that benefit from molecular targeted therapy. Overexpression of eIF4E in histologically “tumor-free” surgical margins of head and neck squamous cell cancer (HNSCC) patients is an independent predictor of recurrence and is functionally activated through the Akt/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibitors are cytostatic agents, best used in combination therapy, we hypothesize that they can be used as long-term single agents in an HNSCC model of minimal residual disease (MRD). CCI-779, an mTOR inhibitor, arrested growth of a phosphatase and tensin homologue deleted on chromosome 10 (PTEN) abnormal HNSCC cell line FaDu, inhibiting phosphorylation of 4E-binding protein 1, resulting in increased association with eIF4E and inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Fluorescence in situ hybridization detected PTEN abnormalities in 68% of patient tumors and 35% of tumor-free margins. CCI-779 inhibited growth of established tumors in nude mice. However, in the MRD model, there were significant differences in the tumor-free rate between the control (4%) and the treatment group (50%), and the median tumor-free time was 7 versus 18 days, respectively (P < 0.0001). In those animals that formed tumors, CCI-779 caused a significant decrease in the tumor volume. The Kaplan-Meier curve showed that CCI-779 significantly increased survival (P < 0.0001). The mTOR pathway was inhibited in peripheral blood mononuclear cells potential surrogate markers of response to therapy. Stable transfection of FaDu with luciferase allowed us to monitor the effects of CCI-779 with bioluminescence imaging in the MRD model. These results pave the way for a clinical trial using targeted molecular therapy with CCI-779 as a single agent for mTOR-activated residual cells. [Cancer Res 2007;67(5):2160–8]
Effect of the Silybin-Phosphatidylcholine Complex (IdB 1016) on the Development of Mammary Tumors in HER-2/neu Transgenic Mice
Authors: Provinciali Mauro , Papalini Francesca , Orlando Fiorenza , Pierpaoli Sara , Donnini Alessia , Morazzoni Paolo , Riva Antonella , Smorlesi Arianna
Published: March 2007

Silybin, a main component of the milk thistle of Silybum marianum, has been reported to possess anticancer activity. We investigated the effects of IdB 1016, a complex of silybin with phosphatidylcholine, on the development of mammary tumors appearing spontaneously in HER-2/neu transgenic mice. The mechanisms involved in the antitumor effect of IdB 1016 were evaluated by studying the apoptosis, senescent-like growth arrest, intratumoral leukocyte infiltrate, and the expression of HER-2/neu and p53 in tumoral mammary glands from transgenic mice and in human breast SKBR3 tumor cells. The administration of IdB 1016 delayed the development of spontaneous mammary tumors, reduced the number and size of mammary tumor masses, and diminished lung metastasization in HER-2/neu transgenic mice. In tumoral mammary glands from IdB 1016–treated mice, a down-regulation of HER-2/neu gene expression was associated with an increased senescent-like growth arrest of tumor cells, and an increased infiltrate of neutrophils, CD4, and CD8 T cells. Both senescent-like growth arrest and apoptosis were significantly increased and were associated with a reduced p185HER-2/neu protein and an increased p53 mRNA in SKBR3 in vitro treated with IdB 1016 in comparison with control cells. The results show the antitumor effect of IdB 1016 in the development of spontaneous mammary tumors in HER-2/neu transgenic mice. The effect of IdB 1016 might be related to the down-regulation of HER-2/neu expression and the induction of senescent-like growth arrest and apoptosis through a p53-mediated pathway in tumor cells. [Cancer Res 2007;67(5):2022–9]
High-Throughput Screening Identifies Novel Agents Eliciting Hypersensitivity in Fanconi Pathway–Deficient Cancer Cells
Authors: Gallmeier Eike , Hucl Tomas , Brody Jonathan R. , Dezentje David A. , Tahir Khola , Kasparkova Jana , Brabec Viktor , Bachman Kurtis E. , Kern Scott E.
Published: March 2007

Inactivation of the Fanconi anemia (FA) pathway occurs in diverse human tumors among the general population and renders those tumors hypersensitive to DNA interstrand-cross-linking (ICL) agents. The identification of novel agents to which FA pathway–deficient cells were hypersensitive could provide new therapeutic opportunities and improve our molecular understanding of the FA genes. Using high-throughput screening, we assessed the growth of isogenic human cancer cells that differed only in the presence or absence of single FA genes upon treatment with 880 active drugs and 40,000 diverse compounds. We identified several compounds to which FA pathway–deficient cells were more sensitive than FA pathway–proficient cells, including two groups of structurally related compounds. We further investigated the compound eliciting the strongest effect, termed 80136342. Its mechanism of action was distinct from that of ICL agents; 80136342 did not cause increased chromosomal aberrations, enhanced FANCD2 monoubiquitination, H2AX phosphorylation, p53 activation, or ICL induction. Similar to ICL agents, however, 80136342 caused a pronounced G2 arrest in FA pathway–deficient cells. When applied in combination with ICL agents, 80136342 had at least additive toxic effects, excluding interferences on ICL-induced toxicity and facilitating a combinational application. Finally, we identified one particular methyl group necessary for the effects of 80136342 on FA–deficient cells. In conclusion, using high-throughput screening in an isogenic human FA cancer model, we explored a novel approach to identify agents eliciting hypersensitivity in FA pathway–deficient cells. We discovered several attractive candidates to serve as lead compounds for evaluating structure-activity relationships and developing therapeutics selectively targeting FA pathway–deficient tumors. [Cancer Res 2007;67(5):2169–77]
Intersex-like (IXL) Is a Cell Survival Regulator in Pancreatic Cancer with 19q13 Amplification
Authors: Kuuselo Riina , Savinainen Kimmo , Azorsa David O. , Basu Gargi D. , Karhu Ritva , Tuzmen Sukru , Mousses Spyro , Kallioniemi Anne
Published: March 2007

Pancreatic cancer is a highly aggressive disease characterized by poor prognosis and vast genetic instability. Recent microarray-based, genome-wide surveys have identified multiple recurrent copy number aberrations in pancreatic cancer; however, the target genes are, for the most part, unknown. Here, we characterized the 19q13 amplicon in pancreatic cancer to identify putative new drug targets. Copy number increases at 19q13 were quantitated in 16 pancreatic cancer cell lines and 31 primary tumors by fluorescence in situ hybridization. Cell line copy number data delineated a 1.1 Mb amplicon, the presence of which was also validated in 10% of primary pancreatic tumors. Comprehensive expression analysis by quantitative real-time reverse transcription-PCR indicated that seven transcripts within this region had consistently elevated expression levels in the amplified versus nonamplified cell lines. High-throughput loss-of-function screen by RNA interference was applied across the amplicon to identify genes whose down-regulation affected cell viability. This screen revealed five genes whose down-regulation led to significantly decreased cell viability in the amplified PANC-1 cells but not in the nonamplified MiaPaca-2 cells, suggesting the presence of multiple biologically interesting genes in this region. Of these, the transcriptional regulator intersex-like (IXL) was consistently overexpressed in amplified cells and had the most dramatic effect on cell viability. IXL silencing also resulted in G0-G1 cell cycle arrest and increased apoptosis in PANC-1 cells. These findings implicate IXL as a novel amplification target gene in pancreatic cancer and suggest that IXL is required for cancer cell survival in 19q13-amplified tumors. [Cancer Res 2007;67(5):1943–9]
Lung Cancer Cell Lines HarboringMETGene Amplification Are Dependent on Met for Growth and Survival
Authors: Lutterbach Bart , Zeng Qinwen , Davis Lenora J. , Hatch Harold , Hang Gaozhen , Kohl Nancy E. , Gibbs Jackson B. , Pan Bo-Sheng
Published: March 2007

Recent clinical successes of small-molecule epidermal growth factor receptor (EGFR) inhibitors in treating advanced non–small cell lung cancer (NSCLC) have raised hopes that the identification of other deregulated growth factor pathways in NSCLC will lead to new therapeutic options for NSCLC. Met, the receptor for hepatocyte growth factor, has been implicated in growth, invasion, and metastasis of many tumors including NSCLC. To assess the functional role for Met in NSCLC, we evaluated a panel of nine lung cancer cell lines for Met gene amplification, Met expression, Met pathway activation, and the sensitivity of the cell lines to short hairpin RNA (shRNA)–mediated Met knockdown. Two cell lines, EBC-1 and H1993, showed significant Met gene amplification and overexpressed Met receptors which were constitutively phosphorylated. The other seven lines did not exhibit Met amplification and expressed much lower levels of Met, which was phosphorylated only on addition of hepatocyte growth factor. We also found a strong up-regulation of tyrosine phosphorylation in β-catenin and p120/δ-catenin in the Met-amplified EBC-1 and H1993 cell lines. ShRNA-mediated Met knockdown induced significant growth inhibition, G1-S arrest, and apoptosis in EBC-1 and H1993 cells, whereas it had little or no effect on the cell lines that do not have Met amplification. These results strongly suggest that Met amplification identifies a subset of NSCLC likely to respond to new molecular therapies targeting Met. [Cancer Res 2007;67(5):2081–8]
Deletion of p37Ing1 in Mice Reveals a p53-Independent Role for Ing1 in the Suppression of Cell Proliferation, Apoptosis, and Tumorigenesis
Authors: Coles Andrew H. , Liang Huiling , Zhu Zhiqing , Marfella Concetta G.A. , Kang Joonsoo , Imbalzano Anthony N. , Jones Stephen N.
Published: March 2007

ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p37Ing1, a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37Ing1-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity. The results show that endogenous levels of p37Ing1 inhibit the proliferation of p53-wild-type and p53-deficient fibroblasts, and that p53 functions are unperturbed in p37Ing1-deficient cells. In addition, loss of p37Ing1 induces Bax expression and increases DNA damage–induced apoptosis in primary cells and mice irrespective of p53 status. Finally, p37Ing1 suppresses the formation of spontaneous follicular B-cell lymphomas in mice. These results indicate that p53 does not require p37Ing1 to negatively regulate cell growth and offers genetic proof that Ing1 suppresses cell growth and tumorigenesis. Furthermore, these data reveal that p37Ing1 can negatively regulate cell growth and apoptosis in a p53-independent manner. [Cancer Res 2007;67(5):2054–61]
Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma
Authors: Hjalgrim Henrik , Ekström Smedby Karin , Rostgaard Klaus , Molin Daniel , Hamilton-Dutoit Stephen , Chang Ellen T. , Ralfkiaer Elisabeth , Sundström Christer , Adami Hans-Olov , Glimelius Bengt , Melbye Mads
Published: March 2007

Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18–44 years) and older (45–74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89–5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86–2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19–7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8–4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (ORIM EBV+ HL versus EBV− HL, 2.68; 95% CI, 1.40–5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies. [Cancer Res 2007;67(5):2382–8]
GATA-1 Is Essential in EGF-Mediated Induction of Nucleotide Excision Repair Activity and ERCC1 Expression through ERK2 in Human Hepatoma Cells
Authors: Andrieux Lise O. , Fautrel Alain , Bessard Anne , Guillouzo André , Baffet Georges , Langouët Sophie
Published: March 2007

The nucleotide excision repair (NER) pathway and its leading gene excision-repair cross-complementary 1 (ERCC1) have been shown to be up-regulated in hepatocellular carcinomas even in the absence of treatment with chemotherapeutics. The aim of this study was to determine the mechanism involved in NER regulation during the liver cell growth observed in hepatocellular carcinoma. Both NER activity and ERCC1 expression were increased after exposure to the epidermal growth factor (EGF) in cultured normal and tumoral human hepatocytes. These increases correlated with the activation of the kinase signaling pathway mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK that is known to be a key regulator in the G1 phase of the hepatocyte cell cycle. Moreover, EGF-mediated activation of ERCC1 was specifically inhibited by either the addition of U0126, a MEK/ERK inhibitor or small interfering RNA-mediated knockdown of ERK2. Basal expression of ERCC1 was decreased in the presence of the phosphoinositide-3-kinase (PI3K) inhibitor and small hairpin RNA (shRNA) against the PI3K pathway kinase FKBP12-rapamycin-associated protein or mammalian target of rapamycin. Transient transfection of human hepatocytes with constructs containing different sizes of the 5′-flanking region of the ERCC1 gene upstream of the luciferase reporter gene showed an increase in luciferase activity in EGF-treated cells, which correlated with the presence of the nuclear transcription factor GATA-1 recognition sequence. The recruitment of GATA-1 was confirmed by chromatin immunoprecipitation assay. In conclusion, these results represent the first demonstration of an up-regulation of NER and ERCC1 in EGF-stimulated proliferating hepatocytes. The transcription factor GATA-1 plays an essential role in the induction of ERCC1 through the mitogen-activated protein kinase (MAPK) pathway, whereas the PI3K signaling pathway contributes to ERCC1 basal expression. [Cancer Res 2007;67(5):2114–23]
Insulin Receptor Substrate-1 Regulates the Transformed Phenotype of BT-20 Human Mammary Cancer Cells
Authors: Dalmizrak Ozlem , Wu An , Chen Jia , Sun Hongzhi , Utama Fransiscus E. , Zambelli Diana , Tran Thai H. , Rui Hallgeir , Baserga Renato
Published: March 2007

Although originating from a human breast cancer, BT-20 cells do not form colonies in soft agar. BT-20 cells do not express insulin receptor substrate-1 (IRS-1), which is known to promote both normal and abnormal growth and to inhibit differentiation. Stable expression of IRS-1 confers to BT-20 cells the ability to form colonies in soft agar. BT-20 cells form tumors in xenografts in mice, but the size of tumors is twice as large when the cells express IRS-1. The increased transformed phenotype is characterized by occupancy of the rDNA and cyclin D1 promoters by IRS-1 and the activation of the cyclin D1, c-myc, and rDNA promoters. In addition, the retinoblastoma protein, which is detectable in the rDNA promoter of quiescent BT-20/IRS-1 cells, is replaced by IRS-1 after insulin-like growth factor-I stimulation. Our results indicate that in BT-20 human mammary cancer cells, expression of IRS-1 activates promoters involved in cell growth and cell proliferation, resulting in a more transformed phenotype. Targeting of IRS-1 could be effective in inhibiting the proliferation of mammary cancer cells. [Cancer Res 2007;67(5):2124–30]
Immunoediting Sculpts Tumor Epitopes during Immunotherapy
Authors: Singh Reshma , Paterson Yvonne
Published: March 2007

Immunoediting of tumor-associated antigens occurs in response to immune pressure. We show that the mutation of residues within epitopes of HER-2/neu leads to the outgrowth of autochthonous tumors after immunizing HER-2/neu transgenic mice with Listeria monocytogenes therapeutic vaccines expressing fragments of HER-2/neu. Three of these vaccines target the extracellular domain (LmLLO-EC1, LmLLO-EC2, and LmLLO-EC3), and two of these vaccines target the intracellular domain (Lm-LLO-IC1 and Lm-LLO-IC2). Mutations occurred in the regions of the HER-2/neu molecule targeted by the Listeria strain expressing that region, which suggests that the rate of generation of escape mutants was a significant factor in the efficacy of each vaccine. A longer delay in the onset of tumors after immunotherapy occurred with the vaccine that targeted the kinase domain. We verified that the mutations in this domain occurred within novel CD8+ T-cell epitopes, and that the mutation of these residues abrogated CTL responses to these epitopes. The long delay in the onset of tumors after immunotherapy targeting the kinase domain may be because this region of HER-2/neu cannot undergo extensive mutations without impairing its ability to signal cell growth. [Cancer Res 2007;67(5):1887–92]
The Adaptive Immunologic Microenvironment in Colorectal Cancer: A Novel Perspective
Authors: Galon Jérôme , Fridman Wolf-Herman , Pagès Franck
Published: March 2007

Colorectal cancer is one of the most common malignancies, often presenting with a poor prognosis. To date, the anatomic extent of disease has been by far the most important prognostic factor. Recently, we obtained evidence that the type, density, and location of immune cells in colorectal cancer could provide a prognostic factor superior and independent to that of criteria related to the anatomic extent of the tumor. Here, we discuss the meaning and potential implications of this novel finding. [Cancer Res 2007;67(5):1883–6]
Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor
Authors: Yeh Tammie C. , Marsh Vivienne , Bernat Bryan A. , Ballard Josh , Colwell Heidi , Evans Ron J. , Parry Janet , Smith Darin , Brandhuber Barbara J. , Gross Stefan , Marlow Allison , Hurley Brian , Lyssikatos Joe , Lee Patrice A. , Winkler James D. , Koch Kevin , Wallace Eli
Published: March 2007

Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models.

Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models.

Results: The IC50 of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor–induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate–induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday.

Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.
Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo
Authors: Wolf Jeffrey S. , Li Guoyan , Varadhachary Atul , Petrak Karel , Schneyer Mark , Li Daqing , Ongkasuwan Julina , Zhang Xiaoyu , Taylor Rodney J. , Strome Scott E. , O'Malley Bert W.
Published: March 2007

Purpose: Human lactoferrin is a naturally occurring glycoprotein that inhibits cancer growth. Our purpose was to evaluate recombinant human lactoferrin as a chemotherapeutic agent against head and neck squamous cell carcinoma.

Experimental Design: Controlled experiments both in vitro and in the murine model evaluating both the effect and mechanism of lactoferrin on cancer growth.

Results: In both human and murine cell lines, lactoferrin induced dose-dependent growth inhibition. Using flow cytometric analysis, lactoferrin was shown to induce G1-G0 growth arrest. This arrest seemed to be modulated by down-regulation of cyclin D1. In the in vitro model, luminex data revealed that lactoferrin inhibited cellular release of proinflammatory and prometastatic cytokines, including interleukin-8, interleukin-6, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-α. Lactoferrin up-regulated the cellular activation of nuclear factor-κB within 4 h of cellular exposure. In C3h/HeJ mice implanted with SCCVII tumors, orally delivered lactoferrin inhibited tumor growth by 75% compared with control mice. Immunohistochemical analysis of harvested tumors revealed up to 20-fold increases of lymphocytes within treated animals. When mice were depleted of CD3+ cells, all lactoferrin-induced tumor inhibition was abrogated.

Conclusion: We conclude that human recombinant lactoferrin can inhibit the growth of head and neck squamous cell carcinoma via direct cellular inhibition as well as systemically via immunomodulation. Our data support the study of human lactoferrin as an immunomodulatory compound with therapeutic potential.
Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications
Authors: Huang Suyun
Published: March 2007

Numerous cytokines, growth factors, and oncogenic proteins activate signal transducer and activator of transcription 3 (Stat3), which has been recognized as one of the common pathways in cancer cells. Stat3 signaling affects the expression and function of a variety of genes that are critical to cell survival, cell proliferation, invasion, angiogenesis, and immune evasion. Evidently, the Stat3 signaling pathway regulates cancer metastasis and constitutes a potential preventive and therapeutic target for cancer metastasis.
Scaling Voice Activity Limitation and Participation Restriction in Dysphonic Individuals
Authors: Ma Estella P.-M. , Yiu Edwin M.-L.
Published: March 2007

The purpose of this study was to determine the most appropriate scaling procedure for evaluating voice activity limitation (AL) and voice participation restriction (PR). In a randomly counterbalanced design, 32 dysphonic individuals rated their self-perceived extents of voice AL and PR using two scaling procedures [equal-appearing interval (EAI) scaling and visual analogue (VA) scaling]. Results revealed that test-retest reliabilities were similar for the two scaling procedures. The overall extents of voice AL and PR obtained from the two scaling procedures were similar. Moreover, the significant linear relationships obtained between the EAI and VA data of voice AL and PR suggest both dimensions as metathetic in nature. Therefore, either EAI or VA scaling procedure would be considered as appropriate for rating voice AL and PR. However, the relative ease to use by consumers favours the choice of EAI over VA scaling procedure for evaluating voice AL and PR.
The Validity of a Simple Outcome Measure to Assess Stuttering Therapy
Authors: Huinck Wendy , Rietveld Toni
Published: March 2007

Objective: The validity of a simple and not time-consuming self-assessment (SA) Scale was tested to establish progress after or during stuttering therapy. Patients and Method: The scores on the SA scale were related to (1) objective measures (percentage of stuttered syllables, and syllables per minute) and (2) (self-)evaluation tests (self-evaluation questionnaires and perceptual evaluations or judgments of disfluency, naturalness and comfort by naïve listeners). Data were collected from two groups of stutterers at four measurement times: pretherapy, posttherapy, 12 months after therapy and 24 months after therapy. The first group attended the Comprehensive Stuttering Program: an integrated program based on fluency shaping techniques, and the second group participated in a Dutch group therapy: the Doetinchem Method that focuses on emotions and cognitions related to stuttering. Results: Results showed similar score patterns on the SA scale, the self-evaluation questionnaires, the objective measures over time, and significant correlations between the SA scale and syllables per minute, percentage of stuttered syllables, Struggle subscale of the Perceptions of Stuttering Inventory and judged fluency on the T1-T2 difference scores. Conclusion: We concluded that the validity of the SA measure was proved and therefore encourage the use of such an instrument when (stuttering) treatment efficacy is studied.
Instillation of Taurolidine/Heparin after Laparotomy Reduces Intraperitoneal Tumour Growth in a Colon Cancer Rat Model
Authors: Opitz I. , Van der Veen H. , Witte N. , Braumann C. , Mueller J.M. , Jacobi C.A.
Published: March 2007

Objective: To investigate whether irrigation of the abdominal cavity after laparotomy for caecum resection with taurolidine/heparin or adhesion prophylactic substances reduces intraperitoneal tumour growth or the local recurrence rate in a colon carcinoma rat model. Methods: 60 BDIX rats underwent caecum resection after intraperitoneal inoculation of 1 × 104 colon carcinoma cells (DHD/K12/TRb). Intergel®, Interceed®, taurolidine/heparin or NaCl 0.9% were intraperitoneally applied after randomisation. Finally, the total number and total weight of intraperitoneal metastases were determined as well as the adhesion score according to Moreno. Metastatic tissue was examined histologically and immunohistochemically (E-cadherin, CD44, β1-integrin). Results: Taurolidine/heparin significantly reduced not only the total number (3 vs. 11 in the control group) but also the total weight (65 vs. 330 mg) of intraperitoneal metastases in comparison to the control group (p = 0.003 and p = 0.005). E-Cadherin expression in the metastatic tissue of animals treated with taurolidine/heparin was significantly decreased (p = 0.016). Conclusion: Taurolidine/heparin effectively reduces intraperitoneal tumour growth when used as an intraoperative lavage. These results represent a good rationale for intraoperative adjuvant irrigation with taurolidine/heparin during resection of colon cancer.
Theories of Delusional Disorders
Authors: Kunert Hanns Jürgen , Norra Christine , Hoff Paul
Published: March 2007

Delusional syndromes can occur in a number of psychiatric, neurological or other disorders. They can also be caused by neurotoxic agents (e.g., heavy metals) as well as substance addiction. There are several hypotheses on the underlying cognitive or emotional processes associated with organic factors of delusional disorders, depending on the patient groups examined and the methods used. The aim of this paper is to provide a comprehensive review and critical assessment of the various, rather heterogeneous theories in this field.
Immunotherapy of Prolactinoma with a T Helper 1 Activator Adjuvant and Autoantigens: A Case Report
Authors: Hazrati Saleh Mohaghegh , Aghazadeh Javad , Mohtarami Fatemeh , Abouzari Mehdi , Rashidi Armin
Published: March 2007

Objective: To date, efforts to reliably manipulate the immune system to promote tumor regression in the brain have been disappointing. We report a unique experience of successful immunotherapy to treat a pituitary macroprolactinoma. Methods: A 31-year-old woman with an established history of pituitary macroprolactinoma who had undergone tumor resection followed by radiation was admitted to our clinic. The diagnosis had been made due to the patient’s symptoms, a serum prolactin (PRL) level of 29,600 mIU/l, a brain MRI revealing a 23 × 19 × 18 mm pituitary mass and a positive PRL immunohistochemistry of the mass. Six months following surgery, she reexperienced headache, excessive sweating and a serum PRL concentration of 2,960 mIU/l despite receiving 30 mg/day bromocriptine. Brain MRI revealed a pituitary mass (3 × 6 × 8 mm) compatible with a pituitary adenoma. Twenty micrograms per milliliter of G2 (as a T helper 1 activator adjuvant) was inoculated intradermally once per week for 24 consecutive weeks (each injection contained 10 µg of G2). The autoantigens were inoculated at the same time with G2. Results: After immunotherapy, serum PRL concentration decreased to 82 mIU/l, the patient’s symptoms disappeared, skin thickness increased to normal and bromocriptine dosage was tapered to 20 mg per week. A follow-up brain MRI revealed almost complete disappearance of the tumor. The patient does not complain of any problems at 1-year follow-up. Conclusion: Activation of both nonspecific (natural killer cells) and specific (cytotoxic T lymphocytes) immunity in relation to the T helper 1 cytokine network is a promising strategy for the treatment of tumors of the central nervous system in humans, especially pituitary macroprolactinomas.
Role of Combined L-Arginine and Prostaglandin E1 in Renal Ischemia-Reperfusion Injury
Authors: Mahmoud Ihab M. , Hussein Abd El-Aziz M. , Sarhan Mohammed E. , Awad Ali A. , El Desoky Ibrahim
Published: March 2007

Background:L-Arginine (L-arg) and Prostaglandin E1 (PGE1) have been used effectively as single agents to ameliorate renal ischemia-reperfusion injury. We hypothesized that combined treatment with L-arg and PGE1 would be more effective. Materials and Methods: The left renal artery of male Sprague-Dawley rats was clamped for 45 min and the right kidney was removed. Fifty six rats were randomly allocated into 5 groups each consisted of 12 rats except sham group (n = 8). (1) sham, underwent right nephrectomy only; (2) control, untreated ischemic rats; (3) L-arg group, L-arg-treated ischemic rats; (4) PGE1 group, PGE1-treated ischemic rats; (5) L-arg+PGE1 group, ischemic rats treated with both L-arg and PGE1. Renal function and histology were assessed on days 2 and 7 postoperatively. Results: All rats, except control ones, showed a significant improvement of renal function towards normal on postoperative day 7. Serum creatinine and creatinine clearance were significantly better in L-arg+PGE1 group compared to all other groups on day 7. With the exception of sham-operated and L-arg+PGE1-treated animals, all other groups showed significant increases in fractional excretion of sodium (FENa) in response to renal ischemia-reperfusion. The severest tubular damage was determined in the kidneys of control rats. Rats treated with L-arg+PGE1 had the least severe tubular damage. Conclusion: The administration of either L-arg or PGE1 attenuates both functional and structural consequences of renal warm ischemia. A near total protection might be achieved when both agents are administered concomitantly.
Recanalization and Outcome After Intra-Arterial Thrombolysis in Middle Cerebral Artery and Internal Carotid Artery Occlusion
Authors: Arnold Marcel , Kappeler Liliane , Nedeltchev Krassen , Brekenfeld Caspar , Fischer Urs , Keserue Borbala , Remonda Luca , Schroth Gerhard , Mattle Heinrich P.
Published: March 2007

Background and Purpose—

Recent studies have reported sex differences in recanalization and outcome after intravenous thrombolysis (IVT) in acute ischemic stroke.

Methods—

We analyzed sex differences in outcome in consecutive patients with middle cerebral artery (MCA) M1 or M2 and internal carotid artery (ICA) occlusion treated with intra-arterial thrombolysis (IAT). Recanalization immediately after thrombolysis and outcome after 3 months were assessed.

Results—

Two hundred five patients (111 men) with MCA and 43 (22 men) with ICA occlusion were identified. Baseline variables did not differ between the sexes except for a higher prevalence of smokers among men in the MCA group (31% vs 12%;
P
=0.001). Partial or complete recanalization (TIMI flow 2 or 3) of the MCA was observed in 71 (75%) women and 80 (72%) men (
P
=0.488). In the ICA group, 14 (67%) women and 11 men (50%) showed TIMI 2 or 3 recanalization (
P
=0.425). Favorable outcome (modified Rankin Scale score 0 to 2) was seen in 57 women (61%) and 63 men (57%) with MCA occlusion (
P
=0.512) and in 6 women (28%) and 4 men (18%) with ICA occlusion (
P
=0.656). After multiple-regression analyses, there was still no association between sex and outcome (
P
=0.763 for MCA and
P
=0.813 for ICA occlusion) or recanalization (
P
=0.488 for MCA and
P
=0.104 for ICA occlusion).

Conclusions—

There was no association between sex and recanalization or outcome after IAT. These findings are in contrast to previous studies reporting better recanalization and outcome after IVT in women and might have implications in the selection of patients for IAT or IVT.
Mechanical Thrombectomy of Intracranial Internal Carotid Occlusion
Authors: Flint Alexander C. , Duckwiler Gary R. , Budzik Ronald F. , Liebeskind David S. , Smith Wade S.
Published: March 2007

Background and Purpose—

Acute stroke from occlusion of the intracranial internal carotid artery (ICA) generally has a poor prognosis and appears to respond poorly to intravenous thrombolysis. Mechanical thrombectomy is a newly available modality for acute stroke therapy, but it is unknown whether this endovascular therapy may have a role in the specific setting of intracranial ICA occlusion. We therefore assessed the success rate of the Merci Retriever mechanical thrombectomy device in recanalization of intracranial ICA occlusions and sought to determine whether ICA recanalization with this therapy can result in better outcomes.

Methods—

All patients with acute stroke from intracranial ICA occlusion were identified in the MERCI and Multi MERCI Part I trials. We determined the success rate of ICA recanalization with endovascular thrombectomy and then assessed clinical outcomes according to whether vessel recanalization was successful.

Results—

Eighty patients with acute stroke from intracranial ICA occlusion were identified. Of these 80 patients, 53% had successful ICA recanalization with the Merci Retriever alone and 63% had ICA recanalization with use of the Merci Retriever plus adjunctive endovascular treatment. Baseline patient characteristics and procedural complications did not differ between the recanalized and nonrecanalized groups. Good clinical outcome, defined by a modified Rankin Scale of 0 to 2 at 90 days, occurred in 39% of patients with ICA recanalization (n=19 of 49) and in 3% of patients without ICA recanalization (n=1 of 30) (
P
<0.001; one patient was lost to follow up for 90-day modified Rankin Scale). Ninety-day mortality was 30% (n=15 of 50) in the recanalized group and 73% (n=22 of 30) in the nonrecanalized group (
P
<0.001). Symptomatic hemorrhage was not significantly different between the recanalized (6% [n=3 of 50]) and nonrecanalized (16.7% [n=5 of 30]) groups (
P
=0.14). Hemorrhage rates were also not found to be influenced by use of intravenous thrombolysis before mechanical thrombectomy. Multivariable logistic regression identified ICA recanalization (OR=28.4, 95% CI=2.6 to >99.9) and lack of history of hypertension (OR=0.15, 95% CI=0.04 to 0.57) as significant predictors of a good 90-day outcome. Failure to recanalize the ICA (OR=0.16, 95% CI=0.05 to 0.51) and age (per decade, OR=1.07, 95% CI=1.03 to 1.13) were significant predictors of mortality at 90 days.

Conclusions—

Mechanical thrombectomy of acute intracranial ICA occlusion using the Merci Retriever device, alone or in combination with adjunctive endovascular therapy, has a high rate of successful vessel recanalization. Subjects with successful ICA recanalization by this method have improved poststroke clinical outcome and survival compared with subjects in which the ICA is not successfully recanalized.
Risk of Rupture of Unruptured Intracranial Aneurysms in Relation to Patient and Aneurysm Characteristics
Authors: Wermer Marieke J.H. , van der Schaaf Irene C. , Algra Ale , Rinkel Gabriël J.E.
Published: March 2007

Background and Purpose—

We updated our previous review from 1996 on the risk of rupture of unruptured intracranial aneurysms, aiming to include the newly published articles.

Methods—

We reviewed all studies from our former meta-analysis and performed a Medline search for new studies published after 1996. We calculated overall risks of rupture for studies with a mean follow-up time of <5, 5 to 10, and >10 years. Relative risks (RR) were calculated by comparing the risk of rupture in patients with and without potential risk factors. We aimed to perform multivariable analyses of the different risk factors with meta-regression analysis.

Results—

We included 19 studies (10 new) with 4705 patients and 6556 unruptured aneurysms (follow-up 26 122 patient-years). The overall rupture risks were 1.2% (follow-up <5 years), 0.6% (follow-up 5 to 10 years), and 1.3% (follow-up >10 years). In the univariable analysis, statistically significant risk factors for rupture were age >60 years (RR 2.0; 95% confidence interval [CI], 1.1 to 3.7), female gender (RR 1.6; 95% CI, 1.1 to 2.4), Japanese or Finnish descent (RR 3.4; 95% CI, 2.6 to 4.4), size >5 mm (RR 2.3; 95% CI, 1.0 to 5.2), posterior circulation aneurysm (RR 2.5; 95% CI, 1.6 to 4.1), and symptomatic aneurysm (RR 4.4; 95% CI, 2.8 to 6.8). Meta-regression analysis yielded implausible results.

Conclusions—

Age, gender, population, size, site, and type of aneurysm should be considered in the decision whether to treat an unruptured aneurysm. Pooled multivariable analyses of individual data are needed to identify independent risk factors and to provide more reliable risk estimates for individual patients.
Physiological Roles of Vascular Nucleoside Transporters
Authors: Löffler Michaela , Morote-Garcia Julio C. , Eltzschig Shelley A. , Coe Imogen R. , Eltzschig Holger K.
Published: March 2007

Nucleoside transporters (NTs) comprise 2 widely expressed families, the equilibrative nucleoside transporters (diffusion-limited channels) and concentrative nucleoside transporters (sodium-dependent transporters). Because of their anatomic position at the blood-tissue interface, vascular NTs are in an ideal position to influence vascular nucleoside levels, particularly adenosine, which among others plays an important role in tissue protection during acute injury. For example, endothelial NTs contribute to preserving the vascular integrity during conditions of limited oxygen availability (hypoxia). Indeed, hypoxia-inducible factor-1-dependent repression of NTs results in enhanced extracellular adenosine signaling and thus attenuates hypoxia-associated increases in vascular leakage. In addition, vascular NTs also contribute to cardiac ischemic preconditioning, coronary vasodilation, and inhibition of platelet aggregation. Moreover, vascular nucleoside uptake via NTs is important for nucleoside recovery, particularly in cells lacking de novo nucleotide synthesis pathways (erythrocytes, leukocytes). Taken together, vascular NTs are critical in modulating adenosine-mediated responses during conditions such as inflammation or hypoxia.
How to Compare Two Quantities? A Computational Model of Flutter Discrimination
Authors: Verguts Tom
Published: March 2007

A task that has been intensively studied at the neural level is f lutter discrimination. I argue that f lutter discrimination entails a combination of a temporal assignment problem and a quantity comparison problem, and propose a neural network model of how these problems are solved. The network combines unsupervised and one-layer supervised training. The unsupervised part clusters input features (stimulus + time window) and the supervised part categorizes the resulting clusters. After training, the model shows a good fit with both neural and behavioral properties. New predictions are outlined and links with other cognitive domains are pointed out.
Topography and Dynamics of Associative Long-term Memory Retrieval in Humans
Authors: Khader Patrick , Knoth Kathrin , Burke Michael , Ranganath Charan , Bien Siegfried , Rösler Frank
Published: March 2007

The present study investigated the neurophysiological processes underlying associative long-term memory retrieval of objects and spatial positions by means of a modified fan paradigm with cued recall and two neuroimaging methods (electroencephalogram [EEG] and functional magnetic resonance imaging). In an acquisition phase, either one stimulus or two stimuli became associated with a noun. During retrieval, probe stimuli comprising noun pairs were presented, and participants had to recall the respective associations and decided whether the nouns are linked to each other via a commonly associated stimulus. With this design, the quality and quantity of recalled associations was systematically varied, whereas the triggering stimuli and response requirements were held constant in all experimental conditions. Recall time proved to be directly related to the number of associations fanning out from a retrieval cue. Correspondingly, the hemodynamic response (blood oxygen level-dependent [BOLD] signal) and the amplitude of slow negative EEG potentials increased monotonically with the number of associations in both left anterior and bilateral posterior cortical areas. These effects were consistently observed with content-specific topographies for the two distinct materials. Furthermore, the multimethod approach revealed a close temporal link between response times and event-related slow potential changes on the one side and a close topographical and amplitude correspondence between slow potentials and BOLD signal changes on the other. The integrated results suggest that the neuronal dynamics of associative memory retrieval are equivalent for different types of associations, but that the structural basis is clearly content-specific.
Interactive Continuous Collision Detection Using Swept Volume for Avatars
Authors: Kim Young J , Redon Stephane , Lin Ming C , Manocha Dinesh , Templeman Jim
Published: March 2007

We present an interactive algorithm for continuous collision detection between a moving avatar and its surrounding virtual environment. Our algorithm is able to compute the first time of contact between the avatar and the environment interactively, and also guarantees within a user-provided error threshold that no collision ever happens before the first contact occurs.

We model the avatar as an articulated body using line skeletons with constant offsets and the virtual environment as a collection of polygonized objects. Given the position and orientation of the avatar at discrete time steps, we use an arbitrary in-between motion to interpolate the path for each link between discrete instances. We bound the swept space of each link using interval arithmetic and dynamically compute a bounding volume hierarchy (BVH) to cull links that are not in close proximity to the objects in the virtual environment. The swept volumes (SVs) of the remaining links are used to check for possible interference and estimate the time of collision between the surface of the SV and the rest of the objects. Furthermore, we use graphics hardware to accelerate collision queries on the dynamically generated swept surfaces.

Our approach requires no precomputation and is applicable to general articulated bodies that do not contain a loop. We have implemented the algorithm on a 2.8 GHz Pentium IV PC with an NVIDIA GeForce 6800 Ultra graphics card and applied it to an avatar with 16 links, moving in a virtual environment composed of hundreds of thousands of polygons. Our prototype system is able to detect all contacts between the moving avatar and the environment in 10–30 ms.
Male Bonding in Ming China
Authors: Lam Joseph
Published: March 2007

Making friends and making music are two fundamental activities through which people construct their personal identities and social relationships in their historical, cultural, and engendered times and spaces. To probe such activities as revealing facets of Ming history and culture, this essay presents three case studies of Ming men making music and bonding with male friends. To highlight the expressive, cultural, and social significance of music, this essay postulates that music catalyzed male bonding in Ming China by providing a tool, a site, and a process for Ming men to express and negotiate their masculine desires, identities, and roles.
Human-Animal Studies in Australia: Current Directions
Authors: Mulcock Jane , Lloyd Natalie
Published: March 2007

In 2004, Natalie Lloyd and Jane Mulcock initiated the Australian Animals & Society Study Group, a network of social science, humanities and arts scholars that quickly grew to include more than 100 participants. In July 2005, about 50 participants attended the group's 4-day inaugural conference at the University of Western Australia, Perth. Papers in this issue emerged from the conference. They exemplify the Australian academy's work in the fields of History, Population Health, Sociology, Geography, and English and address strong themes: human-equine relationships; management of native and introduced animals; and relationships with other domestic, nonhuman animals—from cats and dogs to cattle. Human-Animal Studies is an expanding field in Australia. However, many scholars, due to funding and teaching concerns, focus their primary research in different domains. All authors in this issue—excepting one—are new scholars in their respective fields. The papers represent the diversity and innovation of recent Australian research on human-animal interactions. The authors look at both past and present, then anticipate future challenges in building an effective network to expand this field of study in Australia.