bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential regulation of MMPs and matrix assembly in chicken and turkey growth-plate chondrocytes
Authors: Simsa Stav , Hasdai Aharon , Dan Harel , Ornan Efrat Monsonego
Published: March 2007

Matrix metalloproteinases (MMPs) play a crucial role in growth-plate vascularization and ossification by processes involving proteolytic cleavage and remodeling of the extracellular matrix (ECM). Their regulation in the growth plate is crucial for normal vs. impaired matrix assembly. Tibial dyschondroplasia (TD), a prevalent skeletal abnormality in avian species, is characterized by the formation of a nonvascularized, nonmineralized plaque in the growth plate. Here, we show differential regulation of MMPs in cultured chondrocytes from chickens and turkeys; retinoic acid (RA) elevated MMP-2 activity in both species, but only in chicken did it induce MMP-9 activity. In contrast, phorbol 12-myristate 13-acetate (PMA) treatment induced MMP-9 activity in turkey chondrocytes but not in those of chicken. Moreover, we found different developmental patterns of TD in chickens and turkeys in-vivo as lower concentrations of, and shorter exposure to thiram were required in chicken than in turkey for TD induction. Growth-plate cartilage taken from thiram-induced lesions had lower gelatinolytic and caseinolytic activities compared with normal cartilage. Likewise, thiram reduced MMP-2 and MMP-13 activity in both chicken and turkey chondrocytes in vitro, although 10-fold higher concentrations were required for this effect in the latter. Finally, the combined treatments of RA or PMA with thiram induced MMP-9 activity in turkey but not in chicken chondrocytes. Furthermore, RA combined with thiram synergistically upregulated its activity in turkey but not chicken chondrocytes. Taken together, these results suggest that mechanisms of MMP regulation differ in the growth plates of these closely related avian species, resulting in altered matrix assembly as exemplified by TD development.
How does exercise intensity and type affect equine distal tarsal subchondral bone thickness?
Authors: Murray R. C. , Branch M. V. , Dyson S. J. , Parkin T. D. H. , Goodship A. E.
Published: March 2007

Adaptation of osteochondral tissues is based on the strains experienced during exercise at each location within the joint. Different exercise intensities and types may induce particular site-specific strains, influencing osteochondral adaptation and potentially predisposing to injury. Our hypotheses were that patterns of equine distal tarsal subchondral bone (SCB) thickness relate to the type and intensity of exercise, and that high-intensity exercise leads to site-specific increases in thickness. SCB thickness was measured at defined dorsal and plantar locations on magnetic resonance images of cadaver tarsi collected from horses with a history of low [general purpose ( n = 20) and horse walker ( n = 6)] or high [elite competition ( n = 12), race training ( n = 15), and treadmill training ( n = 4)] exercise intensity. SCB thickness was compared between sites within each exercise group and between exercise groups. SCB thickness in elite competition and race training, but not treadmill training, was greater than low-intensity exercise. For general purpose horses, lateral SCB thickness was greater than medial throughout. Horse walker exercise led to relatively thicker lateral and medial SCB compared with the midline. Elite competition was associated with increased SCB thickness of the proximal small tarsal bones medially and the distal bones laterally. For race training and treadmill training, there were minimal differences between sites overall, although the lateral aspect was greater than medial, and medial greater than midline at a few sites for race training. In conclusion, different types of high-intensity exercise were associated with different patterns of SCB thickness across the joints from medial to lateral and proximal to distal, indicating that both exercise intensity and type of exercise affect the SCB response at any particular site within the equine distal tarsal joints.
Identification of the Benign Mesenchymal Tumor Gene HMGA2 in Lymphangiomyomatosis
Authors: D'Armiento Jeanine , Imai Kazushi , Schiltz John , Kolesnekova Natalya , Sternberg David , Benson Kathleen , Pardo Annie , Selman Moises , Smolarek Theresa , Vundavalli Murty , Sonnet Joshua , Szabolcs Matthias , Chada Kiran
Published: March 2007

The normal expression pattern of HMGA2, an architectural transcription factor, is primarily restricted to cells of the developing mesenchyme before their overt differentiation during organogenesis. A detailed in situ hybridization analysis showed that the undifferentiated mesoderm of the embryonic lung expressed Hmga2 but it was not expressed in the newborn or adult lung. Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. Here, we show that HMGA2 is misexpressed in pulmonary lymphangiomyomatosis (LAM), a severe disorder of unknown etiology consisting of lymphatic smooth muscle cell proliferation that results in the obstruction of airways, lymphatics, and vessels. Immunohistochemistry was done with antibodies to HMGA2 and revealed expression in lung tissue samples obtained from 21 patients with LAM. In contrast, HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation. In vivo studies in transgenic mice show that misexpression of HMGA2 in smooth muscle cells resulted in increased proliferation of these cells in the lung surrounding the epithelial cells. Therefore, similar to the other mesenchymal neoplasms, HMGA2 misexpression in the smooth muscle cell leads to abnormal proliferation and LAM tumorigenesis. These results suggest that HMGA2 plays a central role in the pathogenesis of LAM and is a potential candidate as a therapeutic target. [Cancer Res 2007;67(5):1902–9]
Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation
Authors: Liang Li , Mendonca Marc S. , Deng Li , Nguyen Son C. , Shao Changshun , Tischfield Jay A.
Published: March 2007

Exposure to ionizing radiation (IR) is a risk factor for carcinogenesis because it is a mutagen. However, a single 4-Gy whole body X-ray exposure only induced a modest increase of mutations at the Aprt reporter gene locus in mouse T cells. Intriguingly, when the same dose of IR was given in a fractionated protocol (1 Gy × 4 at weekly intervals), there was a strong induction of Aprt mutations in T cells. Many of these were mutations that arose via interstitial deletions inclusive of Aprt or by intragenic deletions. We hypothesized that the weekly fractionated X-ray exposures select for somatic cells with reduced p53 expression and/or reduced apoptosis, which, in turn, may have facilitated the accumulation of interstitial deletions, as in p53-deficient mice. We indeed found that splenocytes of mice with three previous exposures (1 Gy × 4 in total) were more resistant to X-ray–induced apoptosis than those of mice exposed to X-rays for the first time (1 Gy total). Thus, repeated X-ray radiation selects for reduced apoptosis in vivo. However, this reduced apoptosis is p53-independent, because p53 induction and the up-regulation of genes downstream of p53, such as Bax and p21, were similar between the 1-Gy and 1 Gy × 4 groups. Reduced apoptosis probably allows the generation of more mutations, particularly deletion mutations. Because both reduced apoptosis and increased somatic mutation are risk factors for carcinogenesis, they may contribute to the paradigm in which different radiation exposure schemes are varied in their efficiency in inducing lymphomagenesis. [Cancer Res 2007;67(5):1910–7]
Synthetic Affibody Molecules: A Novel Class of Affinity Ligands for Molecular Imaging of HER2-Expressing Malignant Tumors
Authors: Orlova Anna , Tolmachev Vladimir , Pehrson Rikard , Lindborg Malin , Tran Thuy , Sandström Mattias , Nilsson Fredrik Y. , Wennborg Anders , Abrahmsén Lars , Feldwisch Joachim
Published: March 2007

The Affibody molecule ZHER2:342-pep2, site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-ZHER2:342-pep2 folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of 111In was achieved within 30 min at low (room temperature) and high temperatures (up to 90°C). Tumor uptake of 111In-DOTA-ZHER2:342-pep2 was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of >7.5, and high-contrast gamma camera images were obtained already 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of 111In-DOTA-ZHER2:342-pep2 obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-ZHER2:342-pep2 has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas. [Cancer Res 2007;67(5):2178–86]
Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors
Authors: Pospisil Pavel , Wang Ketai , Al Aowad Ayman F. , Iyer Lakshmanan K. , Adelstein S. James , Kassis Amin I.
Published: March 2007

We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2′-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ2-P) was docked in silico into the X-ray structure of PAP. The data indicate that IQ2-P docked into the PAP active site with a calculated inhibition constant (Ki) more favorable than that of the PAP inhibitor α-benzylaminobenzylphosphonic acid. When 125IQ2-P, the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2′-hydroxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ2-OH). Similarly, the incubation of IQ2-P with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ2-OH crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with 125IQ2-P showed accumulation of radioactive grains (125IQ2-OH) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases. [Cancer Res 2007;67(5):2197–205]
Differential Constitutive Activation of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Cells BearingEGFRGene Mutation and Amplification
Authors: Okabe Takafumi , Okamoto Isamu , Tamura Kenji , Terashima Masaaki , Yoshida Takeshi , Satoh Taroh , Takada Minoru , Fukuoka Masahiro , Nakagawa Kazuhiko
Published: March 2007

The identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however. We have now examined 16 NSCLC cell lines, including eight newly established lines from Japanese NSCLC patients, for the presence of EGFR mutations and amplification. Four of the six cell lines that harbor EGFR mutations were found to be positive for EGFR amplification, whereas none of the 10 cell lines negative for EGFR mutation manifested EGFR amplification, suggesting that these two types of EGFR alteration are closely associated. Endogenous EGFRs expressed in NSCLC cell lines positive for both EGFR mutation and amplification were found to be constitutively activated as a result of ligand-independent dimerization. Furthermore, the patterns of both EGFR amplification and EGFR autophosphorylation were shown to differ between cell lines harboring the two most common types of EGFR mutation (exon 19 deletion and L858R point mutation in exon 21). These results reveal distinct biochemical properties of endogenous mutant forms of EGFR expressed in NSCLC cell lines and may have implications for treatment of this condition. [Cancer Res 2007;67(5):2046–53]
Metabotropic Glutamate Receptor 1 and Glutamate Signaling in Human Melanoma
Authors: Namkoong Jin , Shin Seung-Shick , Lee Hwa Jin , Marín Yarí E. , Wall Brian A. , Goydos James S. , Chen Suzie
Published: March 2007

Recently, several laboratories have started to investigate the involvement of glutamate signaling in cancer. In previous studies, we reported on a transgenic mouse model that develops melanoma spontaneously. Subsequent studies in these mice identified that the aberrant expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes played a critical role in the onset of melanoma. Confirmation of the etiologic role of GRM1 in melanoma development was shown in a second transgenic line with GRM1 expression under the regulation of a melanocyte-specific dopachrome tautomerase promoter. Ectopic expression of GRM1 was also detected in a subset of human melanoma cell lines and biopsies, suggesting that aberrant expression of GRM1 in melanocytes may contribute to the development of human melanoma. GRM1, a seven-transmembrane domain G protein–coupled receptor, is normally expressed and functional in neuronal cells, and its ligand, glutamate, is the major excitatory neurotransmitter. Human melanoma cells are shown here to release elevated levels of glutamate, implying a possible autocrine loop. Treatment of GRM1-expressing human melanoma cells with a GRM1 antagonist (LY367385 or BAY36-7620) or a glutamate release inhibitor (riluzole) leads to a suppression of cell proliferation as well as a decrease in levels of extracellular glutamate. Treatment of human melanoma cell xenografts with riluzole for 18 days via p.o. gavage or i.v. injection leads to inhibition of tumor growth by 50% in comparison with controls. These data suggest the importance of glutamate signaling in human melanoma and imply that the suppression of glutamate signaling may be a new target for melanoma therapy. [Cancer Res 2007;67(5):2298–305]
Twist and Epithelial-Mesenchymal Transition Are Induced by the EBV Oncoprotein Latent Membrane Protein 1 and Are Associated with Metastatic Nasopharyngeal Carcinoma
Authors: Horikawa Toshiyuki , Yang Jing , Kondo Satoru , Yoshizaki Tomokazu , Joab Irene , Furukawa Mitsuru , Pagano Joseph S.
Published: March 2007

Nasopharyngeal carcinoma (NPC), an EBV-associated malignancy, is highly metastatic compared with other head and neck tumors, perhaps because of its viral link. Here, we show that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), induces epithelial-mesenchymal transition (EMT) via Twist, a master transcriptional regulator in embryogenesis and newly implicated in metastasis, which, in turn, are likely to contribute to the highly metastatic character of NPC. LMP1 could induce EMT and its associated cell motility and invasiveness in a cell culture model, whereas expression of Twist small interfering RNA reversed LMP1-induced EMT. In diverse EBV-infected cell lines, expression of Twist correlates with expression of LMP1. Dominant-negative LMP1 could suppress Twist expression in EBV-positive cells, whereas LMP1 could induce Twist in EBV-negative nasopharyngeal cells. LMP1 signals through the nuclear factor-κB pathway, and an IκB superrepressor inhibited induction of Twist by LMP1. Finally, in human NPC tissues, expression of Twist and LMP1 is directly correlated and expression of Twist is associated with metastasis clinically. These results suggest that induction of Twist by a human viral oncoprotein LMP1 directly contributes to the metastatic nature of NPC. [Cancer Res 2007;67(5):1970–8]
CD4 T-Helper Responses to the Anaplastic Lymphoma Kinase (ALK) Protein in Patients with ALK-Positive Anaplastic Large-Cell Lymphoma
Authors: Ait-Tahar Kamel , Barnardo Martin C.N. , Pulford Karen
Published: March 2007

We have previously shown both humoral and CTL responses to anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large-cell lymphoma (ALCL). However, because CD4+ T-helper (Th) cells also play a vital role in developing and maintaining tumor immunity, we investigated the presence of a CD4+ Th response in ALK-positive ALCL. Using an IFN-γ ELISPOT assay, we identified two ALK-derived DRB1-restricted 24-mer promiscuous peptides, ALK1278–301 and ALK2233–256, as being immunogenic in six ALK-positive ALCL patients but not in two ALK-negative ALCL patients or five normal subjects. A significant interleukin-4 response to the ALK peptides was detected in only one ALK-positive patient. CD4+ Th cell lines lysed ALK-positive ALCL cell lines in a MHC class II–restricted manner. This first report of a CD4+ Th response to ALK provides valuable information for developing future immunotherapeutic options for ALK-positive ALCL patients who fail to respond well to conventional therapies. [Cancer Res 2007;67(5):1898–901]
Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b
Authors: Wang Wenjun , Edington Howard D. , Rao Uma N.M. , Jukic Drazen M. , Land Stephanie R. , Ferrone Soldano , Kirkwood John M.
Published: March 2007

Purpose: The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1 plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type I IFNs. The goal of this study was to understand the effects of high-dose IFNα2b (HDI) in relation to the balance of pSTAT1 and pSTAT3.

Experimental Design: We evaluated STAT1 and STAT3 jointly as mediators of IFNα effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies.

Results: HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II).

Conclusion: IFNα2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.
NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 Activity and Expression in Bladder and Ovarian Cancer and Lower NRH:Quinone Oxidoreductase 2 Activity Associated with an NQO2 Exon 3 Single-Nucleotide Polymorphism
Authors: Jamieson David , Wilson Kerrie , Pridgeon Simon , Margetts Jane P. , Edmondson Richard J. , Leung Hing Y. , Knox Richard , Boddy Alan V.
Published: March 2007

Purpose: NRH:quinone oxidoreductase 2 (NQO2) is a homologue of NAD(P)H:quinone oxidoreductase 1 (NQO1). Despite 54% homology with human NQO1, NQO2 has little endogenous enzymatic activity. However, NQO2 has potential as a therapeutic target because the addition of the nonbiogenic electron donor dihydronicotinamide riboside (NRH) selectively potentiates the bioactivation of the alkylating agent tretazicar (CB 1954). The NQO activity of ovarian and bladder tumors was determined and the effect of NQO polymorphisms on NQO activity was investigated.

Experimental Design: Intraperitoneal ovarian metastases and bladder tumor clinical samples were analyzed for NQO1 and NQO2 activity, mRNA expression by semiquantitative reverse transcription-PCR, and genotype by RFLP analysis.

Results: NQO1 activity was higher in the bladder cohort than in the ovarian cohort (0-283 and 0-30 nmol/min/mg, respectively; P < 0.0001). In contrast, NQO2 activity was higher in the ovarian tissue than in the bladder samples (0.15-2.27 and 0-1.14 nmol/min/mg, respectively; P = 0.0004). In both cohorts, the NQO1 C609T single-nucleotide polymorphism (SNP) was associated with ∼7-fold lower NQO1 activity. The NQO2 exon 3 T14055C SNP was associated with lower NQO2 activity relative to wild-type [median values of 0.18 and 0.37 nmol/min/mg in the bladder samples (P = 0.007) and 0.82 and 1.16 nmol/min/mg in the ovarian cohort (P = 0.034)].

Conclusion: This is the first observation reporting an apparent association between an NQO2 exon 3 SNP and lower enzymatic activity. The high NQO2 activity of intraperitoneal ovarian metastases relative to other tissues indicates a potential for tretazicar therapy in the treatment of this disease. In contrast, the low level of NQO1 activity and expression relative to other tissues suggests that NQO1-directed therapies would not be appropriate.
Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51
Authors: Yao Qing , Weigel Brenda , Kersey John
Published: March 2007

Purpose: DNA-damaging agents, such as etoposide, while clinically useful in leukemia therapy, are limited by DNA repair pathways that are not well understood. 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), an inhibitor of the molecular chaperone heat shock protein 90 (Hsp90), inhibits growth and induces apoptosis in FLT3+ leukemia cells. In this study, we evaluated the effects of etoposide and 17-AAG in leukemia cells and the roles of Hsp90, FMS-like tyrosine kinase 3 (FLT3), checkpoint kinase 1 (Chk1), Rad51, and topoisomerase II in this inhibition.

Experimental Design: The single and combined effects of 17-AAG and etoposide and the mechanism of these effects were evaluated. FLT3 and the DNA repair-related proteins, Chk1 and Rad51, were studied in small interfering RNA (siRNA)–induced cell growth inhibition experiments in human leukemia cells with wild-type or mutated FLT3.

Results: We found that etoposide and the Hsp90/FLT3 inhibitor 17-AAG, had synergistic inhibitory effects on FLT3+ MLL-fusion gene leukemia cells. Cells with an internal tandem duplication (ITD) FLT3 (Molm13 and MV4;11) were more sensitive to etoposide/17-AAG than leukemias with wild-type FLT3 (HPB-Null and RS4;11). A critical role for FLT3 was shown in experiments with FLT3 ligand and siRNA targeted to FLT3. An important role for topoisomerase II and the DNA repair-related proteins, Chk1 and Rad51, in the synergistic effects was suggested from the results.

Conclusions: The repair of potentially lethal DNA damage by etoposide in leukemia cells is dependent on intact and functioning FLT3 especially leukemias with ITD-FLT3. These data suggest a rational therapeutic strategy for FLT3+ leukemias that combines etoposide or other DNA-damaging agents with Hsp90/FLT3 inhibitors such as 17-AAG.
Toward Improved Differential Diagnosis of Adductor Spasmodic Dysphonia and Muscle Tension Dysphonia
Authors: Roy Nelson , Mauszycki Shannon C. , Merrill Ray M. , Gouse Manon , Smith Marshall E.
Published: March 2007

Objective: Adductor spasmodic dysphonia (ADSD) is characterized by a strained-strangled voice quality, whose diagnosis relies exclusively on auditory-perceptual features. However, muscle tension dysphonia (MTD) – a functional voice disorder – can mimic ADSD thereby contributing to diagnostic confusion. Unlike MTD, ADSD has been described as ‘task-specific’, implying that certain vocal tasks such as sentences loaded with predominantly voiced consonants will provoke greater sign expression. This investigation examined the diagnostic value of variable sign expression based upon phonetic loading as a means to disambiguate ADSD and MTD. Patients and Methods: Five listeners, who were blinded to the purpose of the study, used a 10-cm visual analog scale to rate the dysphonia severity of two sentences (one all-voiced and one containing primarily voiceless consonants) produced by participants with ADSD (n = 29) or MTD (n = 33). Results: A mixed-design ANOVA, with Group (ADSD vs. MTD) as the between-subjects variable and Sentence Type (all-voiced vs. voiceless) as the within-subjects variable, confirmed a significant Group-by-Sentence Type interaction effect (p = 0.0002). In ADSD, ratings of dysphonia severity for the all-voiced sentence were significantly more severe than for the voiceless sentence (p < 0.0001), whereas in MTD no significant difference was observed (p = 0.9981). The ROC curve confirmed that differences in dysphonia severity between voiced and voiceless sentences represented a highly specific (88–100%), but only 48% sensitive diagnostic marker. Conclusions: Phonetic loading influences sign expression in ADSD, and assists in discriminating ADSD from MTD.
Correlation between the Serum Values of Soluble Intercellular Adhesion Molecule-1 and Total Sialic Acid Levels in Patients with Breast Cancer
Authors: Basoglu M. , Atamanalp S.S. , Yildirgan M.I. , Aydinli B. , Öztürk G. , Akcay F. , Oren D.
Published: March 2007

Background: In this study, we aimed to investigate serum total sialic acid (TSA) and soluble intracellular adhesion molecule-1 (sICAM-1) levels in breast cancer patients to find a correlation with the cancer stage. Methods: The parameters from sera of 61 patients with breast cancer were measured. The concentrations of serum sICAM-1 and TSA were measured in serum samples from 61 patients with breast cancer and 25 healthy control subjects using enzyme-linked immunoassay and thiobarbituric acid method. Results: Mean serum sICAM-1 and TSA levels were significantly higher in the total patient group than in the control group (p < 0.001). Thus, the correlation between TSA and sICAM-1 became more significant in metastatic breast cancer. There were significant positive correlations between TSA and sICAM-1 in stage I+II (r = 0.59, p < 0.05), stage III (r = 0.47, p < 0.05), and stage IV (r = 0.89, p < 0.01), and total patient group (r = 0.56, p < 0.001). Conclusion: SerumsICAM-1 and TSA levels were higher in patients with breast cancer, than that of the control group, and also in the metastatic breast cancer group. Significant correlations between serum sICAM-1 and TSA may reflect the similar function of these molecules as adhesion molecules, and their roles in the carcinogenesis of breast cancer as well as metastasis.
Safety and Efficacy of s-Citalopram in Patients with Co-Morbid Major Depression and Diabetes Mellitus
Authors: Amsterdam Jay D. , Shults Justine , Rutherford Nancy , Schwartz Stanley
Published: March 2007

Objective: The presence of co-morbid depressive symptoms may have a negative impact on the management of diabetes mellitus. Moreover, some antidepressants may adversely affect glycemic control. Selective serotonin reuptake inhibitors (SSRIs) may improve glycemic control and may be beneficial for patients with co-morbid depression and diabetes. We examined the safety and efficacy of s-citalopram therapy in patients with co-morbid depression and diabetes, and its ability to improve glycemic control. Research Design and Methods: 17 patients were enrolled into the trial and 14 patients received open-label s-citalopram therapy for up to 16 weeks. Clinical outcome measures included the 17-item Hamilton depression rating (HAM-D 17) and the clinical global impressions severity (CGI/S) and change (CGI/C) ratings. In addition, fasting glucose, fructosamine, and glycosylated hemoglobin-A1C measures were obtained before and during s-citalopram therapy. Results: We observed a significant reduction in mean HAM-D 17 (p < 0.001), CGI/S (p = 0.001) and CGI/C (p = 0.001) ratings during s-citalopram therapy. We also observed a modest, non-significant reduction in fasting glucose, fructosamine, and glycosylated hemoglobin-A1C levels during s-citalopram therapy. Limitation: Limitations of this study include a modest patient sample size and a 16-week treatment duration which may have been insufficient to demonstrate the full effect of SSRI therapy on glycemic control. Conclusion: We observed a significant reduction in depressive symptoms and modest, non-significant reductions in fasting glucose, fructosamine, and glycosylated hemoglobin-A1C levels during SSRI therapy of co-morbid depression and diabetes.
Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis
Authors: Galvez Anita S. , Diwan Abhinav , Odley Amy M. , Hahn Harvey S. , Osinska Hanna , Melendez Jaime G. , Robbins Jeffrey , Lynch Roy A. , Marreez Yehia , Dorn Gerald W.
Published: March 2007

Regulating the balance between synthesis and proteasomal degradation of cellular proteins is essential for tissue growth and maintenance, but the critical pathways regulating protein ubiquitination and degradation are incompletely defined. Although participation of calpain calcium-activated proteases in post-necrotic myocardial autolysis is well characterized, their importance in homeostatic turnover of normal cardiac tissue is controversial. Hence, we evaluated the consequences of physiologic calpain (calcium-activated protease) activity in cultured cardiomyocytes and unstressed mouse hearts. Comparison of in vitro proteolytic activities of cardiac-expressed calpains 1 and 2 revealed calpain 1, but not calpain 2, activity at physiological calcium concentrations. Physiological calpain 1 activation was evident in adenoviral transfected cultured cardiomyocytes as proteolysis of specific substrates, generally increased protein ubiquitination, and accelerated protein turnover, that were each inhibited by coexpression of the inhibitor protein calpastatin. Conditional forced expression of calpain 1, but not calpain 2, in mouse hearts demonstrated substrate-specific proteolytic activity under basal conditions, with hyperubiquitination of cardiac proteins and increased 26S proteasome activity. Loss of myocardial calpain activity by forced expression of calpastatin diminished ubiquitination of 1 or more specific myocardial proteins, without affecting overall ubiquitination or proteasome activity, and resulted in a progressive dilated cardiomyopathy characterized by accumulation of intracellular protein aggregates, formation of autophagosomes, and degeneration of sarcomeres. Thus, calpain 1 is upstream of, and necessary for, ubiquitination and proteasomal degradation of a subset of myocardial proteins whose abnormal accumulation produces autophagosomes and degeneration of cardiomyocytes with functional decompensation.
Validation of Transcranial Doppler With Computed Tomography Angiography in Acute Cerebral Ischemia
Authors: Tsivgoulis Georgios , Sharma Vijay K. , Lao Annabelle Y. , Malkoff Marc D. , Alexandrov Andrei V.
Published: March 2007

Background and Purpose—

Both transcranial Doppler (TCD) and spiral computed tomography angiography (CTA) are used for noninvasive vascular assessment tools in acute stroke. We aimed to evaluate the diagnostic accuracy of TCD against CTA in patients with acute cerebral ischemia.

Methods—

Consecutive patients presenting to the Emergency Department with symptoms of acute (<24 hours) cerebral ischemia underwent emergent high-resolution brain CTA with a multidetector helical scanner. TCD was performed at bedside with a standardized, fast-track insonation protocol before or shortly (<2 hours) after completion of the CTA. Previously published diagnostic criteria were prospectively applied for TCD interpretation independent of angiographic findings.

Results—

A total of 132 patients (74 men, mean±SD age 63±15 years) underwent emergent neurovascular assessment with brain CTA and TCD. Compared with CTA, TCD showed 34 true-positive, 9 false-negative, 5 false-positive, and 84 true-negative studies (sensitivity 79.1%, specificity 94.3%, positive predictive value 87.2%, negative predictive value 90.3%, and accuracy 89.4%). In 9 cases (7%), TCD showed findings complementary to the CTA (real-time embolization, collateralization of flow with extracranial internal carotid artery disease, alternating flow signals indicative of steal phenomenon).

Conclusions—

Bedside TCD examination yields satisfactory agreement with urgent brain CTA in the evaluation of patients with acute cerebral ischemia. TCD can provide real-time flow findings that are complementary to information provided by CTA.
Mental Practice in Chronic Stroke
Authors: Page Stephen J. , Levine Peter , Leonard Anthony
Published: March 2007

Background and Purpose—

Mental practice (MP) of a particular motor skill has repeatedly been shown to activate the same musculature and neural areas as physical practice of the skill. Pilot study results suggest that a rehabilitation program incorporating MP of valued motor skills in chronic stroke patients provides sufficient repetitive practice to increase affected arm use and function. This Phase 2 study compared efficacy of a rehabilitation program incorporating MP of specific arm movements to a placebo condition using randomized controlled methods and an appropriate sample size.

Method—

Thirty-two chronic stroke patients (mean=3.6 years) with moderate motor deficits received 30-minute therapy sessions occurring 2 days/week for 6 weeks, and emphasizing activities of daily living. Subjects randomly assigned to the experimental condition also received 30-minute MP sessions provided directly after therapy requiring daily MP of the activities of daily living; subjects assigned to the control group received the same amount of therapist interaction as the experimental group, and a sham intervention directly after therapy, consisting of relaxation. Outcomes were evaluated by a blinded rater using the Action Research Arm test and the upper extremity section of the Fugl-Meyer Assessment.

Results—

No pre-existing group differences were found on any demographic variable or movement scale. Subjects receiving MP showed significant reductions in affected arm impairment and significant increases in daily arm function (both at the
P
<0.0001 level). Only patients in the group receiving MP exhibited new ability to perform valued activities.

Conclusions—

The results support the efficacy of programs incorporating mental practice for rehabilitating affected arm motor function in patients with chronic stroke. These changes are clinically significant.
Circulating Apoptotic Progenitor Cells
Authors: Schwartzenberg Shmuel , Deutsch Varda , Maysel-Auslender Sofia , Kissil Sarina , Keren Gad , George Jacob
Published: March 2007

Background—

Progenitor CD34 cells are capable of differentiating into endothelial cells and play a role in neoangiogenesis. Circulating CD34
+
cells and endothelial progenitor cells are increased in acute coronary syndrome (ACS) patients possibly because of peripheral mobilization. We tested the hypothesis that circulating apoptotic progenitors are detectable in healthy subjects and altered in ACS patients.

Methods and Results—

Peripheral blood mononuclear cells were isolated by Ficoll density gradient from 53 patients with ACS undergoing coronary angiography and 27 healthy subjects. Apoptosis in progenitor CD34
+
cells was assessed using the Annexin V-PE/7-AAD detection kit, and fluorescence-activated cell sorter analysis was performed with triple staining for CD34, annexin-V, and 7-AAD. The percentage of apoptotic CD34
+
progenitors was determined in the 2 subject groups and correlated with clinical characteristics. The percentage of apoptotic CD34
+
progenitor cells was significantly increased in patients with ACS as compared with healthy subjects and was associated with the extent of coronary stenosis by angiography. There was no significant correlation between apoptotic progenitor CD34
+
cells and the other parameters that we examined (age, smoking, hypertension, hyperlipidemia, diabetes mellitus, ejection fraction, creatinine levels, or taking any of the various medications, including beta blockers, thiazides, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium blockers, nitrates, or statins).

Conclusion—

We established for the first time to our knowledge an assay to detect circulating apoptotic progenitor cells using fluorescein isothiocyanate–anti-CD34 MAb, annexin V-PE, and 7-AAD and found that apoptotic CD34
+
cells are increased in ACS patients and in patients with more extensive coronary artery disease. This novel assay may shed new light on the factors governing the hemeostasis of progenitor CD34
+
cells.
Selective Visual Dimension Weighting Deficit after Left Lateral Frontopolar Lesions
Authors: Pollmann S. , Mahn K. , Reimann B. , Weidner R. , Tittgemeyer M. , Preul C. , Müller H. J. , von Cramon D. Y.
Published: March 2007

The left lateral frontopolar (LFP) cortex showed dimension change-related activation in previous event-related functional magnetic resonance imaging studies of visual singleton feature search with non-brain-lesioned participants. Here, we tested the hypothesis that LFP actively supports changes of attention from the old to the new target-defining dimension in singleton feature search. Singleton detection was selectively slowed in this task when the target-defining dimension changed in patients with left LFP lesions, compared with patients with frontomedian lesions as well as with matched controls without brain lesions. We discuss a potential role of LFP in change detection when the optimal allocation of dimension-based attention is not clearly defined by the task.
Auditory Brainstem Correlates of Perceptual Timing Deficits
Authors: Johnson Krista L. , Nicol Trent G. , Zecker Steven G. , Kraus Nina
Published: March 2007

Children with language-based learning problems often exhibit pronounced speech perception difficulties. Specifically, these children have increased difficulty separating brief sounds occurring in rapid succession (temporal resolution). The purpose of this study was to better understand the consequences of auditory temporal resolution deficits from the perspective of the neural encoding of speech. The findings provide evidence that sensory processes relevant to cognition take place at much earlier levels than traditionally believed. Thresholds from a psychophysical backward masking task were used to divide children into groups with good and poor temporal resolution. Speech-evoked brainstem responses were analyzed across groups to measure the neural integrity of stimulus-time mechanisms. Results suggest that children with poor temporal resolution do not have an overall neural processing deficit, but rather a deficit specific to the encoding of certain acoustic cues in speech. Speech understanding relies on the ability to attach meaning to rapidly fluctuating changes of both the temporal and spectral information found in consonants and vowels. For this to happen properly, the auditory system must first accurately encode these time-varying acoustic cues. Speech perception difficulties that often co-occur in children with poor temporal resolution may originate as a neural encoding deficit in structures as early as the auditory brainstem. Thus, speech-evoked brainstem responses are a biological marker for auditory temporal processing ability.
Setting the Stage for Automatic Syntax Processing: The Mismatch Negativity as an Indicator of Syntactic Priming
Authors: Hasting Anna S. , Kotz Sonja A. , Friederici Angela D.
Published: March 2007

The present study investigated the automaticity of morphosyntactic processes and processes of syntactic structure building using event-related brain potentials. Two experiments were conducted, which contrasted the impact of local subject-verb agreement violations (Experiment 1) and word category violations (Experiment 2) on the mismatch negativity, an early event-related brain potential component reflecting automatic auditory change detection. The two violation types were realized in two-word utterances comparable with regard to acoustic parameters and structural complexity. The grammaticality of the utterances modulated the mismatch negativity response in both experiments, suggesting that both types of syntactic violations were detected automatically within 200 msec after the violation point. However, the topographical distribution of the grammaticality effect varied as a function of violation type, which indicates that the brain mechanisms underlying the processing of subject-verb agreement and word category information may be functionally distinct even at this earliest stage of syntactic analysis. The findings are discussed against the background of studies investigating syntax processing beyond the level of two-word utterances.
Spatio-temporal Brain Dynamics Underlying Saccade Execution, Suppression, and Error-related Feedback
Authors: Herdman Anthony T. , Ryan Jennifer D.
Published: March 2007

Human and nonhuman animal research has outlined the neural regions that support saccadic eye movements. The aim of the current work was to outline the sequence by which distinct neural regions come on-line to support goal-directed saccade execution and error-related feedback. To achieve this, we obtained behavioral responses via eye movement recordings and neural responses via magnetoencephalography (MEG), concurrently, while participants performed an antisaccade task. Neural responses were examined with respect to the onset of the saccadic eye movements. Frontal eye field and visual cortex activity distinguished subsequently successful goal-directed saccades from (correct and erroneous) reflexive saccades prior to the deployment of the eye movement. Activity in the same neural regions following the saccadic movement distinguished correct from incorrect saccadic responses. Error-related activity in the frontal eye fields preceded that from visual regions, suggesting a potential feedback network that may drive corrective eye movements. This work provides the first empirical demonstration of simultaneous remote eyetracking and MEG recording. The coupling of behavioral and neuroimaging technologies, used here to characterize dynamic brain networks underlying saccade execution and error-related feedback, demonstrates a novel within-paradigm converging evidence approach by which to outline the neural underpinnings of cognition.
ATLAS: A Scalable Network Framework for Distributed Virtual Environments
Authors: Lee Dongman , Lim Mingyu , Han Seunghyun , Lee Kyungmin
Published: March 2007

A distributed virtual environment (DVE) is a software system that allows users in a network to interact with each other by sharing a common view of their states. As users are geographically distributed over large networks like the internet and the number of users increases, scalability is a key aspect to consider for real-time interaction. Various solutions have been proposed to improve the scalability in DVE systems but they are either focused on only specific aspects or customized to a target application. In this paper, we classify the approaches for improving scalability of DVE into five categories: communication architecture, interest management, concurrency control, data replication, and load distribution. We then propose a scalable network framework for DVEs, ATLAS. Incorporated with our various scalable schemes, ATLAS meets the scalability of a system as a whole. The integration experiences of ATLAS with several virtual reality systems ensure the versatility of the proposed solution.
Localizing Sound Sources in a CAVE-Like Virtual Environment with Loudspeaker Array Reproduction
Authors: Gröhn Matti , Lokki Tapio , Takala Tapio
Published: March 2007

In a CAVE-like virtual environment spatial audio is typically reproduced with amplitude panning on loudspeakers behind the screens. We arranged a localization experiment where the subjects' task was to point to the perceived location of a sound source. Measured accuracy for a static source was as good as the accuracy in previous headphone experiments using head-related transfer functions. We also measured the localization accuracy of a moving auditory stimulus. The accuracy was decreased by an amount comparable to the minimum audible movement angle.
Size-Constancy in the CAVE
Authors: Kenyon Robert V , Sandin Daniel , Smith Randall C , Pawlicki Richard , Defanti Thomas
Published: March 2007

The use of virtual environments (VE) for many research and commercial purposes relies on its ability to generate environments that faithfully reproduce the physical world. However, due to its limitations the VE can have a number of flaws that adversely affect its use and believability. One of the more important aspects of this problem is whether the size of an object in the VE is perceived as it would be in the physical world. One of the fundamental phenomena for correct size is size-constancy, that is, an object is perceived to be the same size regardless of its distance from the observer. This is in spite of the fact that the retinal size of the object shrinks with increasing distance from the observer. We examined size-constancy in the CAVE and found that size-constancy is a strong and dominant perception in our subject population when the test object is accompanied by surrounding environmental objects. Furthermore, size-constancy changes to a visual angle performance (i.e., object size changed with distance from the subject) when these surrounding objects are removed from the scene. As previously described for the physical world, our results suggest that it is necessary to provide surrounding objects to aid in the determination of an object's depth and to elicit size-constancy in VE. These results are discussed regarding their implications for viewing objects in projection-based VE and the environments that play a role in the perception of object size in the CAVE.