bluuebunny/crossref_metadata_2025_split huggingface dataset:
Import-Associated Translational Inhibition: Novel In Vivo Evidence for Cotranslational Protein Import intoDictyostelium discoideumMitochondria
Authors: Ahmed Afsar U. , Beech Peter L. , Lay Sui T. , Gilson Paul R. , Fisher Paul R. 
Published: August 2006

ABSTRACTTo investigate protein import into the mitochondria ofDictyostelium discoideum, green fluorescent protein (GFP) was fused as a reporter protein either to variable lengths of the N-terminal region of chaperonin 60 (the first 23, 40, 80, 97, and 150 amino acids) or to the mitochondrial targeting sequence of DNA topoisomerase II. The fusion proteins were expressed in AX2 cells under the actin-15 promoter. Fluorescence images of GFP transformants confirmed thatDictyosteliumchaperonin 60 is a mitochondrial protein. The level of the mitochondrially targeted GFP fusion proteins was unexpectedly much lower than the nontargeted (cytoplasmic) forms. The distinction between targeted and nontargeted protein activities was investigated at both the transcriptional and translational levels in vivo. We found that targeting GFP to the mitochondria results in reduced levels of the fusion protein even though transcription of the fusion gene and the stability of the protein are unaffected. [35S]methionine labeling and GFP immunoprecipitation confirmed that mitochondrially targeted GFP is translated at much slower rates than nontargeted GFP. The results indicate a novel phenomenon, import-associated translational inhibition, whereby protein import into the mitochondria limits the rate of translation. The simplest explanation for this is that import of the GFP fusion proteins occurs cotranslationally, i.e., protein synthesis and import into mitochondria are coupled events. Consistent with cotranslational import, Northern analysis showed that the GFP mRNA is associated with isolated mitochondria. This association occurred regardless of whether the GFP was fused to a mitochondrial leader peptide. However, the presence of an import-competent leader peptide stabilized the mRNA-mitochondria association, rendering it more resistant to extensive EDTA washing. In contrast with GFP, the mRNA of another test protein, aequorin, did not associate with the mitochondria, and its translation was unaffected by import of the encoded polypeptide into the mitochondria.
Is the VO2 slow component in heavy arm-cranking exercise associated with recruitment of type II muscle fibers as assessed by an increase in surface EMG?
Authors: Bernasconi Sylvain , Tordi Nicolas , Perrey Stéphane , Parratte Bernard , Monnier Guy 
Published: August 2006

The recruitment of additional type II muscle fibers is one mechanism often suggested to be responsible for the slow component of oxygen uptake (VO2 SC). We hypothesized that surface electromyogram (EMG) of the biceps brachii, triceps brachii, anterior deltoid, and infraspinatus muscles could be related to the VO2 SC amplitude during arm-cranking exercises above ventilatory threshold (VT). Eight healthy subjects performed transitions from rest to 6-min heavy exercise at a constant power output of approximately 40% between VT and peak VO2. A 2-component exponential model was used to fit the VO2 response. EMG were recorded the last 15 s of each minute to obtain root mean square (RMS) and mean power frequency (MPF). Mean EMG responses for RMS and MPF were calculated by averaging EMG responses of the 4 muscles. The VO2 SC amplitude was of 530 ± 166 mL/min and occurred after 134 ± 31 s of exercise onset. Significant correlations were found for most of the subjects between EMG parameters and the VO2 SC amplitude as determined between the 2nd and the 6th minute. For all muscles, RMS values significantly increased over time during the VO2 SC, whereas MPF decreased significantly. These results suggest a relation between the recruitment of additional type II muscle fibers and the VO2 SC in arm-cranking exercises.
Roles of Ca2+and protein kinase C in the excitatory response to serotonin in embryonic molluscan ciliary cells
Authors: Doran Shandra A. , Goldberg Jeffrey I. 
Published: August 2006

We examined the roles of Ca2+and protein kinase C (PKC) in the cilio-excitatory response to serotonin in pedal ciliary cells from Helisoma trivolvis embryos. Serotonin (5-hydroxytryptamine; 5-HT; 100 µmol/L) induced an increase in ciliary beat frequency (CBF) was abolished by microinjected BAPTA (50 mmol/L), but was only partially inhibited by the phospholipase C inhibitor U-73122 (10 µmol/L). The diacylglycerol analogs 1-oleoyl-2-acetyl-sn-glycerol (100 µmol/L) and 1,2-dioctanoyl-sn-glycerol (100 µmol/L) caused increases in [Ca2+]ithat were smaller than those induced by serotonin. In the absence of extracellular Ca2+, 1,2-dioctanoyl-sn-glycerol (100 µmol/L) failed to elicit an increase in both CBF and [Ca2+]i. In contrast, the serotonin-induced increase in CBF persisted in the absence of extracellular Ca2+, although the increase in [Ca2+]iwas abolished. PKC inhibitors bisindolylmaleimide (10 and 100 nmol/L) and calphostin C (10 nmol/L) partially inhibited the serotonin-induced increase in CBF, but didn’t affect the serotonin-induced change in [Ca2+]i. These findings suggest that an intracellular store-dependent increase in [Ca2+]imediates the cilio-excitatory response to serotonin. Furthermore, although PKC is able to cause an increase in [Ca2+]ithrough calcium influx, it contributes to the cilio-excitatory response to 5-HT through a different mechanism.
Growth-Inhibitory Effects of Human Anti-Insulin-Like Growth Factor-I Receptor Antibody (A12) in an Orthotopic Nude Mouse Model of Anaplastic Thyroid Carcinoma
Authors: Wang Zhuoying , Chakravarty Geetika , Kim Seungwon , Yazici Yasemin D. , Younes Maher N. , Jasser Samar A. , Santillan Alfredo A. , Bucana Corazon D. , El-Naggar Adel K. , Myers Jeffrey N. 
Published: August 2006

Abstract
Purpose: The insulin-like growth factor-I receptor (IGF-IR) and its ligands have been implicated in the pathogenesis and progression of various cancers, including those arising in the thyroid gland. We therefore evaluated whether the IGF-IR could serve as a potential target for therapy of anaplastic thyroid carcinoma (ATC).
Experimental Design: The expression and activation of the IGF-IR and some of its downstream signaling pathway components were evaluated in both human thyroid cancer specimens and thyroid cancer cell lines. The therapeutic potential of a humanized monoclonal antibody (A12) directed against IGF-IR was assessed in vitro and in vivo in an orthotopic model of ATC. Tumor volume and overall survival time were analyzed to evaluate the efficacy of A12 in vivo.
Results: IGF-IR was overexpressed in 94% of the thyroid cancers. Blockade of IGF-IR with A12 was effective in attenuating IGF-IR signaling both in vitro and in vivo. However, the inhibitory effects of A12 on cell proliferation were cell line dependent, as those ATC cell lines that had detectable levels of pIGF-IR were more sensitive to A12 treatment. A12 was equally effective in vivo, where it brought ∼57% (P = 0.041) inhibition in tumor volume. The concomitant use of A12 and irinotecan produced additive effects and resulted in a 93% (P &lt; 0.001) reduction in tumor volume. Blocking IGF-IR blocked Akt phosphorylation and decreased proliferation and microvessel density but increased apoptosis within the tumor xenografts. Our results also highlighted a previously undefined IGF-IR-mediated antiangiogenic effect on tumor-associated endothelium in thyroid cancers.
Conclusion: Blocking the IGF-IR with A12 seems to be a potential avenue for treating patients with ATC by its direct antitumor effects and its effects on the tumor vasculature.
Valproic Acid Prolongs Survival Time of Severe Combined Immunodeficient Mice Bearing Intracerebellar Orthotopic Medulloblastoma Xenografts
Authors: Shu Qin , Antalffy Barbara , Su Jack Meng Feng , Adesina Adekunle , Ou Ching-Nan , Pietsch Torsten , Blaney Susan M. , Lau Ching C. , Li Xiao-Nan 
Published: August 2006

AbstractPurpose: To develop novel orthotopic xenograft models of medulloblastoma in severe combined immunodeficient mice and to evaluate the in vivo antitumor efficacy of valproic acid.Experimental Design: Orthotopic xenografts were developed by injecting 103 to 105 tumor cells from four medulloblastoma cell lines (D283-MED, DAOY, MHH-MED-1, and MEB-MED-8A) into the right cerebellum of severe combined immunodeficient mice. Animals were then examined for reproducibility of tumorigenicity, cell number-survival time relationship, and histopathologic features. Tumor growth was monitored in vivo by serially sectioning the xenograft brains at 2, 4, 6, and 8 weeks postinjection. Valproic acid treatment, administered at 600 μg/h for 2 weeks via s.c. osmotic minipumps, was initiated 2 weeks after injection of 105 medulloblastoma cells, and treated and untreated animals were monitored for differences in survival. Changes in histone acetylation, proliferation, apoptosis, differentiation, and angiogenesis in xenografts were also evaluated.Results: Tumorigenicity was maintained at 100% in D283-MED, DAOY, and MHH-MED-1 cell lines. These cerebellar xenografts displayed histologic features and immunohistochemical profiles (microtubule-associated protein 2, glial fibrillary acidic protein, and vimentin) similar to human medulloblastomas. Animal survival time was inversely correlated with injected tumor cell number. Treatment with valproic acid prolonged survival time in two (D283-MED and MHH-MED-1) of the three models and was associated with induction of histone hyperacetylation, inhibition of proliferation and angiogenesis, and enhancement of apoptosis and differentiation.Conclusion: We have developed intracerebellar orthotopic models that closely recapitulated the biological features of human medulloblastomas and characterized their in vivo growth characteristics. Valproic acid treatment of these xenografts showed potent in vivo anti-medulloblastoma activity. These xenograft models should facilitate the understanding of medulloblastoma pathogenesis and future preclinical evaluation of new therapies against medulloblastoma.
DNA Integrity Assay: A Plasma-Based Screening Tool for the Detection of Prostate Cancer
Authors: Hanley Robert , Rieger-Christ Kimberly M. , Canes David , Emara Norah R. , Shuber Anthony P. , Boynton Kevin A. , Libertino John A. , Summerhayes Ian C. 
Published: August 2006

AbstractPurpose: The aim of this study was to evaluate the utility of the DNA integrity assay (DIA) as a plasma-based screening tool for the detection of prostate cancer.Experimental Design: Blood samples were collected from patients with biopsy-proven prostate cancer prior to prostatectomy (n = 123) and processed as two-spin plasma preparations. The three control groups included: males &lt;40 years old with no history of cancer (group 1, n = 20); cancer-free postprostatectomy patients (group 2, n = 25), and patients with a negative prostate biopsy (group 3, n = 22). DNA in plasma preparations were isolated, hybrid-captured, and DNA fragments (200 bp, 1.3, 1.8, and 2.4 kb) were multiplexed in real-time PCR. A baseline cutoff was determined for individual fragment lengths to establish a DIA score for each patient sample.Results: Patients with prostate cancer (86 of 123; 69.9%) were determined to have a positive DIA score of ≥7. The DIA results from control groups 1, 2, and 3 showed specificities of 90%, 92%, and 68.2%, respectively. Of the patients with negative age-adjusted prostate-specific antigen (PSA) and prostate cancer, 19 of 30 (63%) had a positive DIA score. The area under the receiver operating characteristic curve for DIA was 0.788.Conclusion: While detecting 69.9% of those with prostate cancer, DIA maintained an overall specificity of 68.2% to 92%, a range favorably comparable to that currently accepted for PSA (60-70%). The variability in specificity between control groups is likely explained by the established 19% to 30% detection of prostate cancer on subsequent biopsies associated with control group 3. DIA detected 63% of the prostate cancers undetected by currently accepted PSA ranges.
Endocan Expression and Relationship with Survival in Human Non–Small Cell Lung Cancer
Authors: Grigoriu Bogdan Dragos , Depontieu Florence , Scherpereel Arnaud , Gourcerol Delphine , Devos Patrick , Ouatas Taoufik , Lafitte Jean-Jacques , Copin Marie-Christine , Tonnel Andre-Bernard , Lassalle Philippe ,   The Thoracic Oncology Group
Published: August 2006

Abstract
Purpose: We evaluated the expression of endocan, a soluble lung- and kidney-selective endothelial cell-specific dermatan sulfate proteoglycan, in non–small cell lung tumors compared with normal lung and studied the significance of high levels of circulating endocan in patients with non–small cell lung cancer.
Material and Methods: Endocan and vascular endothelial growth factor mRNA expression were evaluated by semiquantitative PCR in tumoral and nontumoral lung tissue samples from a first series of 24 patients submitted to curative surgery. Relationships between survival, time to tumor progression, and serum levels of endocan were evaluated in a second series of 30 previously untreated patients addressed for staging.
Results: In non–small cell lung cancers, endocan mRNA was overexpressed compared with control lung. Immunohistochemistry shows that endocan was expressed only by tumor endothelium in all cases, especially in the periphery of the tumors, with no differences between adenocarcinoma and squamous cell carcinoma. Endocan and vascular endothelial growth factor mRNA expression was positively correlated in lung tumors. Serum endocan levels, as well as tumor, node, and metastasis status, were correlated with both survival and time to tumor progression. However, endocan serum level was not an independent prognostic factor due to its correlation with the presence of metastasis.
Conclusion: Endocan is overexpressed in non–small cell lung tumors compared with healthy lung and probably represents a response of tumoral endothelium to proangiogenic growth factor stimulation. Circulating levels of endocan might reflect tumor angiogenic stimulation and present prognostic significance.
High Progesterone Receptor Expression Correlates to the Effect of Adjuvant Tamoxifen in Premenopausal Breast Cancer Patients
Authors: Stendahl Maria , Rydén Lisa , Nordenskjöld Bo , Jönsson Per Ebbe , Landberg Göran , Jirström Karin 
Published: August 2006

Abstract
Purpose: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor–positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as “positive” or “negative” using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value.
Experimental Design: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group.
Results: Our findings show a gradually increasing tamoxifen effect in tumors with &gt;10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing &gt;75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70); P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84); P = 0.010] survival.
Conclusions: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing &gt;75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER.
Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice
Authors: Zhang YuJian , Xiang Laiman , Hassan Raffit , Paik Chang H. , Carrasquillo Jorge A. , Jang Beom-su , Le Nhat , Ho Mitchell , Pastan Ira 
Published: August 2006

Abstract
Purpose: To investigate the combined antitumor activity in mice of immunotoxin SS1P and Taxol.
Methods: Immunodeficient mice were implanted with A431/K5 tumors expressing mesothelin. Established tumors were treated i.v. with immunotoxin SS1P alone, i.p. with Taxol alone, or with the two agents together. SS1P was radiolabeled with 111In and used to study the effect of Taxol on its uptake by A431/K5 tumors.
Results: Using doses at which either agent alone caused stabilization of tumor growth, the combination was synergistic causing long-lasting complete remissions in many animals. In contrast, synergy was not observed when the same cells were treated with these agents in vitro. Tumor uptake of 111In-SS1P was not affected by treatment with Taxol.
Conclusion: The combination of Taxol and SS1P exerts a synergistic antitumor effect in animals but not in cell culture. This effect is not secondary to increased tumor uptake of the immunotoxin. Synergy could be due to improved immunotoxin distribution within the tumor or could involve factors released by other cell types in the tumors.
Influence of Garlic (Allium sativum) on the Pharmacokinetics of Docetaxel
Authors: Cox Michael C. , Low Jennifer , Lee James , Walshe Janice , Denduluri Neelima , Berman Arlene , Permenter Matthew G. , Petros William P. , Price Douglas K. , Figg William D. , Sparreboom Alex , Swain Sandra M. 
Published: August 2006

Abstract
Purpose: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate.
Experimental Design: Women with metastatic breast cancer were treated with docetaxel (30 mg/m2) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations.
Results: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m2 [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m2 (95% CI, 15.5-31.8) and 20.0 L/h/m2 (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian).
Conclusions: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.
Mutations Within the Kinase Domain and Truncations of the Epidermal Growth Factor Receptor Are Rare Events in Bladder Cancer: Implications for Therapy
Authors: Blehm Kelly N. , Spiess Philippe E. , Bondaruk Jolanta E. , Dujka Melanie E. , Villares Gabriel J. , Zhao Yi-jue , Bogler Oliver , Aldape Kenneth D. , Grossman H. Barton , Adam Liana , McConkey David J. , Czerniak Bogdan A. , Dinney Colin P. , Bar-Eli Menashe 
Published: August 2006

Abstract
Purpose: It has previously been reported that the patient response to gefitinib depends on the presence of mutations within the kinase domain of epidermal growth factor receptor (EGFR) or the expression of its truncated form, EGFR variant III (EGFRvIII). The focus of this study was to determine if these alterations are present within the tyrosine kinase and ligand-binding domain of EGFR in urothelial carcinoma.
Experimental Design: The kinase domain found within exons 18 to 21 of the EGFR from 11 bladder cancer cell lines and 75 patient tumors were subjected to automated sequencing. EGFRvIII expression was determined by immunohistochemistry using a urothelial carcinoma tissue microarray, and its expression was subsequently verified by reverse transcription PCR, real-time PCR, and Western blot analysis, using an EGFRvIII-transfected glioblastoma cell line and glioblastoma tumors as positive controls.
Results: Our analysis failed to detect mutations within the tyrosine kinase domain of EGFR in the 11 cell lines and 75 patients tested. The initial analysis of EGFRvIII expression by immunohistochemistry revealed that at least 50% of the patient tumors expressed EGFRvIII in a urothelial carcinoma tissue microarray. Conflicting reports exist, however, regarding the extent of EGFRvIII expression in tissues owing to the specificity of the antibodies and the methodologies used. Therefore, we sought to validate this observation by reverse transcription PCR, real-time PCR, and Western blot analysis. In these assays, none of the samples were positive for EGFRvIII except for control transfectants and glioblastomas.
Conclusions: When our results are taken together, we conclude that alterations within the tyrosine kinase domain and expression of EGFRvIII are rare events in bladder cancer. The present study has clinical implications in selecting tyrosine kinase inhibitors for the therapy of urothelial carcinoma.
Effects of Long-term Rofecoxib on Gastric Intestinal Metaplasia: Results of a Randomized Controlled Trial
Authors: Leung Wai K. , Ng Enders K.W. , Chan Francis K.L. , Chan Wing Y. , Chan Kui-fat , Auyeung Alex C.M. , Lam Candice C.H. , Lau James Y.W. , Sung Joseph J.Y. 
Published: August 2006

Abstract
Purpose: Gastric cancer and its premalignant gastric lesion, intestinal metaplasia (IM), frequently express cyclooxygenase-2 (COX-2) at high levels. We tested whether long-term use of specific COX-2 inhibitors regress gastric IM.
Experimental Design: This is a double-blind, randomized, placebo-controlled trial. Individuals with confirmed IM and Helicobacter pylori clearance were randomized to receive rofecoxib 25 mg daily or placebo. Endoscopy was done at baseline, at the end of year 1, and at the end of year 2, with multiple biopsies taken from the antrum and corpus. The primary end point was the proportion of subjects with regression of IM. Secondary end points were the severity of other histologic variables and the proportion of subjects with complete regression of IM.
Results: Two-hundred and thirteen subjects with confirmed IM were randomized. The proportion of subjects with the regression of IM did not differ significantly between rofecoxib and placebo groups (antrum, 24.5% versus 26.9%; P = 0.74; corpus, 4.3% versus 2.2%; P = 0.68). Patients on rofecoxib (19.1%) and on placebo (16.1%) had no IM detected in the stomach (P = 0.59). There was also no significant difference in the severity of IM between the two treatment groups (P ≥ 0.3).
Conclusions: There was no trend to suggest that treatment with rofecoxib for 2 years resulted in the regression of gastric IM. Although our findings cast doubt on the reversibility of gastric IM by COX-2 inhibitor, further studies are needed to establish the role of COX-2 inhibitors in different stages of gastric carcinogenesis.