bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis
Authors: Gavert Nancy , Sheffer Michal , Raveh Shani , Spaderna Simone , Shtutman Michael , Brabletz Thomas , Barany Francis , Paty Phillip , Notterman Daniel , Domany Eytan , Ben-Ze'ev Avri 
Published: August 2007

Abstract
L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of β-catenin-T-cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of β-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy. [Cancer Res 2007;67(16):7703–12]
Use of a Peptide Derived from Foot-and-Mouth Disease Virus for the Noninvasive Imaging of Human Cancer: Generation and Evaluation of 4-[18F]Fluorobenzoyl A20FMDV2 for In vivo Imaging of Integrin αvβ6 Expression with Positron Emission Tomography
Authors: Hausner Sven H. , DiCara Danielle , Marik Jan , Marshall John F. , Sutcliffe Julie L. 
Published: August 2007

Abstract
Expression of the epithelial-specific integrin αvβ6 is low or undetectable in most adult tissues but may be increased during wound healing and inflammation and is up-regulated dramatically by many different carcinomas, making αvβ6 a promising target for the in vivo detection of cancer using noninvasive imaging. In addition, αvβ6 is recognized as promoting invasion and correlates with aggressive behavior of human cancers and thus agents that recognize αvβ6 specifically in vivo will be an essential tool for the future management of αvβ6-positive cancers. Recently, we identified the peptide NAVPNLRGDLQVLAQKVART (A20FMDV2), derived from foot-and-mouth disease virus, as a potent inhibitor of αvβ6. Using flow cytometry and ELISA, we show that this peptide is highly selective, inhibiting αvβ6-ligand binding with a IC50 of 3 nmol/L, an activity 1,000-fold more selective for αvβ6 than for other RGD-directed integrins (αvβ3, αvβ5, and α5β1). A20FMDV2 was radiolabeled on solid-phase using 4-[18F]fluorobenzoic acid, injected into mice bearing both αvβ6-negative and αvβ6-positive (DX3puro/DX3puroβ6 cell lines) xenografts and imaged using a small animal positron emission tomography (PET) scanner. Rapid uptake (&lt;30 min) and selective retention (&gt;5 h) of radioactivity in the αvβ6-positive versus the αvβ6-negative tumor, together with fast renal elimination of nonspecifically bound activity, resulted in specific imaging of the αvβ6-positive neoplasm. These data suggest that PET imaging of αvβ6-positive tumors is feasible and will provide an important new tool for early detection and improved management of many types of cancers. [Cancer Res 2007;67(16):7833–40]
Bin1 Ablation Increases Susceptibility to Cancer during Aging, Particularly Lung Cancer
Authors: Chang Mee Young , Boulden Janette , Katz Jessica B. , Wang Liwei , Meyer Thomas J. , Soler Alejandro Peralta , Muller Alexander J. , Prendergast George C. 
Published: August 2007

Abstract
Age is the major risk factor for cancer, but few genetic pathways that modify cancer incidence during aging have been described. Bin1 is a prototypic member of the BAR adapter gene family that functions in vesicle dynamics and nuclear processes. Bin1 limits oncogenesis and is often attenuated in human cancers, but its role in cancer suppression has yet to be evaluated fully in vivo. In the mouse, homozygous deletion of Bin1 causes developmental lethality, so to assess this role, we examined cancer incidence in mosaic null mice generated by a modified Cre-lox technology. During study of these animals, one notable phenotype was an extended period of female fecundity during aging, with mosaic null animals retaining reproductive capability until the age of 17.3 ± 1.1 months. Through 1 year of age, cancer incidence was unaffected by Bin1 ablation; however, by 18 to 20 months of age, ∼50% of mosaic mice presented with lung adenocarcinoma and ∼10% with hepatocarcinoma. Aging mosaic mice also displayed a higher incidence of inflammation and/or premalignant lesions, especially in the heart and prostate. In mice where colon tumors were initiated by a ras-activating carcinogen, Bin1 ablation facilitated progression to more aggressive invasive status. In cases of human lung and colon cancers, immunohistochemical analyses evidenced frequent attenuation of Bin1 expression, paralleling observations in other solid tumors. Taken together, our findings highlight an important role for Bin1 as a negative modifier of inflammation and cancer susceptibility during aging. [Cancer Res 2007;67(16):7605–12]
Epigenetic Modulation of Estrogen Receptor-α by pRb Family Proteins: A Novel Mechanism in Breast Cancer
Authors: Macaluso Marcella , Montanari Micaela , Noto Paul Bart , Gregorio Valter , Bronner Christian , Giordano Antonio 
Published: August 2007

Abstract
Estrogen receptor-α (ER-α) plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, ER-α gene expression can change during the course of disease and, consequently, therapy resistance can occur. The molecular mechanism governing ER-α transcriptional activity and/or silencing is still unclear. Here, we showed that the presence of a specific pRb2/p130 multimolecular complex on the ER-α promoter strongly correlates with the methylation status of this gene. Furthermore, we suggested that pRb2/p130 could cooperate with ICBP90 (inverted CCAAT box binding protein of 90 kDa) and DNA methyltransferases in maintaining a specific methylation pattern of ER-α gene. The sequence of epigenetic events for establishing and maintaining the silenced state of ER-α gene can be locus- or pathway- specific, and the local remodeling of ER-α chromatin structure by pRb2/p130 multimolecular complexes may influence its susceptibility to specific DNA methylation. Our novel hypothesis could provide a basis for understanding how the complex pattern of ER-α methylation and transcriptional silencing is generated and for understanding the relationship between this pattern and its function during the neoplastic process. [Cancer Res 2007;67(16):7731–7]
One-step Nucleic Acid Amplification for Intraoperative Detection of Lymph Node Metastasis in Breast Cancer Patients
Authors: Tsujimoto Masahiko , Nakabayashi Kadzuki , Yoshidome Katsuhide , Kaneko Tomoyo , Iwase Takuji , Akiyama Futoshi , Kato Yo , Tsuda Hitoshi , Ueda Shigeto , Sato Kazuhiko , Tamaki Yasuhiro , Noguchi Shinzaburo , Kataoka Tatsuki R. , Nakajima Hiromu , Komoike Yoshifumi , Inaji Hideo , Tsugawa Koichiro , Suzuki Koyu , Nakamura Seigo , Daitoh Motonari , Otomo Yasuhiro , Matsuura Nariaki 
Published: August 2007

Abstract
Purpose: Detection of sentinel lymph node (SLN) metastasis in breast cancer patients has conventionally been determined by intraoperative histopathologic examination of frozen sections followed by definitive postoperative examination of permanent sections. The purpose of this study is to develop a more efficient method for intraoperative detection of lymph node metastasis.
Experimental Design: Cutoff values to distinguish macrometastasis, micrometastasis, and nonmetastasis were determined by measuring cytokeratin 19 (CK19) mRNA in histopathologically positive and negative lymph nodes using one-step nucleic acid amplification (OSNA). In an intraoperative clinical study involving six facilities, 325 lymph nodes (101 patients), including 81 SLNs, were divided into four blocks. Alternate blocks were used for the OSNA assay with CK19 mRNA, and the remaining blocks were used for H&E and CK19 immunohistochemistry–based three-level histopathologic examination. The results from the two methods were then compared.
Results: We established CK19 mRNA cutoff values of 2.5 × 102 and 5 × 103 copies/μL. In the clinical study, an overall concordance rate between the OSNA assay and the three-level histopathology was 98.2%. Similar results were obtained with 81 SLNs. The OSNA assay discriminated macrometastasis from micrometastasis. No false positive was observed in the OSNA assay of 144 histopathologically negative lymph nodes from pN0 patients, indicating an extremely low false positive for the OSNA assay.
Conclusion: The OSNA assay of half of a lymph node provided results similar to those of three-level histopathology. Clinical results indicate that the OSNA assay provides a useful intraoperative detection method of lymph node metastasis in breast cancer patients.
Nicotine Induces Hypoxia-Inducible Factor-1α Expression in Human Lung Cancer Cells via Nicotinic Acetylcholine Receptor–Mediated Signaling Pathways
Authors: Zhang Qunzhou , Tang Xudong , Zhang Zuo-Feng , Velikina Rita , Shi Shihong , Le Anh D. 
Published: August 2007

Abstract
Purpose: Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis in various cancers, including lung cancer. Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in human lung cancers, particularly in non–small cell lung cancers (NSCLC), and is closely associated with an advanced tumor grade, increased angiogenesis, and resistance to chemotherapy and radiotherapy. The purpose of this study was to investigate the effects of nicotine on the expression of HIF-1α and its downstream target gene, vascular endothelial growth factor (VEGF), in human lung cancer cells.
Experimental Design: Human NSCLC cell lines A549 and H157 were treated with nicotine and examined for expression of HIF-1α and VEGF using Western blot or ELISA. Loss of HIF-1α function using specific small interfering RNA was used to determine whether HIF-1α is directly involved in nicotine-induced tumor angiogenic activities, including VEGF expression, cancer cell migration, and invasion.
Results: Nicotine increased HIF-1α and VEGF expression in NSCLC cells. Pharmacologically blocking nicotinic acetylcholine receptor–mediated signaling cascades, including the Ca2+/calmodulin, c-Src, protein kinase C, phosphatidylinositol 3-kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and the mammalian target of rapamycin pathways, significantly attenuated nicotine-induced up-regulation of HIF-1α protein. Functionally, nicotine potently stimulated in vitro tumor angiogenesis by promoting tumor cell migration and invasion. These proangiogenic and invasive effects were partially abrogated by treatment with small interfering RNA specific for HIF-1α.
Conclusion: These findings identify novel mechanisms by which nicotine promotes tumor angiogenesis and metastasis and provide further evidences that HIF-1α is a potential anticancer target in nicotine-associated lung cancer.
Decreased Expression of Retinoid Receptors in Melanoma: Entailment in Tumorigenesis and Prognosis
Authors: Chakravarti Nitin , Lotan Reuben , Diwan Abdul H. , Warneke Carla L. , Johnson Marcella M. , Prieto Victor G. 
Published: August 2007

Abstract
Purpose: Retinoids inhibit proliferation and induce differentiation in melanoma cells. Retinoic acid receptors (RAR) and retinoid X receptors (RXR) mediate the various modulatory effects of retinoids in cells. We have studied the in situ expression of each RAR and RXR protein (α, β, γ) in a large series of melanocytic lesions and correlated the expression with clinicopathologic features and prognosis of the patients.
Experimental Design: Tissue microarray blocks of 226 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic and nuclear expression of RAR and RXR protein (α, β, γ).
Results: A significant decrease of RARβ protein (P &lt; 0.0001), nuclear expression of RARγ (P &lt; 0.0001), and RXRα (P &lt; 0.0001) was found in primary and metastatic melanomas as compared with nevi. Loss of nuclear immunoreactivity for RARγ (P = 0.048) and RXRα (P = 0.001) was observed in the lesions showing vertical growth pattern. In addition, in patients with concomitant loss of cytoplasmic staining for RARα and RXRα, the probability of overall survival (log-rank test, P = 0.002) and disease-specific survival (log-rank test, P = 0.014) was significantly lower.
Conclusions: Aberrant expression of retinoid receptors seems to be a frequent event in melanoma and suggests an impairment of the retinoid pathway in this cancer. Our data indicate the loss of retinoid receptor expression with melanoma progression and suggest a possible prognostic significance of the analysis of retinoid receptors in melanoma.
Cyclin E–Associated Kinase Activity Predicts Response to Platinum-Based Chemotherapy
Authors: Bedrosian Isabelle , Lee Christine , Tucker Susan L. , Palla Shana L. , Lu Karen , Keyomarsi Khandan 
Published: August 2007

Abstract
Purpose: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E–associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients.
Experimental Design: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high-grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 by Western blot analysis and assessed for cyclin E–associated kinase activity.
Results: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E–cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E–associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E–associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01 and P = 0.25, respectively).
Conclusions: Cyclin E overexpression and cyclin E–associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process.
p53 Aerosol Formulation with Low Toxicity and High Efficiency for Early Lung Cancer Treatment
Authors: Zou Yiyu , Tornos Carmen , Qiu Xuan , Lia Marie , Perez-Soler Roman 
Published: August 2007

Abstract
Purpose: To develop an optimal nonviral aerosol formulation for locoregional treatment of early lung cancer.
Experimental Design: The formulation was made of polylysine/protamine combination (AND) as the carrier and p53 gene (p53sm) as therapeutic agent. To estimate the aerosol deposition, the aerodynamic size of the AND-p53sm was measured with extrusion-precipitation method. To accurately determine the dose, the aerosol efficiency in mice was measured with a fluorescent dye. The transfection efficiency and DNA protection function of the aerosolized formulation in cultured cells and mouse lungs were detected with reporter gene assays and/or reverse transcription-PCR. The preclinical safety and efficacy of AND-p53sm were studied in healthy mice and mice bearing orthotopic human non–small-cell lung cancer (NSCLC) xenograft.
Results: After aerosolization, AND is 3- to 17-fold more effective than commonly used PEI or cationic lipid formulations in transfecting the NSCLC cells (relative light units, 1,494 versus 534 and 86; P &lt; 0.003). Aerodynamic size of AND-p53sm ranged 0.2 to 3 μm is the optimal aerosol droplets for deposition in the entire human respiratory tract. Significant gene expression was detected in the lungs of mice given aerosolized AND-p53sm and AND-luciferase. Aerosolized AND-p53sm significantly prolonged the life of mice bearing orthotopic human NSCLC xenografts, and it was more effective than an optimal i.v. cisplatin chemotherapy (increased life span, 93% versus 25%; P = 0.014). Inhalation of AND produced low and reversible pulmonary toxicity and no systemic toxicity.
Conclusions: This optimal formulation is suitable for delivering biological materials to human lung with aerosol administration. This therapeutic strategy is an option for patients with early lung cancer and bronchoalveolar carcinoma.
Differential Radiation Protection of Salivary Glands versus Tumor by Tempol with Accompanying Tissue Assessment of Tempol by Magnetic Resonance Imaging
Authors: Cotrim Ana P. , Hyodo Fuminori , Matsumoto Ken-Ichiro , Sowers Anastasia L. , Cook John A. , Baum Bruce J. , Krishna Murali C. , Mitchell James B. 
Published: August 2007

Abstract
Purpose: The nitroxide free radical, Tempol, was evaluated for potential differential radiation protection of salivary glands and tumor using fractionated radiation. Mechanistic information was explored by monitoring the presence and bioreduction of Tempol in both tissues noninvasively by magnetic resonance imaging (MRI).
Experimental Design: Female C3H mice were immobilized using custom-made Lucite jigs for localized irradiation (five daily fractions) either to the oral cavity or tumor-bearing leg. Tempol (275 mg/kg) was administered (i.p.) 10 min before each radiation fraction. Salivary gland damage was assessed 8 weeks after radiation by measuring pilocarpine-mediated saliva output. Tumor growth was assessed by standard radiation regrowth methods. Dynamic T1-weighted magnetic resonance scans were acquired before and after Tempol injection using a 4.7T animal MRI instrument.
Results: Tempol treatment was found to protect salivary glands significantly against radiation damage (∼60% improvement); whereas no tumor protection was observed. Intracellular reduction of Tempol to the nonradioprotective hydroxylamine as assessed by MRI was 2-fold faster in tumor compared with salivary glands or muscle.
Conclusions: Tempol provided salivary gland radioprotection and did not protect tumor, consistent with the hypothesis that differential radioprotection by Tempol resides in faster reduction to the nonradioprotective hydroxylamine in tumor compared with normal tissues. The unique paramagnetic properties of Tempol afforded noninvasive MRI monitoring of dynamic changes of Tempol levels in tissue to support the finding. These data support further development and consideration of Tempol for human clinical trials as a selective protector against radiation-induced salivary gland damage.
Therapeutic ultrasound facilitates antiangiogenic gene delivery and inhibits prostate tumor growth
Authors: Duvshani-Eshet Maayan , Benny Ofra , Morgenstern Avigail , Machluf Marcelle 
Published: August 2007

AbstractGene therapy clinical trials are limited due to several hurdles concerning the type of vector used, particularly, the viral vectors, and transfection efficacy when non–viral vectors are used. Therapeutic ultrasound is a promising non–viral technology that can be used in the clinical setting. Here, for the first time, we show the efficacy of therapeutic ultrasound to deliver genes encoding for hemopexin-like domain fragment (PEX), an inhibitor of angiogenesis, to prostate tumors in vivo. Moreover, the addition of an ultrasound contrast agent (Optison) to the transfection process was evaluated. Prostate cancer cells and endothelial cells (EC) were transfected in vitro with cDNA-PEX using therapeutic ultrasound alone (TUS + pPEX) or with Optison (TUS + pPEX + Optison). The biological activity of the expressed PEX was assessed using proliferation, migration, and apoptosis assays done on EC and prostate cancer cells. TUS + pPEX + Optison led to the inhibition of EC and prostate cancer cell proliferation (&lt;65%), migration (&lt;50%), and an increase in apoptosis. In vivo, C57/black mice were inoculated s.c. with prostate cancer cells. The tumors were treated with TUS + pPEX and TUS + pPEX + Optison either once or repeatedly. Tumor growth was evaluated, after which histology and immunohistochemistry analyses were done. A single treatment of TUS + pPEX led to a 35% inhibition in tumor growth. Using TUS + PEX + Optison led to an inhibition of 50%. Repeated treatments of TUS + pPEX + Optison were found to significantly (P &lt; 0.001) inhibit prostate tumor growth by 80%, along with the angiogenic indices, with no toxicity to the surrounding tissues. These results depict the efficacy of therapeutic ultrasound as a non–viral technology to efficiently deliver genes to tumors in general, and to deliver angiogenic inhibitors to prostate cancer in particular. [Mol Cancer Ther 2007;6(8):2371–82]
Patients with in-stent restenoses
Authors: Nusser T. , Krause B. J. , Kochs M. , Habig T. , Mottaghy F. M. , Kestler H. A. , Hombach V. , Reske S. N. , Wöhrle J. 
Published: August 2007

SummaryAims: We compared the intracoronary β-brachytherapy using a liquid rhenium-188 filled balloon with the slow-release, polymer-based, paclitaxel-eluting Taxus-Express stent for treatment of in-stent restenoses. Patients, methods: During the same study period, patients with restenoses in bare-metal stents were either treated with Taxus- Express stents (n = 50) or β-brachytherapy after successful angioplasty (n = 51). For brachytherapy 30 Gy in 0.5 mm tissue depth were administered. The irradiated segment exceeded the traumatized segment 7.5 mm on both sides. Primary endpoint was the minimal lumen diameter (MLD) at the target lesion at six months follow-up. Angiographic follow-up was available in 78% (n = 79/101) and clinical follow-up in all patients. Results: Baseline parameters did not differ statistically. The Taxus-Express stent resulted in a significantly larger MLD and a significantly lower percent diameter stenosis post intervention compared to β-brachytherapy, which both maintained until angiographic follow-up (primary endpoint 2.44 ± 0.74 mm versus 1.73 ± 0.74 mm, p <0.0001). Therefore, Taxus- Express stents were associated with a lower angiographic restenosis rate compared with β-brachytherapy, both for the target lesion (6.1% versus 17.4%) and the total segment (9.1% versus 23.9%). Moreover, use of Taxus-stent was associated with a clinical benefit based on a significantly lower MACE rate compared with β-brachytherapy (p <0.05). Conclusions: Paclitaxel-eluting Taxus- Express stents resulted in superior clinical and angiographic outcomes compared to intracoronary β-brachytherapy with a liquid 188Re filled balloon for treatment of restenosis within a bare-metal stent.