bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease
Authors: Ardigo Diego , Assimes Themistocles L. , Fortmann Stephen P. , Go Alan S. , Hlatky Mark , Hytopoulos Evangelos , Iribarren Carlos , Tsao Philip S. , Tabibiazar Raymond , Quertermous Thomas
Published: August 2007

Serum inflammatory markers correlate with outcome and response to therapy in subjects with cardiovascular disease. However, current individual markers lack specificity for the diagnosis of coronary artery disease (CAD). We hypothesize that a multimarker proteomic approach measuring serum levels of vascular derived inflammatory biomarkers could reveal a “signature of disease” that can serve as a highly accurate method to assess for the presence of coronary atherosclerosis. We simultaneously measured serum levels of seven chemokines [CXCL10 (IP-10), CCL11 (eotaxin), CCL3 (MIP1α), CCL2 (MCP1), CCL8 (MCP2), CCL7 (MCP3), and CCL13 (MCP4)] in 48 subjects with clinically significant CAD (“cases”) and 44 controls from the ADVANCE Study. We applied three classification algorithms to identify the combination of variables that would best predict case-control status and assessed the diagnostic performance of these models with receiver operating characteristic (ROC) curves. The serum levels of six chemokines were significantly higher in cases compared with controls ( P < 0.05). All three classification algorithms entered three chemokines in their final model, and only logistic regression selected clinical variables. Logistic regression produced the highest ROC of the three algorithms (AUC = 0.95; SE = 0.03), which was markedly better than the AUC for the logistic regression model of traditional risk factors of CAD without (AUC = 0.67; SE = 0.06) or with CRP (AUC = 0.68; SE = 0.06). A combination of serum levels of multiple chemokines identifies subjects with clinically significant atherosclerotic heart disease with a very high degree of accuracy. These results need to be replicated in larger cross-sectional studies and their prognostic value explored.
Serial In vivo Spectroscopic Nuclear Magnetic Resonance Imaging of Lactate and Extracellular pH in Rat Gliomas Shows Redistribution of Protons Away from Sites of Glycolysis
Authors: Provent Peggy , Benito Marina , Hiba Bassem , Farion Régine , López-Larrubia Pilar , Ballesteros Paloma , Rémy Chantal , Segebarth Christoph , Cerdán Sebastián , Coles Jonathan A. , García-Martín María Luisa
Published: August 2007

The acidity of the tumor microenvironment aids tumor growth, and mechanisms causing it are targets for potential therapies. We have imaged extracellular pH (pHe) in C6 cell gliomas in rat brain using 1H magnetic resonance spectroscopy in vivo. We used a new probe molecule, ISUCA [(±)2-(imidazol-1-yl)succinic acid], and fast imaging techniques, with spiral acquisition in k-space. We obtained a map of metabolites [136 ms echo time (TE)] and then infused ISUCA in a femoral vein (25 mmol/kg body weight over 110 min) and obtained two consecutive images of pHe within the tumor (40 ms TE, each acquisition taking 25 min). pHe (where ISUCA was present) ranged from 6.5 to 7.5 in voxels of 0.75 μL and did not change detectably when [ISUCA] increased. Infusion of glucose (0.2 mmol/kg·min) decreased tumor pHe by, on average, 0.150 (SE, 0.007; P < 0.0001, 524 voxels in four rats) and increased the mean area of measurable lactate peaks by 54.4 ± 3.4% (P < 0.0001, 287 voxels). However, voxel-by-voxel analysis showed that, both before and during glucose infusion, the distributions of lactate and extracellular acidity were very different. In tumor voxels where both could be measured, the glucose-induced increase in lactate showed no spatial correlation with the decrease in pHe. We suggest that, although glycolysis is the main source of protons, distributed sites of proton influx and efflux cause pHe to be acidic at sites remote from lactate production. [Cancer Res 2007;67(16):7638–45]
Mitotic Cell Death by Chromosome Fragmentation
Authors: Stevens Joshua B. , Liu Guo , Bremer Steven W. , Ye Karen J. , Xu Wenxin , Xu Jing , Sun Yi , Wu Gen Sheng , Savasan Sureyya , Krawetz Stephen A. , Ye Christine J. , Heng Henry H.Q.
Published: August 2007

Cell death plays a key role for both cancer progression and treatment. In this report, we characterize chromosome fragmentation, a new type of cell death that takes place during metaphase where condensed chromosomes are progressively degraded. It occurs spontaneously without any treatment in instances such as inherited status of genomic instability, or it can be induced by treatment with chemotherapeutics. It is observed within cell lines, tumors, and lymphocytes of cancer patients. The process of chromosome fragmentation results in loss of viability, but is apparently nonapoptotic and further differs from cellular death defined by mitotic catastrophe. Chromosome fragmentation represents an efficient means of induced cell death and is a clinically relevant biomarker of mitotic cell death. Chromosome fragmentation serves as a method to eliminate genomically unstable cells. Paradoxically, this process could result in genome aberrations common in cancer. The characterization of chromosome fragmentation may also shine light on the mechanism of chromosomal pulverization. [Cancer Res 2007;67(16):7686–94]
Epidermal Growth Factor Receptors with Tyrosine Kinase Domain Mutations Exhibit Reduced Cbl Association, Poor Ubiquitylation, and Down-regulation but Are Efficiently Internalized
Authors: Padrón David , Sato Mitsuo , Shay Jerry W. , Gazdar Adi F. , Minna John D. , Roth Michael G.
Published: August 2007

Some non–small cell lung cancers (NSCLC) with epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations require altered signaling through the EGFR for cell survival and are exquisitely sensitive to tyrosine kinase inhibitors. EGFR down-regulation was impaired in two NSCLCs with EGFR tyrosine kinase domain mutations. The mutant receptors were poorly ubiquitylated and exhibited decreased association with the ubiquitin ligase Cbl. Overexpression of Cbl increased the degradation of EGFR. Treatment with geldanamycin, an inhibitor of the chaperone heat shock protein 90, also increased both wild-type and mutant EGFR degradation without affecting internalization. The down-regulation of the mutant EGFRs was still impaired when they were stably expressed in normal human bronchial epithelial cells. Thus, the mutations that altered signaling also decreased the interaction of EGFRs with the mechanisms responsible for endosomal sorting. [Cancer Res 2007;67(16):7695–702]
A Potent Indole-3-Carbinol–Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells
Authors: Weng Jing-Ru , Tsai Chen-Hsun , Kulp Samuel K. , Wang Dasheng , Lin Chia-Hui , Yang Hsiao-Ching , Ma Yihui , Sargeant Aaron , Chiu Chang-Fang , Tsai Ming-Hsui , Chen Ching-Shih
Published: August 2007

Indole-3-carbinol has emerged as a promising chemopreventive agent due to its in vivo efficacy in various animal models. However, indole-3-carbinol exhibits weak antiproliferative potency and is unstable in acidic milieu. Thus, this study was aimed at exploiting indole-3-carbinol to develop potent antitumor agents with improved chemical stability. This effort culminated in OSU-A9 {[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol}, which is resistant to acid-catalyzed condensation, and exhibits 100-fold higher apoptosis-inducing activity than the parent compound. Relative to indole-3-carbinol, OSU-A9 displays a striking qualitative similarity in its effects on the phosphorylation or expression of multiple signaling targets, including Akt, mitogen-activated protein kinases, Bcl-2 family members, survivin, nuclear factor-κB, cyclin D1, p21, and p27. The ability of OSU-A9 to concurrently modulate this broad range of signaling targets underscores its in vitro and in vivo efficacy in prostate cancer cells. Nevertheless, despite this complex mode of mechanism, normal prostate epithelial cells were less susceptible to the antiproliferative effect of OSU-A9 than PC-3 and LNCaP prostate cancer cells. Treatment of athymic nude mice bearing established s.c. PC-3 xenograft tumors with OSU-A9 at 10 and 25 mg/kg i.p. for 42 days resulted in a 65% and 85%, respectively, suppression of tumor growth. Western blot analysis of representative biomarkers in tumor lysates revealed significant reductions in the intratumoral levels of phosphorylated (p-) Akt, Bcl-xL, and RelA, accompanied by robust increases in p-p38 levels. In conclusion, the ability of OSU-A9 to target multiple aspects of cancer cell survival with high potency suggests its clinical value in prostate cancer therapy. [Cancer Res 2007;67(16):7815–24]
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

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

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 (<30 min) and selective retention (>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

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

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

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

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

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 < 0.0001), nuclear expression of RARγ (P < 0.0001), and RXRα (P < 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

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

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 < 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

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

Gene 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 (<65%), migration (<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 < 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]
In vitro P-Glycoprotein-Mediated Transport of (R)-, (S)-, (R,S)-Methadone, LAAM and Their Main Metabolites
Authors: Crettol Séverine , Digon Patricia , Powell Golay Kerry , Brawand Marlyse , Eap Chin B.
Published: August 2007

Methadone and L-α-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.
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

Aims: 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.
Therapy of hepatocellular carcinoma with 131I-lipiodol: patient dosimetry
Authors: Pauleit D. , Palmedo H. , Bender H. , Bucerius J. , Ezziddin S. , Klein V. , Grünwald F. , Biersack H.-J. , Reichmann K. , Risse J. H.
Published: August 2007

Aim: Dosimetry in 131I-lipiodol therapy for hepatocellular carcinoma (HCC) in the hitherto largest existing patient cohort. Patients, methods: 38 courses of intra-arterial 131I-lipiodol therapy with a total activity up to 6.7 GBq were performed in 18 patients with HCC. Liver and tumour volume were measured by computed tomography (CT) and 131I activity by scintigraphy on day 3, 6, 14, 28 and 42 after injection. Lipiodol deposition in tumour nodules as shown by CT rendered definite attachment to scintigraphic data possible. The radiation dose in tumour nodules, liver and lungs was calculated according to the MIRD concept and the tumour dose related to pre-therapeutic tumour volume, response and survival. Results: Mean tumour dose was 23.6 ± 3.6 Gy (14.2 ± 2.1 mGy/MBq) with maximal 162 Gy (90.1 mGy/MBq) after one and 274 Gy after three courses. The dose to nontumourous liver was 1.9 ± 0.2 Gy (1.2 ± 0.1 mGy/MBq) and the mean dose ratio of tumour / nontumourous liver 11.1 ± 1.7 (max. 82). The pulmonary dose was 25.9 ± 1.8 mGy (16.3 ± 1.2 μGy/MBq) and therefore much lower. There was a reciprocal relation between tumour dose and pretherapeutic tumour volume. Tumour dose had no effect on response or survival. Conclusion: High radiation doses are particularly in small tumour nodes achievable but not necessarily related to tumour response. The dose of non-tumourous liver and lungs is much lower.
Procedure guideline for radioiodine test (Version 3)
Authors: Dressler J. , Eschner W. , Lassmann M. , Leisner B. , Reiners C. , Schicha H. , Dietlein M.
Published: August 2007

The version 3 of the procedure guideline for radioiodine test is an update of the guideline previously published in 2003. The procedure guideline discusses the pros and cons of a single measurement or of repeated measurements of the iodine-131 uptake and their optimal timing. Different formulas are described when one, two or three values of the radioiodine kinetic are available. The probe with a sodiumiodine crystal, alternatively or additionally the gammacamera using the ROI-technique are instrumentations for the measurement of iodine-131 uptake. A possible source of error is an inappropriate measurement (sonography) of the target volume. The patients' preparation includes the withdrawal of antithyroid drugs 2–3 days before radioiodine administration. The patient has to avoid iodine-containing medication and the possibility of additives of iodine in vitamin- and electrolyte-supplementation has to be considered.
Procedure guideline for radioiodine therapy and 131iodine whole-body scintigraphy in paediatric patients with differentiated thyroid cancer
Authors: Dietlein M. , Biermann M. , Frühwald M. , Linden T. , Bucsky P. , Reiners C. , Schober O. , Franzius C.
Published: August 2007

The procedure guideline for radioiodine (131I) therapy and 131I whole-body scintigraphy of differentiated thyroid cancer in paediatric patients is the counterpart to the procedure guidelines (version 3) for adult patients and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. Characteristics of thyroid cancer in children are the higher aggressiveness of papillary thyroid cancer, the higher frequency of extrathyroidal extension and of disseminated pulmonary metastases as well as the high risk of local recurrences. Radioiodine therapy is generally recommended in children, the 131I activity depends on the children's body weight. Radioiodine ablation in children with small papillary cancer (≤1 cm) should be considered. TSH stimulation is reached two weeks (children) or three weeks (adolescents) after withdrawal of thyroid hormones. Anti-emetic drugs are highly recommended. CT of the chest and examination of pulmonary function are clearly indicated if there is any suspicion on metastases. 3–6 months after 131I ablation, the 131I whole-body scintigraphy is highly recommended as lymph node metastases are frequently detected in paediatric patients. Follow-up care should be arranged in shorter intervals than in adults to test the compliance and to adapt dosage of thyroid hormones to the children's body weight. Reference values of fT3 are higher in children than in adults. Evidence is insufficient to describe in which constellation the TSH may be kept within the low normal level. Therefore, TSH suppression is generally recommended.
Structure of the Annual-Mean Equatorial Planetary Waves in the ERA-40 Reanalyses
Authors: Dima Ioana M. , Wallace John M.
Published: August 2007

The three-dimensional structure of the annual-mean equatorial planetary waves in the 40-yr ECMWF Re-Analysis (ERA-40) is documented. The features in the free atmosphere are predominantly equatorially symmetric, driven by east–west heating gradients. The geopotential height and wind perturbations are strongest at or just below the 150-hPa level. Below the level of maximum amplitude, the circulations in the waves are thermally direct with latent heat release in deep convective clouds and radiative cooling in the intervening cloud-free regions. Within the overlying capping layer, the wave-related circulations are thermally indirect, with rising of the coldest air and sinking of air that is less cold. At the cold point, just above the 100-hPa (17 km) level, the ERA-40 annual-mean vertical velocity in the equatorial belt ranges up to 3 mm s−1 over the equatorial western Pacific during the boreal winter, implying diabatic heating rates of up to 3°C day−1, an order of magnitude larger than typical clear-sky values. Strong heating is consistent with evidence of widespread thin and subvisible cirrus cloud layers over this region. It is hypothesized that the air mass as a whole is rising (as opposed to just the air in the updrafts of convective clouds) and that this plume of ascending air spreads out horizontally at or just above the cold point, ventilating and lifting the entire lower stratosphere.

El Niño years are characterized by anomalously weak equatorial planetary waves in the Indo-Pacific sector and slightly enhanced waves over the Atlantic sector and cold years of the El Niño–Southern Oscillation (ENSO) cycle by the opposite conditions. Equatorial Pacific sea surface temperature is as well correlated with the strength of the equatorial planetary waves in the upper troposphere over the Indo-Pacific sector as it is with the conventional Southern Oscillation index based on sea level pressure.
Short-Range Forecast Impact from Assimilation of GPS-IPW Observations into the Rapid Update Cycle
Authors: Smith Tracy Lorraine , Benjamin Stanley G. , Gutman Seth I. , Sahm Susan
Published: August 2007

Integrated precipitable water (IPW) estimates derived from time delays in the arrival of global positioning system (GPS) satellite signals are a relatively recent, high-frequency source of atmospheric moisture information available for real-time data assimilation. Different experimental versions of the Rapid Update Cycle (RUC) have assimilated these observations to assess GPS-IPW impact on moisture forecasts. In these tests, GPS-IPW data have proven to be a useful real-time source of moisture information, leading to more accurate short-range moisture forecasts when added to other observations. A multiyear experiment with parallel (one with GPS-IPW processed 24 h after the fact, one without) 3-h cycles using the original 60-km RUC was run from 1999 to 2004 with verification of each cycle against rawinsonde observations. This experiment showed a steady increase in the positive impact in short-range relative humidity (RH) forecasts due to the GPS-IPW data as the number of observing sites increased from 18 to almost 300 (as of 2004) across the United States and Canada. Positive impact from GPS-IPW on 850–700-hPa RH forecasts was also evident in 6- and 12-h forecasts. The impact of GPS-IPW data was also examined on forecasts from the more recent 20-km RUC, including a 1-h assimilation cycle and improved assimilation and physical parameterizations, now using real-time GPS-IPW retrievals available 30 min after valid time. In a 3-month comparison during the March–May 2004 period, 20-km RUC cycles with and without assimilation of GPS-IPW were compared with IPW for 3-, 6-, 9-, and 12-h forecasts. Using this measure, assimilation of GPS-IPW data led to the strongest improvements in the 3- and 6-h forecasts and smaller but still evident improvements in 9- and 12-h forecasts. In a severe convective weather case, inclusion of GPS-IPW data improved forecasts of convective available potential energy, an important predictor of severe storm potential, and relative humidity. Positive impact from GPS-IPW assimilation was found to vary over season, geographical location, and time of day, apparently related to variations in vertical mixing. For example, GPS-IPW has a stronger effect on improving RH forecasts at 850 hPa at nighttime (than daytime) and in cooler seasons (than warmer seasons) when surface moisture observations are less representative of conditions aloft. As a result of these studies, assimilation of GPS-IPW was added to the operational RUC run at NOAA/NCEP in June 2005 and to the operational North American Mesoscale model (also at NCEP) in June 2006 to improve their accuracy for short-range moisture forecasts.
Sensitivity of Cloud-Resolving Simulations of Warm-Season Convection to Cloud Microphysics Parameterizations
Authors: Liu Changhai , Moncrieff Mitchell W.
Published: August 2007

This paper investigates the effects of cloud microphysics parameterizations on simulations of warm-season precipitation at convection-permitting grid spacing. The objective is to assess the sensitivity of summertime convection predictions to the bulk microphysics parameterizations (BMPs) at fine-grid spacings applicable to the next generation of operational numerical weather prediction models. Four microphysical parameterization schemes are compared: simple ice (Dudhia), four-class mixed phase (Reisner et al.), Goddard five-class mixed phase (Tao and Simpson), and five-class mixed phase with graupel (Reisner et al.). The experimentation involves a 7-day episode (3–9 July 2003) of U.S. midsummer convection under moderate large-scale forcing. Overall, the precipitation coherency manifested as eastward-moving organized convection in the lee of the Rockies is insensitive to the choice of the microphysics schemes, and the latent heating profiles are also largely comparable among the BMPs. The upper-level condensate and cloudiness, upper-level radiative cooling/heating, and rainfall spectrum are the most sensitive, whereas the domain-mean rainfall rate and areal coverage display moderate sensitivity. Overall, the three mixed-phase schemes outperform the simple ice scheme, but a general conclusion about the degree of sophistication in the microphysics treatment and the performance is not achievable.
Interaction between Dynamics and Cloud Microphysics in Orographic Precipitation Enhancement: A High-Resolution Modeling Study of Two North Alpine Heavy-Precipitation Events
Authors: Zängl Günther
Published: August 2007

Interactions of atmospheric dynamics and cloud microphysics with the Alpine orography are investigated for two north Alpine heavy-precipitation cases (20–22 May 1999 and 22–23 August 2005). Both cases were related to a deep cyclone propagating slowly eastward along the Alps, advecting moist air of Mediterranean origin toward the northern side of the Alps. A validation against high-resolution rain gauge data reveals that the average model bias is below 15% in the region of interest, but there is a tendency to systematically underestimate very heavy precipitation. A scale decomposition of the discrepancies between model and observations reveals that errors on the meso-β-scale contribute at least as much to the total model error as discrepancies on the meso-γ-scale. On the scale of single mountain ridges and valleys, the formation of precipitation maxima at valley locations is investigated, with particular emphasis on a region in which a valley receives systematically more precipitation than the adjacent mountain ridges. It is found that the downstream advection of precipitation hydrometeors generated in an orographic feeder cloud is essential for the development of valley maxima. Strong ambient winds and (due to the fall speed difference between snow/graupel and rain) a low freezing level favor a large distance of the precipitation maximum from the upstream mountain ridge. Under suitable geometrical conditions, downstream advection of hydrometeors can even lead to systematically more precipitation in the valley than over the adjacent ridges. Another mechanism capable of generating a systematic rainfall maximum at valley locations requires a freezing level between valley bottom and crest height and a mountain wave flow penetrating into the valley. Under such conditions, the increase in the fall velocity related to melting of snow or graupel into rain leads to a locally intensified fallout of hydrometeors and thus to a maximum in the precipitation rate.
A Conceptual Framework for Online Business Protest Tactics and Criteria for Their Effectiveness
Authors: Martin Kelly D. , Kracher Beverly
Published: August 2007

In this article, the authors lay the foundation for the emerging area of research on online protest tactics mobilized against business. The authors offer a definition of online business protest tactics and distinguish them from related activities such as electronic civil disobedience and cybercrime. They also appeal to the interest-group literature as one theoretical foundation for this area of research. Based on the degree to which each tactic involves intrusion, disruption, or damage, the authors categorize the array of online business protest tactics into a typology, providing definitions and illustrative examples from the business press for each. They advance a dualistic framework to evaluate the intermediate and ultimate effectiveness of the various online business protest tactics using a set of criteria relevant to both online and off-line environments, and conclude by suggesting avenues for future research.