bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prominent Microvascular Proliferation in Clinically Aggressive Neuroblastoma
Authors: Peddinti Radhika , Zeine Rana , Luca Dragos , Seshadri Roopa , Chlenski Alexandre , Cole Kristina , Pawel Bruce , Salwen Helen R. , Maris John M. , Cohn Susan L. 
Published: June 2007

Abstract
Purpose: Tumor vasculature is disorganized and glomeruloid microvascular proliferation (MVP) has been identified as a poor prognosticator in some adult cancers. To determine the clinical significance of MVP, including glomeruloid MVP in neuroblastoma, we initially examined vessel architecture in tumor sections from 51 children diagnosed at Children's Memorial Hospital (CMH) and subsequently evaluated 154 neuroblastoma tumors on a tissue microarray constructed at Children's Hospital of Philadelphia (CHOP).
Experimental Design: H&E sections were examined for the presence of structurally abnormal vessels and further characterized by immunostaining for CD31 and von Willebrand factor to highlight endothelial cells and α-smooth muscle actin for pericytes. Tumors with thickened walls containing a complete layer of hypertrophic endothelial cells plus additional layers of vascular mural cells were classified as MVP positive. Associations between MVP and established clinicopathologic features and outcome were assessed.
Results: In both series, MVP was significantly associated with Schwannian stroma-poor histology (CMH, P = 0.008; CHOP, P &lt; 0.001) and decreased survival probability (CMH, P = 0.017; CHOP, P = 0.014). In the CHOP series, MVP was associated with high-risk group classification (P &lt; 0.001), although this association was not seen in the smaller CMH cohort.
Conclusions: The association between MVP and poor outcome provides further support for the concept that angiogenesis plays an important role in determining the biological behavior of neuroblastoma tumors. Our results also indicate that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor neuroblastoma tumors. Further studies investigating the activity of angiogenic inhibitors in children with clinically aggressive stroma-poor neuroblastoma are warranted.
Imaging Tumor Vascular Heterogeneity and Angiogenesis using Dynamic Contrast-Enhanced Magnetic Resonance Imaging
Authors: Jackson Alan , O'Connor James P.B. , Parker Geoff J.M. , Jayson Gordon C. 
Published: June 2007

AbstractThis article reviews the application of dynamic contrast-enhanced magnetic resonance imaging in both clinical studies and early-phase trials of angiogenesis inhibitors. Emphasis is placed on how variation in image acquisition and analysis affects the meaning and use of derived variables. We then review the potential for future developments, with particular reference to the application of dynamic contrast-enhanced magnetic resonance imaging to evaluate the heterogeneity of tumor tissues.
Nuclear Imaging Probes: from Bench to Bedside
Authors: Wester Hans-Jürgen 
Published: June 2007

Abstract
The availability of specific imaging probes is the nuclear fuel for molecular imaging by positron emission tomography and single-photon emission computed tomography. These two radiotracer-based imaging modalities represent the prototype methods for noninvasive depiction and quantification of biochemical processes, allowing a functional characterization of tumor biology. A variety of powerful radiolabeled probes—tracers—are already established in the routine clinical management of human disease and others are currently subject to clinical assessment. Emerging from investigations of the genomic and proteomic signatures of cancer cells, an increasing number of promising targets are being identified, including receptors, enzymes, transporters, and antigens. Corresponding probes for these newly identified targets need to be developed and transferred into the clinical setting. Starting with a brief summary of the characteristics and prerequisites for a “good tracer,” an overview of tracer concepts, target selection, and development strategies is given. The influence of the imaging concepts on tracer development is also discussed.
Potential Applications for Circulating Tumor Cells Expressing the Insulin-Like Growth Factor-I Receptor
Authors: de Bono Johann S. , Attard Gerhardt , Adjei Alex , Pollak Michael N. , Fong Peter C. , Haluska Paul , Roberts Luisa , Melvin Carrie , Repollet Madeline , Chianese David , Connely Mark , Terstappen Leon W.M.M. , Gualberto Antonio 
Published: June 2007

Abstract
Purpose: To detect insulin-like growth factor-IR (IGF-IR) on circulating tumor cells (CTC) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-IR.
Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (CellTracks) was adapted for detecting IGF-IR–positive CTCs with a diagnostic antibody targeting a different IGF-IR epitope to CP-751,871. This assay was used in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma.
Results: There was no interference between the analytic and therapeutic antibodies. Eighty patients were enrolled on phase I studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Before treatment, 26 patients (33%) had CTCs, with 23 having detectable IGF-IR–positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-IR–positive CTCs; these increased toward the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11 of 20). Detectable IGF-IR expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of prostate-specific antigen decline by &gt;50% (6 of 10 versus 2 of 8 patients). A relationship was observed between sustained decreases in CTC counts and prostate-specific antigen declines by &gt;50%.
Conclusions: IGF-IR expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer.
An Open-Label, Two-Arm, Phase I Trial of Recombinant Human Interleukin-21 in Patients with Metastatic Melanoma
Authors: Davis Ian D. , Skrumsager Birte K. , Cebon Jonathan , Nicholaou Theo , Barlow John W. , Moller Niels Peter Hundahl , Skak Kresten , Lundsgaard Dorthe , Frederiksen Klaus Stensgaard , Thygesen Peter , McArthur Grant A. 
Published: June 2007

AbstractPurpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8+ T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors.Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 μg/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9).Results: Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 μg/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 μg/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8+ cells. One partial tumor response observed after treatment with IL-21 for 2 × 6 weeks (3/wk) became complete 3 months later.Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 μg/kg in the 5+9 regimen.
Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria
Authors: Liu Tongzu , Hannafon Bethany , Gill Lance , Kelly William , Benbrook Doris 
Published: June 2007

Abstract
Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-xL, and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het–induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent Flex-Het mitochondrial or apoptosis effects. Bcl-2 and Bcl-xL levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis. [Mol Cancer Ther 2007;6(6):1814–22]
Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes
Authors: Herlevsen Mikael , Oxford Gary , Owens Charles R. , Conaway Mark , Theodorescu Dan 
Published: June 2007

Abstract
The major vault protein (MVP) is the major constituent of the vault particle, the largest known ribonuclear protein complex. To date, vaults have no clear function, although their low expression levels in de novo chemosensitive and curable tumors, such as testicular cancer, make them attractive candidates as contributors to intrinsic drug resistance. Here, we show that MVP knockdown in human bladder cancer cells via small interfering RNA results in sensitization toward doxorubicin in two distinct exposure protocols. The drug was detected in the nucleus immediately following addition and was subsequently sequestered to lysosomes, predominantly located adjacent to the nucleus. MVP knockdown leads to increased sensitivity toward doxorubicin and an enhanced nuclear accumulation of the drug as well as a loss of its perinuclear sequestration. Not only doxorubicin subcellular distribution was perturbed by MVP knockdown but lysosomal markers, such as pH-sensitive LysoSensor, pinocytosed dextran conjugates after 24-h chase period, and the lysosomal specific antigen Lamp-1, also showed a markedly different staining compared with controls. Lysosomes appeared dispersed through the cytoplasm without a clear organization adjacent to the nucleus. Microtubules, however, appeared unperturbed in cells with reduced MVP expression. Based on these data, we hypothesize that MVP and, by extension, vault complexes are important for lysosomal function and may influence cellular drug resistance by virtue of this role. [Mol Cancer Ther 2007;6(6):1804–13]
Modifications enhance the apoptosis-inducing activity of FADD
Authors: Takashina Tomoki , Nakayama Manabu 
Published: June 2007

AbstractThe ability to enhance apoptosis-inducing activity in specific cells, despite the presence of cellular antiapoptotic proteins, would allow the removal of target cells from a cell population. Here, we show that modification of Fas-associated protein with death domain (FADD) by fusing the tandem death effector domains (DED) of FADD to the E protein of λ phage, a head coat protein with self-assembly activity, greatly increases the apoptosis-inducing activity of FADD in both adherent NIH3T3 and HEK293 cells. Induction of apoptosis in cell lines that stably express modified FADD (2DEDplusE) resulted in rapid blebbing, and most cells detached from the flask within 5 h. In contrast, following induction of apoptosis, it took over 24 h for the cells expressing unmodified FADD to exhibit these signs. The cells expressing the modified FADD underwent apoptosis through the typical apoptosis cascade via activation of caspase-3, and apoptosis was inhibited by a caspase inhibitor (i.e., z-VAD-fmk). Theoretically, as our adhesive stable cell lines undergo apoptosis rapidly and in synchrony following mifepristone- or tetracycline-controlled production of a single apoptosis protein without affecting any other cellular pathways, they provide excellent model systems in which to analyze the phenomenon of apoptosis in adhesive cell lines, in particular, blebbing and detachment. [Mol Cancer Ther 2007;6(6):1793–803]
Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism
Authors: Kobune Masayoshi , Chiba Hiroki , Kato Junji , Kato Kazunori , Nakamura Kiminori , Kawano Yutaka , Takada Kohichi , Takimoto Rishu , Takayama Tetsuji , Hamada Hirofumi , Niitsu Yoshiro 
Published: June 2007

Abstract
Adhesion of myeloma cells to bone marrow stromal cells is now considered to play a critical role in chemoresistance. However, little is known about the molecular mechanism governing cell adhesion–mediated drug resistance (CAM-DR) of myeloma cells. In this study, we focused our interests on the implication of the Wnt signal in CAM-DR. We first screened the expression of Wnt family in myeloma cell lines and found that Wnt3 was overexpressed in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human bone marrow stromal cells, and accumulation of β-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human bone marrow stromal. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against doxorubicin. This CAM-DR was significantly reduced by anti-integrin β1 antibody, anti-integrin α6 antibody and a Wnt-receptor competitor, secreted Frizzled-related protein-1, and Rho kinase inhibitor Y27632, but not by the specific inhibitor of canonical signaling (Dickkopf-1), indicating that Wnt-mediated CAM-DR that is dependent on integrin α6/β1 (VLA-6)–mediated attachment to stromal cells is induced by the Wnt/RhoA/Rho kinase pathway signal. This CAM-DR was also significantly reduced by Wnt3 small interfering RNA transfer to KMS-5. These results indicate that Wnt3 contributes to VLA-6–mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells in an autocrine manner. Thus, the Wnt3 signaling pathway could be a promising molecular target to overcome CAM-DR of myeloma cells. [Mol Cancer Ther 2007;6(6):1774–82]
Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-κB expression and proteasome activation in head and neck squamous carcinoma cell lines
Authors: Skvortsov Sergej , Skvortsova Ira , Stasyk Taras , Schiefermeier Natalia , Neher Andreas , Gunkel Andreas R. , Bonn Guenther K. , Huber Lukas A. , Lukas Peter , Pleiman Christopher M. , Zwierzina Heinz 
Published: June 2007

AbstractThis study aimed to characterize the antitumor activity of 5-Chloro-N-{2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-trifluoromethyl-phenyl}-2-hydroxy-benzamide (CTFB), a novel anticancer agent, in head and neck cancer cell lines, FaDu, SCC-25 and cisplatin-resistant CAL-27. CTFB was generated as a result of an extensive medicinal chemistry effort on a lead compound series discovered in a high-throughput screen for inducers of apoptosis. All cell lines showed significant growth delay in response to CTFB treatment at a concentration of 1 μmol/L with 17.16 ± 2.08%, 10.92 ± 1.22%, and 27.03 ± 1.86% of cells surviving at 120 h in FaDu, CAL-27, and SCC-25, respectively. To define proteins involved in the mechanism of action of CTFB, we determined differences in the proteome profile of cell lines before and after treatment with CTFB using two-dimensional difference gel electrophoresis followed by computational image analysis and mass spectrometry. Eight proteins were found to be regulated by CTFB in all cell lines. All these proteins are involved in cytoskeleton formation and function and/or in cell cycle regulation. We showed that CTFB-induced cell growth delay was accompanied by cell cycle arrest at the G0-G1 phase that was associated with the up-regulation of p21/WAF1 and p27/Kip1 expression and the down-regulation of cyclin D1. Furthermore, we showed that activity of CTFB depended on the down-regulation of nuclear factor-κB (NF-κB) and NF-κB p65 phosphorylated at Ser536. The level of proteasome activity correlated with the response to CTFB treatment, and the down-regulation of NF-κB is accompanied by enhanced proteasome activity in all investigated head and neck cancer cell lines. In this report, we show that CTFB reveals multiple effects that lead to delayed cell growth. Our data suggest that this compound should be studied further in the treatment of head and neck cancer. [Mol Cancer Ther 2007;6(6):1898–908]
Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma
Authors: Wong W. Wei-Lynn , Clendening James W. , Martirosyan Anna , Boutros Paul C. , Bros Christina , Khosravi Fereshteh , Jurisica Igor , Stewart A. Keith , Bergsagel P. Leif , Penn Linda Z. 
Published: June 2007

AbstractStatins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM. [Mol Cancer Ther 2007;6(6):1886–97]
Gam1-associated alterations of drug responsiveness through activation of apoptosis
Authors: Wu Fangting , Chiocca Susanna , Beck William T. , Mo Yin-Yuan 
Published: June 2007

AbstractAn early gene product, Gam1, encoded by the avian adenovirus CELO, is an inhibitory protein for the sumoylation machinery, which has been implicated in regulating a variety of cellular pathways. In this study, we found that Gam1 effectively suppressed both constitutive and inducible sumoylation and caused significant cell growth inhibition. This Gam1-mediated cell growth inhibition was associated with induction of apoptosis. In particular, Gam1 induced caspase-3 activity as detected by immunostaining and Western blot. Of interest, like the Ubc9 dominant-negative mutant, Gam1 also sensitized cells to DNA-damaging agents such as topotecan and doxorubicin and non–DNA-damaging agents such as paclitaxel and vincristine. Taken together, our findings suggest that activation of the caspase pathways is at least in part responsible for the increased apoptosis in Gam1-expressing cells and, thus, contributes to the growth inhibition and enhanced chemosensitivity. [Mol Cancer Ther 2007;6(6):1823–30]
Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA
Authors: Courtête Jérôme , Sibler Annie-Paule , Zeder-Lutz Gabrielle , Dalkara Deniz , Oulad-Abdelghani Mustapha , Zuber Guy , Weiss Etienne 
Published: June 2007

Abstract
Cervical cancer is caused by high-risk types of human papillomaviruses (HPV) that encode the E6 and E7 oncogenes. Silencing of E6 gene expression in HPV-positive cell lines by transfection of small interfering RNA (siRNA) with cationic lipids restores the dormant p53 tumor suppressor pathway. Because cationic lipids can also be used for intracytoplasmic delivery of proteins, we tested whether the delivery of monoclonal antibodies that bind to HPV16 E6 and neutralize its biological activity in vitro could restore p53 function in tumor cells. Here, we show that the 4C6 antibody is efficiently delivered into the cell cytoplasm using a lipidic reagent used for siRNA transfection. The delivery of 4C6 resulted in the nuclear accumulation of p53 protein in CaSki and SiHa cells but not in HeLa cells. Furthermore, the antibody-mediated p53 response was dramatically increased when a peptide corresponding to the 4C6 epitope and bearing a COOH-terminal cysteine residue was added to the transduction mixture. We found that a fraction of the added peptides were dimers that allowed the formation of antibody polymers adsorbed onto the lipidic matrix. With this system, the proliferation of CaSki and SiHa cells was strongly diminished, but no apoptosis was detectable. Remarkably, cell growth was almost totally suppressed by the addition of E6-specific siRNA to the transduction complex. The results indicate that the activity of E6 oncoprotein can be down-regulated in vivo by lipid-mediated antibody delivery and that antibodies and siRNA act synergistically when codelivered. This novel targeting strategy is simple to implement and may find therapeutic applications. [Mol Cancer Ther 2007;16(5):1728–35]