bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-29 Binds to Melanoma Cells Inducing Jak-STAT Signal Transduction and Apoptosis
Authors: Guenterberg Kristan D. , Grignol Valerie P. , Raig Ene T. , Zimmerer Jason M. , Chan Anthony N. , Blaskovits Farriss M. , Young Gregory S. , Nuovo Gerard J. , Mundy Bethany L. , Lesinski Gregory B. , Carson William E. 
Published: January 2010

Abstract
Interleukin-29 (IL-29) is a member of the type III IFN family that has been shown to have antiviral activity and to inhibit cell growth. Melanoma cell lines were tested for expression of the IL-29 receptor (IL-29R) and their response to IL-29. Expression of IL-28R1 and IL-10R2, components of IL-29R, was evaluated using reverse transcription-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29–induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/propridium iodide staining. In situ PCR for IL-29R was done on paraffin-embedded melanoma tumors. Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5, and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10–1,000 ng/mL) led to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Microarray analysis and quantitative reverse transcription-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but not in benign nevi specimens. In conclusion, IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples, and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis. Mol Cancer Ther; 9(2); 510–20
Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice
Authors: Matsunaka Toshihiro , Miyamoto Shin'ichi , Shitara Kenya , Ochiai Atsushi , Chiba Tsutomu 
Published: January 2010

Abstract
Insulin-like growth factors (IGF-I and IGF-II) play important roles in intestinal tumorigenesis. To investigate the effectiveness of IGF-targeting strategies, we conducted an in vivo study using anti-mouse neutralizing antibodies IGF-I (KM3168) and IGF-II (KM1468). Six- and 10-week-old Apc+/− mice were given KM3168 and/or KM1468 i.p. at two doses (0.01 or 0.1 μg/g weight) once or twice weekly for 4 weeks. To clarify the source of IGFs in vivo, we evaluated the expression levels of IGFs in the liver, normal small intestine, and polyps of the small intestine of Apc+/− mice. The phosphorylation status of IGF signal–related molecules was examined using immunostaining to understand the mechanism underlying the effects of IGF-neutralizing antibody. The plasma half-life was 168 for KM3168 and 85 hours for KM1468. In two lineages of Apc+/− mice (Apc1309 and ApcMin/+), a low dose (0.01 μg/g weight) of KM3168 and KM1468 significantly reduced the number of polyps when given once and twice weekly, respectively. Combined administration of the effective dose of each antibody had an additive effect. The liver was the main source of IGF-I, whereas the polyps of the small intestine and normal small intestine were the main source of IGF-II. IGF-neutralizing antibodies decreased the phosphorylation of IGF type 1 receptor and inhibited the signal transduction of the Akt pathway. These results suggest that IGF-I and IGF-II play important roles in polyp formation in Apc+/− mice and that specific antibodies to IGF-I and IGF-II may be promising antitumor agents. Mol Cancer Ther; 9(2); 419–28
Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation
Authors: Lagas Jurjen S. , van Waterschoot Robert A.B. , Sparidans Rolf W. , Wagenaar Els , Beijnen Jos H. , Schinkel Alfred H. 
Published: January 2010

Abstract
Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. We studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, we orally administered sorafenib to wild-type, Abcb1a/1b−/−, Abcg2−/−, and Abcb1a/1b;Abcg2−/− mice, completely lacking functional Abcb1a/1b, Abcg2, or both, respectively, and we studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2−/− mice and 9.3-fold increased in Abcb1a/1b;Abcg2−/− mice. Moreover, when wild-type mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that observed for Abcb1a/1b;Abcg2−/− mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, that is, ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clinically, our findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319–26
Herbal Compound Farnesiferol C Exerts Antiangiogenic and Antitumor Activity and Targets Multiple Aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) Signaling Cascades
Authors: Lee Jae-Ho , Choi Sun , Lee Yoonji , Lee Hyo-Jeong , Kim Kwan-Hyun , Ahn Kyoo-Seok , Bae Hyunsoo , Lee Hyo-Jung , Lee Eun-Ok , Ahn Kwang-Seok , Ryu Shi Yong , Lü Junxuan , Kim Sung-Hoon 
Published: January 2010

Abstract
Farnesiferol C (FC) is one of the major compounds isolated from Ferula assafoetida, an Asian herbal spice used for cancer treatment as a folk remedy. Here, we examined the hypothesis that novel antiangiogenic activities of FC contribute to anticancer efficacy. In human umbilical vein endothelial cells (HUVEC), exposure to the 10 to 40 μmol/L concentration range of FC inhibited vascular endothelial growth factor (VEGF)–induced cell proliferation, migration, invasion, tube formation, and the expression of matrix metalloproteinase-2. In addition, FC inhibited the angiogenic sprouting of VEGF-treated rat aorta in an ex vivo model. Furthermore, FC inhibited the in vivo growth of mouse Lewis lung cancer allograft model by 60% (P &lt; 0.001) at a daily i.p. dosage of 1 mg/kg body weight without any negative effect on the weight of the host mice. Immunohistochemistry staining showed decreased microvessel density (CD34) and proliferative index (Ki-67) without affecting the apoptotic (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) index. Mechanistically, FC decreased the binding of VEGF to VEGFR1/Flt-1, but not to VEGFR2/KDR/Flk-1. In terms of early signaling, FC exerted a rapid inhibitory action (examined within 10 minutes) on VEGF-induced autophosphorylation of VEGFR1 without affecting that of VEGFR2. Nevertheless, FC decreased the phosphorylation of most of the kinases downstream of VEGFR2: focal adhesion kinase, Src, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-jun-NH2-kinase without affecting AKT. Computer simulation suggests that FC may inhibit Src or focal adhesion kinase protein activities directly through its docking to their ATP-binding sites. Taken together, the multitargeting actions of FC, particularly VEGFR1 inhibition, may make it a novel drug candidate to complement current VEGF/VEGFR2-targeting antiangiogenic modalities for cancer. Mol Cancer Ther; 9(2); 389–99
Noncanonical Wnt11 Inhibits Hepatocellular Carcinoma Cell Proliferation and Migration
Authors: Toyama Takashi , Lee Han Chu , Koga Hironori , Wands Jack R. , Kim Miran 
Published: January 2010

Abstract
The canonical Wnt signaling is frequently activated due to overexpression and/or mutations in components of this pathway in hepatocellular carcinoma (HCC). However, the biological role of noncanonical Wnt-mediated signaling in HCC with respect to the signaling pathways involved and their physiologic function is unknown. Here, we report the role of Wnt11, a member of the noncanonical cascade, in hepatic oncogenesis. The expression levels of Wnt11 mRNA and protein were significantly downregulated in human HCC tumors compared with the adjacent uninvolved liver as measured by quantitative real-time reverse transcription-PCR and Western blot analysis. In human HCC cell lines, overexpression of Wnt11 activated protein kinase C signaling. Protein kinase C antagonized the canonical signaling through phosphorylation of β-catenin and reduced T-cell factor–mediated transcriptional activity, resulting in a decrease of cell proliferation. Furthermore, ectopic expression of Wnt11 promotes RhoA/Rho kinase activation. We found that activated Rho kinase inhibited Rac1 to reduce cell motility and migration. These observations suggest a novel role for Wnt11 as a tumor suppressor during hepatocarcinogenesis because loss of expression promotes the malignant phenotype via both canonical and noncanonical Wnt signaling pathways. Mol Cancer Res; 8(2); 254–65
Green Tea Polyphenols Prevent UV-Induced Immunosuppression by Rapid Repair of DNA Damage and Enhancement of Nucleotide Excision Repair Genes
Authors: Katiyar Santosh K. , Vaid Mudit , van Steeg Harry , Meeran Syed M. 
Published: January 2010

AbstractUV radiation–induced immunosuppression has been implicated in the development of skin cancers. Green tea polyphenols (GTP) in drinking water prevent photocarcinogenesis in the skin of mice. We studied whether GTPs in drinking water (0.1-0.5%, w/v) prevent UV-induced immunosuppression and (if so) potential mechanisms of this effect in mice. GTPs (0.2% and 0.5%, w/v) reduced UV-induced suppression of contact hypersensitivity (CHS) in response to a contact sensitizer in local (58-62% reductions; P &lt; 0.001) and systemic (51-55% reductions; P &lt; 0.005) models of CHS. Compared with untreated mice, GTP-treated mice (0.2%, w/v) had a reduced number of cyclobutane pyrimidine dimer–positive (CPD+) cells (59%; P &lt; 0.001) in the skin, showing faster repair of UV-induced DNA damage, and had a reduced (2-fold) migration of CPD+ cells from the skin to draining lymph nodes, which was associated with elevated levels of nucleotide excision repair (NER) genes. GTPs did not prevent UV-induced immunosuppression in NER-deficient mice but significantly prevented it in NER-proficient mice (P &lt; 0.001); immunohistochemical analysis of CPD+ cells indicated that GTPs reduced the numbers of UV-induced CPD+ cells in NER-proficient mice (P &lt; 0.001) but not in NER-deficient mice. Southwestern dot-blot analysis revealed that GTPs repaired UV-induced CPDs in xeroderma pigmentosum complementation group A (XPA)–proficient cells of a healthy person but did not in XPA-deficient cells obtained from XPA patients, indicating that a NER mechanism is involved in DNA repair. This study is the first to show a novel NER mechanism by which drinking GTPs prevents UV-induced immunosuppression and that inhibiting UV-induced immunosuppression may underlie the chemopreventive activity of GTPs against photocarcinogenesis. Cancer Prev Res; 3(2); 179–89
Cyclooxygenase-2 Inhibition for the Prophylaxis and Treatment of Preinvasive Breast Cancer in a Her-2/Neu Mouse Model
Authors: Tran-Thanh Danh , Buttars Stephen , Wen Yanxia , Wilson Christine , Done Susan J. 
Published: January 2010

AbstractDuctal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer. Several molecular alterations have been identified in DCIS. Among them, cyclooxygenase 2 (COX-2) overexpression has been shown in 60% to 80% of DCIS cases. Celecoxib is a nonsteroidal anti-inflammatory drug that selectively inhibits COX-2. In this study, we evaluated whether COX-2 inhibition by celecoxib can reduce the incidence of preinvasive breast cancer and its progression to invasive breast cancer in a mouse model exhibiting a similar phenotype to human solid-pattern DCIS. We have used the mouse model mouse mammary tumor virus (MMTV)-Neu to investigate this possibility. These mice carry a rat Her-2/Neu transgene and are known to develop DCIS-like lesions. Our results showed that celecoxib (500 ppm) given as prophylaxis was neither able to prevent tumor development nor delay tumor appearance compared with untreated mice. Furthermore, when the drug was given early in tumorigenesis, it did not reduce the progression of preinvasive to invasive tumors nor prevent lung metastasis. Reduction of prostaglandin levels was, however, achieved in mammary tumors of treated mice. In addition, celecoxib treatment caused an increase in apoptosis and decreased vascular endothelial growth factor expression in treated animals. Our results contrast with some previously published studies and highlight the complexity of the relationship between COX-2 and breast cancer. Cancer Prev Res; 3(2); 202–11
A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer
Authors: Stratton Steven P. , Alberts David S. , Einspahr Janine G. , Sagerman Paul M. , Warneke James A. , Curiel-Lewandrowski Clara , Myrdal Paul B. , Karlage Kelly L. , Nickoloff Brian J. , Brooks Chris , Saboda Kathylynn , Yozwiak Michael L. , Krutzsch Mary F. , Hu Chengcheng , Lluria-Prevatt Maria , Dong Zigang , Bowden G. Timothy , Bartels Peter H. 
Published: January 2010

Abstract
The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene–induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P &lt; 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary. Cancer Prev Res; 3(2); 160–9
Synergistic Effects of Combined Phytochemicals and Skin Cancer Prevention in SENCAR Mice
Authors: Kowalczyk Magdalena C. , Kowalczyk Piotr , Tolstykh Olga , Hanausek Margaret , Walaszek Zbigniew , Slaga Thomas J. 
Published: January 2010

AbstractThe purpose of our study was to determine the inhibitory effect of combined phytochemicals on chemically induced murine skin tumorigenesis. Our hypothesis was that concurrent topical and dietary treatment with selected compounds would lead to more efficient prevention of skin cancer. We tested ellagic acid and calcium D-glucarate as components of diets, while resveratrol was applied topically; grape seed extract was applied topically or in the diet. The 4-week inflammatory-hyperplasia assay based on the 7,12-dimethylbenz[a]anthracene (DMBA)–induced skin carcinogenesis model in SENCAR mice was used. We have found that all the selected combinations caused a marked decrease of epidermal thickness compared with the DMBA-treated group and also with groups treated with a single compound and DMBA. All combinations of resveratrol with other compounds showed a synergistic effect on hyperplasia and Ha-ras mutations. Skin tissue of mice receiving the combinations showed decreased cell proliferation and Bcl2 expression; decreased p21, a regulator of cell cycle; and decreased marker of inflammation cyclooxygenase-2. All the selected combinations diminished the DMBA-induced mRNA expression of the CYP1B1 level, and also caused a marked decrease of proto-oncogenes c-jun and c-fos, components of transcription factor activator protein. In conclusion, all combinations showed either additive or synergistic effects and their joint actions allowed for decreasing the doses of the compounds. Especially, resveratrol combinations with ellagic acid, grape seed extract, and other phytochemicals are very potent inhibitors of skin tumorgenesis, based on the suppression of epidermal hyperplasia as well as on the modulation of intermediate biomarkers of cell proliferation, cell survival, inflammation, oncogene mutation, and apoptosis. Cancer Prev Res; 3(2); 170–8
A survey of aviation English tests
Authors: Alderson J. Charles 
Published: January 2010

The Lancaster Language Testing Research Group was commissioned in 2006 by the European Organisation for the Safety of Air Navigation (Eurocontrol) to conduct a validation study of the development of a test called ELPAC (English Language Proficiency for Aeronautical Communication), intended to assess the language proficiency of air traffic controllers. As part of that study, Internet searches for other tests of air traffic control identified a number of tests but found very little evidence available to attest to the quality of these tests. Therefore, it was decided to conduct an independent survey of tests of aviation English, since the consequences of inadequate language tests being used in licensing pilots, air traffic controllers and other aviation personnel are potentially very serious. A questionnaire was developed, based on the Guidelines for Good Practice of the European Association for Language Testing and Assessment (EALTA, 2006), and sent to numerous organizations whose tests were thought to be used for licensure of pilots and air traffic controllers. Twenty-two responses were received, which varied considerably in quantity and quality. This probably reflects a variation in the quality of the tests, in the availability of evidence to support claims of quality, and in low awareness of appropriate procedures for test development, maintenance and validation. We conclude that we can have little confidence in the meaningfulness, reliability, and validity of several of the aviation language tests currently available for licensure. We therefore recommend that the quality of language tests used in aviation be monitored to ensure they follow accepted professional standards for language tests and assessment procedures.
Assessing the accuracy and consistency of language proficiency classification under competing measurement models
Authors: Bo Zhang  
Published: January 2010

This article investigates how measurement models and statistical procedures can be applied to estimate the accuracy of proficiency classification in language testing. The paper starts with a concise introduction of four measurement models: the classical test theory (CTT) model, the dichotomous item response theory (IRT) model, the testlet response theory (TRT) model, and the polytomous item response theory (Poly-IRT) model. Following this, two classification procedures are presented: the Livingston and Lewis method for CTT and the Rudner method for the three IRT-based models. The utility of these models and procedures are then evaluated by examining the accuracy of classifying 5000 language test takers from a large-scale language certification examination into two proficiency categories. The most important finding is that the testlet format (multiple questions based on one prompt), which language tests usually rely on, has a great impact on the proficiency classification. All testlets in this study show a strong testlet effect. Hence, the TRT model is recommended for proficiency classification. Using the standard IRT model would inflate the classification accuracy due to the underestimated measurement error. Meanwhile, using the Poly-IRT model would give slightly less accurate classification results. Concerning the CTT model, while its classification accuracy is comparable to that of the TRT, there exists considerable inconsistency between their classification results.
Fish Oil-induced Yellow Fat Disease in Rats I. Histological Changes
Authors: Danse L. H. J. C. , Verschuren P. M. 
Published: January 2010

Yellow fat disease was induced in young rats given a vitamin E-deficient diet supplemented with 15% fish oil. The changes in adipose tissue of this oil-induced disorder were different from those of natural yellow fat disease in horse, pig and mink. In the natural disease all fat depots had the early stage of yellow fat disease with interstitial lipofuscin-laden macrophages exclusively. In the rat, however, this change was seen only in the subcutaneous fat depot. Moreover, affected adipose tissue of animals with natural disease had extensive fibrosis, but in the rat fibrosis was always absent. Rats with fish oil-induced yellow fat disease had degenerative changes in various fat depots that occurred at various times but in the horse, pig and mink fat depots were affected simultaneously. Lipofuscin accumulated in the reticuloendothelial system in rats. Accumulation in spleen and liver was dependent on vitamin E deficiency, but only the accumulation in the Kupffer cells was correlated with yellow fat disease. Lipofuscin accumulation in the mesenteric lymph node did not depend on vitamin E deficiency.
Fish Oil-induced Yellow Fat Disease in Rats; II. Enzyme Histochemistry of Adipose Tissue
Authors: Danse L. H. J. C. , Steenbergen-Botterweg W. A. 
Published: January 2010

Adipose tissue in various stages of fish oil-induced yellow fat disease in the rat had the same acid phosphatase and 5-nucleotidase activity pattern as similar stages of the disorder in mink and pig. A weak acid phosphatase and 5-nucleotidase activity was seen in interstitial lipofuscin-laden macrophages in “stage M” yellow fat disease without fat cell degeneration. Activity of these macrophagic enzymes increased when there was fat cell degeneration (“stage S” and “stage E” yellow fat disease). This different phosphatase activity in the same cell type may result from phagocytosis of substrates with variable digestibility. Macrophages directly surrounding affected fat cells in steatitis areas (“stage S” and “stage E”) had strong acid phosphatase and 5-nucleotidase activity. As in the pig, increased 5-nucleotidase activity was found in affected fat cells, which probably indicates plasma membrane damage. Increased nonspecific esterase activity occurred around affected fat cells. Only a small part of this esterase activity originated from inflammatory cells. This indicates that an increase of esterase activity in degenerating adipose tissue may be an endogeneous process in this tissue.