bluuebunny/crossref_metadata_2025 huggingface dataset:
Delineating the angiogenic gene expression profile before pulmonary vascular remodeling in a lamb model of congenital heart disease
Authors: Tian Jing , Fratz Sohrab , Hou Yali , Lu Qing , Görlach Agnes , Hess John , Schreiber Christian , Datar Sanjeev A. , Oishi Peter , Nechtman John , Podolsky Robert , She Jin-Xiong , Fineman Jeffrey R. , Black Stephen M.
Published: October 2010

Disordered angiogenesis is implicated in pulmonary vascular remodeling secondary to congenital heart diseases (CHD). However, the underlying genes are not well delineated. We showed previously that an ovine model of CHD with increased pulmonary blood flow (PBF, Shunt) has an “angiogenesis burst” between 1 and 4 wk of age. Thus we hypothesized that the increased PBF elicited a proangiogenic gene expression profile before onset of vessel growth. To test this we utilized microarray analysis to identify genes that could be responsible for the angiogenic response. Total RNA was isolated from lungs of Shunt and control lambs at 3 days of age and hybridized to Affymetrix gene chips for microarray analyses ( n = 8/group). Eighty-nine angiogenesis-related genes were found to be upregulated and 26 angiogenesis-related genes downregulated in Shunt compared with control lungs (cutting at 1.2-fold difference, P < 0.05). We then confirmed upregulation of proangiogenic genes FGF2, Angiopoietin2 (Angpt2), and Birc5 at mRNA and protein levels and upregulation of ccl2 at mRNA level in 3-day Shunt lungs. Furthermore, we found that pulmonary arterial endothelial cells (PAEC) isolated from fetal lambs exhibited increased expression of FGF2, Angpt2, Birc5, and ccl2 and enhanced angiogenesis when exposed to elevated shear stress (35 dyn/cm2) compared with cells exposed to more physiological shear stress (20 dyn/cm2). Finally, we demonstrated that blocking FGF2, Angpt2, Birc5, or ccl2 signaling with neutralizing antibodies or small interfering RNA (siRNA) significantly decreased the angiogenic response induced by shear stress. In conclusion, we have identified a “proangiogenic” gene expression profile in a lamb model of CHD with increased PBF that precedes onset of pulmonary vascular remodeling. Our data indicate that FGF2, Angpt2, Birc5, and ccl2 may play important roles in the angiogenic response.
Identifying Subalpine Fir (Abies lasiocarpa) Attacked by the Balsam Woolly Adelgid (Adelges piceae) Using Spectral Measurements of the Foliage
Authors: Cook Stephen P. , Humes Karen S. , Hruska Ryan , Fraley Grant , Williams Christopher J.
Published: October 2010

Balsam woolly adelgid is an invasive pest of firs in the United States. Aerial surveys are conducted for detection of adelgid infestations but other remotely sensed data may also be useful. Our objective was to determine if high spectral resolution, branch-level data can be used to distinguish infested from noninfested trees. Stepwise discriminant analysis yielded a three-variable model (the red-green index and two narrow-bands (one at 670 nm and the other at 1912 nm)) that classified infested versus non-infested trees with 94% accuracy compared with the 83% accuracy obtained with a single-variable model. The response of trees in narrow spectral bands was integrated across wavebands to simulate measurements from the multispectral SPOT5-HRVIR sensor. Stepwise discriminant analysis again yielded a three-variable model (simple ratio, the SPOT5-HRVIR band in the SWIR region and NDVI) with similar accuracy (93%) at discriminating infested from non-infested trees compared with the 83% accuracy obtained with a single-variable model.
Primary Leiomyosarcoma of the Male Breast: A Case Report
Authors: Masannat Yazan , Sumrien Haytham , Sharaiha Yousef
Published: October 2010

Primary leiomyosarcoma of the breast is a rare tumour with only around thirty cases reported in the literature. Most of the cases reported are in females, while only a few are reported in males. We present a case of primary breast leiomyosarcoma in a 59-year-old man that presented with a subareolar lump which felt to be benign clinically and radiologically but proven to be a leiomyosarcoma on excision.
Progress in Studies on Carbon and Silicon Carbide Nanocomposite Materials
Authors: Xiao Peng , Chen Jie , Xu Xian-feng
Published: October 2010

Silicon carbide nanofiber and carbon nanotubes are introduced. The structure and application of nanotubers (nanofibers) in carbon/carbon composites are emphatically presented. Due to the unique structure of nanotubers (nanofibers), they can modify the microstructure of pyrocarbon and induce the deposition of pyrocarbon with high text in carbon/carbon composites. So the carbon/carbon composites modified by CNT/CNF have more excellent properties.
Nona-Arginine Facilitates Delivery of Quantum Dots into Cells via Multiple Pathways
Authors: Xu Yi , Liu Betty Revon , Lee Han-Jung , Shannon Katie B. , Winiarz Jeffrey G. , Wang Tien-Chun , Chiang Huey-Jenn , Huang Yue-wern
Published: October 2010

Semiconductor quantum dots (QDs) have recently been used to deliver and monitor biomolecules, such as drugs and proteins. However, QDs alone have a low efficiency of transport across the plasma membrane. In order to increase the efficiency, we used synthetic nona-arginine (SR9), a cell-penetrating peptide, to facilitate uptake. We found that SR9 increased the cellular uptake of QDs in a noncovalent binding manner between QDs and SR9. Further, we investigated mechanisms of QD/SR9 cellular internalization. Low temperature and metabolic inhibitors markedly inhibited the uptake of QD/SR9, indicating that internalization is an energy-dependent process. Results from both the pathway inhibitors and the RNA interference (RNAi) technique suggest that cellular uptake of QD/SR9 is predominantly a lipid raft-dependent process mediated by macropinocytosis. However, involvement of clathrin and caveolin-1 proteins in transducing QD/SR9 across the membrane cannot be completely ruled out.
Silencing of Autocrine Motility Factor Induces Mesenchymal-to-Epithelial Transition and Suppression of Osteosarcoma Pulmonary Metastasis
Authors: Niinaka Yasufumi , Harada Kiyoshi , Fujimuro Masahiro , Oda Masamitsu , Haga Arayo , Hosoki Misa , Uzawa Narikazu , Arai Naoya , Yamaguchi Satoshi , Yamashiro Masashi , Raz Avraham
Published: October 2010

Phosphoglucose isomerase (PGI) is a multifunctional enzyme that functions in glucose metabolism as a glycolytic enzyme catalyzing an interconversion between glucose and fructose inside the cell, while it acts as cytokine outside the cell, with properties that include autocrine motility factor (AMF)–regulating tumor cell motility. Overexpression of AMF/PGI induces epithelial-to-mesenchymal transition with enhanced malignancy. Recent studies have revealed that silencing of AMF/PGI resulted in mesenchymal-to-epithelial transition (MET) of human lung fibrosarcoma cells and breast cancer cells with reduced malignancy. Here, we constructed a hammerhead ribozyme specific against GUC triplet at the position G390 in the human, mouse, and rat AMF/PGI mRNA sequence. Mesenchymal human osteosarcoma MG-63, HS-Os-1, and murine LM8 cells were stably transfected with the ribozyme specific for AMF/PGI. The stable transfectant cells showed effective downregulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphologic change with reduced growth, motility, and invasion. Silencing of AMF/PGI induced MET, in which upregulation of E-cadherin and cytokeratins, as well as downregulation of vimentin, were noted. The MET guided by AMF/PGI gene silencing induced osteosarcoma MG-63 to terminally differentiate into mature osteoblasts. Furthermore, MET completely suppressed the tumor growth and pulmonary metastasis of LM8 cells in nude mice. Thus, acquisition of malignancy might be completed in part by upregulation of AMF/PGI, and waiver of malignancy might also be controlled by downregulation of AMF/PGI. Cancer Res; 70(22); 9483–93. ©2010 AACR.
mTOR Complex Component Rictor Interacts with PKCζ and Regulates Cancer Cell Metastasis
Authors: Zhang Fei , Zhang Xiaofang , Li Menghui , Chen Peng , Zhang Bin , Guo Hua , Cao Wenfeng , Wei Xiying , Cao Xuchen , Hao Xishan , Zhang Ning
Published: October 2010

Epidermal growth factor (EGF) mediates breast cancer cell chemotaxis and metastasis through mechanisms that involve the growth-regulatory mammalian target of rapamycin (mTOR) complex mTORC2, but the mechanisms involved remain obscure. Here, we report that the rapamycin-insensitive mTORC2 component protein Rictor is a critical mediator of metastasis in breast cancer cells. In patients with ductal carcinoma, Rictor expression was associated with increased lymph node metastasis. EGF induced translocation and colocalization of Rictor with protein kinase Cζ (PKCζ), a pivotal molecule in chemotaxis signaling. Further, Rictor coimmunoprecipitated with PKCζ in the absence of the mTORC2 complex. Small interfering RNA–mediated knockdown of Rictor inhibited EGF-induced PKCζ phosphorylation and translocation along with phosphorylation of the key F-actin binding protein cofilin. In parallel, Rictor knockdown reduced cellular chemotactic capacity and ablated pulmonary metastasis in a xenograft mouse model of breast cancer. Our findings identify Rictor as an important mediator of chemotaxis and metastasis in breast cancer cells. Cancer Res; 70(22); 9360–70. ©2010 AACR.
BRAF Inactivation Drives Aneuploidy by Deregulating CRAF
Authors: Kamata Tamihiro , Hussain Jahan , Giblett Susan , Hayward Robert , Marais Richard , Pritchard Catrin
Published: October 2010

Aspartate-594 is the third most common BRAF residue mutated in human cancer. Mutants of this residue are kinase inactive, and the mechanism(s) by which they contribute to cancer has remained perplexing. Using a conditional knock-in mouse model, we show that the D594ABraf mutant does not drive tumor development per se but is able to induce aneuploidy in murine splenocytes and mouse embryonic fibroblasts and contributes to immortalization through the propagation of aneuploid cells. D594ABraf lacks kinase activity but induces the related gene product Craf as well as the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway. Here, we show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells. These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf. Cancer Res; 70(21); 8475–86. ©2010 AACR.
Human Papillomavirus Infection and Reinfection in Adult Women: the Role of Sexual Activity and Natural Immunity
Authors: Trottier Helen , Ferreira Silvaneide , Thomann Patricia , Costa Maria C. , Sobrinho Joao S. , Prado José Carlos M. , Rohan Thomas E. , Villa Luisa L. , Franco Eduardo L.
Published: October 2010

There is a paucity of data on whether or not women can be reinfected with human papillomavirus (HPV) types to which they were exposed to earlier in life and on the role of natural immunity. The observation of HPV infection at older ages may be explained by the reactivation of a latent infection or new exposure from sexual activity. Our objective was to analyze the association between reinfection and sexual activity. We analyzed data from 2,462 women enrolled in the Ludwig-McGill cohort and followed every 4 to 6 months for up to 10 years. We performed HPV typing and viral load measurements via PCR and determined HPV-16 seroreactivity at enrollment. Incidence of infection and reinfection were estimated for individual types. Adjusted relative risks (RR) for the association between infection/reinfection and new sexual partners were calculated using Cox regression. Rates of initial infection and reinfection postclearance were statistically comparable. RRs of initial infection or reinfection were consistently associated with new sexual partners [2.4 (95% confidence intervals; 95% CI, 2.0–3.1) for first infection, 3.7 (1.1–13.8) for reinfection with the same type, and 2.3 (1.5–3.7) for reinfection with a different type]. Reinfection in older women was also associated with new sexual partners (RR, 2.8; 95% CI, 1.4–5.3) as were new infections with HPV-16 among women with serologic evidence of prior HPV-16 exposure (RR, 3.0; 95% CI, 1.6–5.3). Viral loads at initial infection and at reinfection were comparable. HPV infection and reinfection were strongly associated with sexual activity. This study suggests that natural immunity does not play a role in controlling the extent of reinfections. Cancer Res; 70(21); 8569–77. ©2010 AACR.
In vivo Imaging of Inflammation- and Tumor-Induced Lymph Node Lymphangiogenesis by Immuno–Positron Emission Tomography
Authors: Mumprecht Viviane , Honer Michael , Vigl Benjamin , Proulx Steven T. , Trachsel Eveline , Kaspar Manuela , Banziger-Tobler Nadja E. , Schibli Roger , Neri Dario , Detmar Michael
Published: October 2010

Metastasis to regional lymph nodes (LN) is a prognostic indicator for cancer progression. There is a great demand for sensitive and noninvasive methods to detect metastasis to LNs. Whereas conventional in vivo imaging approaches have focused on the detection of cancer cells, lymphangiogenesis within tumor-draining LNs might be the earliest sign of metastasis. In mouse models of LN lymphangiogenesis, we found that systemically injected antibodies to lymphatic epitopes accumulated in the lymphatic vasculature in tissues and LNs. Using a 124I-labeled antibody against the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), we imaged, for the first time, inflammation- and tumor-draining LNs with expanded lymphatic networks in vivo by positron emission tomography (PET). Anti-LYVE-1 immuno-PET enabled visualization of lymphatic vessel expansion in LNs bearing metastases that were not detected by [18F]fluorodeoxyglucose-PET, which is clinically applied to detect cancer metastases. Immuno-PET with lymphatic-specific antibodies may open up new avenues for the early detection of metastasis, and the images obtained might be used as biomarkers for the progression of diseases associated with lymphangiogenesis. Cancer Res; 70(21); 8842–51. ©2010 AACR.
Serum Vitamin D and Risk of Bladder Cancer
Authors: Mondul Alison M. , Weinstein Stephanie J. , Männistö Satu , Snyder Kirk , Horst Ronald L. , Virtamo Jarmo , Albanes Demetrius
Published: October 2010

Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH)D; i.e., <25, 25 to <37.5, 37.5 to <50, ≥50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (versus ≥50 nmol/L; <25 nmol/L: OR, 1.73; 95% CI, 1.03–2.91; 25 to <37.5 nmol/L: OR, 1.81; 95% CI, 1.05–3.14; 37.5 to <50 nmol/L: OR, 1.76; 95% CI, 1.02–3.02; P trend = 0.04). Similarly, increased risks for the lowest vitamin D category were observed when season-specific quartiles were used (Q1 versus Q4: OR, 1.63; 95% CI, 0.96–2.75; P trend = 0.03). In this prospective study of male smokers, lower serum 25(OH)D was associated with an increased risk of bladder cancer. Future studies should examine the association in other populations, especially nonsmokers and women. Cancer Res; 70(22); 9218–23. ©2010 AACR.
Pesticide Use Modifies the Association Between Genetic Variants on Chromosome 8q24 and Prostate Cancer
Authors: Koutros Stella , Beane Freeman Laura E. , Berndt Sonja I. , Andreotti Gabriella , Lubin Jay H. , Sandler Dale P. , Hoppin Jane A. , Yu Kai , Li Qizhai , Burdette Laura A. , Yuenger Jeffrey , Yeager Meredith , Alavanja Michael C.R.
Published: October 2010

Genome-wide association studies have identified 8q24 region variants as risk factors for prostate cancer. In the Agricultural Health Study, a prospective study of licensed pesticide applicators, we observed increased prostate cancer risk with specific pesticide use among those with a family history of prostate cancer. Thus, we evaluated the interaction among pesticide use, 8q24 variants, and prostate cancer risk. The authors estimated odds ratios (OR) and 95% confidence intervals (95% CI) for interactions among 211 8q24 variants, 49 pesticides, and prostate cancer risk in 776 cases and 1,444 controls. The ORs for a previously identified variant, rs4242382, and prostate cancer increased significantly (P < 0.05) with exposure to the organophosphate insecticide fonofos, after correction for multiple testing, with per allele ORnonexposed of 1.17 (95% CI, 0.93–1.48), per allele ORlow of 1.30 (95% CI, 0.75–2.27), and per allele ORhigh of 4.46 (95% CI, 2.17–9.17; P-interaction = 0.002, adjusted P-interaction = 0.02). A similar effect modification was observed for three other organophosphate insecticides (coumaphos, terbufos, and phorate) and one pyrethroid insecticide (permethrin). Among ever users of fonofos, subjects with three or four risk alleles at rs7837328 and rs4242382 had approximately three times the risk of prostate cancer (OR, 3.14; 95% CI, 1.41–7.00) compared with subjects who had zero risk alleles and never used fonofos. We observed a significant interaction among variants on chromosome 8q24, pesticide use, and risk of prostate cancer. Insecticides, particularly organophosphates, were the strongest modifiers of risk, although the biological mechanism is unclear. This is the first report of effect modification between 8q24 and an environmental exposure on prostate cancer risk. Cancer Res; 70(22); 9224–33. ©2010 AACR.
Expression Profiling in Progressive Stages of Fumarate-Hydratase Deficiency: The Contribution of Metabolic Changes to Tumorigenesis
Authors: Ashrafian Houman , O'Flaherty Linda , Adam Julie , Steeples Violetta , Chung Yuen-Li , East Phil , Vanharanta Sakari , Lehtonen Heli , Nye Emma , Hatipoglu Emine , Miranda Melroy , Howarth Kimberley , Shukla Deepa , Troy Helen , Griffiths John , Spencer-Dene Bradley , Yusuf Mohammed , Volpi Emanuela , Maxwell Patrick H. , Stamp Gordon , Poulsom Richard , Pugh Christopher W. , Costa Barbara , Bardella Chiara , Di Renzo Maria Flavia , Kotlikoff Michael I. , Launonen Virpi , Aaltonen Lauri , El-Bahrawy Mona , Tomlinson Ian , Pollard Patrick J.
Published: October 2010

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by mutations in the Krebs cycle enzyme fumarate hydratase (FH). It has been proposed that “pseudohypoxic” stabilization of hypoxia-inducible factor-α (HIF-α) by fumarate accumulation contributes to tumorigenesis in HLRCC. We hypothesized that an additional direct consequence of FH deficiency is the establishment of a biosynthetic milieu. To investigate this hypothesis, we isolated primary mouse embryonic fibroblast (MEF) lines from Fh1-deficient mice. As predicted, these MEFs upregulated Hif-1α and HIF target genes directly as a result of FH deficiency. In addition, detailed metabolic assessment of these MEFs confirmed their dependence on glycolysis, and an elevated rate of lactate efflux, associated with the upregulation of glycolytic enzymes known to be associated with tumorigenesis. Correspondingly, Fh1-deficient benign murine renal cysts and an advanced human HLRCC-related renal cell carcinoma manifested a prominent and progressive increase in the expression of HIF-α target genes and in genes known to be relevant to tumorigenesis and metastasis. In accord with our hypothesis, in a variety of different FH-deficient tissues, including a novel murine model of Fh1-deficient smooth muscle, we show a striking and progressive upregulation of a tumorigenic metabolic profile, as manifested by increased PKM2 and LDHA protein. Based on the models assessed herein, we infer that that FH deficiency compels cells to adopt an early, reversible, and progressive protumorigenic metabolic milieu that is reminiscent of that driving the Warburg effect. Targets identified in these novel and diverse FH-deficient models represent excellent potential candidates for further mechanistic investigation and therapeutic metabolic manipulation in tumors. Cancer Res; 70(22); 9153–65. ©2010 AACR.
Heat Shock Protein 60 Regulation of the Mitochondrial Permeability Transition Pore in Tumor Cells
Authors: Ghosh Jagadish C. , Siegelin Markus D. , Dohi Takehiko , Altieri Dario C.
Published: October 2010

Mitochondrial apoptosis plays a critical role in tumor maintenance and dictates the response to therapy in vivo; however, the regulators of this process are still largely elusive. Here, we show that the molecular chaperone heat shock protein 60 (Hsp60) directly associates with cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. This interaction occurs in a multichaperone complex comprising Hsp60, Hsp90, and tumor necrosis factor receptor-associated protein-1, selectively assembled in tumor but not in normal mitochondria. Genetic targeting of Hsp60 by siRNA triggers CypD–dependent mitochondrial permeability transition, caspase-dependent apoptosis, and suppression of intracranial glioblastoma growth in vivo. Therefore, Hsp60 is a novel regulator of mitochondrial permeability transition, contributing to a cytoprotective chaperone network that antagonizes CypD-dependent cell death in tumors. Cancer Res; 70(22); 8988–93. ©2010 AACR.
Inactivation of theAPCGene Is Constant in Adrenocortical Tumors from Patients with Familial Adenomatous Polyposis but Not Frequent in Sporadic Adrenocortical Cancers
Authors: Gaujoux Sébastien , Pinson Stéphane , Gimenez-Roqueplo Anne-Paule , Amar Laurence , Ragazzon Bruno , Launay Pierre , Meatchi Tchao , Libé Rossella , Bertagna Xavier , Audebourg Anne , Zucman-Rossi Jessica , Tissier Frédérique , Bertherat Jérôme
Published: October 2010

Purpose: In adrenocortical tumors (ACT), Wnt/β-catenin pathway activation can be explained by β-catenin somatic mutations only in a subset of tumors. ACT is observed in patients with familial adenomatous polyposis (FAP) with germline APC mutations, as well as in patients with Beckwith-Wiedemann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/β-catenin pathway regulation and may play a role in ACT tumorigenesis. The aim of this study was to report if APC and WTX may be associated with FAP-associated and sporadic ACT.

Experimental Design: ACTs from patients with FAP and sporadic adrenocortical carcinomas (ACC) with abnormal β-catenin localization on immunohistochemistry but no somatic β-catenin mutations were studied. APC was analyzed by denaturing high-performance liquid chromatography followed by direct sequencing and by multiplex ligation–dependent probe amplification when allelic loss was suspected. WTX was studied by direct sequencing.

Results: Four ACTs were observed in three patients with FAP and were ACC, adrenocortical adenoma, and bilateral macronodular adrenocortical hyperplasia, all with abnormal β-catenin localization. Biallelic inactivation of APC was strongly suggested by the simultaneous existence of somatic and germline alterations in all ACTs. In the 20 sporadic ACCs, a silent heterozygous somatic mutation as well as a rare heterozygous polymorphism in APC was found. No WTX mutations were observed.

Conclusions: ACT should be considered a FAP tumor. Biallelic APC inactivation mediates activation of the Wnt/β-catenin pathway in the ACTs of patients with FAP. In contrast, APC and WTX genetic alterations do not play a significant role in sporadic ACC. Clin Cancer Res; 16(21); 5133–41. ©2010 AACR.
Inhalation Delivery of a Novel Diindolylmethane Derivative for the Treatment of Lung Cancer
Authors: Ichite Nkechi , Chougule Mahavir , Patel Apurva R. , Jackson Tanise , Safe Stephen , Singh Mandip
Published: October 2010

The purpose of this study was to determine the anticancer efficacy of 1,1-bis (3′-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC6H5) by inhalation delivery alone and in combination with i.v. docetaxel in a murine model for lung cancer. An aqueous DIM-C-pPhC6H5 formulation was characterized for its aerodynamic properties. Tumor-bearing athymic nude mice were exposed to nebulized DIM-C-pPhC6H5, docetaxel, or combination (DIM-C-pPhC6H5 plus docetaxel) using a nose-only exposure technique. The aerodynamic properties included mass median aerodynamic diameter of 1.8 ± 0.3 μm and geometric SD of 2.31 ± 0.02. Lung weight reduction in mice treated with the drug combination was 64% compared with 40% and 47% in mice treated with DIM-C-pPhC6H5 aerosol and docetaxel alone, respectively. Combination treatment decreased expression of Akt, cyclin D1, survivin, Mcl-1, NF-κB, IκBα, phospho-IκBα, and vascular endothelial growth factor (VEGF) and increased expression of c-Jun NH2-terminal kinase 2 and Bad compared with tumors collected from single-agent treatment and control groups. DNA fragmentation was also enhanced in mice treated with the drug combination compared with docetaxel or DIM-C-pPhC6H5 alone. Combination treatment decreased expressions of VEGF and CD31 compared with single-agent treated and control groups. These results suggest that DIM-C-pPhC6H5 aerosol enhanced the anticancer activity of docetaxel in a lung cancer model by activating multiple signaling pathways. The study provides evidence that DIM-C-pPhC6H5 can be used alone or in combination with other drugs for the treatment of lung cancer using the inhalation delivery approach. Mol Cancer Ther; 9(11); 3003–14. ©2010 AACR.
Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models
Authors: Thompson Curtis B. , Shepard H. Michael , O'Connor Patrick M. , Kadhim Salam , Jiang Ping , Osgood Ryan J. , Bookbinder Louis H. , Li Xiaoming , Sugarman Barry J. , Connor Robert J. , Nadjsombati Sinisa , Frost Gregory I.
Published: October 2010

Hyaluronan (HA) is a glycosaminoglycan polymer that often accumulates in malignancy. Megadalton complexes of HA with proteoglycans create a hydrated connective tissue matrix, which may play an important role in tumor stroma formation. Through its colloid osmotic effects, HA complexes contribute to tumor interstitial fluid pressure, limiting the effect of therapeutic molecules on malignant cells. The therapeutic potential of enzymatic remodeling of the tumor microenvironment through HA depletion was initially investigated using a recombinant human HA-degrading enzyme, rHuPH20, which removed HA-dependent tumor cell extracellular matrices in vitro. However, rHuPH20 showed a short serum half-life (t1/2 < 3 minutes), making depletion of tumor HA in vivo impractical. A pegylated variant of rHuPH20, PEGPH20, was therefore evaluated. Pegylation improved serum half-life (t1/2 = 10.3 hours), making it feasible to probe the effects of sustained HA depletion on tumor physiology. In high-HA prostate PC3 tumors, i.v. administration of PEGPH20 depleted tumor HA, decreased tumor interstitial fluid pressure by 84%, decreased water content by 7%, decompressed tumor vessels, and increased tumor vascular area >3-fold. Following repeat PEGPH20 administration, tumor growth was significantly inhibited (tumor growth inhibition, 70%). Furthermore, PEGPH20 enhanced both docetaxel and liposomal doxorubicin activity in PC3 tumors (P < 0.05) but did not significantly improve the activity of docetaxel in low-HA prostate DU145 tumors. The ability of PEGPH20 to enhance chemotherapy efficacy is likely due to increased drug perfusion combined with other tumor structural changes. These results support enzymatic remodeling of the tumor stroma with PEGPH20 to treat tumors characterized by the accumulation of HA. Mol Cancer Ther; 9(11); 3052–64. ©2010 AACR.
Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity
Authors: Gujar Shashi A. , Marcato Paola , Pan Da , Lee Patrick W.K.
Published: October 2010

Tumor-associated immunosuppressive strategies, such as lack of tumor antigen recognition and failure of lymphocyte activation and homing, resist the development of tumor-specific immunity and hamper the immune response–mediated elimination of cancerous cells. In this report, we show that reovirus virotherapy overrides such a tumor immune evasion and establishes clinically meaningful antitumor immunity capable of protecting against subsequent tumor challenge. Reovirus-mediated destruction of tumor cells facilitates the recognition of tumor antigens by promoting the display of otherwise inaccessible tumor-specific immunogenic peptides on the surface of dendritic cells (DC). Furthermore, on exposure to reovirus, DCs produce IL-1α, IL-1β, IL-6, IL-12p40/70, IL-17, CD30L, eotaxin, GM-CSF, KC, MCP-1, MCP-5, M-CSF, MIG, MIP-1α, RANTES, TNF-α, VCAM-1, VSGF, CXCL-16, AXL, and MCP-2; undergo maturation; and migrate into the tumor microenvironment along with CD8 T cells. These reovirus-activated DCs also acquire the capacity to prime tumor antigen–specific transgenic T cells in vitro and intrinsic antitumor T-cell response in vivo. Further, reovirus virotherapy augments the efficacy of DC- or T cell–based anticancer immunotherapies and synergistically enhances the survival in tumor-bearing mice. Most importantly, antitumor cellular immune responses initiated during reovirus oncotherapy protect the host against subsequent tumor challenge in a reovirus-independent but antigen-dependent manner. These reovirus oncotherapy–initiated antitumor immune responses represent an anticancer therapeutic entity that can maintain a long-term cancer-free health even after discontinuation of therapy. Mol Cancer Ther; 9(11); 2924–33. ©2010 AACR.
PUMA Induction by FoxO3a Mediates the Anticancer Activities of the Broad-Range Kinase Inhibitor UCN-01
Authors: Dudgeon Crissy , Wang Peng , Sun Xiameng , Peng Rui , Sun Quanhong , Yu Jian , Zhang Lin
Published: October 2010

Most targeted anticancer drugs are inhibitors of kinases that are aberrantly activated in cancer cells. However, the mechanisms by which kinase inhibitors suppress tumor growth remain unclear. In this study, we found that UCN-01, a staurosporine analogue and broad-range kinase inhibitor used in clinical trials, inhibits colon cancer cell growth by inducing apoptosis via PUMA, a BH3-only Bcl-2 family member and a p53 target. PUMA expression was markedly elevated in a p53-independent fashion following UCN-01 treatment. The induction of PUMA by UCN-01 was mediated by direct binding of FoxO3a to the PUMA promoter following inhibition of AKT signaling. Deficiency in PUMA abrogated UCN-01–induced apoptosis, caspase activation, and mitochondrial dysfunction, and rendered UCN-01 resistance in a clonogenic assay, whereas elevated PUMA expression or a BH3 mimetic sensitized UCN-01 induced apoptosis. Chemosensitization by UCN-01 seemed to involve simultaneous PUMA induction through both p53-dependent and p53-independent mechanisms. Furthermore, deficiency in PUMA suppressed the antitumor effects of UCN-01 in a xenograft model, concurrent with reduced apoptosis and caspase activation in vivo. These results suggest that PUMA-mediated apoptosis is pivotal for the anticancer activities of UCN-01, and possibly other clinically used kinase inhibitor drugs, and that PUMA manipulation may be useful for improving their anticancer activities. Mol Cancer Ther; 9(11); 2893–902. ©2010 AACR.
An MLH1 Mutation Links BACH1/FANCJ to Colon Cancer, Signaling, and Insight toward Directed Therapy
Authors: Xie Jenny , Guillemette Shawna , Peng Min , Gilbert Candace , Buermeyer Andrew , Cantor Sharon B.
Published: October 2010

Defects in MLH1, as with other mismatch repair (MMR) proteins, are the primary cause of hereditary nonpolyposis colon cancer (HNPCC). Mutations in MMR genes often disrupt mismatch repair and MMR signaling functions. However, some HNPCC-associated mutations have unknown pathogenicity. Here, we uncover an MLH1 clinical mutation with a leucine (L)-to-histidine (H) amino acid change at position 607 that ablates MLH1 binding to FANCJ. Given that a DNA helicase is not essential for mammalian MMR in vitro, we considered that loss of MLH1 binding to FANCJ could alter MMR signaling. Consistent with this hypothesis, FANCJ-deficient cells exhibit delayed MMR signaling and apoptotic responses that generate resistance to agents that induce O6-methylguanine lesions. Our data indicate that the delay in MMR signaling provides time for the methylguanine methyltransferase (MGMT) enzyme to reverse DNA methylation. In essence, FANCJ deficiency alters the competition between two pathways: MGMT-prosurvival versus MMR-prodeath. This outcome could explain the HNPCC familial cancers that present as microsatellite stable and with intact MMR, such as MLHL607H. Importantly, the link between FANCJ and HNPCC provides insight toward directed therapies because loss of the FANCJ/MLH1 interaction also uniquely sensitizes cells to DNA cross-linking agents. Cancer Prev Res; 3(11); 1409–16. ©2010 AACR.
Increased Dkk3 protein expression in platelets and megakaryocytes of patients with myeloproliferative neoplasms
Authors: Tzankov Alexandar , Kern Johann , Pircher Andreas , Hermann Martin , Ott Helmut-Werner , Gastl Günther , Medinger Michael , Untergasser Gerold , Gunsilius Eberhard
Published: October 2010

Dickkopf-3 (Dkk3) has been proposed as tumour suppressor gene and a marker for tumour blood vessels. We analysed the expression and function of Dkk3 in platelets and megakaryocytes from healthy controls and patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN). Dkk3 protein and gene expression in platelets was compared with endothelial and other blood cell populations by ELISA, real-time PCR, and immunofluorescence. Moreover, megakaryocytes were isolated from bone marrow aspirates by CD61 microbeads. Immunohisto-chemical studies of Dkk3 expression were performed in essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF) and control reactive bone marrow cases (each n=10). Compared to all other blood cell populations platelets showed the highest concentration of Dkk3 protein (150 ± 19 ng/mg total protein). A strong DKK3 gene and protein expression was also observed in isolated megakaryocytes. Dkk3 co-localised with VEGF in α-granules of platelets and was released similar to VEGF upon stimulation. Addition of recombinant Dkk3 had no influence on blood coagulation (aPTT, INR) and platelet aggregation. Significantly more Dkk3+ megakaryocytes/mm2 could be found in bone marrow biopsies from patients with MPN (ET 40 ± 10, PV 31 ± 4, PMF 22 ± 3) than in controls (15 ± 3). The mean proportion of Dkk3+ megakaryocytes was increased in MPN as well (ET 83% ± 15%; PV 84% ± 12%; PMF 77% ± 8%) compared to controls (53% ± 11%). Dkk3+ megakaryocytes correlated with microvessel density in PV and PMF. We conclude that Dkk3 might be involved in the pathogenesis of MPN.
Factor Market Distortion and the Current Account Surplus in China
Authors: Huang Yiping , Tao Kunyu
Published: October 2010

China's large current account surpluses not only destabilize its own macroeconomic conditions, but are also a focal point for global rebalancing discussions. Existing explanations by the literature fail either to account for the recent surge or to offer actionablepolicy responses. In this study, we propose an alternative hypothesis: asymmetric market liberalization and associated cost distortions. These distortions are producer subsidy equivalents, which contributed to both extraordinary growth performance and the growing structural imbalances. Our rough estimates of such factor cost distortions offer some explanations for recent movements of the current account. We argue that China needs to adopt a comprehensive reform package to rebalance its economy.
Why Does China Invest So Much?
Authors: Knight John , Ding Sai
Published: October 2010

China has had a remarkably high ratio of investment to output ever since economic reform began in 1978, surpassing almost all other economies. This is an important proximate determinant of China's high growth rate. This paper gathers together the available evidence to explain why investment is so high: factors both on the demand and on the supply side, and in the latter case the availability of both resources and funds. It analyzes the rate of return on capital and its evolution, and the factors that have kept it up. It draws on the literature to explain the high saving rate, and considers why the imperfect capital market and institutional deficiencies have not constrained investment. The state-owned and private sectors are treated separately because of their different objectives, behavior, and funding.
R. v. Munyaneza: Pondering Canada’s First Core Crimes Conviction
Authors: Currie Robert J. , Stancu Ion
Published: October 2010

Canada recently completed its first genocide trial, which resulted in the conviction of the Rwandan accused, Desire Munyaneza, for crimes committed during the Rwandan genocide. While the case is still under appeal, it represents a significant success for Canada’s relatively new core crimes legislation, the Crimes Against Humanity and War Crimes Act, and was the first prosecution undertaken pursuant to that law. Drawing upon the Munyaneza case, the authors analyze the legislation and evaluate its effectiveness. They conclude that the model is an effective one that both bodes well for Canada’s future participation in the battle against impunity, and provides a model upon which other states might wish to draw.
Is There a Need for the ICTY to Clarify the Difference(s) between Life Imprisonment and Imprisonment for the Remainder of the Offender’s Life? The Galić and Lukić Decisions
Authors: Mujuzi Jamil Ddamulira
Published: October 2010

Since Nuremberg, war criminals have been sentenced to life imprisonment. The International Military Tribunal for Nuremberg sentenced three offenders to life imprisonment. The International Military Tribunal for the Far East sentenced 16 offenders to life imprisonment. The ICTR has sentenced several offenders to both life imprisonment and to imprisonment for the remainder of their lives. The ICC is empowered to sentence offenders to life imprisonment. The ICTY has sentenced one offender (Milan Lukić ) to imprisonment for the remainder of his life and another (Stanislav Galić) to life imprisonment. This article analyses two cases in which the ICTY has sentenced one offender to life imprisonment and another to imprisonment for the remainder of his life. The author argues that although the ICTY imposed different sentences in the two different judgements, in practice both sentences are likely to have the same effect.
Hydrologic Effects of Urbanization and Climate Change on the Flint River Basin, Georgia
Authors: Viger Roland J. , Hay Lauren E. , Markstrom Steven L. , Jones John W. , Buell Gary R.
Published: October 2010

The potential effects of long-term urbanization and climate change on the freshwater resources of the Flint River basin were examined by using the Precipitation-Runoff Modeling System (PRMS). PRMS is a deterministic, distributed-parameter watershed model developed to evaluate the effects of various combinations of precipitation, temperature, and land cover on streamflow and multiple intermediate hydrologic states. Precipitation and temperature output from five general circulation models (GCMs) using one current and three future climate-change scenarios were statistically downscaled for input into PRMS. Projections of urbanization through 2050 derived for the Flint River basin by the Forecasting Scenarios of Future Land-Cover (FORE-SCE) land-cover change model were also used as input to PRMS. Comparison of the central tendency of streamflow simulated based on the three climate-change scenarios showed a slight decrease in overall streamflow relative to simulations under current conditions, mostly caused by decreases in the surface-runoff and groundwater components. The addition of information about forecasted urbanization of land surfaces to the hydrologic simulation mitigated the decreases in streamflow, mainly by increasing surface runoff.
High Level of Proteinuria During Treatment With Renin—Angiotensin Inhibitors Is a Strong Predictor of Renal Outcome in Nondiabetic Kidney Disease
Authors: Xie Di , Hou Fan Fan , Fu Bi Ling , Zhang Xun , Liang Min
Published: October 2010

This study investigated whether proteinuria not only could serve as a marker of renal outcome but also could monitor the renoprotection of renin‐angiotensin system (RAS) inhibitor treatment in patients with nondiabetic chronic kidney disease (CKD). Data from the Renoprotection of Optimal Antiproteinuric Doses (ROAD) trial were used to examine the contribution of the antiproteinuric effect of benazepril and losartan on renal outcome (the primary composite end point of doubling of serum creatinine and end‐stage renal disease or death) in 339 Chinese nondiabetic CKD patients with overt proteinuria and renal insufficiency. The degree of proteinuria at month 6 of treatment (residual proteinuria) and during follow‐up (time‐average proteinuria) showed a close relationship with renal end points. Lowering of proteinuria reduced the risk of renal progression in patients with high, as well as low, proteinuria at baseline. After adjustment for baseline risk markers, therapy‐induced change in these variables at month 6 and during follow‐up—high residual proteinuria and time‐average proteinuria (≥1.0 g/d)—remained the independent predictors for renal end points. Therefore, minimization of proteinuria at least to less than 1.0 g/d should be a therapeutic goal in the management of nondiabetic patients with heavy proteinuria and renal insufficiency.
Letting People Off the Hook: When Do Good Deeds Excuse Transgressions?
Authors: Effron Daniel A. , Monin Benoît
Published: October 2010

Three studies examined when and why an actor’s prior good deeds make observers more willing to excuse—or license—his or her subsequent, morally dubious behavior. In a pilot study, actors’ good deeds made participants more forgiving of the actors’ subsequent transgressions. In Study 1, participants only licensed blatant transgressions that were in a different domain than actors’ good deeds; blatant transgressions in the same domain appeared hypocritical and suppressed licensing (e.g., fighting adolescent drug use excused sexual harassment, but fighting sexual harassment did not). Study 2 replicated these effects and showed that good deeds made observers license ambiguous transgressions (e.g., behavior that might or might not represent sexual harassment) regardless of whether the good deeds and the transgression were in the same or in a different domain—but only same-domain good deeds did so by changing participants’ construal of the transgressions. Discussion integrates two models of why licensing occurs.
Methods and Complications of Nasoenteral Intubation
Authors: Halloran Owen , Grecu Bianca , Sinha Ashish
Published: October 2010

Nasoenteral intubation is among the most common procedures performed by clinicians across all medical specialties. The most common technique for nasoenteral intubation is blind passage, as it does not require the use of sophisticated or expensive medical equipment. Unfortunately, blind placement too frequently results in trauma and is a source of significant morbidity and mortality. It is apparent that altered mental status, a preexisting endotracheal tube, and critical illness put a patient in a higher risk group for malposition and complications. Nasoenteral intubation should be attempted only with an understanding of the possibility for difficult placement and the potential complications that can arise from trauma or malposition.
Risky Pleasures: Using the Work of Graffiti Writers to Theorize the Act of Ethnography
Authors: Holmes Rachel
Published: October 2010

Graffiti artists who deface and vandalize also highly aestheticise and politicize landscapes marking boundaries that are both territorial and ideological. Similarly, the privileged “I” within reflexive research seems to subvert a process of territorialisation of the (un)authored research text with a kind of repetitious “tagging.” This article will consider how the idea of graffiti tagging might be used to theorize acts of ethnography (and ethnographer) in an early years classroom to destabilize what might otherwise remain an unproblematic inscription or stain in data. I will draw from excerpts of classroom data to open up ways to think about particular understandings of the researcher as “I,” casting shadows over the “I” that is written into versions of the child and the classroom.
Transitioning From Doctoral Study to the Academy: Theorizing Trenzas of Identity for Latina Sister Scholars
Authors: Espino Michelle M. , Muñoz Susana M. , Marquez Kiyama Judy
Published: October 2010

This article focuses on multiple truths pertaining to doctoral education as expressed by three Latina doctoral recipients. These scholars successfully navigated various educational processes with the support of one another, their families, faculty, and their chosen discipline. The authors, as sister scholars, retell their educational journeys through testimonio and analyze how their trenzas de identidades multiples (multiple strands of identity, that is, motherhood, social class, and public intellectual) now inform their work. By interrogating the extent to which intersections of identity affect educational and career pathways, the authors use plática (dialogue) to theorize their doctoral experiences and examine how their challenges and successes manifest in their professional lives in academia.
Aggression and Sexual Behavior in Best-Selling Pornography Videos: A Content Analysis Update
Authors: Bridges Ana J. , Wosnitzer Robert , Scharrer Erica , Sun Chyng , Liberman Rachael
Published: October 2010

This current study analyzes the content of popular pornographic videos, with the objectives of updating depictions of aggression, degradation, and sexual practices and comparing the study’s results to previous content analysis studies. Findings indicate high levels of aggression in pornography in both verbal and physical forms. Of the 304 scenes analyzed, 88.2% contained physical aggression, principally spanking, gagging, and slapping, while 48.7% of scenes contained verbal aggression, primarily name-calling. Perpetrators of aggression were usually male, whereas targets of aggression were overwhelmingly female. Targets most often showed pleasure or responded neutrally to the aggression.
Cognitive Functioning and Family Risk Factors in Relation to Symptom Behaviors of ADHD and ODD in Adolescents
Authors: Forssman Linda , Eninger Lilianne , Tillman Carin M. , Rodriguez Alina , Bohlin Gunilla
Published: October 2010

Objective: In this study, the authors investigated whether ADHD and oppositional defiant disorder (ODD) behaviors share associations with problems in cognitive functioning and/or family risk factors in adolescence. This was done by examining independent as well as specific associations of cognitive functioning and family risk factors with ADHD and ODD behaviors. Method: A sample of 120 adolescents from the general population was assessed on various cognitive tasks. ADHD and ODD behaviors were measured through parental and teacher ratings based on Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria. Parents and adolescents provided information regarding measures of family risk factors. Results: The results show that only cognitive functioning was associated with ADHD behaviors, and family risk factors were, independent of cognitive functioning, associated with ODD behaviors. Conclusion: These results suggest that cognitive performance bears a specific significance for ADHD behaviors, whereas family risk factors have specific importance for ODD behaviors.