bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prospective Study of Meat and Fat Intake in Relation to Small Intestinal Cancer
Authors: Cross Amanda J. , Leitzmann Michael F. , Subar Amy F. , Thompson Frances E. , Hollenbeck Albert R. , Schatzkin Arthur 
Published: November 2008

Abstract
Diets high in red and processed meats are associated with carcinogenesis of the large intestine, but no prospective study has examined meat and fat intake in relation to cancer of the small intestine. We prospectively investigated meat and fat intakes, estimated from a food frequency questionnaire, in relation to small intestinal cancer among half a million men and women enrolled in the NIH-AARP Diet and Health Study. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). During up to 8 years of follow-up, 60 adenocarcinomas and 80 carcinoid tumors of the small intestine were diagnosed. Despite slightly elevated HRs for red meat, there were no clear associations for red or processed meat intake and either adenocarcinoma or carcinoid tumors of the small intestine. In contrast, we noted a markedly elevated risk for carcinoid tumors of the small intestine with saturated fat intake in both the categorical (highest versus lowest tertile: HR, 3.18; 95% CI, 1.62–6.25) and continuous data (HR, 3.72; 95% CI, 1.79–7.74 for each 10-g increase in intake per 1,000 kcal). Our findings suggest that the positive associations for meat intake reported in previous case-control studies may partly be explained by saturated fat intake.[Cancer Res 2008;68(22):9274–9]
Palomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular Permeability
Authors: Xue Qi , Hopkins Benjamin , Perruzzi Carole , Udayakumar Durga , Sherris David , Benjamin Laura E. 
Published: November 2008

Abstract
It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. [Cancer Res 2008;68(22):9551–7]
Ku80 Deletion Suppresses Spontaneous Tumors and Induces a p53-Mediated DNA Damage Response
Authors: Holcomb Valerie B. , Rodier Francis , Choi YongJun , Busuttil Rita A. , Vogel Hannes , Vijg Jan , Campisi Judith , Hasty Paul 
Published: November 2008

Abstract
Ku80 facilitates DNA repair and therefore should suppress cancer. However, ku80−/− mice exhibit reduced cancer, although they age prematurely and have a shortened life span. We tested the hypothesis that Ku80 deletion suppresses cancer by enhancing cellular tumor-suppressive responses to inefficiently repaired DNA damage. In support of this hypothesis, Ku80 deletion ameliorated tumor burden in APCMIN mice and increased a p53-mediated DNA damage response, DNA lesions, and chromosomal rearrangements. Thus, contrary to its assumed role as a caretaker tumor suppressor, Ku80 facilitates tumor growth most likely by dampening baseline cellular DNA damage responses. [Cancer Res 2008;68(22):9497–502]
Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth
Authors: Alpini Gianfranco , Invernizzi Pietro , Gaudio Eugenio , Venter Julie , Kopriva Shelley , Bernuzzi Francesca , Onori Paolo , Franchitto Antonio , Coufal Monique , Frampton Gabriel , Alvaro Domenico , Lee Sum P. , Marzioni Marco , Benedetti Antonio , DeMorrow Sharon 
Published: November 2008

Abstract
Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines, compared with normal cholangiocytes, and tissue and bile from cholangiocarcinoma patients. Specifically, there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin, respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represent the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies. [Cancer Res 2008;68(22):9184–93]
The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk
Authors: Fleming Jessica L. , Huang Tim H-M. , Toland Amanda Ewart 
Published: November 2008

AbstractEpigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influence cancer risk are inherited through the germline from parent to child and are observed in multiple generations. Epigenetic changes may be inherited as Mendelian, non-Mendelian, or environmentally induced traits. Here, we will discuss Mendelian, non-Mendelian, and environmentally induced patterns of multigenerational epigenetic alterations as well as some possible mechanisms for how these events may be occurring. [Cancer Res 2008;68(22):9116–21]
Genetic Predictors of MEK Dependence in Non–Small Cell Lung Cancer
Authors: Pratilas Christine A. , Hanrahan Aphrothiti J. , Halilovic Ensar , Persaud Yogindra , Soh Junichi , Chitale Dhananjay , Shigematsu Hisayuki , Yamamoto Hiromasa , Sawai Ayana , Janakiraman Manickam , Taylor Barry S. , Pao William , Toyooka Shinichi , Ladanyi Marc , Gazdar Adi , Rosen Neal , Solit David B. 
Published: November 2008

Abstract
Hyperactivated extracellular signal-regulated kinase (ERK) signaling is common in human cancer and is often the result of activating mutations in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of lung cancers harboring BRAF kinase domain mutations, we screened a large panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for BRAF mutations. We found that non–small cell lung cancers (NSCLC) cells with both V600E and non-V600E BRAF mutations were selectively sensitive to MEK inhibition compared with those harboring mutations in epidermal growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions. Supporting its classification as a “driver” mutation in the cells in which it is expressed, MEK inhibition in V600EBRAF NSCLC cells led to substantial induction of apoptosis, comparable with that seen with EGFR kinase inhibition in EGFR mutant NSCLC models. Despite high basal ERK phosphorylation, EGFR mutant cells were uniformly resistant to MEK inhibition. Conversely, BRAF mutant cell lines were resistant to EGFR inhibition. These data, together with the nonoverlapping pattern of EGFR and BRAF mutations in human lung cancer, suggest that these lesions define distinct clinical entities whose treatment should be guided by prospective real-time genotyping. To facilitate such an effort, we developed a mass spectrometry-based genotyping method for the detection of hotspot mutations in BRAF, KRAS, and EGFR. Using this assay, we confirmed that BRAF mutations can be identified in a minority of NSCLC tumors and that patients whose tumors harbor BRAF mutations have a distinct clinical profile compared with those whose tumors harbor kinase domain mutations in EGFR. [Cancer Res 2008;68(22):9375–83]
PEA-15 Induces Autophagy in Human Ovarian Cancer Cells and Is Associated with Prolonged Overall Survival
Authors: Bartholomeusz Chandra , Rosen Daniel , Wei Caimiao , Kazansky Anna , Yamasaki Fumiyuki , Takahashi Takeshi , Itamochi Hiroaki , Kondo Seiji , Liu Jinsong , Ueno Naoto T. 
Published: November 2008

AbstractPhospho-enriched protein in astrocytes (PEA-15) is a 15-kDa phosphoprotein that slows cell proliferation by binding to and sequestering extracellular signal–regulated kinase (ERK) in the cytoplasm, thereby inhibiting ERK-dependent transcription and proliferation. In previous studies of E1A human gene therapy for ovarian cancer, we discovered that PEA-15 induced the antitumor effect of E1A by sequestering activated ERK in the cytoplasm of cancer cells. Here, we investigated the role of PEA-15 in ovarian cancer tumorigenesis, the expression levels of PEA-15 in human ovarian cancer, and whether PEA-15 expression correlated with overall survival in women with ovarian cancer. We overexpressed PEA-15 in low-PEA-15-expressing cells and knocked down PEA-15 in high-PEA-15-expressing cells and analyzed the effects on proliferation, anchorage-independent growth, and cell cycle progression. We then assessed PEA-15 expression in an annotated tissue microarray of tumor samples from 395 women with primary epithelial ovarian cancer and tested whether PEA-15 expression was linked with overall survival. PEA-15 expression inhibited proliferation, and cell cycle analysis did not reveal apoptosis but did reveal autophagy, which was confirmed by an increase in LC3 cleavage. Inhibition of the ERK1/2 pathway decreased PEA-15–induced autophagy. These findings suggest that the antitumor activity of PEA-15 is mediated, in part, by the induction of autophagy involving activation of the ERK1/2 pathway. Multivariable analyses indicated that the women with high-PEA-15-expressing tumors survived longer than those with low-PEA-15-expressing tumors (hazard ratio, 1.973; P = 0.0167). Our findings indicate that PEA-15 expression is an important prognostic marker in ovarian cancer. [Cancer Res 2008;68(22):9302–10]
Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal
Authors: Godlewski Jakub , Nowicki Michal O. , Bronisz Agnieszka , Williams Shanté , Otsuki Akihiro , Nuovo Gerard , RayChaudhury Abhik , Newton Herbert B. , Chiocca E. Antonio , Lawler Sean 
Published: November 2008

Abstract
MicroRNAs (miR) show characteristic expression signatures in various cancers and can profoundly affect cancer cell behavior. We carried out miR expression profiling of human glioblastoma specimens versus adjacent brain devoid of tumor. This revealed several significant alterations, including a pronounced reduction of miR-128 in tumor samples. miR-128 expression significantly reduced glioma cell proliferation in vitro and glioma xenograft growth in vivo. miR-128 caused a striking decrease in expression of the Bmi-1 oncogene, by direct regulation of the Bmi-1 mRNA 3′-untranslated region, through a single miR-128 binding site. In a panel of patient glioblastoma specimens, Bmi-1 expression was significantly up-regulated and miR-128 was down-regulated compared with normal brain. Bmi-1 functions in epigenetic silencing of certain genes through epigenetic chromatin modification. We found that miR-128 expression caused a decrease in histone methylation (H3K27me3) and Akt phosphorylation, and up-regulation of p21CIP1 levels, consistent with Bmi-1 down-regulation. Bmi-1 has also been shown to promote stem cell self-renewal; therefore, we investigated the effects of miR-128 overexpression in human glioma neurosphere cultures, possessing features of glioma “stem-like” cells. This showed that miR-128 specifically blocked glioma self-renewal consistent with Bmi-1 down-regulation. This is the first example of specific regulation by a miR of a neural stem cell self-renewal factor, implicating miRs that may normally regulate brain development as important biological and therapeutic targets against the “stem cell–like” characteristics of glioma. [Cancer Res 2008;68(22):9125–30]
Synergistic Proapoptotic Activity of Recombinant TRAIL Plus the Akt Inhibitor Perifosine in Acute Myelogenous Leukemia Cells
Authors: Tazzari Pier Luigi , Tabellini Giovanna , Ricci Francesca , Papa Veronica , Bortul Roberta , Chiarini Francesca , Evangelisti Camilla , Martinelli Giovanni , Bontadini Andrea , Cocco Lucio , McCubrey James A. , Martelli Alberto M. 
Published: November 2008

AbstractTo potentiate the response of acute myelogenous leukemia (AML) cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) cytotoxicity, we have examined the efficacy of a combination with perifosine, a novel phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor. The rationale for using such a combination is that perifosine was recently described to increase TRAIL-R2 receptor expression and decrease the cellular FLICE-inhibitory protein (cFLIP) in human lung cancer cell lines. Perifosine and TRAIL both induced cell death by apoptosis in the THP-1 AML cell line, which is characterized by constitutive PI3K/Akt activation, but lacks functional p53. Perifosine, at concentrations below IC50, dephosphorylated Akt and increased TRAIL-R2 levels, as shown by Western blot, reverse transcription-PCR, and flow cytometric analysis. Perifosine also decreased the long isoform of cFLIP (cFLIP-L) and the X-linked inhibitor of apoptosis protein (XIAP) expression. Perifosine and TRAIL synergized to activate caspase-8 and induce apoptosis, which was blocked by a caspase-8–selective inhibitor. Up-regulation of TRAIL-R2 expression was dependent on a protein kinase Cα/c-Jun-NH2-kinase 2/c-Jun signaling pathway activated by perifosine through reactive oxygen species production. Perifosine also synergized with TRAIL in primary AML cells displaying constitutive activation of the Akt pathway by inducing apoptosis, Akt dephosphorylation, TRAIL-R2 up-regulation, cFLIP-L and XIAP down-regulation, and c-Jun phosphorylation. The combined treatment negatively affected the clonogenic activity of CD34+ cells from patients with AML. In contrast, CD34+ cells from healthy donors were resistant to perifosine and TRAIL treatment. Our findings suggest that the combination of perifosine and TRAIL might offer a novel therapeutic strategy for AML. [Cancer Res 2008;68(22):9394–403]
Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways
Authors: Fels Diane R. , Ye Jiangbin , Segan Andrew T. , Kridel Steven J. , Spiotto Michael , Olson Michael , Koong Albert C. , Koumenis Constantinos 
Published: November 2008

Abstract
Hypoxia is a dynamic feature of the tumor microenvironment that contributes to drug resistance and cancer progression. We previously showed that components of the unfolded protein response (UPR), elicited by endoplasmic reticulum (ER) stress, are also activated by hypoxia in vitro and in vivo animal and human patient tumors. Here, we report that ER stressors, such as thapsigargin or the clinically used proteasome inhibitor bortezomib, exhibit significantly higher cytotoxicity toward hypoxic compared with normoxic tumor cells, which is accompanied by enhanced activation of UPR effectors in vitro and UPR reporter activity in vivo. Treatment of cells with the translation inhibitor cycloheximide, which relieves ER load, ameliorated this enhanced cytotoxicity, indicating that the increased cytotoxicity is ER stress–dependent. The mode of cell death was cell type–dependent, because DLD1 colorectal carcinoma cells exhibited enhanced apoptosis, whereas HeLa cervical carcinoma cells activated autophagy, blocked apoptosis, and eventually led to necrosis. Pharmacologic or genetic ablation of autophagy increased the levels of apoptosis. These results show that hypoxic tumor cells, which are generally more resistant to genotoxic agents, are hypersensitive to proteasome inhibitors and suggest that combining bortezomib with therapies that target the normoxic fraction of human tumors can lead to more effective tumor control. [Cancer Res 2008;68(22):9323–30]
Humanized Radioiodinated Minibody For Imaging of Prostate Stem Cell Antigen–Expressing Tumors
Authors: Leyton Jeffrey V. , Olafsen Tove , Lepin Eric J. , Hahm Scott , Bauer Karl B. , Reiter Robert E. , Wu Anna M. 
Published: November 2008

AbstractPurpose: Prostate stem cell antigen (PSCA) is a cell surface glycoprotein that is overexpressed in prostate cancer, including hormone refractory disease. Previous preclinical studies showed the intact anti-PSCA antibodies, 1G8 and hu1G8, localized specifically to PSCA-expressing xenografts. Optimal micro positron emission tomography (microPET) imaging using hu1G8, however, required a delay of 168 hours postinjection. In this study, the 2B3 minibody (an 80-kDa engineered antibody fragment) has been produced for rapid targeting and imaging.Experimental Design: A gene encoding a PSCA-specific minibody, VL-linker-VH-hinge-huIgG1 CH3, was assembled. The minibody was expressed by secretion from mammalian cells and purified by cation exchange chromatography. Relative affinity and specificity were determined by competition ELISA and flow cytometry. Serial microPET imaging using a 124I-labeled minibody was conducted at 4 and 21 hours in mice bearing LAPC-9 AD, LAPC-9 AI, PC-3, and LNCaP-PSCA human prostate cancer xenografts. Tumor and tissue biodistribution was determined, and region of interest analysis of the images was conducted.Results: Yields of 20 mg/L purified 2B3 minibody were obtained that showed specific binding to LNCaP-PSCA cells. Purified 2B3 minibody showed specific binding to LNCaP-PSCA cells with an apparent affinity of 46 nmol/L. Radioiodinated 2B3 minibody showed rapid nontarget tissue and blood clearance kinetics (t1/2β = 11.2 hours). MicroPET scanning using the 124I-2B3 minibody showed both androgen-dependent and -independent tumors as early as 4 hours and excellent high contrast images at 21 hours postinjection.Conclusions: Imaging PSCA-positive prostate cancer is feasible using an intermediate size antibody fragment at 21 hours.
Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer
Authors: Manning H. Charles , Merchant Nipun B. , Foutch A. Coe , Virostko John M. , Wyatt Shelby K. , Shah Chirayu , McKinley Eliot T. , Xie Jingping , Mutic Nathan J. , Washington M. Kay , LaFleur Bonnie , Tantawy Mohammed Noor , Peterson Todd E. , Ansari M. Sib , Baldwin Ronald M. , Rothenberg Mace L. , Bornhop Darryl J. , Gore John C. , Coffey Robert J. 
Published: November 2008

Abstract
Purpose: To evaluate noninvasive molecular imaging methods as correlative biomarkers of therapeutic efficacy of cetuximab in human colorectal cancer cell line xenografts grown in athymic nude mice. The correlation between molecular imaging and immunohistochemical analysis to quantify epidermal growth factor (EGF) binding, apoptosis, and proliferation was evaluated in treated and untreated tumor-bearing cohorts.
Experimental Design: Optical imaging probes targeting EGF receptor (EGFR) expression (NIR800-EGF) and apoptosis (NIR700-Annexin V) were synthesized and evaluated in vitro and in vivo. Proliferation was assessed by 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) positron emission tomography. Assessment of inhibition of EGFR signaling by cetuximab was accomplished by concomitant imaging of NIR800-EGF, NIR700-Annexin V, and [18F]FLT in cetuximab-sensitive (DiFi) and insensitive (HCT-116) human colorectal cancer cell line xenografts. Imaging results were validated by measurement of tumor size and immunohistochemical analysis of total and phosphorylated EGFR, caspase-3, and Ki-67 immediately following in vivo imaging.
Results: NIR800-EGF accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab. NIR700-Annexin V accumulation correlated with cetuximab-induced apoptosis as assessed by immunohistochemical staining of caspase-3. No significant difference in tumor proliferation was noted between treated and untreated animals by [18F]FLT positron emission tomography or Ki-67 immunohistochemistry.
Conclusions: Molecular imaging can accurately assess EGF binding, proliferation, and apoptosis in human colorectal cancer xenografts. These imaging approaches may prove useful for serial, noninvasive monitoring of the biological effects of EGFR inhibition in preclinical studies. It is anticipated that these assays can be adapted for clinical use.
The N Staging System in Nasopharyngeal Carcinoma with Radiation Therapy Oncology Group Guidelines for Lymph Node Levels Based on Magnetic Resonance Imaging
Authors: Mao Yan-Ping , Liang Shao-Bo , Liu Li-Zhi , Chen Yong , Sun Ying , Tang Ling-Long , Tian Li , Lin Ai-Hua , Liu Meng-Zhong , Li Li , Ma Jun 
Published: November 2008

Abstract
Purpose: To evaluate the prognostic value of variables including nodal size, level, laterality, extranodal neoplastic spread (ENS), and necrosis in patients with nasopharyngeal carcinoma (NPC) and further explore the feasibility of an N-staging system using Radiation Therapy Oncology Group (RTOG) guidelines for lymph node levels based on magnetic resonance imaging (MRI).
Experimental Design: The MRI scans of 924 patients with histologically diagnosed nondisseminated NPC were reviewed retrospectively. The distribution of the tumors was mapped using RTOG guidelines and laterality. The multiplicity of each tumor was calculated, as well as the size and status of ENS and the necrosis of individual nodes.
Results: Nodal level, cervical lymph node laterality, and ENS were independent prognostic factors for disease failure and distant failure in multivariate analyses. There was no significant difference in the hazard ratios (HR) for distant failure between level II and retropharyngeal, level Ib, level V, or level III involvement, whereas patients with level IV and supraclavicular fossa involvement had a significant increase in HRs. The subsets that made up a given N stage group had similar HRs for distant failure. Both the HRs for disease failure and distant failure by the proposed N staging system between one stage and the next were statistically significant (P &lt; 0.05). The survival curves of disease-free survival and distant metastasis-free survival for all subclassifications of N stage showed significant difference from the adjacent stage (P &lt; 0.05). The overall distribution pattern of the proposed N staging was more equitable than that of the 6th American Joint Committee on Cancer N staging.
Conclusions: Nodal variables including level, cervical lymph node laterality, and ENS are independent prognostic factors for NPC. The proposed N staging system of NPC using RTOG guidelines based on MRI is highly predictive and may provide a more objective method for staging NPCs.