bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sarcopenia in an Overweight or Obese Patient Is an Adverse Prognostic Factor in Pancreatic Cancer
Authors: Tan Benjamin H.L. , Birdsell Laura A. , Martin Lisa , Baracos Vickie E. , Fearon Kenneth C.H. 
Published: November 2009

Abstract
Purpose: The average weight-losing pancreatic cancer patient undergoing palliative therapy is frequently overweight rather than underweight, and this can confound conventional measures used for risk stratification. The aim of this study was to evaluate if weight and body composition, specifically sarcopenia, assessed from diagnostic computed tomography (CT) scans, is of prognostic value in patients with pancreatic cancer. The nature and extent of tissue loss over subsequent months was also evaluated.
Experimental Design: A total of 111 patients entering a palliative therapy program, who had CT images and had undergone nutritional screening, were studied. In patients for whom follow-up scans were available (n = 44), longitudinal changes in body composition were studied at a mean of 230 62 and 95 60 days prior to demise.
Results: Sixty-two patients (55.9) were sarcopenic, 44 (39.6) were overweight/obese, and 18 (16.2) were both. Age 59 years (hazard ratio, 1.71; 95 confidence interval, 1.10-2.66; P = 0.018), and overweight/obese sarcopenia (hazard ratio, 2.07; 95 confidence interval, 1.23-3.50; P = 0.006) were identified as independent predictors of survival on multivariate analysis. Longitudinal analysis revealed that total fat-free mass index decreased from 15.5 2.5 kg/m2 to 14.5 2.0 kg/m2 (P = 0.002), and total fat mass index decreased from 7.5 2.0kg/m2 to 6.0 1.5kg/m2 (P &lt; 0.0001) over 135 days.
Conclusions: Sarcopenia in overweight/obese patients with advanced pancreatic cancer is an occult condition but can be identified using CT scans. This condition is an independent adverse prognostic indicator that should be considered for stratification of patients' entering clinical trials, systemic therapy, or support care programs. (Clin Cancer Res 2009;15(22):69739)
Snail Promotes CXCR2 LigandDependent Tumor Progression in NonSmall Cell Lung Carcinoma
Authors: Yanagawa Jane , Walser Tonya C. , Zhu Li X. , Hong Longsheng , Fishbein Michael C. , Mah Vei , Chia David , Goodglick Lee , Elashoff David A. , Luo Jie , Magyar Clara E. , Dohadwala Mariam , Lee Jay M. , St. John Maie A. , Strieter Robert M. , Sharma Sherven , Dubinett Steven M. 
Published: November 2009

Abstract
Purpose: As a transcriptional repressor of E-cadherin, Snail has predominantly been associated with epithelial-mesenchymal transition, invasion, and metastasis. However, other important Snail-dependent malignant phenotypes have not been fully explored. Here, we investigate the contributions of Snail to the progression of nonsmall cell lung cancer (NSCLC).
Experimental Design: Immunohistochemistry was done to quantify and localize Snail in human lung cancer tissues, and tissue microarray analysis was used to correlate these findings with survival. NSCLC cell lines gene-modified to stably overexpress Snail were evaluated in vivo in two severe combined immunodeficiency murine tumor models. Differential gene expression between Snail-overexpressing and control cell lines was evaluated using gene expression microarray analysis.
Results: Snail is upregulated in human NSCLC tissue, and high levels of Snail expression correlate with decreased survival (P &lt; 0.026). In a heterotopic model, mice bearing Snail-overexpressing tumors developed increased primary tumor burden (P = 0.008). In an orthotopic model, mice bearing Snail-overexpressing tumors also showed a trend toward increased metastases. In addition, Snail overexpression led to increased angiogenesis in primary tumors as measured by MECA-32 (P &lt; 0.05) positivity and CXCL8 (P = 0.002) and CXCL5 (P = 0.0003) concentrations in tumor homogenates. Demonstrating the importance of these proangiogenic chemokines, the Snail-mediated increase in tumor burden was abrogated with CXCR2 blockade. Gene expression analysis also revealed Snail-associated differential gene expression with the potential to affect angiogenesis and diverse aspects of lung cancer progression.
Conclusion: Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands. (Clin Cancer Res 2009;15(22):68209)
Gene Expression Profiling of Paraffin-Embedded Primary Melanoma Using the DASL Assay Identifies Increased Osteopontin Expression as Predictive of Reduced Relapse-Free Survival
Authors: Conway Caroline , Mitra Angana , Jewell Rosalyn , Randerson-Moor Juliette , Lobo Samira , Nsengimana Jrmie , Edward Sara , Sanders D. Scott , Cook Martin , Powell Barry , Boon Andy , Elliott Faye , de Kort Floor , Knowles Margaret A. , Bishop D. Timothy , Newton-Bishop Julia 
Published: November 2009

Abstract
Purpose: Gene expression studies in melanoma have been few because tumors are small and cryopreservation is rarely possible. The purpose of this study was to evaluate the Illumina DASL Array Human Cancer Panel for gene expression studies in formalin-fixed melanoma primary tumors and to identify prognostic biomarkers.
Experimental Design: Primary tumors from two studies were sampled using a tissue microarray needle. Study 1: 254 tumors from a melanoma cohort recruited from 2000 to 2006. Study 2: 218 tumors from a case-control study of patients undergoing sentinel node biopsy.
Results: RNA was obtained from 76 of blocks; 1.4 of samples failed analysis (transcripts from &lt;250 of the 502 genes on the DASL chip detected). Increasing age of the block and increased melanin in the tumor were associated with reduced number of genes detected. The gene whose expression was most differentially expressed in association with relapse-free survival in study 1 was osteopontin (SPP1; P = 2.11 106) and supportive evidence for this was obtained in study 2 used as a validation set (P = 0.006; unadjusted data). Osteopontin level in study 1 remained a significant predictor of relapse-free survival when data were adjusted for age, sex, tumor site, and histologic predictors of relapse. Genes whose expression correlated most strongly with osteopontin were PBX1, BIRC5 (survivin), and HLF.
Conclusion: Expression data were obtained from 74 of primary melanomas and provided confirmatory evidence that osteopontin expression is a prognostic biomarker. These results suggest that predictive biomarker studies may be possible using stored blocks from mature clinical trials. (Clin Cancer Res 2009;15(22):693946)
Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach
Authors: Ma Xiaoli , Ma Quanfu , Liu Jia , Tian Yuan , Wang Beibei , Taylor Kathryn M. , Wu Peng , Wang Daowen , Xu Gang , Meng Li , Wang Shixuan , Ma Ding , Zhou Jianfeng 
Published: November 2009

Abstract
Histone deacetylase inhibitors (HDACi) show promise as a novel class of antitumoral agents and have shown the ability to induce apoptosis of tumor cells. To gain a better understanding of the action of HDACi, we conducted a functional gene screen approach named suppression of mortality by antisense rescue technique to identify the key genes responsible for the tumor-selective killing trichostatin A. Over 20 genes associated with HDACi-induced mortality were identified. One of the confirmed positive hits is LIV1, a putative zinc transporter. LIV1 is significantly induced by treatment with HDACi in a number of tumor cells, but not in normal cells. Knockdown of LIV1 suppressed apoptosis induced by HDACi in tumor cells. Although HDACi induced a slight increase in the free intracellular zinc concentration, knockdown of LIV1 significantly enhanced the intracellular zinc level, which was associated with resistance to apoptosis. On the other hand, pretreatment of the cells with a specific zinc chelator TPEN reversed the apoptosis resistance conferred by knockdown of LIV1. However, the biological effects of TPEN were abolished by addition of physiologic concentrations of zinc. Taken together, the present study identifies LIV1 as a critical mediator responsible for HDACi-induced apoptosis. The effect of LIV1 is, at least in part, mediated by affecting intracellular zinc homeostasis, which may be related to alteration of the catalytic activity of the Caspase 3 and expression of some BCL-2 family genes. As such, these findings highlight a novel mechanism underlying the action of HDACi that could be potentially useful in the clinical setting. [Mol Cancer Ther 2009;8(11):3108–16]
CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo
Authors: Burns Christopher J. , Fantino Emmanuelle , Phillips Ian D. , Su Stephen , Harte Michael F. , Bukczynska Patricia E. , Frazzetto Mark , Joffe Max , Kruszelnicki Irma , Wang Bing , Wang Yue , Wilson Neil , Dilley Rodney J. , Wan Soo S. , Charman Susan A. , Shackleford David M. , Fida Rosa , Malcontenti-Wilson Cathy , Wilks Andrew F. 
Published: November 2009

Abstract
CYT997 is a wholly synthetic compound that possesses highly potent cytotoxic activity in vitro through inhibition of microtubule polymerization. CYT997 blocks the cell cycle at the G2-M boundary, and Western blot analysis indicates an increase in phosphorylated Bcl-2, along with increased expression of cyclin B1. Caspase-3 activation is also observed in cells treated with CYT997 along with the generation of poly(ADP-ribose) polymerase. The compound possesses favorable pharmacokinetic properties, is orally bioavailable, and is efficacious per os in a range of in vivo cancer models, including some refractory to paclitaxel treatment. CYT997 exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 possesses a useful combination of pharmacologic and pharmacokinetic properties and has considerable potential as a novel anticancer agent. [Mol Cancer Ther 2009;8(11):3036–45]
JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia
Authors: Manthey Carl L. , Johnson Dana L. , Illig Carl R. , Tuman Robert W. , Zhou Zhao , Baker Judith F. , Chaikin Margery A. , Donatelli Robert R. , Franks Carol F. , Zeng Lee , Crysler Carl , Chen Yanmin , Yurkow Edward J. , Boczon Lisa , Meegalla Sanath K. , Wilson Kenneth J. , Wall Mark J. , Chen Jinsheng , Ballentine Shelley K. , Ott Heidi , Baumann Christian , Lawrence Danielle , Tomczuk Bruce E. , Molloy Christopher J. 
Published: November 2009

Abstract
There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80+ tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141–treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1–dependent macrophages and osteoclasts contribute to tumor growth and skeletal events. [Mol Cancer Ther 2009;8(11):3151–61]
Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas
Authors: Hu Kaiji , Lee Cathy , Qiu Dexin , Fotovati Abbas , Davies Alastair , Abu-Ali Samah , Wai Daniel , Lawlor Elizabeth R. , Triche Timothy J. , Pallen Catherine J. , Dunn Sandra E. 
Published: November 2009

Abstract
Rhabdomyosarcoma, consisting of alveolar (aRMS) and embryonal (eRMS) subtypes, is the most common type of sarcoma in children. Currently, there are no targeted drug therapies available for rhabdomyosarcoma. In searching for new molecular therapeutic targets, we carried out genome-wide small interfering RNA (siRNA) library screens targeting human phosphatases (n = 206) and kinases (n = 691) initially against an aRMS cell line, RH30. Sixteen phosphatases and 50 kinases were identified based on growth inhibition after 72 hours. Inhibiting polo-like kinase 1 (PLK1) had the most remarkable impact on growth inhibition (∼80%) and apoptosis on all three rhabdomyosarcoma cell lines tested, namely, RH30, CW9019 (aRMS), and RD (eRMS), whereas there was no effect on normal muscle cells. The loss of PLK1 expression and subsequent growth inhibition correlated with decreased p-CDC25C and Cyclin B1. Increased expression of WEE 1 was also noted. The induction of apoptosis after PLK1 silencing was confirmed by increased p-H2AX, propidium iodide uptake, and chromatin condensation, as well as caspase-3 and poly(ADP-ribose) polymerase cleavage. Pediatric Ewing's sarcoma (TC-32), neuroblastoma (IMR32 and KCNR), and glioblastoma (SF188) models were also highly sensitive to PLK1 inhibition. Finally, based on cDNA microarray analyses, PLK1 mRNA was overexpressed (&gt;1.5 fold) in 10 of 10 rhabdomyosarcoma cell lines and in 47% and 51% of primary aRMS (17 of 36 samples) and eRMS (21 of 41 samples) tumors, respectively, compared with normal muscles. Similarly, pediatric Ewing's sarcoma, neuroblastoma, and osteosarcoma tumors expressed high PLK1. We conclude that PLK1 could be a promising therapeutic target for the treatment of a wide range of pediatric solid tumors including rhabdomyosarcoma. [Mol Cancer Ther 2009;8(11):3024–35]
Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer
Authors: Qamri Zahida , Preet Anju , Nasser Mohd W. , Bass Caroline E. , Leone Gustavo , Barsky Sanford H. , Ganju Ramesh K. 
Published: November 2009

Abstract
Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis. [Mol Cancer Ther 2009;8(11):3117–29]
Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking β-catenin and cyclooxygenase-2
Authors: Lim Kyu , Han Chang , Dai Yifan , Shen Miaoda , Wu Tong 
Published: November 2009

Abstract
Hepatocellular carcinoma (HCC) is a common human cancer with high mortality, and currently, there is no effective chemoprevention or systematic treatment. Recent evidence suggests that cyclooxygenase-2 (COX-2)–derived PGE2 and Wnt/β-catenin signaling pathways are implicated in hepatocarcinogenesis. Here, we report that ω-3 polyunsaturated fatty acids (PUFA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) inhibit HCC growth through simultaneously inhibition of COX-2 and β-catenin. DHA and EPA treatment resulted in a dose-dependent reduction of cell viability with cleavage of poly ADP ribose polymerase, caspase-3, and caspase-9 in three human HCC cell lines (Hep3B, Huh-7, HepG2). In contrast, AA, a ω-6 PUFA, exhibited no significant effect. DHA and EPA treatment caused dephosphorylation and thus activation of GSK-3β, leading to β-catenin degradation in Hep3B cells. The GSK-3β inhibitor, LiCl, partially prevented DHA-induced β-catenin protein degradation and apoptosis. Additionally, DHA induced the formation of β-catenin/Axin/GSK-3β binding complex, which serves as a parallel mechanism for β-catenin degradation. Furthermore, DHA inhibited PGE2 signaling through downregulation of COX-2 and upregulation of the COX-2 antagonist, 15-hydroxyprostaglandin dehydrogenase. Finally, the growth of HCC in vivo was significantly reduced when mouse HCCs (Hepa1-6) were inoculated into the Fat-1 transgenic mice, which express a Caenorhabditis elegans desaturase converting ω-6 to ω-3 PUFAs endogenously. These findings provide important preclinical evidence and molecular insight for utilization of ω-3 PUFAs for the chemoprevention and treatment of human HCC. [Mol Cancer Ther 2009;8(11):3046–55]
Selective metastatic tumor labeling with green fluorescent protein and killing by systemic administration of telomerase-dependent adenoviruses
Authors: Kishimoto Hiroyuki , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: November 2009

AbstractWe previously constructed telomerase-dependent, replication-selective adenoviruses OBP-301 (Telomelysin) and OBP-401 [Telomelysin-green fluorescent protein (GFP); TelomeScan], the replication of which is regulated by the human telomerase reverse transcriptase promoter. By intratumoral injection, these viruses could replicate within the primary tumor and subsequent lymph node metastasis. The aim of the present study was to evaluate the possibility of systemic administration of these telomerase-dependent adenoviruses. We assessed the antitumor efficacy of OBP-301 and the ability of OBP-401 to deliver GFP in hepatocellular carcinoma (HCC) and metastatic colon cancer nude mouse models. We showed that i.v. administration of OBP-301 significantly inhibited colon cancer liver metastases and orthotopically implanted HCC. Further, we showed that OBP-401 could visualize liver metastases by tumor-specific expression of the GFP gene after portal venous or i.v. administration. Thus, systemic administration of these adenoviral vectors should have clinical potential to treat and detect liver metastasis and HCC. [Mol Cancer Ther 2009;8(11):3001–8]
Is the Prose Tale of Job in Late Biblical Hebrew?
Authors: Young Ian 
Published: November 2009

AbstractAn influential article published in 1974 by Avi Hurvitz argues that the language of the Prose Tale of Job (Job 1:1-2:13; 42:7-17) is incompatible with a date prior to the exile. Hurvitz's suggested Late Biblical Hebrew (LBH) linguistic forms are examined, and while some forms are rejected, Hurvitz's judgement that the Prose Tale contains LBH linguistic elements is found to be correct. However, these do not occur in a sufficient accumulation for the text to be considered LBH according to Hurvitz's own methodology, but rather the accumulation is consistent with a classification as Early Biblical Hebrew (EBH). This conclusion has no chronological implications, however, since EBH and LBH represent not two chronological phases but co-existing styles of Hebrew in the post-exilic and quite possibly pre-exilic periods.
Justice in the Sermon on the Mount: An Aristotelian Reading
Authors: Thom Johan 
Published: November 2009

AbstractThe frequent occurrence of the term δıκαıoσυνη ("righteousness, justice") in the Sermon of the Mount (Matt 5-7) (SM) indicates one of the main themes of the text. This impression is strengthened by the fact that the term is found in strategically important locations in the composition of the SM. This article does not, however, focus on the meaning and use of δıκαıoσυνη as such. Instead, I discuss the role justice, an important component of δıκαıoσυνη, plays in the SM. To help us gain perspective on how justice was popularly conceived, a brief survey of one of the most influential ancient analyses of justice, that by Aristotle in bk. 5 of his Nicomachean Ethics, is provided. Against this background, the way the notion of justice operates in selected passages of the SM is investigated. I try to show that the text frequently manipulates and overturns conventional conceptions of justice and that this reinforces the SM's demand for a δıκαıoσυνη exceeding popular expectations.
The Septuagint Version of Isaiah 53 and the Early Christian Formula "He Was Delivered for Our Trespasses"
Authors: Breytenbach Cilliers 
Published: November 2009

AbstractDid Isaiah 53 (LXX) and its παραδıδóναı-terminology influence the early Christian notion of Jesus being delivered "for our sins" (Rom 4:25 etc.)? And if so, is that to be understood as a specific Jewish backdrop for the interpretation of the death of Jesus? The way in which the Septuagint deviates from the Hebrew text suggests another view. To render various terms of his Vorlage the translator of the LXX made use of the widespread Greek notion of delivering somebody unto a hostile force. If early Christian explication of the death of Jesus drew on Isaiah 53, it was influenced by its Greek translation.
Heterozygous deletion of the PU.1 locus in human AML
Authors: Bonadies Nicola , Pabst Thomas , Mueller Beatrice U. 
Published: November 2009

Abstract
The transcription factor PU.1 is essential for myeloid development. Targeted disruption of an upstream regulatory element (URE) decreases PU.1 expression by 80% and leads to acute myeloid leukemia (AML) in mice. Here, we sequenced the URE sequences of PU.1 in 120 AML patients. Four polymorphisms (single nucleotide polymorphisms [SNPs]) in the URE were observed, with homozygosity in all SNPs in 37 patients. Among them, we compared samples at diagnosis and remission, and one patient with cytogenetically normal acute myeloid leukemia M2 was identified with heterozygosity in 3 of the SNPs in the URE at remission. Loss of heterozygosity was further found in this patient at 2 polymorphic sites in the 5′ promoter region and in 2 intronic sites flanking exon 4, thus suggesting loss of heterozygosity covering at least 40 kb of the PU.1 locus. Consistently, PU.1 expression in this patient was markedly reduced. Our study suggests that heterozygous deletion of the PU.1 locus can be associated with human AML.