bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of Molecular Markers and Physical Activity on Mortality in Patients with Colon Cancer
Authors: Meyerhardt Jeffrey A. , Ogino Shuji , Kirkner Gregory J. , Chan Andrew T. , Wolpin Brian , Ng Kimmie , Nosho Katsuhiko , Shima Kaori , Giovannucci Edward L. , Loda Massimo , Fuchs Charles S. 
Published: September 2009

Abstract
Purpose: Physical activity in colon cancer survivors has been associated with lower cancer recurrences and improved survival. Whether molecular features of the tumor portend more or less likelihood for benefit from exercise is unknown.
Experimental Design: Using two large prospective cohort studies with physical activity assessments after colon cancer diagnosis, we examined expression of fatty acid synthase, p53, p21, and p27 and mutational status of K-ras and phosphatidylinositol 3-kinase(PI3KCA). We calculated hazard ratios (HR) of colon cancer–specific mortality, adjusted for tumor and patient characteristics, and tested for molecular interactions with exercise.
Results: In a cohort of 484 men and women with stage I to III colon cancer, patients who engaged in at least 18 metabolic equivalent task (MET)–hours per week after diagnosis had an adjusted HR for colon cancer–specific mortality of 0.64 [95% confidence interval (95% CI), 0.33-1.23] and for overall mortality of 0.60 (95% CI, 0.41-0.86). A statistically significant interaction was detected based on p27 expression (P = 0.03). For tumors with loss of p27 (n = 195), physical activity of ≥18 MET-hours/week led to a HR for colon cancer mortality of 1.40 (95% CI, 0.41-4.72), compared with those with &lt;18 MET-hours/week. However, for tumors with expression of p27 (n = 251), the adjusted HR was 0.33 (95% CI, 0.12-0.85). Molecular status of fatty acid synthase, K-ras, p53, p21, and PI3KCA did not influence the association between exercise and colon cancer–specific or overall mortality.
Conclusion: The benefit of physical activity on outcomes in patients with stage I to III colon cancer may be influenced by p27 status. Further studies are warranted to confirm these findings. (Clin Cancer Res 2009;15(18):5931–6)
A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors
Authors: Demetri George D. , Casali Paolo G. , Blay Jean-Yves , von Mehren Margaret , Morgan Jeffrey A. , Bertulli Rossella , Ray-Coquard Isabelle , Cassier Philippe , Davey Monica , Borghaei Hossein , Pink Daniel , Debiec-Rychter Maria , Cheung Wing , Bailey Stuart M. , Veronese Maria Luisa , Reichardt Annette , Fumagalli Elena , Reichardt Peter 
Published: September 2009

Abstract
Purpose: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors.
Experimental Design: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done.
Results: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group.
Conclusions: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation. (Clin Cancer Res 2009;15(18):5910–6)
Prostate-derived factor—a novel inhibitor of drug-induced cell death in colon cancer cells
Authors: Proutski Irina , Stevenson Leanne , Allen Wendy L. , McCulla Andrea , Boyer John , McLean Estelle G. , Longley Daniel B. , Johnston Patrick G. 
Published: September 2009

Abstract
We investigated the role of the divergent transforming growth factor-β superfamily member, prostate-derived factor (PDF), in regulating response to chemotherapies used in the treatment of colorectal cancer. A clear p53-dependent expression pattern of PDF was shown in a panel of colorectal cancer cell lines following acute exposure to oxaliplatin, 5-fluorouracil, and SN38. PDF gene silencing before chemotherapy treatment significantly sensitized cells expressing wild-type p53, but not p53-null or p53-mutant cells, to drug-induced apoptosis. Similarly, knockdown of PDF expression sensitized HCT116 drug-resistant daughter cell lines to their respective chemotherapies. Inducible PDF expression and treatment with recombinant PDF both significantly attenuated drug-induced apoptosis. Further analysis revealed that PDF activated the Akt but not the extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, cotreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin abrogated PDF-mediated resistance to chemotherapy-induced apoptosis. Together, these data suggest that PDF may be a novel inhibitor of drug-induced cell death in colorectal cancer cells and that the mature secreted form of the protein activates the phosphatidylinositol 3-kinase/Akt pathway as an acute mechanism of chemoresistance. [Mol Cancer Ther 2009;8(9):2566–74]
Targeting NF-κB signaling pathway suppresses tumor growth, angiogenesis, and metastasis of human esophageal cancer
Authors: Li Bin , Li Yuk Yin , Tsao Sai Wah , Cheung Annie L.M. 
Published: September 2009

Abstract
Esophageal cancer is the eighth most common malignancy, and one of the leading causes of cancer-related deaths worldwide. The overall 5-year survival rate of patients with esophageal cancer remains low at 10% to 40% due to late diagnosis, metastasis, and resistance of the tumor to radiotherapy and chemotherapy. NF-κB is involved in the regulation of cell growth, survival, and motility, but little is known about the role of this signaling pathway in the tumorigenesis of human esophageal squamous cell carcinoma (ESCC), the most common form of esophageal cancer. This study aims to explore the functions of NF-κB in human ESCC progression and to determine whether targeting the NF-κB signaling pathway might be of therapeutic value against ESCC. Our results from human ESCC cell lines and ESCC tissue indicated that NF-κB is constitutively active in ESCC. Exposure of ESCC cells to two NF-κB inhibitors, Bay11-7082 and sulfasalazine, not only reduced cancer cell proliferation, but also induced apoptosis and enhanced sensitivity to chemotherapeutic drugs, 5-fluorouracil, and cisplatin. In addition, Bay11-7082 and sulfasalazine suppressed the migration and invasive potential of ESCC cells. More importantly, the results from tumor xenograft and experimental metastasis models showed that Bay11-7082 had significant antitumor effects on ESCC xenografts in nude mice by promoting apoptosis, and inhibiting proliferation and angiogenesis, as well as reduced the metastasis of ESCC cells to the lungs without significant toxic effects. In summary, our data suggest that NF-κB inhibitors may be potentially useful as therapeutic agents for patients with esophageal cancer. [Mol Cancer Ther 2009;8(9):2635–44]
AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer
Authors: Yang Shu , Ngo Van Chanh , Lew Guo Bin , Chong Lih Wen Valerie , Lee Swee Shean , Ong Wei Jie Richard , Lam Wei Ling Irene , Thng Choon Hua , Koong Heng Nung , Ong Hock Soo , Chung Alexander , Chow Pierce , Lee Jonathan , Soo Khee Chee , Huynh Hung 
Published: September 2009

AbstractGastric cancer is a deadly disease for which current therapeutic options are extremely limited. Vascular endothelial growth factor receptors and platelet-derived growth factor receptors regulate gastric cancer cell proliferation, invasion, and tumor angiogenesis. In the present study, we report that sorafenib therapy effectively inhibited tumor growth and angiogenesis in tumor xenografts. These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951, c-Kit Tyr568/570, platelet-derived growth factor receptor-β Tyr1021, and Akt Ser473 and Thr308, down-regulation of positive cell cycle regulators, increased apoptosis, and up-regulation of p27. Sorafenib treatment also caused up-regulation of p-c-Raf Ser338 and p-extracellular signal-regulated kinase (ERK) Thr202/Tyr204 in gastric cancer xenografts. The combination of sorafenib and MAP/ERK kinase inhibitor AZD6244 enhances the effectiveness of each compound alone. Potential effect of sorafenib/AZD6244 included increase in proapoptotic Bim. Our data show that MAP/ERK kinase inhibition enhances the antitumor activity of sorafenib in vivo, supporting a rationale for multitargeted suppression of the angiogenesis and ERK signaling network in gastric cancer therapy. [Mol Cancer Ther 2009;8(9):2537–45]
Chemokine CXC receptor 4–mediated glioma tumor tracking by bone marrow–derived neural progenitor/stem cells
Authors: Xu Qijin , Yuan Xiangpeng , Xu Minlin , McLafferty Fred , Hu Jinwei , Lee Bong Seop , Liu Gentao , Zeng Zhaohui , Black Keith L. , Yu John S. 
Published: September 2009

Abstract
Malignant gliomas manifest frequent tumor recurrence after surgical resection and/or other treatment because of their nature of invasiveness and dissemination. The recognized brain tumor-tracking property of neural progenitor/stem cells opened the possibility of targeting malignant brain tumors using neural progenitor/stem cells. We and others have previously shown that fetal neural progenitor/stem cells can be used to deliver therapeutic molecules to brain tumors. Our recent work has further shown that gene delivery by bone marrow–derived neural progenitor/stem cells achieves therapeutic effects in a glioma model. In this study, we isolate and characterize bone marrow–derived neural progenitor/stem cells, which also express the chemokine receptor chemokine CXC receptor 4 (CXCR4). We show that CXCR4 is required for their chemotaxis and extracellular matrix invasion against a gradient of glioma soluble factors. Furthermore, β-galactosidase-labeled bone marrow–derived neural progenitor/stem cells implanted in the contralateral side of the brain were shown to track gliomas as early as day 1 and increased through days 3 and 7. Intracranial glioma tracking by bone marrow–derived neural progenitor/stem cells is significantly inhibited by preincubation of bone marrow–derived neural progenitor/stem cells with a blocking anti–CXCR4 antibody, suggesting a CXCR4–dependent tracking mechanism. Glioma tracking bone marrow–derived neural progenitor/stem cells were found to express progenitor/stem cell markers, as well as CXCR4. Although bromodeoxyuridine incorporation assays and proliferating antigen staining indicated that tumor tracking bone marrow–derived neural progenitor/stem cells were mostly nonproliferating, these cells survive in the local tumor environment with little apoptosis. Elucidating the molecular mechanism of brain tumor tracking by adult source stem cells may provide basis for the development of future targeted therapy for malignant brain tumors. [Mol Cancer Ther 2009;8(9):2746–53]
Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines
Authors: Bill Matthew A. , Bakan Courtney , Benson, Don M. , Fuchs James , Young Gregory , Lesinski Gregory B. 
Published: September 2009

Abstract
Curcumin has potential as a chemopreventative and chemotherapeutic agent, but its interactions with clinically relevant cytokines are poorly characterized. Because cytokine immunotherapy is a mainstay of treatment for malignant melanoma, we hypothesized that curcumin could modulate the cellular responsiveness to interferons and interleukins. As a single agent, curcumin induced a dose-dependent increase in apoptosis of human melanoma cell lines, which was most prominent at doses &gt;10 μmol/L. Immunoblot analysis confirmed that curcumin induced apoptosis and revealed caspase-3 processing, poly ADP ribose polymerase cleavage, reduced Bcl-2, and decreased basal phosphorylated signal transducers and activators of transcription 3 (STAT3). Despite its proapoptotic effects, curcumin pretreatment of human melanoma cell lines inhibited the phosphorylation of STAT1 protein and downstream gene transcription following IFN-α and IFN-γ as determined by immunoblot analysis and real time PCR, respectively. Pretreatment of peripheral blood mononuclear cells from healthy donors with curcumin also inhibited the ability of IFN-α, IFN-γ, and interleukin-2 to phosphorylate STAT proteins critical for their antitumor activity (STAT1 and STAT5, respectively) and their respective downstream gene expression as measured by real time PCR. Finally, stimulation of natural killer (NK) cells with curcumin reduced the level of interleukin-12–induced IFN-γ secretion, and production of granzyme b or IFN-γ upon coculture with A375 melanoma cells or NK-sensitive K562 cells as targets. These data show that although curcumin can induce apoptosis of melanoma cells, it can also adversely affect the responsiveness of immune effector cells to clinically relevant cytokines that possess antitumor properties. [Mol Cancer Ther 2009;8(9):2726–35]
Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells
Authors: Mak Duncan H. , Schober Wendy D. , Chen Wenjing , Konopleva Marina , Cortes Jorge , Kantarjian Hagop M. , Andreeff Michael , Carter Bing Z. 
Published: September 2009

Abstract
The advent of Bcr-Abl tyrosine kinase inhibitors (TKI) has revolutionized the treatment of chronic myelogenous leukemia (CML). However, resistance evolves due to BCR-ABL mutations and other mechanisms. Furthermore, patients with blast crisis CML are less responsive and quiescent CML stem cells are insensitive to these inhibitors. We found that triptolide, a diterpenoid, at nanomolar concentrations, promoted equally significant death of KBM5 cells, a cell line derived from a Bcr-Abl–bearing blast crisis CML patient and KBM5STI571 cells, an imatinib-resistant KBM5 subline bearing the T315I mutation. Similarly, Ba/F3 cells harboring mutated BCR-ABL were as sensitive as Ba/F3Bcr-Ablp210wt cells to triptolide. Importantly, triptolide induced apoptosis in primary samples from blast crisis CML patients, who showed resistance to Bcr-Abl TKIs in vivo, with less toxicity to normal cells. Triptolide decreased X-linked inhibitor of apoptosis protein, Mcl-1, and Bcr-Abl protein levels in K562, KBM5, and KBM5STI571 cells and in cells from blast crisis CML patients. It sensitized KBM5, but not KBM5STI571, cells to imatinib. More importantly, triptolide also induced death of quiescent CD34+ CML progenitor cells, a major problem in the therapy of CML with TKIs. Collectively, these results suggest that triptolide potently induces blast crisis CML cell death independent of the cellular responses to Bcr-Abl TKIs, suggesting that triptolide could eradicate residual quiescent CML progenitor cells in TKI-treated patients and benefit TKI-resistant blast crisis CML patients. [Mol Cancer Ther 2009;8(9):2509–16]
Cell Motility and Spreading Are Suppressed by HOXA4 in Ovarian Cancer Cells: Possible Involvement of β1 Integrin
Authors: Klausen Christian , Leung Peter C.K. , Auersperg Nelly 
Published: September 2009

Abstract
HOX genes are transcription factors that control morphogenesis, organogenesis and differentiation. Increasing evidence suggests that HOX genes play a role in ovarian cancer progression; however few studies have defined functional roles and mechanisms of action. We showed previously that HOXA4 expression is increased in invasive, compared to noninvasive, epithelial ovarian tumors. However, HOXA4 suppressed cell migration suggesting that elevated HOXA4 expression in invasive tumors constitutes a homeostatic response. In the present study, we used siRNA and forced-expression in multiple cell lines to define the role of HOXA4 in the regulation of transwell migration/invasion and cellular/colony morphology. Knockdown of endogenous HOXA4 increased migration, but not Matrigel invasion, of OVCAR-8 and OVCAR-3 cells. HOXA4 knockdown also increased cell spreading on plastic or fibronectin, reduced cell-cell adhesion, and increased filopodia in two- and three-dimensional cultures. These changes were not associated with significant changes in αV or β3 integrin and E- or N-cadherin. However, down-regulation of HOXA4 significantly reduced β1 integrin protein levels within cell colonies and cell aggregates, but not of single, nonadherent cells. It had no effect on β1 integrin, α5 integrin, or fibronectin mRNA levels. Conversely, overexpression of HOXA4 in CaOV-3 cells suppressed transwell migration and increased β1 integrin protein levels. Our results confirm that HOXA4 inhibits cell motility, show that it suppresses cell spreading and filopodia formation while enhancing cell-cell adhesion, and suggest a role for β1 integrin in mediating these changes. These observations support the hypothesis that overexpression of HOXA4 in invasive ovarian tumors is a homeostatic, invasion-suppressive response. (Mol Cancer Res 2009;7(9):1425–37)
Oncogenic Ras Signals through Activation of Both Phosphoinositide 3-Kinase and Rac1 to Induce c-Jun NH2-Terminal Kinase–Mediated, Caspase-Independent Cell Death
Authors: Byun Joo-Yun , Kim Min-Jung , Yoon Chang-Hwan , Cha Hyukjin , Yoon Gyesoon , Lee Su-Jae 
Published: September 2009

Abstract
Cells avert the development of malignancy in response to deregulated oncogene expression by activating a regulated cell death pathway. However, the molecular mechanism underlying this oncogene-induced cellular death process remains unclear. Here, we show that retroviral expression of oncogenic H-ras induced cell death in a caspase-independent manner in normal cells. Inhibition of c-Jun NH2-terminal kinase (JNK) by pretreatment with SP600125 or a dominant-negative form of JNK blocked cell death. Rac1 and phosphoinositide 3-kinase (PI3K) were activated in cells overexpressing oncogenic H-ras. Inhibition of Rac1 with RacN17, a dominant-negative form of Rac1, attenuated oncogenic H-ras–induced JNK activation and subsequent cell death. Interestingly, inhibition of PI3K with LY294002 or by small interfering RNA–mediated knockdown of PI3K p85 or p110 subunits also clearly attenuated JNK activation and cell death. No cross talk was observed between Rac1 and PI3K, indicating that these pathways operate in parallel. Our findings show that JNK is necessary for oncogenic H-ras–induced, caspase-independent cell death, and that both PI3K and Rac1 activities are required for JNK activation and cell death. Determining the molecular mechanisms that mediate cell death responses to deregulated oncogenes provides a more refined understanding of cellular disposal processes in normal cells and increases our appreciation of these events as a mechanism for protecting against malignant progression. (Mol Cancer Res 2009;7(9):1534–42)
MicroRNAs in Plasma of Pancreatic Ductal Adenocarcinoma Patients as Novel Blood-Based Biomarkers of Disease
Authors: Wang Jin , Chen Jinyun , Chang Ping , LeBlanc Aimee , Li Donghui , Abbruzzesse James L. , Frazier Marsha L. , Killary Ann M. , Sen Subrata 
Published: September 2009

Abstract
Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls. We have profiled four miRNAs, miR-21, miR-210, miR-155, and miR-196a, all implicated in the development of pancreatic cancer with either proven or predicted target genes involved in critical cancer-associated cellular pathways. Of these, miR-155 has recently been identified as a candidate biomarker of early pancreatic neoplasia, whereas elevated expression of miR196a has been shown to parallel progression of disease. The results revealed a sensitivity of 64% and a specificity of 89% with the analyses of plasma levels for this panel of four miRNAs. The area under the receiver operating characteristic curve were estimated at 0.82 and 0.78 without and with leave-one-out cross-validation scheme, respectively. These observations, although a “proof of principle” finding at this time, show the feasibility of developing plasma miRNA profiling as a sensitive and specific blood-based biomarker assay for pancreatic cancer that has the potential of translation to the clinic with additional improvements in the future.
The Effect of Early Hyaluronic Acid Delivery on the Development of an Acute Articular Cartilage Lesion in a Sheep Model
Authors: Kaplan Lee D. , Lu Yan , Snitzer Jonathan , Nemke Brett , Hao Zhengling , Biro Steven , Albiero William , Stampfli Herman F. , Markel Mark , Popkin Charles , Baum Samuel Z. 
Published: September 2009

Background Partial-thickness articular cartilage lesions occur with knee trauma and may progress to osteoarthritis. This study evaluates the effectiveness of hyaluronic acid on cartilage healing after acute knee injury in sheep. Hypothesis Early administration of hyaluronic acid to an acute cartilage injury will prevent chondrocyte death and improve cartilage metabolism. Study Design Controlled laboratory study. Methods A 10 × 10 mm partial-thickness articular cartilage lesion was created on the medial condyle of 16 adult sheep stifles (hindlimbs). Eight sheep received intra-articular hyaluronic acid injections at days 0, 8, and 15, and 8 controls received saline. Contralateral stifles were nonoperated controls. All sheep were sacrificed at 12 weeks after surgery. Synovial fluid was drawn before surgery and after euthanasia for collagen II, nitric oxide, and interleukin-1 beta analysis. The medial condyle was analyzed by gross appearance, confocal laser microscopy for cell viability, histologic analysis for cartilage morphology, and dimethylmethylene blue assay for proteoglycan. Results At 12 weeks, histologic analysis revealed that the hyaluronic acid group had significantly better scores than the saline group ( P = .001). The hyaluronic acid group had significantly greater glycosaminoglycan content than the saline group ( P = .011), and showed a trend of reduced chondrocyte death compared with the saline group ( P = .07). Synovial fluid showed no significant differences between the groups in collagen II, nitric oxide, and interleukin-1 beta levels. Conclusion The results demonstrated that early administration of hyaluronic acid shows a significant improvement in cartilage histologic analysis and increased glycosaminoglycan content after acute traumatic cartilage injury. Clinical Relevance Early hyaluronic acid treatment for acute partial-thickness articular cartilage lesions may decrease or delay articular degeneration.