bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tgfbr1Haploinsufficiency Is a Potent Modifier of Colorectal Cancer Development
Authors: Zeng Qinghua , Phukan Sharbani , Xu Yanfei , Sadim Maureen , Rosman Diana S. , Pennison Michael , Liao Jie , Yang Guang-Yu , Huang Chiang-Ching , Valle Laura , Di Cristofano Antonio , de la Chapelle Albert , Pasche Boris 
Published: January 2009

AbstractTransforming growth factor-β (TGF-β) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with ApcMin/+ mice, we show that ApcMin/+;Tgfbr1+/− mice develop twice as many intestinal tumors as ApcMin/+;Tgfbr1+/+ mice, as well as adenocarcinoma of the colon, without loss of heterozygosity at the Tgfbr1 locus. Decreased Smad2 and Smad3 phosphorylation and increased cellular proliferation are observed in the colonic epithelium crypts of ApcMin/+; Tgfbr1+/− mice. Smad-mediated TGF-β signaling is preserved in both ApcMin/+;Tgfbr1+/+ and ApcMin/+;Tgfbr1+/− intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in ApcMin/+;Tgfbr1+/− tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-β signaling significantly enhances colorectal cancer development and results in increased tumor cell proliferation. These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer. [Cancer Res 2009;69(2):678–86]
Prognostic Value of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) and TRAIL Receptors in Renal Cell Cancer
Authors: Macher-Goeppinger Stephan , Aulmann Sebastian , Tagscherer Katrin E. , Wagener Nina , Haferkamp Axel , Penzel Roland , Brauckhoff Antje , Hohenfellner Markus , Sykora Jaromir , Walczak Henning , Teh Bin T. , Autschbach Frank , Herpel Esther , Schirmacher Peter , Roth Wilfried 
Published: January 2009

Abstract
Purpose: The death ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC).
Experimental Design: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed.
Results: High TRAIL-R2 expression levels were associated with high-grade RCCs (P &lt; 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P &lt; 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery).
Conclusion: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs.
Phase I and Pharmacokinetic Study of XRP6258 (RPR 116258A), a Novel Taxane, Administered as a 1-Hour Infusion Every 3 Weeks in Patients with Advanced Solid Tumors
Authors: Mita Alain C. , Denis Louis J. , Rowinsky Eric K. , DeBono Johann S. , Goetz Andrew D. , Ochoa Leonel , Forouzesh Bahram , Beeram Muralidhar , Patnaik Amita , Molpus Kathleen , Semiond Dorothée , Besenval Michèle , Tolcher Anthony W. 
Published: January 2009

Abstract
Purpose: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity.
Experimental Design: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m2. Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course.
Results: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m2 dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean Vss, 2,034 L/m2). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses.
Conclusion: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m2. The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.
Mitochondrial Mutations Contribute to HIF1α Accumulation via Increased Reactive Oxygen Species and Up-regulated Pyruvate Dehydrogenease Kinase 2 in Head and Neck Squamous Cell Carcinoma
Authors: Sun Wenyue , Zhou Shaoyu , Chang Steven S. , McFate Thomas , Verma Ajay , Califano Joseph A. 
Published: January 2009

Abstract
Purpose: Mitochondrial mutations have been identified in head and neck squamous cell carcinoma (HNSCC), but the pathways by which phenotypic effects of these mutations are exerted remain unclear. Previously, we found that mitochondrial ND2 mutations in primary HNSCC increased reactive oxygen species (ROS) and conferred an aerobic, glycolytic phenotype with HIF1α accumulation and increased cell growth. The purpose of the present study was to examine the pathways relating these alterations.
Experimental Design: Mitochondrial mutant and wild-type ND2 constructs were transfected into oral keratinocyte immortal cell line OKF6 and head and neck cancer cell line JHU-O19 and established transfectants. The protein levels of HIF1α, pyruvate dehydrogenease (PDH), phosphorylated PDH, and pyruvate dehydrogenease kinase 2 (PDK2), together with ROS generation, were compared between the mutant and the wild type. Meanwhile, the effects of small molecule inhibitors targeting PDK2 and mitochondria-targeted catalase were evaluated on the ND2 mutant transfectants.
Results: We determined that ND2 mutant down-regulated PDH expression via up-regulated PDK2, with an increase in phosphorylated PDH. Inhibition of PDK2 with dichloroacetate decreased HIF1α accumulation and reduced cell growth. Extracellular treatment with hydrogen peroxide, a ROS mimic, increased PDK2 expression and HIF1α expression, and introduction of mitochondria-targeted catalase decreased mitochondrial mutation-mediated PDK2 and HIF1α expression and suppressed cell growth.
Conclusions: Our findings suggest that mitochondrial ND2 mutation contributes to HIF1α accumulation via increased ROS production, up-regulation of PDK2, attenuating PDH activity, thereby increasing pyruvate, resulting in HIF1α stabilization. This may provide insight into a potential mechanism, by which mitochondrial mutations contribute to HNSCC development.
Clinical Applications of Metabolomics in Oncology: A Review
Authors: Spratlin Jennifer L. , Serkova Natalie J. , Eckhardt S. Gail 
Published: January 2009

Abstract
Metabolomics, an omic science in systems biology, is the global quantitative assessment of endogenous metabolites within a biological system. Either individually or grouped as a metabolomic profile, detection of metabolites is carried out in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry. There is potential for the metabolome to have a multitude of uses in oncology, including the early detection and diagnosis of cancer and as both a predictive and pharmacodynamic marker of drug effect. Despite this, there is lack of knowledge in the oncology community regarding metabolomics and confusion about its methodologic processes, technical challenges, and clinical applications. Metabolomics, when used as a translational research tool, can provide a link between the laboratory and clinic, particularly because metabolic and molecular imaging technologies, such as positron emission tomography and magnetic resonance spectroscopic imaging, enable the discrimination of metabolic markers noninvasively in vivo. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker for cancer diagnosis, prognosis, and therapeutic evaluation.
Targeting the Apoptosome for Cancer Therapy
Authors: Ledgerwood Elizabeth C. , Morison Ian M. 
Published: January 2009

Abstract
Apoptosis is a programmed mechanism of cell death that ensures normal development and tissue homeostasis in metazoans. Avoidance of apoptosis is an important contributor to the survival of tumor cells, and the ability to specifically trigger tumor cell apoptosis is a major goal in cancer treatment. In vertebrates, numerous stress signals engage the intrinsic apoptosis pathway to induce the release of cytochrome c from mitochondria. Cytochrome c binds to apoptosis protease activating factor-1, triggering formation of the apoptosome, a multisubunit protein complex that serves as a platform for caspase activation. In this review we summarize the mechanisms of apoptosome assembly and activation, and our current understanding of the regulation of these processes. We detail the evidence that loss-of-function of the apoptosome pathway may contribute to the development of specific cancers. Finally we discuss recent results showing enhanced sensitivity of some tumor cells to cytochrome c–induced apoptosis, suggesting that agents able to directly or indirectly trigger apoptosome-catalyzed caspase activation in tumor cells could provide new approaches to cancer treatment.
DNA Repair Gene Polymorphisms and Risk of Pancreatic Cancer
Authors: Li Donghui , Suzuki Hideo , Liu Bingrong , Morris Jeffrey , Liu Jun , Okazaki Taro , Li Yanan , Chang Ping , Abbruzzese James L. 
Published: January 2009

Abstract
Purpose: The current research was undertaken to examine the association between genetic variations in DNA repair and pancreatic cancer risk.
Experimental Design: We analyzed 9 single nucleotide polymorphisms of 7 DNA repair genes (LIG3, LIG4, OGG1, ATM, POLB, RAD54L, and RECQL) in 734 patients with pancreatic adenocarcinoma and 780 healthy controls using the Taqman method. Information on cigarette smoking, alcohol consumption, medical history, and other risk factors was collected by personal interview.
Results: The homozygous mutant genotype of LIG3 G-39A [odds ratio (OR), 0.23; 95% confidence interval (CI), 0.06-0.82; P = 0.027] and ATM D1853N (OR, 2.55; 95% CI, 1.08-6.00; P = 0.032) was significantly associated with altered risk for pancreatic cancer. A statistically significant interaction of ATM D1853N and LIG4 C54T genotype with diabetes on the risk of pancreatic cancer was also detected. Compared with nondiabetics with the ATM D1853N GG genotype, nondiabetics with the GA/AA, diabetics with the GG, and diabetics with the GA/AA genotypes, respectively, had ORs (95% CI) of 0.96 (0.74-1.24), 1.32 (0.89-1.95), and 3.23 (1.47-7.12; Pinteraction = 0.032, likelihood ratio test). The OR (95% CI) was 0.91 (0.71-1.17), 1.11 (0.73-1.69), and 2.44 (1.34-4.46) for nondiabetics carrying the LIG4 CT/TT genotype, diabetics with the CC genotype, and diabetics carrying the CT/TT genotype, respectively, compared with nondiabetics carrying the CC genotype (Pinteraction = 0.02).
Conclusions: These observations suggest that genetic variations in DNA repair may act alone or in concert with other risk factors on modifying a patient's risk for pancreatic cancer.
Targeted Knockdown ofNotch1Inhibits Invasion of Human Prostate Cancer Cells Concomitant with Inhibition of Matrix Metalloproteinase-9 and Urokinase Plasminogen Activator
Authors: Bin Hafeez Bilal , Adhami Vaqar Mustafa , Asim Mohammad , Siddiqui Imtiaz A. , Bhat Kumar M. , Zhong Weixiong , Saleem Mohammad , Din Maria , Setaluri Vijayasaradhi , Mukhtar Hasan 
Published: January 2009

AbstractPurpose: Notch, a type 1 transmembrane protein, plays a key role in the development of many tissues and organ types. Aberrant Notch signaling, found in a wide variety of human cancers, contributes to tumor development. Because Notch1 was found to be overexpressed in prostate cancer (PCa) cells and human PCa tissue, we therefore tested our hypothesis that overexpression of Notch1 in PCa promotes tumor invasion.Experimental Design: Notch1 expression was evaluated in human PCa cells and human PCa tissues. PCa cells were transiently transfected with Notch1-specific small interfering RNAs in concentrations ranging from 30 to 120 nmol/L and subsequently evaluated for effects on invasion and expression analysis for molecules involved in invasion.Results: Small interfering RNA–mediated knockdown of Notch1 in PC3 and 22Rν1 PCa cells dramatically decreased their invasion. Focused cDNA array revealed that Notch1 knockdown resulted in significant reduction in the expression of urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP9) gene transcripts. These data were further verified by reverse transcription-PCR, real-time reverse transcription-PCR, and immunoblot analysis. Knockdown of Notch1 was also observed to significantly reduce the mRNA expression and protein levels of uPA and its receptor uPAR. A significant reduction in MMP9 expression in Notch1 knockdown cells suggested a role for Notch1 in augmenting MMP9 transcription.Conclusions: Our data show the involvement of Notch1 in human PCa invasion and that silencing of Notch1 inhibits invasion of human PCa cells by inhibiting the expression of MMP9 and uPA. Thus, targeting of Notch1 could be an effective therapeutic approach against PCa.
Combination of Proteasome and HDAC Inhibitors for Uterine Cervical Cancer Treatment
Authors: Lin Zhenhua , Bazzaro Martina , Wang Mei-Cheng , Chan Kwun C. , Peng Shiwen , Roden Richard B.S. 
Published: January 2009

Abstract
Purpose: Cervical cancer cells are addicted to the expression of the human papillomavirus (HPV) oncoproteins E6 and E7. The oncogencity of E6 is mediated in part by targeting p53 and PDZ-family tumor suppressor proteins for rapid proteasomal degradation, whereas the E7 oncoprotein acts in part by coopting histone deacetylases (HDAC)1/2. Here, we examine the hypothesis that inhibition of proteasome function and HDAC activity would synergistically and specifically trigger cervical cancer cell death by the interruption of E6 and E7 signaling.
Experimental Design: The sensitivity and molecular responses of keratinocytes and HPV-positive and HPV-negative cervical cancer cells and xenografts to combinations of proteasome and HDAC inhibitors were tested. The expression of HDAC1/HDAC2 in situ was examined in cervical cancer, its precursors, and normal epithelium.
Results: Cervical cancer cell lines exhibit greater sensitivity to proteasome inhibitors than do HPV-negative cervical cancers or primary human keratinocytes. Treatment of cervical cancer cells with bortezomib elevated the level of p53 but not hDlg, hScribble or hMAGI. Immunohistochemical analysis revealed elevated HDAC1/HDAC2 expression in cervical dysplasia and cervical carcinoma versus normal cervical epithelium. The combination of bortezomib and HDAC inhibitor trichostatin A or vorinostat shows synergistic killing of HPV-positive, but not HPV-negative, cervical cancer cell lines. Similarly, treatment of HeLa xenografts with the combination of bortezomib and trichostatin A retarded tumor growth significantly more effectively than either agent alone.
Conclusions: A combination of proteasome and HDAC inhibitors, including bortezomib and vorinostat, respectively, warrants exploration for the treatment of cervical cancer.
Silibinin Suppresses Growth of Human Prostate Carcinoma PC-3 Orthotopic Xenograft via Activation of Extracellular Signal-Regulated Kinase 1/2 and Inhibition of Signal Transducers and Activators of Transcription Signaling
Authors: Singh Rana P. , Raina Komal , Deep Gagan , Chan Daniel , Agarwal Rajesh 
Published: January 2009

Abstract
Purpose: Silibinin is currently under phase II clinical trial in prostate cancer patients; however, its antitumor effects and mechanisms are not completely understood. Herein, we studied the efficacy and associated mechanisms of silibinin against orthotopically growing advanced human prostate carcinoma PC-3 tumors.
Experimental Design: Athymic male mice were orthotopically implanted with PC-3 cells in prostate and 1 week later after surgical recovery were gavaged daily with silibinin (100 mg/kg body weight) for 7 weeks.
Results: Silibinin treatment reduced the lower urogenital weight (including tumor, prostate, and seminal vesicle) by 40% (P &lt; 0.05) without any toxicity in mice. Silibinin decreased proliferating cell nuclear antigen expression and proliferating cells (P &lt; 0.001) but increased cleaved caspase-3-positive cells (P &lt; 0.01) and apoptotic cells (P &lt; 0.001) and suppressed tumor microvessel density (P &lt; 0.001) and vascular endothelial growth factor expression (P = 0.02). Decreased levels of cyclin-dependent kinases 2, 4, and 6, CDC2, and cyclins D1, D3, E, and A were observed, indicating an inhibitory effect of silibinin on cell cycle progression. Silibinin showed a tremendous increase in extracellular signal-regulated kinase 1/2 phosphorylation but decreased c-Jun NH2-terminal kinase 1/2 and p38 mitogen-activated protein kinase phosphorylation. A moderate decrease in phosphorylated and total levels of Akt was also noted. A marked inhibitory effect of silibinin on signal transducers and activators of transcription (STAT) 1 (Tyr701), STAT1 (Ser727), STAT3 (Tyr705), STAT3 (Ser727), and STAT5 (Tyr794) phosphorylation together with a decrease in their total levels was also observed.
Conclusions: These findings provide evidence for antitumor efficacy of silibinin against orthotopically growing prostate tumor in mice with multitargeted mechanistic insights and support its clinical investigation in prostate cancer.
Phase I and Pharmacokinetic Studies of Erlotinib Administered Concurrently with Radiotherapy for Children, Adolescents, and Young Adults with High-Grade Glioma
Authors: Broniscer Alberto , Baker Suzanne J. , Stewart Clinton F. , Merchant Thomas E. , Laningham Fred H. , Schaiquevich Paula , Kocak Mehmet , Morris E. Brannon , Endersby Raelene , Ellison David W. , Gajjar Amar 
Published: January 2009

Abstract
Purpose: To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy, and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants.
Experimental Design: Five dosage levels (70, 90, 120, 160, and 200 mg/m2 per day) were planned in this phase I study. Dose-limiting toxicities (DLT) were evaluated during first 8 weeks of therapy. Local radiotherapy (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was done in tumor tissue.
Results: Median age at diagnosis of 23 patients was 10.7 years (range, 3.7-22.5 years). MTD of erlotinib was 120 mg/m2 per day. Skin rash and diarrhea were generally well controlled with supportive care. Dose-limiting toxicities were diarrhea (n = 1), increase in serum lipase (n = 1), and rash with pruritus (n = 1). The pharmacokinetic variables of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n = 1) or PTEN (n = 1).
Conclusions: Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120 mg/m2 per day, pharmacokinetic studies showed wide interpatient variability in drug exposure.
Enhanced Delivery of Cisplatin to Intraperitoneal Ovarian Carcinomas Mediated by the Effects of Bortezomib on the Human Copper Transporter 1
Authors: Jandial Danielle D. , Farshchi-Heydari Salman , Larson Christopher A. , Elliott Gregory I. , Wrasidlo Wolfgang J. , Howell Stephen B. 
Published: January 2009

AbstractPurpose: The copper transporter 1 (CTR1) is a major influx transporter for platinum drugs. However, the accumulation of cisplatin in human ovarian carcinoma cells is limited by the fact that cisplatin triggers the down-regulation and proteasomal degradation of CTR1, thereby limiting its own uptake. We sought to determine whether proteasome inhibition using bortezomib would prevent human CTR1 (hCTR1) degradation and increase platinum accumulation in ovarian cancer cells.Experimental Design: The effects of bortezomib on human hCTR1 expression and cisplatin accumulation were measured by Western blot, flow cytometric, and confocal digital imaging analyses. Platinum accumulation was measured by inductively coupled plasma mass spectrometry and bortezomib concentrations by liquid chromatography/mass spectrometry.Results: Bortezomib blocked the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increased cisplatin uptake 1.6- to 2.4-fold. Median effect analysis showed a combination index of 0.37 at 50% cell kill, indicating a high level of synergy. The effect of bortezomib was muted in cells lacking both alleles of CTR1, showing that bortezomib was working primarily through its effect on blocking hCTR1 degradation. I.p. administration of bortezomib produced a peritoneal/plasma area under the curve ratio of 252 in a murine model. I.p. administration of bortezomib before i.p. cisplatin increased platinum accumulation in peritoneal tumors by 33% (P = 0.006).Conclusions: Proteasomal inhibition prevented cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner. Bortezomib shows a large pharmacologic advantage when administered i.p. There is a strong rationale for the combined i.p. administration of bortezomib and cisplatin.
A Systems Approach to Analysis of Molecular Complexity in Breast Cancer
Authors: Hennessy Bryan T. , Gonzalez-Angulo Ana Maria , Carey Mark S. , Mills Gordon B. 
Published: January 2009

Abstract
In this issue of Clinical Cancer Research, Andre et al. apply high-resolution arrays to elucidate copy number anomalies in breast cancer. They identify distinct copy number anomaly patterns in different breast cancer subtypes that implicate a number of genes as potential therapeutic targets and as potential markers of therapy responsiveness.