bluuebunny/crossref_metadata_2025 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

Transforming 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

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 < 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 < 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

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

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

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

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

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

Purpose: 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

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

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 < 0.05) without any toxicity in mice. Silibinin decreased proliferating cell nuclear antigen expression and proliferating cells (P < 0.001) but increased cleaved caspase-3-positive cells (P < 0.01) and apoptotic cells (P < 0.001) and suppressed tumor microvessel density (P < 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

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

Purpose: 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

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.
Sphingosine-1-Phosphate Regulates Glioblastoma Cell Invasiveness through the Urokinase Plasminogen Activator System and CCN1/Cyr61
Authors: Young Nicholas , Pearl Dennis K. , Van Brocklyn James R.
Published: January 2009

Glioblastoma multiforme (GBM) is an aggressively invasive brain neoplasm with poor patient prognosis. We have previously shown that the bioactive lipid sphingosine-1-phosphate (S1P) stimulates in vitro invasiveness of GBM cells and that high expression levels of the enzyme that forms S1P, sphingosine kinase-1 (SphK1), correlate with shorter survival time of GBM patients. We also recently showed that S1P induces expression of CCN1 (also known as Cyr61), a matricellular protein known to correlate with poor patient prognosis, in GBM cells. In this study, we further explored the role of CCN1 as well as the urokinase plasminogen activator (uPA), a protein known to stimulate GBM cell invasiveness, in S1P-induced invasion using a spheroid invasion assay. We also investigated the roles of various S1P receptors in stimulating invasiveness through these pathways. S1P induced expression of uPA and its receptor, uPAR, in GBM cells. Whereas S1P1, S1P2, and S1P3 receptors all contribute, at least partially, S1P1 overexpression led to the most dramatic induction of the uPA system and of spheroid invasion, even in the absence of added S1P. Furthermore, neutralizing antibodies directed against uPA or CCN1 significantly decreased both basal and S1P-stimulated GBM cell invasiveness. Inhibition of SphK blocked basal expression of uPA and uPAR, as well as glioma cell invasion; however, overexpression of SphK did not augment S1P receptor–mediated enhancement of uPA activity or invasion. Thus, SphK is necessary for basal activity of the uPA system and glioma cell invasion, whereas S1P receptor signaling enhances invasion, partially through uPA and CCN1. (Mol Cancer Res 2009;7(1):23–32)
The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth
Authors: Zoubeidi Amina , Rocha Joice , Zouanat Fatima Z. , Hamel Lucie , Scarlata Eleonora , Aprikian Armen G. , Chevalier Simone
Published: January 2009

Androgen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgen-independent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6–mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate cancer. (Mol Cancer Res 2009;7(1):142–55)
Direct Progesterone Receptor and Indirect Androgen Receptor Interactions with the Kallikrein-Related Peptidase 4 Gene Promoter in Breast and Prostate Cancer
Authors: Lai John , Myers Stephen A. , Lawrence Mitchell G. , Odorico Dimitri M. , Clements Judith A.
Published: January 2009

Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at −2419 bp and −1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor ∼2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (−2496 to −2283), which harbors K4.pPRE. This is the first study to show that progesterone-regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at −2419 bp. (Mol Cancer Res 2009;7(1):129–41)
Mutual Regulation of Hypoxia-Inducible Factor and Mammalian Target of Rapamycin as a Function of Oxygen Availability
Authors: Knaup Karl X. , Jozefowski Katrin , Schmidt Regina , Bernhardt Wanja M. , Weidemann Alexander , Juergensen Jan Steffen , Warnecke Christina , Eckardt Kai-Uwe , Wiesener Michael S.
Published: January 2009

The mammalian target of rapamycin (mTOR) regulates cellular growth and proliferation, mainly by controlling cellular translation. Most tumors show constitutive activation of the mTOR pathway. In hypoxia, mTOR is inactivated, which is believed to be part of the program of the cell to maintain energy homeostasis. However, certain proteins are believed to be preferentially translated during hypoxia via 5′ terminal oligopyrimidine tract mechanisms with controversial discussion about the involvement of the mTOR-dependent ribosomal protein S6 (rpS6). The hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxic adaptation and itself strongly implicated in tumor growth. HIF is translationally regulated by mTOR. The regulatory features and the involvement of molecular oxygen itself in this regulation of HIF by mTOR are poorly understood. mTOR inhibition leads to profound attenuation of HIFα protein in the majority of primary and cancer cells studied. Under severe hypoxia, no influence of mTOR inhibitors was observed; thus, stimulation of HIFα by mTOR may only be relevant under mild hypoxia or even normoxia. HIF expression and phosphorylated rpS6 negatively correlate in experimental tumors. In cell culture, prolonged hypoxia abolishes rpS6 phosphorylation, which seems to be partly independent of the upstream p70S6 kinase. We show that hypoxic repression of rpS6 is largely dependent on HIF, implicating a negative feedback loop, which may influence cellular translational rates and metabolic homeostasis. These data implicate that the hypoxic microenvironment renders tumor cells resistant to mTOR inhibition, at least concerning hypoxic gene activation, which would add to the difficulties of other established therapeutic strategies in hypoxic cancer tissues. (Mol Cancer Res 2009;7(1):88–98)
Focused PCR Screen Reveals p53 Dependence of Nitric Oxide-Induced Apoptosis and Up-Regulation of Maspin and Plasminogen Activator Inhibitor-1 in Tumor Cells
Authors: Lim Shuhui , Hung Amos C. , Porter Alan G.
Published: January 2009

We investigated p53-dependent gene expression in nitric oxide (NO)-induced apoptosis of two tumor cell types. Seventy-seven putative p53-regulated genes were screened for NO-mediated expression changes. Twenty-four genes were up-regulated and three genes were down-regulated significantly by NO in human neuroblastoma cells. Genes known to be involved in apoptosis, which were up-regulated by ≥2-fold, included FAS, CASP-1, BIK, PUMA, DR4 and the serpins maspin (SERPINB5), and plasminogen activator inhibitor-1 (PAI-1). Real-time PCR confirmed maspin and PAI-1 mRNAs exhibited the greatest NO-induced induction, which occurred in a p53-dependent manner. The substantial NO-mediated up-regulation of these serpins mRNAs correlated with large increases in their protein levels, which occurred before or coinciding with apoptosis. p53-deficient neuroblastoma cells were largely resistant to NO killing and showed much reduced maspin and PAI-1 mRNA and protein levels after NO treatment. p53 was activated by NO mainly in the nuclei of neuroblastoma cells. p53−/− HCT116 colon carcinoma cells were strongly resistant to NO-induced apoptosis and failed to up-regulate maspin and PAI-1 (in contrast to p53+/+ HCT116 cells). Our results suggest that both apoptosis and induction of the two serpins by NO require the transcriptional activity of p53. Because maspin is a tumor suppressor and PAI-1 can promote senescence and regulate cell death, it will now be worth investigating whether their p53-mediated expression contributes to the NO-induced p53-dependent death of tumor cells. (Mol Cancer Res 2009;7(1):55–66)
Prison Warden Attitudes Toward Prison Rape and Sexual Assault
Authors: Moster Aviva N. , Jeglic Elizabeth L.
Published: January 2009

This study examines the attitudes and beliefs of U.S. state prison wardens toward prison rape since the implementation of the Prison Rape Elimination Act (PREA), signed into law in 2003. PREA mandates a zero-tolerance policy for sexual assaults within correctional systems and requires comprehensive collection of national data on prison rape and sexual assault. Prison wardens play a key role in the implementation and enforcement of prison policies and it is important to assess their attitudes and beliefs toward prison rape. To date, there has been only one study conducted that examines wardens' attitudes toward prison sexual assault, and it was completed before the implementation of PREA. It found that a majority of the wardens surveyed reported that their prison rape and sexual assault policies were considerably less effective than staff training and increased inmate supervision. The current study replicates the prior study in a post-PREA environment.
Influence of Urban Form on Travel Behaviour in Four Neighbourhoods of Shanghai
Authors: Haixiao Pan  , Qing Shen  , Ming Zhang
Published: January 2009

Since the 1980s, much of the new urban development in China has departed significantly from the traditional pedestrian and bicycle-oriented urban form. This study examines the effects of the urban spatial transformation on travel, based on a travel survey of 1709 individuals from four selected neighbourhoods of Shanghai. Although pedestrian/ cyclist-friendly urban form may not avert the general trend of motorisation growth induced by rising income, it does help to slow down the pace of growth and reduces the need for high levels of motor vehicle ownership. In the pedestrian/cyclist-friendly neighbourhoods, residents travel shorter distances than in other neighbourhoods even though the same modes of travel are used. Pedestrian/cyclist-friendly urban form makes the non-motorised modes feasible options, which is essential to limit automobile dependence. These findings suggest that land use planning and urban design can effectively influence people's mobility demand and travel behaviour towards achieving `green transport' in urban China.
`Ageing in Place'? Exploring Elderly People's Housing Preferences in Spain
Authors: Costa-Font Joan , Elvira David , Mascarilla-Miró Oscar
Published: January 2009

The greater visibility of societal ageing and higher share of individuals with disabilities have created new challenges for housing and urban policies. Housing needs can influence individual choice of living environment and the willingness to undertake housing improvements. This is especially relevant in southern European countries where the family is still the main provider of care for the elderly. This study makes an empirical analysis of the underlying preferences for housing and perceptions of housing suitability in the event of dependency in old age, drawing upon a new representative database of the Spanish population. It explores whether preferences are stable for different age-groups and different levels of individual affluence, calculated in terms of income and housing assets. The study found preferences for `ageing in place', which became stronger as individuals grew older. The effect of affluence, or the `wealth effect', was considerable. Acting independently and exhibiting higher health needs, it restrained individuals from choosing institutional care options. Those respondents who preferred to `age in place' were relatively less affluent. Those with relatively less formal education, preferred living with their relatives.
The Shophouse Hotel: Vernacular Heritage in a Creative City
Authors: Chang T.C. , Teo Peggy
Published: January 2009

In creative cities, new enterprises emerge all the time catering to the changing needs and lifestyles of visitors and local communities. Reputable institutions, cultural activities, iconic buildings as well as small, local businesses all play a role in `branding' the creative city. This study presents one such small enterprise in the form of historical shophouse hotels in Singapore. These shophouse inns are locally owned, housed in architecturally unique buildings and are regarded as emblems of Singaporean identity. It is argued that the urban vernacular, exemplified through the hotels, is a dynamic concept evolving over time, across place and for different groups of people and users. First, the paper explores how the shophouse vernacular provides a platform for the celebration of Singaporean identity by new boutique hoteliers. Secondly, a critique is presented of the commodification of the shophouse as modern hoteliers (business and budget inns) jump onto the heritage bandwagon to create new urban spaces of identity. Finally, contestations are discussed, as different people consider different vernaculars to be worthy of a place in the transforming city. As Singapore evolves as a creative city, the multidimensionality of the vernacular provides a fitting emblem to showcase the creative possibilities of historical buildings, traditional architecture and urban environments.
Specialisation and Growth: Evidence from Australia's Regional Cities
Authors: Beer Andrew , Clower Terry
Published: January 2009

This paper draws upon the 2001 census to examine the impact of national economic reform on the growth of regional cities. The paper argues that regional cities in Australia have taken on new roles within both their region and the national economy. It argues that deregulation of the economy has contributed to the growth of some regional cities and especially those that have been able to deepen their economies. Through the use of regression analysis, the paper suggests that regional centres that have witnessed an increase in the level of specialisation within their economy have, on average, grown more quickly than other cities. The paper concludes with a discussion of the implications for our understanding of the evolution of urban systems.
Has Exposure to Poor Neighbourhoods Changed in America? Race, Risk and Housing Locations in Two Decades
Authors: de Souza Briggs Xavier , Keys Benjamin J.
Published: January 2009

While extreme concentrations of poor racial minorities, briefly `rediscovered' as a social problem by media in the wake of Hurricane Katrina, declined significantly in the 1990s, no research has determined whether the trend reduced exposure to poor neighbourhoods over time or changed racial gaps in exposure. Yet most hypotheses about the social and economic risks of distressed neighbourhoods hinge on such exposure. Using a geocoded, national longitudinal survey matched to three censuses, it is found that: housing mobility continued to be the most important mode of exit from poor tracts for both Whites and Blacks; reductions for Blacks were mainly in exposure to extremely poor neighbourhoods, where neighbourhood change had a huge impact; Blacks remained far more likely than Whites to endure long, uninterrupted exposure; and, racial gaps in the odds of falling back into a poor neighbourhood after exiting one—a major driver of exposure duration that Black renters dominate—widened in the 1990s.
Parallel Lives: Towards a Greater Understanding of What Mixed Communities Can Offer
Authors: Camina M.M. , Wood M.J.
Published: January 2009

The creation of mixed communities has become a key element of UK housing policy but empirical research in such areas is limited. Through interviews with and diaries kept by residents of three mature estates, planned as mixed tenure from the start, levels of neighbourhood usage and social interaction are analysed. The techniques used deliberately replicate earlier work in mixed-tenure regeneration areas. While giving some support to the conventional wisdom that owners and renters tend to live separate lives, the distinctions are not as strong as previously suggested and the estates studied differ from each other. Explanations are drawn from both physical planning and community development. The authors indicate the parameters needed for such developments to meet residents' aspirations and draw out the lessons for policy.
Perfecting Patient Care
Authors: Castle Nicholas G. , Bost Fran Sheedy
Published: January 2009

The authors describe the principles of Perfecting Patient Care (PPC) and provide case examples of work redesign and measurable outcomes at one nursing home. The impact of PPC was evaluated by examining employee, family, and resident satisfaction scores. PPC helped with process redesign to eliminate linen shortages and to decrease the resident fall rate. For the employee job satisfaction survey, improved scores resulted for nine questions; six scores were similar to baseline; and four scores were lower than at baseline. For the family satisfaction survey improved scores resulted for 17 questions; five scores were similar to those at baseline; and no scores were lower than baseline. For the resident satisfaction survey scores on 13 questions improved compared to baseline; eight scores were similar to those at baseline; and one score was lower than baseline. Thus, we found using PPC, improvements in work processes were implemented at this pilot facility.
Pigment Dispersing Factor: An Output Regulator of the Circadian Clock in the German Cockroach
Authors: Lee Chi-Mei , Su Ming-Tsan , Lee How-Jing
Published: January 2009

Pigment-dispersing factor (PDF) is a neuropeptide that is synthesized specifically and constantly in the circadian clock cells of many insects. The functions of PDF have not been fully determined, but it might serve as the output and coupling signal of circadian locomotor rhythms. In this experiment, we explore the functions of PDF in the German cockroach with RNA interference technique. Since the 2nd day after pdf double-strand RNA (dsRNA) injection, the amount of pdf mRNA decreased significantly, and this knockdown effect could persist at least 56 days. With immunostaining technique, the clock cells of pdf dsRNA-injected cockroaches could not be stained by anti-PDF antibody. In the behavioral study, pdf dsRNA injection caused rhythmic males to become arrhythmic in light-dark cycles or in constant darkness. In addition, due to the nocturnal nature of the German cockroaches, the locomotor activity increased after lights-off or entering subjective night. However, this activity peak gradually disappeared after pdf dsRNA injection. Based on these 2 lines of evidences, PDF serves as an output regulator of locomotor circadian rhythm in the German cockroach.
Cry1 Circadian Phase in vitro: Wrapped Up with an E-Box
Authors: Fustin J.M. , O'Neill J.S. , Hastings M.H. , Hazlerigg D.G. , Dardente H.
Published: January 2009

The circadian timing of gene expression is determined by transcriptional regulation through upstream response elements present throughout the genome. Central to this regulation are the actions of a core group of transcriptional activators and repressors, which act through, and are themselves regulated by, a small set of canonical circadian response elements. Among these, the E-box (CACGTG) is crucial for daytime transcriptional activity. The mammalian Period ( Per1-3) and Cryptochrome ( Cry1-2) genes are E-box—regulated genes, but in peripheral tissues peak Cry1 mRNA expression is delayed by several hours relative to that of Per. It has been proposed that this delay originates from interactions between the proximal E-box and retinoic acid—related orphan receptor response elements (RORE) present in the Cry1 promoter. By using real-time luciferase reporter assays in NIH3T3 cells the authors show here that a proximal 47-bp E-box containing region of the Cry1 promoter is both necessary and sufficient to drive circadian Cry1 transcription with an appropriate phase delay (around 4 h) relative to Per2. The results therefore suggest that, at least in this in vitro model of the clock, RORE are not necessary for the appropriate circadian regulation of Cry1 expression and rather suggest that sequences surrounding the proximal E-boxes confer gene-specific circadian phasing.
Process Evaluation of Baltimore Healthy Stores: A Pilot Health Intervention Program With Supermarkets and Corner Stores in Baltimore City
Authors: Gittelsohn Joel , Suratkar Sonali , Song Hee-Jung , Sacher Suzanne , Rajan Radha , Rasooly Irit R. , Bednarek Erin , Sharma Sangita , Anliker Jean A.
Published: January 2009

Reduced access to affordable healthy foods is linked to higher rates of chronic diseases in low-income urban settings. The authors conduct a feasibility study of an environmental intervention (Baltimore Healthy Stores) in seven corner stores owned by Korean Americans and two supermarkets in low-income East Baltimore. The goal is to increase the availability of healthy food options and to promote them at the point of purchase. The process evaluation is conducted largely by external evaluators. Participating stores stock promoted foods, and print materials are displayed with moderate to high fidelity. Interactive consumer taste tests are implemented with high reach and dose. Materials developed specifically for Korean American corner store owners are implemented with moderate to high fidelity and dose. Results indicate that small food store—based intervention programs are feasible to implement and are a viable means of increasing healthy food availability and a good location for point-of-purchase promotions in low-income urban settings.
Strategic Free Agency in Baseball
Authors: Rockerbie Duane W.
Published: January 2009

This article investigates whether a greater supply of free-agent baseball players at a particular position has any effect on negotiated salaries. A simple auction model of free-agent salaries with many bidders is developed that suggests that a greater supply of positional free-agent players should lower the path of winning bids in sequential player auctions. A drop in the valuation of the marginal bidder in a sequence of player auctions also drops the path of winning bids. There may be an incentive to defer free agency by including an option year in a player contract. The effect of the number of free agents on salaries is tested using free-agent salary settlements for the 1997-2002 seasons.