bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Canal Plugging on the Vestibuloocular Reflex and Vestibular Nerve Discharge During Passive and Active Head Rotations
Authors: Sadeghi Soroush G. , Goldberg Jay M. , Minor Lloyd B. , Cullen Kathleen E.
Published: September 2009

Mechanical occlusion (plugging) of the slender ducts of semicircular canals has been used in the clinic as well as in basic vestibular research. Here, we investigated the effect of canal plugging in two macaque monkeys on the horizontal vestibuloocular reflex (VOR) and the responses of vestibular-nerve afferents during passive head rotations. Afferent responses to active head movements were also studied. The horizontal VOR gain decreased after plugging to <0.1 for frequencies <2 Hz but rose to about 0.6 as frequency was increased to 15 Hz. Afferents innervating plugged horizontal canals had response sensitivities that increased with the frequency of passive rotations from <0.01 (spikes/s)/(°/s) at 0.5 Hz to values of about 0.2 and 0.5 (spikes/s)/(°/s) at 8 Hz for regular and irregular afferents, respectively (<50% of responses in controls). An increase in phase lead was also noted following plugging in afferent discharge, but not in the VOR. Because the phase discrepancy between the VOR and afferent discharge is much larger than that seen in control animals, this suggests that central adaptation shapes VOR dynamics following plugging. The effect of canal plugging on afferent responses can be modeled as an increase in stiffness and a reduction in the dominant time constant and gain in the transfer function describing canal dynamics. Responses were also evident during active head rotations, consistent with the frequency content of these movements. We conclude that canal plugging in macaques is effective only at frequencies <2 Hz. At higher frequencies, afferents show significant responses, with a nearly 90° phase lead, such that they encode near-rotational acceleration. Our results demonstrate that afferents innervating plugged canals respond robustly during voluntary movements, a finding that has implications for understanding the effects of canal plugging in clinical practice.
A New Approach to Nonsinusoidal Steady‐State Power System Analysis
Authors: Ketabi A. , Khoshkholgh M. , Feuillet R.
Published: September 2009

A new analysis method using wavelet domain for steady‐state operating condition of power system is developed and introduced. Based on wavelet‐Galerkin theory, the system components such as resistor, inductor, capacitor, transmission lines, and switching devices are modeled in discrete wavelet domain for the purpose of steady‐state analysis. To solve system equations, they are transferred to wavelet domain by forming algebraic matrix‐vector relations using the wavelet transform coefficients and the equivalent circuit is thus built for system simulation. After describing the new algorithm, two‐case studies are presented and compared with the simulations in the time domain to verify the accuracy and computational performance.
Did Bank Capital Regulation Exacerbate the Subprime Mortgage Crisis?
Authors: Petersen M. A. , Senosi M. C. , Mukuddem-Petersen J. , Mulaudzi M. P. , Schoeman I. M.
Published: September 2009

This contribution is the second in a series of papers on discrete‐time modeling of bank capital
regulation and its connection with the subprime mortgage crisis (SMC). The latter was caused
by, amongst other things, the downturn in the U.S. housing market, risky lending and borrowing
practices, inaccurate credit ratings, credit default swap contracts as well as excessive individual
and corporate debt levels. The Basel II Capital Accord′s primary tenet is that banks should
be given more freedom to decide how much risk exposure to permit; a practice brought into
question by the SMC. For instance, institutions worldwide have badly misjudged the risk related
to investments ranging from subprime mortgage loans to mortgage‐backed securities (MBSs).
Also, analysts are now questioning whether Basel II has failed by allowing these institutions
to provision less capital for subprime mortgage loan losses from highly rated debt, including
MBSs. Other unintended consequences of Basel II include the procyclicality of credit ratings
and changes in bank lending behavior. Our main objective is to model the dependence of bank
credit and capital on the level of macroeconomic activity under Basel I and Basel II as well as
its connection with banking behavior for the period before and during the SMC.
Improving Effort Estimation by Voting Software Estimation Models
Authors: Capretz Luiz Fernando , Marza Venus
Published: September 2009

Estimating software development effort is an important task in the management of large software projects. The task is challenging, and it has been receiving the attentions of researchers ever since software was developed for commercial purpose. A number of estimation models exist for effort prediction. However, there is a need for novel models to obtain more accurate estimations. The primary purpose of this study is to propose a precise method of estimation by selecting the most popular models in order to improve accuracy. Consequently, the final results are very precise and reliable when they are applied to a real dataset in a software project. Empirical validation of this approach uses the International Software Benchmarking Standards Group (ISBSG) Data Repository Version 10 to demonstrate the improvement in software estimation accuracy.
Confounding Effects in “A Six-Gene Signature Predicting Breast Cancer Lung Metastasis”
Authors: Culhane Aedín C. , Quackenbush John
Published: September 2009

The majority of breast cancer deaths result from metastases rather than from direct effects of the primary tumor itself. Recently, Landemaine and colleagues described a six-gene signature purported to predict lung metastasis risk. They analyzed gene expression in 23 metastases from breast cancer patients (5 lung, 18 non-lung) identifying a 21-gene signature. Expression of 16 of these was analyzed in primary breast tumors from 72 patients with known outcome, and six were selected that were predictive of lung metastases: DSC2, TFCP2L1, UGT8, ITGB8, ANP32E, and FERMT1. Despite the value of such a signature, our analysis indicates that this analysis ignored potentially important confounding factors and that their signature is instead a surrogate for molecular subtype. [Cancer Res 2009;69(18):7480–5]
Colorectal Cancer Risk Is Not Associated with Increased Levels of Homozygosity in a Population from the United Kingdom
Authors: Spain Sarah L. , Cazier Jean-Baptiste ,   The CORGI Consortium,, Houlston Richard , Carvajal-Carmona Luis , Tomlinson Ian
Published: September 2009

Genome-wide association studies have identified several common single nucleotide polymorphisms (SNP) associated with an increased risk of colorectal cancer (CRC), although they have failed to identify any recessively acting alleles that contribute to disease risk. However, two recent studies have suggested that inbreeding and runs of homozygosity (ROH) increase the risk of developing cancer, perhaps by exposing recessive alleles as a result of autozygosity. To examine these results in a relatively large case-control series, we analyzed samples from a cohort in the United Kingdom comprising 921 colorectal tumor cases and 929 controls. Individuals were genotyped using a 550,000 tagging SNP panel. Additionally, we identified from these SNPs a set of ∼30,000 SNPs in low pairwise linkage disequilibrium. To determine whether homozygosity was associated with CRC, we performed multiple tests to assess homozygosity at individual SNPs and ROHs in cases and controls. No association was found between CRC and (i) homozygosity at any individual SNP, (ii) overall homozygosity or level of inbreeding, (iii) total length or number of ROHs per individual, or (iv) a ROH at any particular genomic location. In conclusion, our results from a large case-control series do not replicate those of previous studies and suggest that homozygosity/autozygosity is not a major risk factor for CRC in an outbred population. [Cancer Res 2009;69(18):7422–9]
Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma
Authors: Hoshida Yujin , Nijman Sebastian M.B. , Kobayashi Masahiro , Chan Jennifer A. , Brunet Jean-Philippe , Chiang Derek Y. , Villanueva Augusto , Newell Philippa , Ikeda Kenji , Hashimoto Masaji , Watanabe Goro , Gabriel Stacey , Friedman Scott L. , Kumada Hiromitsu , Llovet Josep M. , Golub Todd R.
Published: September 2009

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum α-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of β-catenin mutation but rather was the result of transforming growth factor-β activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease. [Cancer Res 2009;69(18):7385–92]
Phosphatidylinositol 3′-Kinase Catalytic Subunit α Gene Amplification Contributes to the Pathogenesis of Mantle Cell Lymphoma
Authors: Psyrri Amanda , Papageorgiou Sotirios , Liakata Elisavet , Scorilas Andreas , Rontogianni Dimitra , Kontos Christos K. , Argyriou Pinelopi , Pectasides Dimitrios , Harhalakis Nikolaos , Pappa Vassiliki , Kolialexi Aggeliki , Economopoulou Christina , Kontsioti Frida , Maratou Eirini , Dimitriadis George , Economopoulou Panagiota , Economopoulos Theofanis
Published: September 2009

Purpose: Activation of phosphatidylinositol 3′-kinase pathway is implicated in the pathogenesis of mantle cell lymphoma (MCL). The genetic change in phosphatidylinositol 3′-kinase catalytic subunit α (PIK3CA) in MCL has not been identified.

Experimental Design: Thirty-five primary MCL cases and 2 MCL cell lines (GRANTA-519 and Rec-1) were used to investigate somatic mutation and gene copy number of PIK3CA. Gene copy number was determined using quantitative real-time PCR and fluorescence in situ hybridization. We used quantitative real-time reverse transcription-PCR to measure PIK3CA transcription levels. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and phoshorylated AKT protein levels were analyzed using Western blotting and immunohistochemistry. Flow cytometry was used to assess apoptosis after treatment of MCL cell lines and one control cell line with LY294002, a specific inhibitor of PI3KCA.

Results: Fifteen of 22 (68%) MCL cases and the MCL cell lines harbored a gain (≥3) of PIK3CA gene copy number. In addition, cases with increased PIK3CA gene copy number had elevated PIK3CA mRNA levels. Furthermore, amplification of PIK3CA correlated with the status of AKT phosphorylation in 7 of 12 (58%) primary MCL cases. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by Western blotting, whereas 5 of 33 (15%) cases tested by immunohistochemistry had loss of PTEN expression.

Conclusions: We conclude that a gain of gene copy number of PIK3CA is frequent genetic alteration that contributes to MCL progression. PIK3CA is a promising therapeutic target in MCL. (Clin Cancer Res 2009;15(18):5724–32)
Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer
Authors: Krishnaswamy Soundararajan , Kanteti Rajani , Duke-Cohan Jonathan S. , Loganathan Sivakumar , Liu Wanqing , Ma Patrick C. , Sattler Martin , Singleton Patrick A. , Ramnath Nithya , Innocenti Federico , Nicolae Dan L. , Ouyang Zheng , Liang Jie , Minna John , Kozloff Mark F. , Ferguson Mark K. , Natarajan Viswanathan , Wang Yi-Ching , Garcia Joe G.N. , Vokes Everett E. , Salgia Ravi
Published: September 2009

Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53.

Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies.

Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies.

Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. (Clin Cancer Res 2009;15(18):5714–23)
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

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 <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

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

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

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

Gastric 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

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

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 >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

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

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

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

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.
Carotid Duplex Ultrasound Velocity Measurements Versus Intravascular Ultrasound in Detecting Carotid In-Stent Restenosis
Authors: Yan Bryan P. , Clark David J. , Jaff Michael R. , Kiernan Thomas J. , Schainfeld Robert M. , Lessio Sara , Rosenfield Kenneth
Published: September 2009

Background—

Duplex ultrasonography criteria for assessing the severity of carotid artery (CA) in-stent restenosis are not well established.

Methods and Results—

We analyzed 39 patients (40 CAs) who underwent CA stenting with baseline and 6-month follow-up carotid duplex ultrasonography and intravascular ultrasound. Intravascular ultrasound measurements included minimum luminal diameter, percent diameter, and lumen area stenosis. Duplex ultrasonography measurements included peak systolic velocity (PSV), percentage change in PSV, end-diastolic velocity (EDV), and internal-to-common CA PSV ratio (ICA/CCA). Receiver operating characteristic curves assessed each duplex measurement to detect ≥50% diameter, ≥75% lumen area stenosis, and minimum luminal diameter <3 mm at follow-up. At 6-month intravascular ultrasound follow-up, ≥50% diameter and ≥75% lumen area CA in-stent restenosis occurred in 20% and 25%, respectively; minimum luminal diameter <3 cm occurred in 48%. Area under receiver operating characteristic curves for PSV, EDV, and ICA/CCA were 0.85, 0.96, and 0.89 for ≥50% diameter stenosis and 0.89, 0.93, and 0.88 for ≥75% lumen area stenosis, respectively. Optimal PSV, EDV, and ICA/CCA criteria to detect ≥50% diameter and ≥75% lumen area CA in-stent restenosis were greater compared with those for native CA. A >98% increase in PSV had the highest specificity, whereas the combination of EDV >41 cm/s and ICA/CCA >2 had the highest sensitivity in detecting ≥75% lumen area CA in-stent restenosis.

Conclusions—

PSV, EDV, and ICA/CCA PSV ratio were good discriminators for detecting significant diameter and lumen area greater compared with those for native CA. The combination of duplex velocity criteria increases diagnostic accuracy.
Significantly Improved Vascular Complications Among Women Undergoing Percutaneous Coronary Intervention
Authors: Ahmed Bina , Piper Winthrop D. , Malenka David , VerLee Peter , Robb John , Ryan Thomas , Herne Michael , Phillips William , Dauerman Harold L.
Published: September 2009

Background—

Women are at a higher risk for bleeding/vascular complications (VC) related to cardiovascular procedures. Although the overall incidence of percutaneous coronary intervention (PCI)-related bleeding/VC has declined, the impact of this decline, specifically in women, is unknown.

Methods and Results—

We studied 13 653 female and 32 334 male consecutive cases, from 2002 to 2007, in the Northern New England PCI Registry. We sought to (1) compare absolute rates of bleeding/VC in women and men over time, (2) define predictors of bleeding/VC in women and men undergoing PCI, and (3) trend the impact of female gender in predicting bleeding/VC over time. Bleeding/VC was defined as any access-site vessel injury requiring surgical intervention or bleeding requiring transfusion. The overall risk of bleeding/VC was significantly higher in women versus men (4.5�1.3% versus 1.6�0.5%;
P
<0.004). Over time, there was a significant (
P
<0.001) 50% decrease in absolute bleeding/VC rates in both women and men. After adjustment for baseline differences, female gender remained a significant predictor of increased risk in 2007 (odds ratio, 2.6; 95% CI, 1.74 to 3.91). Independent predictors of increased risk of bleeding/VC in women included older age, shock, renal failure, presentation with non-ST-elevation myocardial infraction and larger sheath sizes, whereas the use of fluoroscopy-guided access, closure devices, history of dyslipidemia or prior PCI, and use of bivalirudin were protective.

Conclusion—

Women undergoing PCI have had a significant decline in bleeding/VC rates during the last 6 years. Despite the improvement in procedural safety, female gender continues to be associated with a >2-fold risk of bleeding/VC compared with men.
Investigating the Double-Deficit Hypothesis in Greek
Authors: Papadopoulos Timothy C. , Georgiou George K. , Kendeou Panayiota
Published: September 2009

This study examined longitudinally the double-deficit hypothesis in Greek, an orthographically consistent language, following a group of children from kindergarten to Grade 2. Four groups were formed on the basis of two composite scores of phonological and naming-speed criterion measures: a double-deficit group (DD; n = 17), a phonological deficit group (PD; n = 33), a naming deficit group (ND; n = 33), and a control group exhibiting no deficits (CnD; n = 159). The four groups were identified in Grade 1, and they were compared retrospectively in kindergarten only on the criterion measures, and in Grades 1 and 2 on measures of word-reading fluency and accuracy, orthographic processing, and passage comprehension. The effects of verbal and nonverbal ability, age, gender, and parental education were controlled among the groups. Results showed that the DD group exhibited greater dysfunction in reading and orthographic processing compared to the single-deficit and CnD groups. Also, although the three deficit groups were not easily differentiated in kindergarten, their differences were maximized in Grade 1 and retained in Grade 2. The type and severity of reading deficits found in the ND group were mostly associated with naming speed at both the word- and text-reading levels, deficits that persisted across development. The PD group showed mostly deficient orthographic and poor decoding skills that improved across development. Implications of the findings for the double-deficit hypothesis in languages with transparent orthographies are discussed.
Normalizing the Fraughtness
Authors: Buehler Jennifer , Ruggles Gere Anne , Dallavis Christian , Shaw Haviland Victoria
Published: September 2009

Preservice teachers seeking to develop cultural competence can face a struggle fraught with multiple challenges, even when they are committed to culturally relevant pedagogy. This article closely analyzes one White beginning teacher’s negotiations with cultural competence during a lesson in her student teaching semester, then traces how she made sense of that lesson in the weeks and months that followed. Findings indicate that taking on cultural competence posed both cognitive and affective challenges. More specifically, emotional responses to racialized situations, inner conflicts over Whiteness, and the dynamics of the school context combined to mediate the development of cultural competence. This study suggests that teacher educators should focus not only on the achievement of cultural competence but also on the struggle involved in enacting it. By giving more attention to how beginning teachers develop cultural competence, teacher educators will be better prepared to help beginning teachers normalize the fraughtness involved in the struggle.
Prisoners’ fantasies in Weimar film
Authors: Ashkenazi Ofer
Published: September 2009

Prison cells constituted a unique sphere in post-World War I German films. Unlike most of the modern city spheres, it was a realm in which the private and the public often merged, and in which reality and fantasy incessantly intertwined. This article analyses the ways in which filmmakers of the Weimar Republic envisaged the experience within the prison, focusing on its frequent association with fantasies and hallucinations. Through the analysis of often-neglected films from the period, I argue that this portrayal of the prison enabled Weimar filmmakers to engage in public criticism against the conservative, inefficient and prejudiced institutions of law and order in Germany. Since German laws forbade direct defamation of these institutions, filmmakers such as Joe May, Wilhelm Dietherle and Georg C. Klaren employed the symbolism of the prisoner’s fantasy to propagate the urgent need for thorough reform. Thus this article suggests that Weimar cinema, contrary to common notions, was not dominated by either escapism or extremist, anti-liberal worldviews. Instead, the prison films examined in this article are in fact structured as a warning against the decline of liberal bourgeois society in the German urban centres of the late 1920s.
Criminalization: Carl Schmitt and Walter Benjamin’s concept of criminal politics
Authors: Greenberg Udi E.
Published: September 2009

The two most celebrated intellectuals of the Weimar period — Carl Schmitt on the right and Walter Benjamin on the left — were fascinated by the role of crime in modern politics. In order to shed light on this neglected element of their work, this article explains how crime became a central category in their political theory and a crucial component in their narratives of modern history. Furthermore, it elucidates how both men simultaneously came to characterize their society as a whole, and not only fractions of it, as criminal in essence. Though many have seen the connection between Schmitt and Benjamin as a continuous dialogue, this study contends that the similarity between their theories of criminal politics should be interpreted not as a direct discussion, but within the context of wide debates regarding the origins of crime as well as the blending of criminal and political discourses that occurred during the Weimar period.
Explaining crime
Authors: Siemens Daniel
Published: September 2009

In the turbulent years of the Weimar Republic, well-known journalists working for leading newspapers regularly covered the proceedings of the criminal court in Berlin-Moabit. In seeking sensational news as well as stories about everyday life in the metropolis, the court provided them with insights into contemporary urban problems such as unemployment, political struggle, gender-based conflict, and crimes of passion. The court and the journalistic coverage of its activities are historically important because they were a locus of legal and social conflicts intermingled with popular entertainment and mass media. This article sheds light on the engagement of the press with criminal trials in Weimar Berlin. By examining material never previously discussed, it claims that, contrary to what is generally believed today, German public opinion did not on the whole accept the idea that criminals could be categorized as a genetically inferior social class. In fact, most crime reporters — who reflected and formed public opinion — argued that the psychological problems of overstrained individuals and inferior living conditions were responsible for most crimes. Offenders were therefore considered as unfortunate ‘ordinary men’, or, more generally, as ‘victims of society’. Some journalists even claimed that crimes passionelles were the result of society’s oppression. This article goes on to argue that the extreme popularity of these reports shows that the journalists’ perspective on criminality met with the approval of contemporary readers and accorded with common views on crime. As part of the larger discourse on ‘victimization’ so important to the Weimar period, this journalistic coverage of the court can help us understand the unique role the criminal played as a central symbol of the German press and public.
A biological threat or a social disease?
Authors: Lewy Jonathan
Published: September 2009

Racial hygiene — cleansing the Volk of those deemed undesirable by the regime such as anti-socials, biologically defective individuals and races — was at the heart of Nazi policy. This essay will explore whether the Nazi wrath was also directed against drug addicts; or, in other words: was drug addiction considered a biological disease to be eradicated? The answer is no. The Germans believed that drug addiction, unlike mental deficiency and alcoholism, was not hereditary. Not being hereditary, it presented no danger to the master race but could be cured, despite patients’ relapses. Those who were not considered a threat to the race were deemed worthy of life and were treated relatively well.