bluuebunny/crossref_metadata_2025_split huggingface dataset:
Introducing a ‘stochastic movement simulator’ for estimating habitat connectivity
Authors: Palmer Stephen C. F. , Coulon Aurélie , Travis Justin M. J. 
Published: November 2010

Summary1. Estimating and improving landscape connectivity has become a key topic in conservation biology. While a range of connectivity indices exist and are widely used to inform spatial planning, they have potentially serious limitations.2. We introduce a new method for modelling animals moving between habitat patches across a heterogeneous matrix. Our approach integrates features of least cost path analysis with stochastic movement modelling. Importantly, it relaxes assumptions that are implicit in the least cost path algorithm: our method does not assume omniscience nor does it assume that an individual has a planned destination when it leaves a habitat patch. The algorithm incorporates resistance values for matrix elements and parameters that relate to both perceptual range and to the degree of correlation in movement. By simulating sets of movements for individuals emigrating from habitat patches, relative connectivities between habitat patches are estimated.3. Using an already published stylised landscape, we demonstrate that the connectivities estimated using our new method can differ considerably from those provided by structural methods and by least cost path analysis. Further, our results emphasise the sensitivity of the relative connectivities to an organism’s perceptual range and the degree of correlation between movement steps.4. We believe that using stochastic movement modelling can improve estimates of connectivity and also provide a method for determining how robust the indices derived from simpler methods are likely to be for different types of organisms.
Head-to-Tail Intramolecular Interaction of Herpes Simplex Virus Type 1 Regulatory Protein ICP27 Is Important for Its Interaction with Cellular mRNA Export Receptor TAP/NXF1
Authors: Hernandez Felicia P. , Sandri-Goldin Rozanne M. 
Published: November 2010

ABSTRACT
Herpes simplex virus type 1 (HSV-1) protein ICP27 has many important functions during infection that are achieved through interactions with a number of cellular proteins. In its role as a viral RNA export protein, ICP27 interacts with TAP/NXF1, the cellular mRNA export receptor, and both the N and C termini of ICP27 must be intact for this interaction to take place. Here we show by bimolecular fluorescence complementation (BiFC) that ICP27 interacts directly with TAP/NXF1 during infection, and this interaction failed to occur with an ICP27 mutant bearing substitutions of serines for cysteines at positions 483 and 488 in the C-terminal zinc finger. Recently, we showed that ICP27 undergoes a head-to-tail intramolecular interaction, which could make the N- and C-terminal regions accessible for binding to TAP/NXF1. To determine the importance of intramolecular association of ICP27 to its interaction with TAP/NXF1, we performed BiFC-based fluorescence resonance energy transfer (FRET) by acceptor photobleaching. BiFC-based FRET showed that the interaction between ICP27 and TAP/NXF1 occurred in living cells upon head-to-tail intramolecular association of ICP27, further establishing that TAP/NXF1 interacts with both the N and C termini of ICP27.

IMPORTANCE
ICP27 is a key regulatory protein during herpes simplex virus type 1 (HSV-1) infection. ICP27 interacts with a number of cellular proteins, and an important question asks how these interactions are regulated during infection. We showed previously that ICP27 undergoes a head-to-tail intramolecular interaction, and here we show that the cellular mRNA export receptor protein TAP/NXF1 interacts with ICP27 after its head-to-tail association. Several proteins that interact with ICP27 require that the N and C termini of ICP27 be intact. These results demonstrate that the head-to-tail interaction of ICP27 may regulate some of its protein interactions perhaps through alternating between open and closed configurations.
Clinical Effectiveness and Safety of Acupuncture in the Treatment of Irradiation-Induced Xerostomia in Patients with Head and Neck Cancer: A Systematic Review
Authors: O'Sullivan E M , Higginson I J 
Published: November 2010

Background Irradiation-induced xerostomia seriously reduces quality of life for patients with head and neck cancer (HNC). Anecdotal evidence suggests that acupuncture may be beneficial. Objective To systematically review evidence on clinical effectiveness and safety of acupuncture in irradiation-induced xerostomia in patients with HNC. Methods A detailed search was performed to identify randomised controlled trials (RCTs) and systematic reviews of RCTs on acupuncture in irradiation-induced xerostomia, using AMED, BNIA, CINAHL, Cochrane, Embase, HPSI, PsycInfo and Medline. Grey literature was explored and 11 journals hand searched. Search terms included: acupuncture, xerostomia, salivary hypofunction, hyposalivation, dry mouth, radiotherapy, irradiation, brachytherapy, external beam. Two authors independently extracted data for analysis using predefined selection criteria and quality indicators. Results 43 of the 61 articles identified were excluded on title/abstract. 18 articles underwent full-text review; three were deemed eligible for inclusion. Two trials had moderate risk of bias; one had high risk. Two trials compared acupuncture with sham acupuncture; one control arm received ‘usual care’. Outcome measurements included salivary flow rates (SFRs) in two trials and subjective questionnaires in three. All three trials reported significant reduction in xerostomia versus baseline SFR (p<0.05); one reported greater effect in the intervention group for stimulated SFR (p<0.01). Subjective assessment reported significant differences between real acupuncture and control in two trials (p<0.02–0.05). Insufficient evidence was presented to undertake risk/benefit assessment. Conclusions Limited evidence suggests that acupuncture is beneficial for irradiation-induced xerostomia. Although current evidence is insufficient to recommend this intervention, it is sufficient to justify further studies. Highlighted methodological limitations must be dealt with.
CHUA'S SINGULARITIES: GREAT MIRACLE IN CIRCUIT THEORY
Authors: ŠPÁNY VIKTOR , GALAJDA PAVOL , GUZAN MILAN , PIVKA LADISLAV , OLEJÁR MARTIN 
Published: November 2010

In the work [Chua, 1992], a deep intuition of its author gave rise to the choice of singularities corresponding to Chua's circuit. Therefore, it is the only one probably exhibiting three saddle points named Chua's singularities in this paper. One of the singularities is a saddle in forward time (dt > 0) of integration, whereas the other two are saddles in backward time (dt < 0) of integration. In the following, the term Chua's Chaos denotes chaos related to Chua's singularities. These singularities are the source of all special surfaces that are the subject of this contribution. We named the surface to which all other surfaces are bound as the Double-Arm Stable Manifold (DASM). The beauty and multifunctionality of this surface represents the unfathomable Intelligence in the sense of [Tolle, 2003]. The presence of the DASM in the state space is a sufficient condition for the generation of Chua's chaos or corresponding periodic windows. Since Chua's singularities are not limited by circuit morphology or the order of state equations, the research on Chua's chaos seems to be still very promising.
Critical Roles of DMP1 in Human Epidermal Growth Factor Receptor 2/neu-Arf-p53 Signaling and Breast Cancer Development
Authors: Taneja Pankaj , Maglic Dejan , Kai Fumitake , Sugiyama Takayuki , Kendig Robert D. , Frazier Donna P. , Willingham Mark C. , Inoue Kazushi 
Published: November 2010

AbstractHuman epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3′-kinase-Akt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1 promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neu mice, and mammary tumorigenesis was significantly accelerated in both Dmp1+/− and Dmp1−/− mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in &gt;50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1+/−, Dmp1−/−, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis. Cancer Res; 70(22); 9084–94. ©2010 AACR.
Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression In vivo
Authors: Takeuchi Shinji , Takahashi Akiko , Motoi Noriko , Yoshimoto Shin , Tajima Tomoko , Yamakoshi Kimi , Hirao Atsushi , Yanagi Shigeru , Fukami Kiyoko , Ishikawa Yuichi , Sone Saburo , Hara Eiji , Ohtani Naoko 
Published: November 2010

Abstract
Although the p16INK4a and p21Waf1/Cip1 cyclin-dependent kinase (CDK) inhibitors are known to play key roles in cellular senescence in vitro, their roles in senescence remain rather poorly understood in vivo. This situation is partly due to the possibility of compensatory effect(s) between p16INK4a and p21Waf1/Cip1 or to the upregulation of functionally related CDK inhibitors. To directly address the cooperative roles of p16INK4a and p21Waf1/Cip1 in senescence in vivo, we generated a mouse line simply lacking both p16INK4a and p21Waf1/Cip1 genes [double-knockout (DKO)]. Mouse embryonic fibroblasts (MEF) derived from DKO mice displayed no evidence of cellular senescence when cultured serially in vitro. Moreover, DKO MEFs readily escaped Ras-induced senescence and overrode contact inhibition in culture. This was not the case in MEFs lacking either p16INK4a or p21Waf1/Cip1, indicating that p16INK4a and p21Waf1/Cip1 play cooperative roles in cellular senescence and contact inhibition in vitro. Notably, we found the DKO mice to be extremely susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate–induced skin carcinogenesis that involves oncogenic mutation of the H-ras gene. Mechanistic investigations suggested that the high incidence of cancer in DKO mice likely reflected a cooperative effect of increased benign skin tumor formation caused by p21Waf1/Cip1 loss, with increased malignant conversion of benign skin tumors caused by p16INK4a loss. Our findings establish an intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo. Cancer Res; 70(22); 9381–90. ©2010 AACR.
Induction of DNA Damage-Inducible Gene GADD45β Contributes to Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Cells
Authors: Ou Da-Liang , Shen Ying-Chun , Yu Sung-Liang , Chen Kuen-Feng , Yeh Pei-Yen , Fan Hsiang-Hsuan , Feng Wen-Chi , Wang Ching-Tzu , Lin Liang-In , Hsu Chiun , Cheng Ann-Lii 
Published: November 2010

Abstract
Markers that could accurately predict responses to the general kinase inhibitor sorafenib are needed to better leverage its clinical applications. In this study, we examined a hypothesized role in the drug response for the growth arrest DNA damage-inducible gene 45β (GADD45β), which is commonly underexpressed in hepatocellular carcinoma (HCC) where sorafenib may offer an important new therapeutic option. The anticancer activity of sorafenib-induced GADD45β expression was tested in a panel of HCC cell lines and xenograft models. We found that GADD45β mRNA and protein expression were induced relatively more prominently in HCC cells that were biologically sensitive to sorafenib treatment. GADD45β induction was not found after treatment with either the mitogen-activated protein kinase–extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 or the Raf inhibitor ZM336372, suggesting that GADD45β induction by sorafenib was independent of Raf/MEK/ERK signaling activity. However, c-Jun NH2-terminal kinase (JNK) kinase activation occurred preferentially in sorafenib-sensitive cells. Small interfering RNA–mediated knockdown of GADD45βor JNK kinase limited the proapoptotic effects of sorafenib in sorafenib-sensitive cells. We defined the −339/−267 region in the GADD45β promoter containing activator protein-1 and SP1-binding sites as a crucial region for GADD45β induction by sorafenib. Together, our findings suggest that GADD45β induction contributes to sorafenib-induced apoptosis in HCC cells, prompting further studies to validate its potential value in predicting sorafenib efficacy. Cancer Res; 70(22); 9309–18. ©2010 AACR.
PET Imaging of Tumor Neovascularization in a Transgenic Mouse Model with a Novel 64Cu-DOTA-Knottin Peptide
Authors: Nielsen Carsten H. , Kimura Richard H. , Withofs Nadia , Tran Phuoc T. , Miao Zheng , Cochran Jennifer R. , Cheng Zhen , Felsher Dean , Kjær Andreas , Willmann Juergen K. , Gambhir Sanjiv S. 
Published: November 2010

Abstract
Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on the positive attributes of positron emission tomography/computed tomography (PET/CT) to allow for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT followed by characterization with the use of small animal PET with a novel 64Cu–1,4,7,10-tetra-azacylododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)–knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01 ± 0.61 versus 4.36 ± 0.68; P &lt; 0.05). Ex vivo biodistribution showed 64Cu-DOTA-knottin 2.5F to have a fast renal clearance combined with low nonspecific accumulation in the thorax. Collectively, these results show 64Cu-DOTA-knottin 2.5F to be a promising candidate for clinical translation for earlier detection and improved characterization of lung cancer. Cancer Res; 70(22); 9022–30. ©2010 AACR.
MicroRNA miR-302 Inhibits the Tumorigenecity of Human Pluripotent Stem Cells by Coordinate Suppression of the CDK2 and CDK4/6 Cell Cycle Pathways
Authors: Lin Shi-Lung , Chang Donald C. , Ying Shao-Yao , Leu Davey , Wu David T.S. 
Published: November 2010

Abstract
miR-302 is the major microRNA found in human embryonic stem cells and induced pluripotent stem cells, but its function has been unclear. In mice, there is evidence that miR-302 may silence p21Cip1 (CDKN1A) to promote cell proliferation, whereas studies in human reprogrammed pluripotent stem cells suggested that elevated miR-302 expression inhibited cell cycle transit. Here, we clarify this difference, reporting that in human cells, miR-302 simultaneously suppressed both the cyclin E-CDK2 and cyclin D-CDK4/6 pathways to block &gt;70% of the G1-S cell cycle transition. Concurrent silencing of BMI-1, a cancer stem cell marker targeted by miR-302, further promoted tumor suppressor functions of p16Ink4a and p14/p19Arf directed against CDK4/6–mediated cell proliferation. Among all G1 phase checkpoint regulators, human p21Cip1 was found not to be a valid target of miR-302. Overall, our findings indicate that miR-302 inhibits human pluripotent stem cell tumorigenicity by enhancing multiple G1 phase arrest pathways rather than by silencing p21Cip1. Cancer Res; 70(22); 9473–82. ©2010 AACR.
Combined Analysis of Estrogen Receptor β-1 and Progesterone Receptor Expression Identifies Lung Cancer Patients with Poor Outcome
Authors: Stabile Laura P. , Dacic Sanja , Land Stephanie R. , Lenzner Diana E. , Dhir Rajiv , Acquafondata Marie , Landreneau Rodney J. , Grandis Jennifer R. , Siegfried Jill M. 
Published: November 2010

Abstract
Purpose: Steroid hormones and growth factors affect lung cancer, and it is possible they act in concert to influence patient outcome.
Experimental Design: Primary lung tumors and normal lung tissue were analyzed for expression and localization of estrogen receptor α and β-1 (ERα and ERβ), aromatase, progesterone receptor (PR), and epidermal growth factor receptor (EGFR).
Results: Tumors expressed higher levels of ERβ compared to matched normal lung, whereas the reverse was true of PR. High cytoplasmic ERβ expression was identified as an independent negative prognostic predictor of overall survival (OS; HR = 1.67), and low total PR was identified as an independent negative predictor of time to progression (TTP; HR = 1.59). After adjusting for stage, age, sex, and smoking, combined high cytoplasmic ERβ and low total PR showed enhanced effects on OS (HR = 2.64) and on TTP (HR = 6.02). Further effects on OS were observed when EGFR expression was included (HR = 5.32). Patients with low cytoplasmic ERβ, low aromatase, low EGFR, and high total PR had shorter OS than patients with the opposite pattern (HR = 6.60). Contribution of these markers to survival showed no significant sex differences in a multivariable model. ERα was elevated in tumors but was not predictive of survival, and appears to represent a variant ERα protein that is only recognized by a C-terminal antibody.
Conclusions: Hormonal and EGFR pathways together may contribute to lung cancer prognosis. Lung tumors with high ERβ-1/low PR may define patients with aggressive biology. A validation study is necessary to fully assess the predictive value of these markers. Clin Cancer Res; 17(1); 154–64. ©2010 AACR.
Phase III Clinical Trial Development: A Process of Chutes and Ladders
Authors: Dilts David M. , Cheng Steven K. , Crites Joshua S. , Sandler Alan B. , Doroshow James H. 
Published: November 2010

Abstract
Purpose: The Institute of Medicine report on cooperative groups and the National Cancer Institute (NCI) report from the Operational Efficiency Working Group both recommend changes to the processes for opening a clinical trial. This article provides evidence for the need for such changes by completing the first comprehensive review of all the time and steps required to open a phase III oncology clinical trial and discusses the effect of time to protocol activation on subject accrual.
Methods: The Dilts and Sandler method was used at four cancer centers, two cooperative groups, and the NCI Cancer Therapy Evaluation Program. Accrual data were also collected.
Results: Opening a phase III cooperative group therapeutic trial requires 769 steps, 36 approvals, and a median of approximately 2.5 years from formal concept review to study opening. Time to activation at one group ranged from 435 to 1,604 days, and time to open at one cancer center ranged from 21 to 836 days. At centers, group trials are significantly more likely to have zero accruals (38.8%) than nongroup trials (20.6%; P &lt; 0.0001). Of the closed NCI Cancer Therapy Evaluation Program–approved phase III clinical trials from 2000 to 2007, 39.1% resulted in &lt;21 accruals.
Conclusions: The length, variability, and low accrual results demonstrate the need for the NCI clinical trials system to be reengineered. Improvements will be of only limited effectiveness if done in isolation; there is a need to return to the collaborative spirit with all parties creating an efficient and effective system. Recommendations put forth by the Institute of Medicine and Operational Efficiency Working Group reports, if implemented, will aid this renewal. Clin Cancer Res; 16(22); 5381–9. ©2010 AACR.
Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer
Authors: Suda Kenichi , Murakami Isao , Katayama Tatsuya , Tomizawa Kenji , Osada Hirotaka , Sekido Yoshitaka , Maehara Yoshihiko , Yatabe Yasushi , Mitsudomi Tetsuya 
Published: November 2010

Abstract
Purpose: In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.
Experimental Design: Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.
Results: HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (&lt;4-fold), and in only 8% (1 of 13) of tumors with MET amplification (≥4-fold).
Conclusions: These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes. Clin Cancer Res; 16(22); 5489–98. ©2010 AACR.