bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternaria alternataserine proteases induce lung inflammation and airway epithelial cell activation via PAR2
Authors: Boitano Scott , Flynn Andrea N. , Sherwood Cara L. , Schulz Stephanie M. , Hoffman Justin , Gruzinova Irina , Daines Michael O.
Published: February 2011

Allergens are diverse proteins from mammals, birds, arthropods, plants, and fungi. Allergens associated with asthma (asthmagens) share a common protease activity that may directly impact respiratory epithelial biology and lead to symptoms of asthma. Alternaria alternata is a strong asthmagen in semiarid regions. We examined the impact of proteases from A. alternata on lung inflammation in vivo and on cleaving protease-activated receptor-2 (PAR2) in vitro . A. alternata filtrate applied to the airway in nonsensitized Balb/c mice induced a protease-dependent lung inflammation. Moreover, A. alternata filtrate applied to human bronchial epithelial cells (16HBE14o-) induced changes in intracellular Ca2+concentration ([Ca2+]i), consistent with PAR2activation. These effects were blocked by heat inactivation or by serine protease inhibition of A. alternata filtrates, and mimicked by PAR2specific ligands SLIGRL-NH2or 2-furoyl-LIGRLO-NH2, but not the PAR1-specific ligand TFLLR-NH2. Desensitization of PAR2in 16HBE14o- cells with 2-furoyl-LIGRLO-NH2or trypsin prevented A. alternata-induced [Ca2+]ichanges while desensitization of PAR1, PAR3, and PAR4with thrombin had no effect on A. alternata-induced Ca2+responses. Furthermore, the Ca2+response to A. alternata filtrates was dependent on PAR2expression in stably transfected HeLa cell models. These data demonstrate that A. alternata proteases act through PAR2to induce rapid increases in human airway epithelial [Ca2+]iin vitro and cell recruitment in vivo . These responses are likely critical early steps in the development of allergic asthma.
Hot Transcriptomics
Authors: Walther Jasper , Sierocinski Pawel , van der Oost John
Published: February 2011

DNA microarray technology allows for a quick and easy comparison of complete transcriptomes, resulting in improved molecular insight in fluctuations of gene expression. After emergence of the microarray technology about a decade ago, the technique has now matured and has become routine in many molecular biology laboratories. Numerous studies have been performed that have provided global transcription patterns of many organisms under a wide range of conditions. Initially, implementation of this high-throughput technology has lead to high expectations for ground breaking discoveries. Here an evaluation is performed of the insight that transcriptome analysis has brought about in the field of hyperthermophilic archaea. The examples that will be discussed have been selected on the basis of their impact, in terms of either biological insight or technological progress.
The Dynamical Systems Properties of the HOG Signaling Cascade
Authors: Miermont Agnès , Uhlendorf Jannis , McClean Megan , Hersen Pascal
Published: February 2011

The High Osmolarity Glycerol (HOG) MAP kinase pathway in the budding yeastSaccharomyces cerevisiaeis one of the best characterized model signaling pathways. The pathway processes external signals of increased osmolarity into appropriate physiological responses within the yeast cell. Recent advances in microfluidic technology coupled with quantitative modeling, and techniques from reverse systems engineering have allowed yet further insight into this already well-understood pathway. These new techniques are essential for understanding the dynamical processes at play when cells process external stimuli into biological responses. They are widely applicable to other signaling pathways of interest. Here, we review the recent advances brought by these approaches in the context of understanding the dynamics of the HOG pathway signaling.
Demographic Disparities in Patterns of Care and Survival Outcomes for Patients with Resected Gastric Adenocarcinoma
Authors: Stessin Alexander M. , Sherr David L.
Published: February 2011

Background: Several reports showed incomplete adoption of adjuvant radiotherapy (RT) for resectable gastric cancer since the publication of Intergroup 0116 trial results. The aims of this study were to identify demographic factors associated with omission of adjuvant RT and assess the impact of this omission on survival.

Methods: SEER database was queried for cases of resected gastric cancer. Multivariate analyses with logistic and Cox regressions were used to examine (a) likelihood of receiving adjuvant RT for different patient and county demographics and (b) effect of demographics on survival outcomes.

Results: A total of 7,348 patients met the study criteria. Adjuvant RT was used in 33.1% of cases diagnosed in 1998–2001 and in 45.3% of cases in 2002–2007 (P < 0.001). Controlling for independent covariates, African Americans were 8.9% less likely to receive adjuvant RT than Caucasians or Asians (P < 0.001). Correspondingly, overall survival rates were significantly lower for African Americans than other races (HR = 1.38, P < 0.001). Furthermore, both the likelihood of receiving RT and the survival rates were significantly affected by county demographics: percent of population without high school education, percent of households below the poverty line, and median household income. Survival rates were highest among Asians, but this finding did not reflect more frequent use of RT.

Conclusions: Race and socioeconomic factors are significant predictors of treatment and survival outcomes for patients with resectable gastric cancer.

Impact: The findings of this and similar studies may aide the medical community in designing more effective strategies to ameliorate the standards of care nationwide. Cancer Epidemiol Biomarkers Prev; 20(2); 223–33. ©2011 AACR.
Smoking Concordance in Lung and Colorectal Cancer Patient-Caregiver Dyads and Quality of Life
Authors: Weaver Kathryn E. , Rowland Julia H. , Augustson Erik , Atienza Audie A.
Published: February 2011

Background: Distress may be heightened among members of cancer patient-caregiver dyads that are mismatched on smoking status (either the patient or caregiver smokes, but the other does not), negatively affecting quality of life (QoL). The purpose of this study was to examine associations between patient-caregiver smoking concordance, caregiver psychological adjustment, and caregiver and patient mental and physical QoL.

Methods: Lung and colorectal patient-caregiver dyads (N = 742) were identified from the Cancer Care Outcomes Research and Surveillance (CanCORS) and CanCORS Caregiver studies. The majority of the cancer patients were male (67.0%) with local (45.6%) or regional (12.9%) disease. The majority of the informal caregivers were females (78.6%), under 65 years of age (69.6%), and often spouses (57.8%) of the patients.

Results: Lung and colorectal cancer caregivers, who were members of dyads where one or both members continued to smoke, reported worse mental health QoL than nonsmoking dyads. For colorectal cancer patients, continuing to smoke when the caregiver did not was associated with worse mental health QoL compared with nonsmoking dyads. Dyad smoking was less strongly associated with physical QoL for both caregivers and patients.

Conclusion: Results highlight the importance of assessing smoking in both cancer patients and their caregivers and referring families to appropriate psychosocial and smoking cessation services.

Impact: This is the first study to show associations between cancer patient-caregiver smoking status and QoL for both dyad members. Future studies will need to confirm these associations longitudinally and investigate potential mechanisms linking dyad smoking and QoL. Cancer Epidemiol Biomarkers Prev; 20(2); 239–48. ©2010 AACR.
Effects of a Decision Support Intervention on Decisional Conflict Associated with Microsatellite Instability Testing
Authors: Hall Michael J. , Manne Sharon L. , Winkel Gary , Chung Daniel S. , Weinberg David S. , Meropol Neal J.
Published: February 2011

Background: Decision support to facilitate informed consent is increasingly important for complicated medical tests. Here, we test a theoretical model of factors influencing decisional conflict in a study examining the effects of a decision support aid that was designed to assist patients at high risk for hereditary nonpolyposis colorectal cancer (CRC) deciding whether to pursue the microsatellite instability (MSI) test.

Methods: Participants were 239 CRC patients at high familial risk for a genetic mutation who completed surveys before and after exposure to the intervention. Half of the sample was assigned to the CD-ROM aid and half received a brief description of the test. Structural equation modeling was employed to examine associations among the intervention, knowledge, pros and cons to having MSI testing, self-efficacy, preparedness, and decisional conflict.

Results: The goodness of fit for the model was acceptable [FIML, full information maximum likelihood, χ2 (df = 280) = 392.24; P = 0.00]. As expected, the paths to decisional conflict were significant for postintervention pros of MSI testing (t = −2.43; P < 0.05), cons of MSI testing (t = 2.78; P < 0.05), and preparedness (t = −7.27; P < 0.01). The intervention impacted decisional conflict by increasing knowledge about the MSI test and knowledge exerted its effects on decisional conflict by increasing preparedness to make a decision about the test and by increases in perceived benefits of having the test.

Conclusion: Increasing knowledge, preparedness, and perceived benefits of undergoing the MSI test facilitate informed decision making for this test.

Impact: Understanding mechanisms underlying health decisions is critical for improving decisional support. Individuals with Lynch syndrome have an elevated lifetime risk of CRC. Risk of Lynch syndrome may be assessed with a tumor-based screening test (MSI testing or immunohistochemical tissue staining). Cancer Epidemiol Biomarkers Prev; 20(2); 249–54. ©2011 AACR.
Incident Cervical HPV Infections in Young Women: Transition Probabilities for CIN and Infection Clearance
Authors: Insinga Ralph P. , Perez Gonzalo , Wheeler Cosette M. , Koutsky Laura A. , Garland Suzanne M. , Leodolter Sepp , Joura Elmar A. , Ferris Daron G. , Steben Marc , Hernandez-Avila Mauricio , Brown Darron R. , Elbasha Elamin , Muñoz Nubia , Paavonen Jorma , Haupt Richard M.
Published: February 2011

Background: We describe transition probabilities for incident human papillomavirus (HPV) 16/18/31/33/35/45/52/58/59 infections and cervical intraepithelial neoplasia (CIN) 1 lesions.

Methods: Women ages 16 to 23 years underwent cytology and cervical swab PCR testing for HPV at approximately 6-month intervals for up to 4 years in the placebo arm of an HPV vaccine trial. The cumulative proportion of incident HPV infections with diagnosed CIN, clearing (infection undetectable), or persisting without CIN, were estimated.

Results: Most incident infections cleared, without detection of CIN, ranging at 36 months from 66.9% for HPV31 to 91.1% for HPV59. There was little variation in the 36-month proportion of incident HPV16, 18, and 31 infections followed by a CIN1 lesion positive for the relevant HPV type (range 16.7%–18.6%), with lower risks for HPV59 (6.4%) and HPV33 (2.9%). Thirty-six–month transition probabilities for CIN2 ranged across types from 2.2% to 9.1%; however, the number of events was generally too small for statistically significant differences to be seen across types for this endpoint, or CIN3.

Conclusions: Some incident HPV types appear more likely to result in diagnosed CIN1 than others. The relative predominance of HPV16, vis-à-vis some other high-risk HPV types (e.g., HPV33) in prevalent CIN2/3, appears more directly associated with relatively greater frequency of incident HPV16 infections within the population, than a higher risk of infection progression to CIN2/3.

Impact: Nearly all incident HPV infections either manifest as detectable CIN or become undetectable within 36 months. Some HPV types (e.g., 16 and 33) appear to have similar risk of CIN2/3 despite widely varied incidence. Cancer Epidemiol Biomarkers Prev; 20(2); 287–96. ©2011 AACR.
Higher Fecal Immunochemical Test Cutoff Levels: Lower Positivity Rates but Still Acceptable Detection Rates for Early-Stage Colorectal Cancers
Authors: Terhaar sive Droste Jochim S. , Oort Frank A. , van der Hulst René W.M. , van Heukelem Henk A. , Loffeld Ruud J.L.F. , van Turenhout Sietze T. , Ben Larbi Ilhame , Kanis Shannon L. , Neerincx Maarten , Räkers Mirre , Coupé Veerle M.H. , Bouman Anneke A. , Meijer Gerrit A. , Mulder Chris J.J.
Published: February 2011

Background: Adjusting the threshold for positivity of quantitative fecal immunochemical tests (FIT) allows for controlling the number of follow-up colonoscopies in a screening program. However, it is unknown to what extent higher cutoff levels affect detection rates of screen-relevant neoplasia. This study aimed to assess the effect of higher cutoff levels of a quantitative FIT on test positivity rate and detection rate of early-stage colorectal cancers (CRC).

Methods: Subjects above 40 years old scheduled for colonoscopy in 5 hospitals were asked to sample a single FIT (OC sensor) before colonoscopy. Screen-relevant neoplasia were defined as advanced adenoma or early-stage cancer (stage I and II). Positivity rate, sensitivity, and specificity were evaluated at increasing cutoff levels of 50 to 200 ng/mL.

Results: In 2,145 individuals who underwent total colonoscopy, 79 patients were diagnosed with CRC, 38 of which were with early-stage disease. Advanced adenomas were found in 236 patients. When varying cutoff levels from ≥50 to ≥200 ng/mL, positivity rates ranged from 16.5% to 10.2%. With increasing cutoff levels, sensitivity for early-stage CRCs and for screen-relevant neoplasia ranged from 84.2% to 78.9% and 47.1% to 37.2%, respectively.

Conclusions: Higher FIT cutoff levels substantially decrease test positivity rates with only limited effects on detection rates of early-stage CRCs. However, spectrum bias resulting in higher estimates of sensitivity than would be expected in a screening population may be present.

Impact: Higher cutoff levels can reduce strain on colonoscopy capacity with only a modest decrease in sensitivity for curable cancers. Cancer Epidemiol Biomarkers Prev; 20(2); 272–80. ©2010 AACR.
Circulating Sex Steroids during Pregnancy and Maternal Risk of Non-epithelial Ovarian Cancer
Authors: Chen Tianhui , Surcel Helja-Marja , Lundin Eva , Kaasila Marjo , Lakso Hans-Ake , Schock Helena , Kaaks Rudolf , Koskela Pentti , Grankvist Kjell , Hallmans Goran , Pukkala Eero , Zeleniuch-Jacquotte Anne , Toniolo Paolo , Lehtinen Matti , Lukanova Annekatrin
Published: February 2011

Background: Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiologic data are available.

Methods: A case–control study was nested within the Finnish Maternity Cohort, the world's largest biorepository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n = 171). OR and 95% CI associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol, and sex hormone–binding globulin (SHBG) were estimated through conditional logistic regression.

Results: For SCST, doubling of testosterone, androstenedione, and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25–3.74), 2.16 (1.20–3.87), and 2.62 (1.27–5.38), respectively]. These associations remained largely unchanged after excluding women within 2-, 4-, or 6-year lag time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT.

Conclusions: This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST.

Impact: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC. Cancer Epidemiol Biomarkers Prev; 20(2); 324–36. ©2010 AACR.
Metformin and the Incidence of Prostate Cancer in Patients with Type 2 Diabetes
Authors: Azoulay Laurent , Dell'Aniello Sophie , Gagnon Bruno , Pollak Michael , Suissa Samy
Published: February 2011

Background: Several in vitro studies have indicated that metformin may reduce the risk of prostate cancer; however, epidemiologic studies have been inconclusive. The objective of this study was to determine whether metformin decreases the risk of prostate cancer in patients with type 2 diabetes.

Methods: A nested case–control analysis was conducted within a population-based cohort from the UK General Practice Research Database. The cohort included patients over the age of 40 who were prescribed a first oral hypoglycemic agent (OHA) between 1988 and 2009. Cases of prostate cancer were matched up to ten controls on year of birth, date of cohort entry, and duration of follow-up. Adjusted rate ratios (RR) were estimated using conditional logistic regression.

Results: The cohort included 63,049 incident users of OHAs, in which 739 cases of prostate cancer were matched to 7,359 controls. Metformin use did not decrease the risk of prostate cancer (RR: 1.23, 95% CI: 0.99–1.52). In secondary analyses, prostate cancer risk was found to increase as a function of the number of metformin prescriptions received (one to seven prescriptions: RR: 1.05, 95% CI: 0.80–1.37; seven to eighteen prescriptions: RR: 1.29, 95% CI: 0.99–1.69; eighteen to thirty-six prescriptions: RR: 1.37, 95% CI: 1.04–1.81; more than thirty-six prescriptions: RR: 1.40, 95% CI: 1.03–1.89).

Conclusion: The results of this study indicate that metformin does not reduce the risk of prostate cancer in patients with type 2 diabetes.

Impact: The secondary analyses need to be interpreted with caution given the inverse association between type 2 diabetes and prostate cancer. Cancer Epidemiol Biomarkers Prev; 20(2); 337–44. ©2010 AACR.
Assessment of Type of Allergy and Antihistamine Use in the Development of Glioma
Authors: McCarthy Bridget J. , Rankin Kristin , Il'yasova Dora , Erdal Serap , Vick Nicholas , Ali-Osman Francis , Bigner Darell D. , Davis Faith
Published: February 2011

Background: Allergies have been associated with decreased risk of glioma; but, associations between duration and timing of allergies, and antihistamine use and glioma risk have been less consistent. The objective was to investigate this association by analyzing types, number, years since diagnosis, and age at diagnosis of allergies, and information on antihistamine usage, including type, duration, and frequency of exposure.

Methods: Self-report data on medically diagnosed allergies and antihistamine use were obtained for 419 glioma cases and 612 hospital-based controls from Duke University and NorthShore University HealthSystem.

Results: High- and low-grade glioma cases were statistically significantly less likely to report any allergy than controls (OR = 0.66, 95% CI: 0.49–0.87 and OR = 0.44, 95% CI: 0.25–0.76, respectively). The number of types of allergies (seasonal, medication, pet, food, and other) was inversely associated with glioma risk in a dose–response manner (P value for trend < 0.05). Age at diagnosis and years since diagnosis of allergies were not associated with glioma risk. Oral antihistamine use was statistically significantly inversely associated with glioma risk, but when stratified by allergy status, remained significant only for those with high-grade glioma and no medically diagnosed allergy.

Conclusions: All types of allergies appear to be protective with reduced risk for those with more types of allergies. Antihistamine use, other than in relationship with allergy status, may not influence glioma risk.

Impact: A comprehensive study of allergies and antihistamine use using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development. Cancer Epidemiol Biomarkers Prev; 20(2); 370–8. ©2011 AACR.
Relationship between Menopausal Symptoms and Risk of Postmenopausal Breast Cancer
Authors: Huang Yi , Malone Kathleen E. , Cushing-Haugen Kara L. , Daling Janet R. , Li Christopher I.
Published: February 2011

Background: Prior studies indicate that women with menopausal symptoms have lower estrogen levels because they go through menopause as compared with women who do not experience them. Given the central role of hormones in the etiology of breast cancer, a link between menopausal symptoms and breast cancer is plausible. However, no prior studies have evaluated the association between menopausal symptoms and breast cancer risk.

Methods: Utilizing data from a population-based case–control study we examined associations between menopausal symptoms and risks of different histologic types of breast cancer among postmenopausal women. We calculated multivariate adjusted odds ratios (OR) using polytomous logistic regression and evaluated several potential effect modifiers.

Results: Women who ever experienced menopausal symptoms had lower risks of invasive ductal carcinoma [(IDC) OR = 0.5; 95% CI: 0.3–0.7], invasive lobular carcinoma (ILC, OR = 0.5; 95% CI: 0.3–0.8), and invasive ductal-lobular carcinoma (IDLC, OR = 0.7; 95% CI: 0.4–1.2), and these reductions in risk were independent of recency and timing of hormone therapy use, age at menopause, and body mass index. Increasing intensity of hot flushes among women who ever experienced hot flushes was also associated with decreasing risks of all three breast cancer subtypes (P values for trend all ≤0.017).

Conclusion: This is the first study to report that women who ever experienced menopausal symptoms have a substantially reduced risk of breast cancer, and that severity of hot flushes is also inversely associated with risk.

Impact: If confirmed, these findings could enhance our understanding of breast cancer etiology and factors potentially relevant to prevention. Cancer Epidemiol Biomarkers Prev; 20(2); 379–88. ©2011 AACR.
Coordinated Cancer Germline Antigen Promoter and Global DNA Hypomethylation in Ovarian Cancer: Association with the BORIS/CTCF Expression Ratio and Advanced Stage
Authors: Woloszynska-Read Anna , Zhang Wa , Yu Jihnhee , Link Petra A. , Mhawech-Fauceglia Paulette , Collamat Golda , Akers Stacey N. , Ostler Kelly R. , Godley Lucy A. , Odunsi Kunle , Karpf Adam R.
Published: February 2011

Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined.

Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer.

Results: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat-α methylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival.

Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC. Clin Cancer Res; 17(8); 2170–80. ©2011 AACR.
Batf Promotes Growth Arrest and Terminal Differentiation of Mouse Myeloid Leukemia Cells
Authors: Liao Juan , Humphrey Sean E. , Poston Stacie , Taparowsky Elizabeth J.
Published: February 2011

Batf is a basic leucine zipper transcription factor belonging to the activator protein-1 superfamily. Batf expression is regulated following stimulation of both lymphoid and myeloid cells. When treated with leukemia inhibitory factor, mouse M1 myeloid leukemia cells commit to a macrophage differentiation program that is dependent on Stat3 and involves the induction of Batf gene transcription via the binding of Stat3 to the Batf promoter. RNA interference was employed to block Batf induction in this system and the cells failed to growth arrest or to terminally differentiate. Restoring Batf expression not only reversed the differentiation-defective phenotype but also caused the cells to display signs of spontaneous differentiation in the absence of stimulation. Efforts to define genetic targets of the Batf transcription factor in M1 cells led to the identification of c-myb, a proto-oncogene known to promote blood cell proliferation and to inhibit the differentiation of M1 cells. These results provide strong evidence that Batf mediates the differentiation-inducing effects of Stat3 signaling in M1 cells and suggest that Batf may play a similar role in other blood cell lineages where alterations to the Jak–Stat pathway are hallmarks of disrupted development and disease. Mol Cancer Res; 9(3); 350–63. ©2011 AACR.
Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis
Authors: Phipps Laura E. , Hino Satoshi , Muschel Ruth J.
Published: February 2011

TNF-related apoptosis-inducing ligand (TRAIL) is a current focus for the development of new cancer therapies, because of its selective induction of apoptosis in cancer cells. TRAIL has previously been shown to be important for tumor cell clearance from the liver; however, many cancer cell lines show some resistance toward TRAIL, posing a problem for the future use of TRAIL therapies. In this study, we show that interfering with a cell's ability to attach and spread onto a matrix can sensitize tumor cells to TRAIL-induced apoptosis in vitro. We targeted different members of the integrin signaling pathway using siRNA or inhibitors, including β-integrins, talin, Src, and downstream survival pathways PI3K and MAPK. Targeting any of these molecules could sensitize both MDA-MB-231 human breast cancer cells and TRAIL-resistant 1205Lu melanoma cells to TRAIL-induced apoptosis in vitro. Transcriptionally targeting the cytoskeleton, using myocardin-related transcription factor depletion to disrupt the transcription of cytoskeletal proteins, also caused TRAIL sensitization in MDA-MB-231 cells. We showed that this sensitivity to TRAIL correlated with increased activation of the intrinsic pathway of apoptosis. Manipulation of cell spreading therefore presents a potential method by which disseminated tumor cells could be sensitized to TRAIL therapies in vivo. Mol Cancer Res; 9(3); 249–58. ©2011 AACR.
Plasticity and Imaging Research in Healthy Aging: Core Ideas and Profile of the International Normal Aging and Plasticity Imaging Center (INAPIC)
Authors: Zöllig Jacqueline , Mérillat Susan , Eschen Anne , Röcke Christina , Martin Mike , Jäncke Lutz
Published: February 2011

The key objective of the International Normal Aging and Plasticity Imaging Center (INAPIC) at the University of Zürich is to facilitate research on normal healthy behavioral and neural development and aging to explore the potential for plasticity and compensation across the lifespan. The INAPIC invites international research groups to submit proposals for collaborative projects on these subjects. It is unique in Europe in giving partner groups ‘plug and play’ access to state-of-the-art neuroimaging techniques, technical support, and assistance in data collection. This article introduces the core ideas of the INAPIC, its key research areas, and the available infrastructure.
Hidden Markov Models for the Stimulus-Response Relationships of Multistate Neural Systems
Authors: Escola Sean , Fontanini Alfredo , Katz Don , Paninski Liam
Published: February 2011

Given recent experimental results suggesting that neural circuits may evolve through multiple firing states, we develop a framework for estimating state-dependent neural response properties from spike train data. We modify the traditional hidden Markov model (HMM) framework to incorporate stimulus-driven, non-Poisson point-process observations. For maximal flexibility, we allow external, time-varying stimuli and the neurons’ own spike histories to drive both the spiking behavior in each state and the transitioning behavior between states. We employ an appropriately modified expectation-maximization algorithm to estimate the model parameters. The expectation step is solved by the standard forward-backward algorithm for HMMs. The maximization step reduces to a set of separable concave optimization problems if the model is restricted slightly. We first test our algorithm on simulated data and are able to fully recover the parameters used to generate the data and accurately recapitulate the sequence of hidden states. We then apply our algorithm to a recently published data set in which the observed neuronal ensembles displayed multistate behavior and show that inclusion of spike history information significantly improves the fit of the model. Additionally, we show that a simple reformulation of the state space of the underlying Markov chain allows us to implement a hybrid half-multistate, half-histogram model that may be more appropriate for capturing the complexity of certain data sets than either a simple HMM or a simple peristimulus time histogram model alone.
Good fences make good neighbours: the role of landmarks in territory partitioning in the rose bitterling (Rhodeus ocellatus)
Authors: Smith Carl
Published: February 2011

Territorial animals sometimes use conspicuous natural landmarks as boundaries to their territories. The utilization of territory-demarcating landmarks may have evolved to limit the costs of territorial defence, since the adoption of clearly defined boundaries by opponents in adjacent territories can reduce the overall rate of aggressive encounters, which can be energetically expensive or might result in injury. Here the role of artificial landmarks as boundaries was tested in territorial male rose bitterling (Rhodeus ocellatus), a fish with a resourcebased mating system. Pairs of size-matched territorial males were permitted to interact for short periods in an otherwise featureless aquarium with an obvious landmark at the shared boundary of their territory either present or absent. The presence of the territory-demarcating landmark significantly reduced both the frequency of territorial incursions by males into adjacent territories and the rate of territorial displays. Males showed individual differences in their propensity to enter the territory of a rival, irrespective of the presence of a territorydemarcating landmark. These results suggest that the cost of defence of a territory may be reduced by utilizing territory-demarcating landmarks, in accordance with the predictions of theoretical models.
Mate availability facilitates cannibalistic behaviour in a nest brooding fish: effects of timing during the brood cycle
Authors: Kohda Masanori , Ohnishi Nobuhiro , Okuda Noboru , Takeyama Tomohiro , Myint Omar
Published: February 2011

Filial cannibalism, eating one's own viable offspring, is accepted as an adaptive response to trade-offs between current and future reproduction. Theoretical models predict that high mate availability may induce more filial cannibalism, but this prediction is rarely tested. To examine this prediction, we performed laboratory experiments using the nest breeding goby Rhinogobius flumineus. Subject males were allowed to mate with a gravid female and care for the broods. A separate gravid female housed in a small cage (stimulus-female) was shown to the subject males at one of three different points during the brood cycle: prior to spawning, within 1 day after spawning and 1 week after spawning. Empty cages were shown as a control. Males that were shown the stimulus-female before spawning cannibalised more eggs than control males. In contrast, males that were shown the stimulus-females after spawning cannibalised as few eggs as control males did. Additionally, males that were shown the stimulus-female prior to spawning did not court females more intensively than other males. Thus, we suggest that the presence of an additional mate, rather than energy expenditure associated with courtship directed toward an additional mate, can facilitate males to cannibalise their eggs.
Religious Morphology, Hermeneutics and Initiation in Andrei Scrima's Il padre spirituale (The Spiritual Father)
Authors: Toti Marco
Published: February 2011

L'articolo in oggetto concerne alcuni temi tratti dalla versione italiana del libro di A. Scrima Timpul Rugului Aprins. Maestrul spiritual în tradiţia răsăriteană ('Il tempo del Roveto Ardente. Il maestro spirituale nella tradizione orientale'), pubblicato a Bucarest nel 1996 e parzialmente tradotto in italiano nel 2000. Scrima (1925–2000), monaco romeno, fu uno dei più raffinati teologi ortodossi del XX secolo. Gli aspetti qui considerati sono, da un lato, l'abbozzo da parte di Scrima stesso di una 'morfologia religiosa' fondata su di una profonda 'ermeneutica' intellettuale e spirituale, anche a mezzo dell'utilizzo della comparazione in specie tra Cristianesimo, Islâm ed Induismo (ciò che dà luogo al tentativo di rinnovare il linguaggio teologico cristiano); dall'altro, la discussione sulla valenza di un particolare rito cui il teologo romeno si riferisce esplicitamente, la 'benedizione di grazia', una 'iniziazione' trasmessa nel Rugul Aprins—un cenacolo esicasta di monaci e laici cui il giovane Scrima prese parte, e che operò dal 1944 al 1958, in particolare nel monastero Antim a Bucarest, sotto la direzione del giornalista e scrittore Sandu Tudor, in religione padre Agathon (1899–1960?)—ad opera del padre Ioan Kulygin (1885-?). Quest'ultimo tema è strettamente connesso alle relazioni intellettuali che Scrima ebbe con i maggiori rappresentanti dell''orientamento tradizionale' (René Guénon [1886–1951], Frithjof Schuon [1907–1998]), anche per quanto concerne la questione dell''universalismo' perennialista; su ciò, come spesso accade, Scrima assume posizioni molto sfumate. È chiaro che, data la complessità e la sottigliezza dei temi qui trattati, il presente contributo costituisce unicamente un saggio iniziale di una discussione più ampia (alla quale stiamo attualmente lavorando).
Revisiting the Termination of the Sino–Vietnamese Alliance, 1975–1979
Authors: Khoo Nicholas
Published: February 2011

This article argues that Vietnamese co-operation with China's principal enemy, the Soviet Union, was the necessary and sufficient cause for the termination of China's alliance with Vietnam in the second-half of the 1970's.
A.A.M. Stols, Publisher: ‘We are not collaborators’
Authors: Chen Salma , van Faassen Sjoerd
Published: February 2011

This article is a critical appraisal of the publishing activities during the Second World War of the renowned publisher A.A.M. Stols. The research presented shows that subsequent statements made by Stols regarding this period cannot all be taken at face value. Despite the commercially fruitful activities that he developed during the occupation of the Netherlands, after the war Stols failed to maintain the position of eminence that he had achieved before it.
Contraband and Private Property in the Age of Imperialism
Authors: Howland Douglas
Published: February 2011

A belligerent declaration of war binds all of its subjects, so that merchants of a belligerent state are forbidden from trading with the enemy. But when a neutral state declares neutrality, that act does not bind all subjects of the neutral state. Neutral merchants are free to trade with belligerents – even in contraband, at their own risk. This essay examines international negotiations over contraband during the first decade of the 1900s while highlighting, in particular, the contradiction between the wish to maintain belligerent rights to determine contraband and to capture it on the high seas and, at the same time, to uphold neutral rights of free trade, which meant protecting private property in trade, including contraband. This asymmetry of the rules of contraband demonstrated that war is not a relation exclusively between states and, as a consequence, some within the international community proposed making individuals subjects of international law or, as an alternative, making neutral states responsible for prohibiting their subjects from trading contraband.
Sovereignty and the Chinese Red Cross Society: The Differentiated Practice of International Law in Shandong, 1914–1916
Authors: Reeves Caroline
Published: February 2011

This article looks at the strategic manipulation of national Red Cross Societies as markers of sovereignty during a period of heightened world nationalism in the early twentieth century. Using Chinese archival materials, it examines how in 1916, on China's much contested Shandong Peninsula, a Japanese delegation set up a Japanese Red Cross chapter and hospital in the Chinese port city of Longkou, in flagrant disregard of widely recognized principles of sovereignty and international law. Occurring just as the larger “Shandong Question” was roiling the international legal community, this incident shows how the local practice of international legal statutes diverged from a more publicized, transnational discussion of those same principles. The article explores this disjuncture, and considers one instance of what I term the differentiated practice of international law: the early twentiethcentury Japanese “double policy” – “one policy for the East and another for the West.” Revealing much about the use of humanitarian activity and the laws of war to further national agendas, the Longkou Incident was later used by the Chinese Red Cross Society as precedent for checking further incursions into China's sovereignty.
Beyond International Law: The Theories of World Law in Tanaka Kōtarō and Tsunetō Kyō
Authors: Doak Kevin
Published: February 2011

A remarkably prescient debate broke out among Japanese legal scholars in the 1930s over the possibility of moving beyond international law as the dominant jurisprudence for a world that had already become quite integrated. At the very time when some were turning away from the ideal of world order to more parochial claims of national or regional autonomy, Tanaka Kōtarō (1890–1974) and Tsunetō Kyō (1888–1967), two of twentieth-century Japan's leading legal scholars, offered the jurisprudence of world law (sekai hō) as a substitute for what they believed was an outmoded concept of international law (kokusai hō). Tanaka sparked the debate with his prize-winning 1932 study A Theory of World Law, and Tsunetō joined it with his 1936 essay, “The Essence of World Law and its Social Function.” The debate has continued throughout the twentieth century in various forms. More broadly, the jurisprudence of world law introduced by Tanaka and Tsunetō underlies Jacques Maritain's influential Man and the State (1951) and – through Maritain – Pope Benedict XVI's recent call for a “true world political authority.” Below, I critically engage this theory of world law, focusing on the difference between Tanaka's transcendental approach and Tsunetō's social deterministic approach, and offer some reflections on how world law might provide a useful way to think beyond the customary binaries of nationalism/internationalism and society/nature that still encumber so much thinking about law and social order today.
Self-determination and Indigenous Women – “Whose Voice Is It We Hear in the Sámi Parliament?”
Authors: Kuokkanen Rauna
Published: February 2011

The Sámi self-determination discourse has always been state-centric in its tendency to invoke the central role of the Nordic states in shaping national policies and legislation on Sámi rights. This article examines the meaning of Sámi self-determination from the perspective of Sámi women: how do Sámi women understand the concept, how do they evaluate the current efforts to implement self-determination by Sámi political institutions and what kind of forms their socio-political participation takes in contemporary Sámi society? It argues that Sámi self-determination is often understood in relational terms as discussed by Iris Marion Young.
The Incorporation of Ruusbroec's Spiritual Espousals into the Sixteenth-Century Arnhem Mystical Sermons. A Comparative Textual Analysis
Authors: Cornet Ineke
Published: February 2011

The anonymous Arnhem Mystical Sermons (Royal Library, The Hague, ms. 133 H 13), copied around 1560–1575 in the St. Agnes convent in Arnhem, is the largest sermon collection that has no other corresponding compilation. Till now, no concrete sources had been identified. This article elaborates on my discovery that one sermon (111) has incorporated a part of Ruusbroec's Spiritual Espousals with significant adaptations. This article provides a detailed analysis of the similarities and modifications, thereby showing the continuity and discontinuity with the fourteenth-century Ruusbroec and relating these differences to the context of the sixteenth-century by showing parallels with other mystical works from the region of Arnhem, namely the Evangelical Pearl and the Temple of Our Soul.
Competing Visions of the International System: Role-identity Incommensurability and U.S.-Russian Relations
Authors: Aleprete Jr. Michael
Published: February 2011

U.S. and Russian foreign policy elites view the international system in fundamentally different ways. The predominant view held by American elites is that the United States is a unipolar power with unique leadership responsibilities. Russian elites view the international system to be a multipolar arrangement, one in which a group of great powers, including the Russian Federation, possess roughly equal international responsibilities and prerogatives. This essay reviews the key doctrinal statements produced by the Russian and U.S. governments since 1991 that outline the assumptions underlying each state's foreign policy, and discusses how these doctrines developed from each sides' experiences in the post-Cold War era. Particular attention is given to the United States' National Security Strategy, which is published every four years, and to the Russian Foreign Policy Concept, which has been published at the beginning of each Russian presidency. The essay also addresses the consequences this role-identity incommensurability will likely have on the prospects for future cooperation between the two states.
Home Exercise Equipment-Related Injuries Among Children in the United States
Authors: Martinez Antonio , Snyder Ashley J. , Smith Gary A.
Published: February 2011

This study investigated home exercise equipment—related injuries to children in the United States. Data from the National Electronic Injury Surveillance System were analyzed for children 18 years old and younger. An estimated 241 573 children with home exercise equipment—related injuries were treated in US hospital emergency departments from 1990 through 2008, averaging 12 714 children per year. There was a statistically significant increase in the annual number (41.9%) and rate of home exercise equipment—related injuries during the study period. Children younger than 10 years accounted for 71.4% of these injuries. Laceration (37.2%) was the leading injury diagnosis, and the most commonly injured body regions were the head (28.6%), finger/hand (22.0%), and foot (10.9%). The majority of injuries were associated with stationary bicycles (26.5%), treadmills (25.3%), and jump ropes (21.5%). The increasing number and rate of home exercise equipment—related injuries to US children underscores the need for increased efforts to prevent these injuries.
Cell Differentiation and Matrix Organization in Engineered Teeth
Authors: Lechguer A. Nait , Couble M.L. , Labert N. , Kuchler-Bopp S. , Keller L. , Magloire H. , Bleicher F. , Lesot H.
Published: February 2011

Embryonic dental cells were used to check a series of criteria to be achieved for tooth engineering. Implantation of cultured cell-cell re-associations led to crown morphogenesis, epithelial histogenesis, organ vascularization, and root and periodontium development. The present work aimed to investigate the organization of predentin/dentin, enamel, and cementum which formed and mineralized after implantation. These implants were processed for histology, transmission electron microscopy, x-ray microanalysis, and electron diffraction. After two weeks of implantation, the re-associations showed gradients of differentiating odontoblasts. There were ciliated, polarized, and extended cell processes in predentin/dentin. Ameloblasts became functional. Enamel crystals showed a typical oriented arrangement in the inner and outer enamel. In the developing root, odontoblasts differentiated, cementogenesis occurred, and periodontal ligament fibroblasts interacted with the root surface and newly formed bone. The implantation of cultured dental cell re-associations allows for reproduction of complete functional differentiation at the cell, matrix, and mineral levels.
Ihh Signaling Regulates Mandibular Symphysis Development and Growth
Authors: Sugito H. , Shibukawa Y. , Kinumatsu T. , Yasuda T. , Nagayama M. , Yamada S. , Minugh-Purvis N. , Pacifici M. , Koyama E.
Published: February 2011

Symphyseal secondary cartilage is important for mandibular development, but the molecular mechanisms underlying its formation remain largely unknown. Here we asked whether Indian hedgehog (Ihh) regulates symphyseal cartilage development and growth. By embryonic days 16.5 to 18.5, Sox9-expressing chondrocytes formed within condensed Tgfβ-1/Runx2-expressing mesenchymal cells at the prospective symphyseal joint site, and established a growth-plate-like structure with distinct Ihh, collagen X, and osteopontin expression patterns. In post-natal life, mesenchymal cells expressing the Ihh receptor Patched1 were present anterior to the Ihh-expressing secondary cartilage, proliferated, differentiated into chondrocytes, and contributed to anterior growth of alveolar bone. In Ihh-null mice, however, symphyseal development was defective, mainly because of enhanced chondrocyte maturation and reduced proliferation of chondroprogenitor cells. Proliferation was partially restored in dual Ihh;Gli3 mutants, suggesting that Gli3 is normally a negative regulator of symphyseal development. Thus, Ihh signaling is essential for symphyseal cartilage development and anterior mandibular growth.