bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic Embolism and Septic Shock Complicated Left Atrial Myxoma: Case Report
Authors: Trimeche B. , Bouraoui H. , Garbaa R. , Mahdhaoui A. , Ben Rhomdane M. , Ernez-Hajri S. , Jeridi G.
Published: February 2010

Myxoma is the most common primary tumor of the heart. The rarity of infected cardiac myxomas leads to numerous diagnostic and therapeutic difficulties. We present a case of infected left atrial myxoma caused by methicillin-sensibleStaphylococcus aureusin a 48-year-old woman complicated by systemic embolism and septic shock.
Image Processing Techniques for Assessing Contractility in Isolated Adult Cardiac Myocytes
Authors: Bazan Carlos , Barba David Torres , Blomgren Peter , Paolini Paul
Published: February 2010

We describe a computational framework for the comprehensive assessment of contractile responses of enzymatically dissociated adult cardiac myocytes. The proposed methodology comprises the following stages: digital video recording of the contracting cell, edge preserving total variation‐based image smoothing, segmentation of the smoothed images, contour extraction from the segmented images, shape representation by Fourier descriptors, and contractility assessment. The different stages are variants of mathematically sound and computationally robust algorithms very well established in the image processing community. The physiologic application of the methodology is evaluated by assessing overall contraction in enzymatically dissociated adult rat cardiocytes. Our results demonstrate the effectiveness of the proposed approach in characterizing the true, two‐dimensional, “shortening” in the contraction process of adult cardiocytes. We compare the performance of the proposed method to that of a popular edge detection system in the literature. The proposed method not only provides a more comprehensive assessment of the myocyte contraction process but also can potentially eliminate historical concerns and sources of errors caused by myocyte rotation or translation during contraction. Furthermore, the versatility of the image processing techniques makes the method suitable for determining myocyte shortening in cells that usually bend or move during contraction. The proposed method can be utilized to evaluate changes in contractile behavior resulting from drug intervention, disease modeling, transgeneity, or other common applications to mammalian cardiocytes.
Dynamics of a Stage Structure Pest Control Model with Impulsive Effects at Different Fixed Time
Authors: Liu Bing , Duan Ying , Gao Yinghui
Published: February 2010

Many existing pest control models, which control pests by releasing natural
enemies, neglect the effect that natural enemies may get killed. From this point
of view, we formulate a pest control model with stage structure for the pest with
constant maturation time delay (through‐stage time delay) and periodic releasing
natural enemies and natural enemies killed at different fixed time and perform a
systematic mathematical and ecological study. By using the comparison theorem
and analysis method, we obtain the conditions for the global attractivity of the
pest‐eradication periodic solution and permanence of the system. We also present
a pest management strategy in which the pest population is kept under the economic
threshold level (ETL) when the pest population is uniformly permanent. We
show that maturation time delay, impulsive releasing, and killing natural enemies can
bring great effects on the dynamics of the system. Numerical simulations confirm
our theoretical results.
A Survey of Perioperative and Postoperative Anesthetic Practices for Cesarean Delivery
Authors: Aiono-Le Tagaloa Leinani , Butwick Alexander J. , Carvalho Brendan
Published: February 2010

The aim of this survey was to review cesarean delivery anesthetic practices. An online survey was sent to members of the Society of Obstetric Anesthesia and Perinatology (SOAP). The mode of anesthesia, preferred neuraxial local anesthetic and opioid agents, postoperative analgesic regimens, and monitoring modalities were assessed. 384 responses from 1,081 online survey requests were received (response rate = 36%). Spinal anesthesia is most commonly used for elective cesarean delivery (85% respondents), with 90% of these respondents preferring hyperbaric bupivacaine 0.75%. 79% used intrathecal fentanyl and 77% used morphine (median [range] dose 200 mcg [50–400]). 91% use respiratory rate, 61% use sedation scores, and 30% use pulse oximetry to monitor for postoperative respiratory depression after administration of neuraxial opioids. Postoperative analgesic regimens include: nonsteroidal anti-inflammatory agents, acetaminophen, oxycodone, and hydrocodone by 81%, 45%, 25%, and 27% respondents respectively. The majority of respondents use spinal anesthesia and neuraxial opioids for cesarean delivery anesthesia. There is marked variability in practices for monitoring respiratory depression postdelivery and for providing postoperative analgesia. These results may not be indicative of overall practice in the United States due to the select group of anesthesiologists surveyed and the low response rate.
Low Phase Noise and High Conversion Gain Oscillator Mixer Constructed with a 0.18-μm CMOS Technology
Authors: Yang Chin-Lung , Peng Chih-Hsiang , Chiang Yi-Chyun
Published: February 2010

This paper presents a compact down-conversion oscillator mixer fabricated with a 0.18-μm CMOS technology. The oscillator mixer consists of a conventional nMOS differential coupled oscillator, a switch stage, and a pMOS cross-coupled pair which is used to release the design constraint between the conversion gain and the start-up condition. Since the switch stage and the pMOS cross-coupled pair are stacked on the nMOS differential oscillator, the bias currents of the switch stage and the pMOS cross-coupled pair can be entirely reused, so as to reduce the power dissipation. The experimental results show a conversion gain of 6.5 dB at 2.1 GHz associated with a single-sideband (SSB) noise figure of below 13 dB. The oscillator mixer also exhibits a tuning range of 184 MHz and a phase noise of −116 dBc/Hz at 1-MHz offset from the LO frequency of 6.8 GHz, and it consumes 11 mA from 1.8 V bias voltage.
Accurate and Scalable Techniques for the Complex/Pathway Membership Problem in Protein Networks
Authors: Çamoğlu Orhan , Can Tolga , Singh Ambuj K.
Published: February 2010

A protein network shows physical interactions as well as functional associations. An important
usage of such networks is to discover unknown members of partially known complexes and
pathways. A number of methods exist for such analyses, and they can be divided into two main
categories based on their treatment of highly connected proteins. In this paper, we show that
methods that are not affected by the degree (number of linkages) of a protein give more accurate
predictions for certain complexes and pathways. We propose a network flow-based technique
to compute the association probability of a pair of proteins. We extend the proposed technique
using hierarchical clustering in order to scale well with the size of proteome. We also show that
top-k queries are not suitable for a large number of cases, and threshold queries are more meaningful
in these cases. Network flow technique with clustering is able to optimize meaningful
threshold queries and answer them with high efficiency compared to a similar method that uses
Monte Carlo simulation.
Cross‐Talk between PPARγand Insulin Signaling and Modulation of Insulin Sensitivity
Authors: Leonardini Anna , Laviola Luigi , Perrini Sebastio , Natalicchio Annalisa , Giorgino Francesco
Published: February 2010

PPARγactivation in type 2 diabetic patients results in a marked improvement in insulin and glucose parameters, resulting from an improvement of whole‐body insulin sensitivity. Adipose tissue is the major mediator of PPARγaction on insulin sensitivity. PPARγactivation in mature adipocytes induces the expression of a number of genes involved in the insulin signaling cascade, thereby improving insulin sensitivity. PPARγis the master regulator of adipogenesis, thereby stimulating the production of small insulin‐sensitive adipocytes. In addition to its importance in adipogenesis, PPARγplays an important role in regulating lipid, metabolism in mature adipocytes by increasing fatty acid trapping. Finally, adipose tissue produces several cytokines that regulate energy homeostasis, lipid and glucose metabolism. Disturbances in the production of these factors may contribute to metabolic abnormalities, and PPARγactivation is also associated with beneficial effects on expression and secretion of a whole range of cytokines.
A Human Recombinant Autoantibody-Based Immunotoxin Specific for the Fetal Acetylcholine Receptor Inhibits Rhabdomyosarcoma Growth In Vitro and in a Murine Transplantation Model
Authors: Gattenlöhner S. , Jörißen H. , Huhn M. , Vincent A. , Beeson D. , Tzartos S. , Mamalaki A. , Etschmann B. , Muller-Hermelink H. K. , Koscielniak E. , Barth S. , Marx A.
Published: February 2010

Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR)γ-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMSpost partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA). While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms.
Hunting for Serine 276-Phosphorylated p65
Authors: Spooren Anneleen , Kolmus Krzysztof , Vermeulen Linda , Van Wesemael Karlien , Haegeman Guy , Gerlo Sarah
Published: February 2010

The transcription factor nuclear factor kappaB (NF-B) is one of the central mediators of inflammatory gene expression. Several posttranslational modifications of NF-B, regulating its transactivation ability, have been described. Especially phosphorylation of the NF-B subunit p65 has been investigated in depth and several commercial phosphospecific antibodies, targeting selected p65 residues, are available. One of the p65 residues, that is subject to phosphorylation by protein kinase A (PKA) as well as by mitogen-stimulated kinase-1 (MSK-1), is the serine at position 276. Here, we have performed a detailed analysis of the performance of the most commonly used commercial anti-P-p65 Ser276 antibodies. Our findings indicate that at least three widely used anti-P-p65 Ser276 antibodies do not detect p65 in vivo via Western Blot, but instead crossreact with PKA-regulated proteins. As PKA is one of the main kinases responsible for phosphorylation of p65 at Ser276, this observation warrants cautious interpretation of data generated using the tested antibodies.
On the Predictability of Long‐Range Dependent Series
Authors: Li Ming , Li Jia-Yue
Published: February 2010

This paper points out that the predictability analysis of conventional time series may in general be invalid for long‐range dependent (LRD) series since the conventional mean‐square error (MSE) may generally not exist for predicting LRD series. To make the MSE of LRD series prediction exist, we introduce a generalized MSE. With that, the proof of the predictability of LRD series is presented in Hilbert space.
Two-Dimensional Liquid Chromatography Technique Coupled with Mass Spectrometry Analysis to Compare the Proteomic Response to Cadmium Stress in Plants
Authors: Visioli Giovanna , Marmiroli Marta , Marmiroli Nelson
Published: February 2010

Plants are useful in studies of metal toxicity, because their physiological responses to different metals are correlated with the metal exposure dose and chemical state. Moreover a network of proteins and biochemical cascades that may lead to a controlled homeostasis of metals has been identified in many plant species. This paper focuses on the global protein variations that occur in aPopulus nigraspp. clone (Poli) that has an exceptional tolerance to the presence of cadmium. Protein separation was based on a two-dimensional liquid chromatography technique. A subset of 20 out of 126 peaks were identified as being regulated differently under cadmium stress and were fingerprinted by MALDI-TOF. Proteins that were more abundant in the treated samples were located in the chloroplast and in the mitochondrion, suggesting the importance of these organelles in the response and adaptation to metal stress.
Common Fixed Points for Generalized "Equation missing" -Pair Mappings on Cone Metric Spaces
Authors: Sabetghadam F , Masiha HP
Published: February 2010

We define the concept of generalized "Equation missing"-pair mappings and prove some common fixed point theorems for this type of mappings. Our results generalize some recent results.
Heat Transfer Mechanisms and Clustering in Nanofluids
Authors: Wong Kaufui V. , Castillo Michael J.
Published: February 2010

This paper surveys heat transfer in nanofluids. It summarizes and analyzes the theories regarding heat transfer mechanisms in nanofluids, and it discusses the effects of clustering on thermal conductivity. The heat transfer associated with conduction is presented through various experiments followed by a discussion of the theories developed. Relationships between thermal conductivity and various factors such as temperature, concentration, and particle size are also displayed along with a discussion on clustering. There is a brief discussion on convection where the number of studies is limited. There is research currently being performed on the manipulation of the properties governing the thermal conductivity of nanofluids—the particle size, shape, and surface area. Other factors that affect heat transfer are the material of the nanoparticle, particle volume concentration, and the fluid used. Although the interest in this relatively new class of fluids has generated many experimental studies, there is still disagreement over several aspects of heat transfer in nanofluids, primarily concerning the mechanisms behind the increased thermal conductivity. Although nanoparticles have greatly decreased the risks, there is still evidence of unwanted agglomeration which causes erosion and affect the overall conductivity. Research is currently being conducted to determine how to minimize this unwanted clustering.
The Dicey Role of Dicer: Implications for RNAi Therapy
Authors: Merritt William M. , Bar-Eli Menashe , Sood Anil K.
Published: February 2010

The dynamic properties of RNA interference (RNAi) in cancer biology have led investigators to pursue with significant interest its role in tumorigenesis and cancer therapy. We recently reported that decreased expression of key RNAi enzymes, Dicer and Drosha, in epithelial ovarian cancers was associated with poor clinical outcome in patients. Dicer expression was also functionally relevant in that targeted silencing was limited with RNAi fragments that require Dicer function compared with those that do not. Together, this and other studies suggest that RNAi machinery expression may affect key pathways in tumorigenesis and cancer biology. Understanding alterations in the functional RNAi machinery is of fundamental importance as we strive to develop novel therapies using RNAi strategies. Cancer Res; 70(7); 2571–4
Activation of Hedgehog Signaling by the Environmental Toxicant Arsenic May Contribute to the Etiology of Arsenic-Induced Tumors
Authors: Fei Dennis Liang , Li Hua , Kozul Courtney D. , Black Kendall E. , Singh Samer , Gosse Julie A. , DiRenzo James , Martin Kathleen A. , Wang Baolin , Hamilton Joshua W. , Karagas Margaret R. , Robbins David J.
Published: February 2010

Exposure to the environmental toxicant arsenic, through both contaminated water and food, contributes to significant health problems worldwide. In particular, arsenic exposure is thought to function as a carcinogen for lung, skin, and bladder cancer via mechanisms that remain largely unknown. More recently, the Hedgehog signaling pathway has also been implicated in the progression and maintenance of these same cancers. Based on these similarities, we tested the hypothesis that arsenic may act in part through activating Hedgehog signaling. Here, we show that arsenic is able to activate Hedgehog signaling in several primary and established tissue culture cells as well as in vivo. Arsenic activates Hedgehog signaling by decreasing the stability of the repressor form of GLI3, one of the transcription factors that ultimately regulate Hedgehog activity. We also show, using tumor samples from a cohort of bladder cancer patients, that high levels of arsenic exposure are associated with high levels of Hedgehog activity. Given the important role Hedgehog signaling plays in the maintenance and progression of a variety of tumors, including bladder cancer, these results suggest that arsenic exposure may in part promote cancer through the activation of Hedgehog signaling. Thus, we provide an important insight into the etiology of arsenic-induced human carcinogenesis, which may be relevant to millions of people exposed to high levels of arsenic worldwide. Cancer Res; 70(5); 1981–8
The Proteasome Inhibitor Bortezomib Sensitizes Melanoma Cells toward Adoptive CTL Attack
Authors: Seeger Jens Michael , Schmidt Patrick , Brinkmann Kerstin , Hombach Andreas A. , Coutelle Oliver , Zigrino Paola , Wagner-Stippich Diana , Mauch Cornelia , Abken Hinrich , Krönke Martin , Kashkar Hamid
Published: February 2010

Adoptive transfer of tumor-specific cytolytic T lymphocytes (CTL) results in target cell lysis by activating the intrinsic apoptotic cell death program. Not surprisingly, deregulation of the apoptotic machinery is one of the central mechanisms by which tumor cells escape immune destruction despite specific CTL recognition. Here we show that treatment with the proteasome inhibitor bortezomib sensitizes previously resistant tumor cells for cytolytic T-cell attack. Human T cells were redirected toward melanoma cells by engineered expression of an immunoreceptor with binding specificity for high molecular weight–melanoma-associated antigen. Established melanoma cell lines as well as primary melanoma cells from tumor biopsies, which are notoriously resistant toward T-cell lysis, became sensitive upon bortezomib treatment. Detailed analysis of the underlying molecular mechanism revealed that bortezomib treatment induced mitochondrial accumulation of NOXA, which potentiated the release of mitochondrial second mitochondria-derived activator of caspase (SMAC) in response to CTL effector functions, including caspase-8 and granzyme B. Our data indicate that proteasome inhibition increases the sensitivity of tumor cells toward cytolytic T-cell attack by NOXA-mediated enhancement of mitochondrial SMAC release. Cancer Res; 70(5); 1825–34
Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling
Authors: Shrotriya Sangeeta , Kundu Joydeb Kumar , Na Hye-Kyung , Surh Young-Joon
Published: February 2010

An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH2-terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK- or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene–initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. Cancer Res; 70(5); 1932–40
A Phase II Clinical Trial of Ixabepilone (Ixempra; BMS-247550; NSC 710428), an Epothilone B Analog, in Patients with Metastatic Renal Cell Carcinoma
Authors: Huang Hui , Menefee Michael , Edgerly Maureen , Zhuang Sen , Kotz Herb , Poruchynsky Marianne , Huff Lyn Mickley , Bates Susan , Fojo Tito
Published: February 2010

Purpose: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma.

Experimental Design: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m2 ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing.

Results: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response.

Conclusion: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies. Clin Cancer Res; 16(5); 1634–41
Everolimus
Authors: Houghton Peter J.
Published: February 2010

Everolimus, an orally administered rapamycin analog, has recently been approved by the U.S. Food and Drug Administration for treatment of renal cell carcinoma (RCC) refractory to inhibitors of vascular endothelial growth factor (VEGF) receptor signaling. Everolimus significantly increased progression-free survival (median PFS for the everolimus treated group was 4.0 months versus 1.9 months for the placebo group), although tumor regressions were observed only infrequently. Although the target for everolimus, [the serine-threonine kinase mammalian target of rapamycin (mTOR)] is well established, the mechanism by which this agent retards tumor growth is not well defined. Further, biomarkers that predict tumor sensitivity are still elusive. The mechanism of action, preclinical antitumor activity, and clinical activity of everolimus against RCC are reviewed. Clin Cancer Res; 16(5); 1368–72
Lestaurtinib Enhances the Antitumor Efficacy of Chemotherapy in Murine Xenograft Models of Neuroblastoma
Authors: Iyer Radhika , Evans Audrey E. , Qi Xiaoxue , Ho Ruth , Minturn Jane E. , Zhao Huaqing , Balamuth Naomi , Maris John M. , Brodeur Garrett M.
Published: February 2010

Purpose: Neuroblastoma, a common pediatric tumor of the sympathetic nervous system, is characterized by clinical heterogeneity. The Trk family neurotrophin receptors play an important role in this behavior. Expression of TrkA is associated with favorable clinical features and outcome, whereas TrkB expression is associated with an unfavorable prognosis. We wanted to determine if the Trk-selective inhibitor lestaurtinib had therapeutic efficacy in a preclinical neuroblastoma model.

Experimental Design: We performed intervention trials of lestaurtinib alone or in combination with other agents in TrkB-overexpressing neuroblastoma xenograft models.

Results: Lestaurtinib alone significantly inhibited tumor growth compared to vehicle-treated animals [P = 0.0004 for tumor size and P = 0.011 for event-free survival (EFS)]. Lestaurtinib also enhanced the antitumor efficacy of the combinations of topotecan plus cyclophosphamide (P < 0.0001 for size and P < 0.0001 for EFS) or irinotecan plus temozolomide (P = 0.011 for size and P = 0.012 for EFS). There was no additive benefit of combining either 13-cis-retinoic acid or fenretinide with lestaurtinib compared to lestaurtinib alone. There was dramatic growth inhibition combining lestaurtinib with bevacizumab (P < 0.0001), but this combination had substantial systemic toxicity.

Conclusions: We show that lestaurtinib can inhibit the growth of neuroblastoma both in vitro and in vivo and can substantially enhance the efficacy of conventional chemotherapy, presumably by inhibition of the Trk/brain-derived neurotrophic factor autocrine survival pathway. It may also enhance the efficacy of selected biological agents, but further testing is required to rule out unanticipated toxicities. Our data support the incorporation of Trk inhibitors, such as lestaurtinib, in clinical trials of neuroblastoma or other tumors relying on Trk signaling pathways for survival. Clin Cancer Res; 16(5); 1478–85
Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer with Acquired Endocrine Resistance
Authors: Leary Alexandra F. , Drury Suzanne , Detre Simone , Pancholi Sunil , Lykkesfeldt Anne E. , Martin Lesley-Ann , Dowsett Mitch , Johnston Stephen R.D.
Published: February 2010

Purpose: Acquired endocrine resistance in estrogen receptor (ER)α+/human epidermal growth factor receptor 2–negative (HER2−) breast cancer has been associated with modest adaptive increases in HER2, although exactly how aberrant HER2 signaling affects the ERα pathway is poorly understood. We investigated (a) whether the epidermal growth factor receptor/HER2 inhibitor lapatinib could restore endocrine responsiveness in cell models of acquired endocrine resistance with modest increases in HER2, and (b) the nature of ERα-HER2 cross-talk in this process.

Methods: Combination growth studies, ERα transcription, immunoblot, and gene expression assays were conducted in two models of acquired resistance to (a) estrogen deprivation (long-term estrogen-deprived cells) and (b) tamoxifen (long-term tamoxifen-treated cells), and in hormone sensitive controls. Changes in ERα, PgR, and HER2 were assessed in samples from patients treated with tamoxifen.

Results: Both cell models of acquired endocrine resistance showed modest adaptive upregulation in HER2, and lapatinib restored endocrine sensitivity in both. The effect of lapatinib on ERα signaling varied markedly depending on the nature of the HER2/ERα cross-talk. In long-term estrogen-deprived cells characterized by enhanced ERα function, lapatinib suppressed ERα genomic activity (as measured by pERSer118, ERα transcriptional activity, and PGR gene expression). In contrast, in long-term tamoxifen-treated cells with reduced ERα activation, lapatinib reactivated ERα genomic function. Twenty percent of tamoxifen-resistant patients relapsed with modest increases in HER2 and either suppressed or enhanced ERα/PgR expression.

Conclusions: Aberrant GFR signaling can augment or suppress ERα function. Regardless, interrupting the HER2/ERα cross-talk with lapatinib can restore endocrine sensitivity and should be investigated as a therapeutic strategy in combination with endocrine therapy in ERα+/HER2− patients with acquired endocrine resistance. Clin Cancer Res; 16(5); 1486–97
High-Resolution Array Comparative Genomic Hybridization in Sporadic and Celiac Disease–Related Small Bowel Adenocarcinomas
Authors: Diosdado Begoña , Buffart Tineke E. , Watkins Russell , Carvalho Beatriz , Ylstra Bauke , Tijssen Marianne , Bolijn Anne S. , Lewis Fraser , Maude Karen , Verbeke Caroline , Nagtegaal Iris D. , Grabsch Heike , Mulder Chris J.J. , Quirke Phil , Howdle Peter , Meijer Gerrit A.
Published: February 2010

Purpose: The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment.

Experimental Design: Forty-eight small bowel adenocarcinomas (33 non–celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease–related and non–celiac disease–related small bowel adenocarcinomas.

Results: DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease–related and non–celiac disease–related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non–celiac disease–related and 73% celiac disease–related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non–celiac disease–related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease–related small bowel adenocarcinomas were microsatellite unstable.

Conclusions: Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease–related and non–celiac disease–related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease–related than in non–celiac disease–related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease–related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391–401
Comparative Profiling of the Novel Epothilone, Sagopilone, in Xenografts Derived from Primary Non–Small Cell Lung Cancer
Authors: Hammer Stefanie , Sommer Anette , Fichtner Iduna , Becker Michael , Rolff Jana , Merk Johannes , Klar Ulrich , Hoffmann Jens
Published: February 2010

Purpose: Characterization of new anticancer drugs in a few xenograft models derived from established human cancer cell lines frequently results in the discrepancy between preclinical and clinical results. To take the heterogeneity of tumors into consideration more thoroughly, we describe here a preclinical approach that may allow a more rational clinical development of new anticancer drugs.

Experimental Design: We tested Sagopilone, an optimized fully synthetic epothilone, in 22 well-characterized patient-derived non–small cell lung cancer models and correlated results with mutational and genome-wide gene expression analysis.

Results: Response analysis according to clinical trial criteria revealed that Sagopilone induced overall responses in 64% of the xenograft models (14 of 22), with 3 models showing stable disease and 11 models showing partial response. A comparison with response rates for established drugs showed the strong efficacy of Sagopilone in non–small cell lung cancer. In gene expression analyses, Sagopilone induced tubulin isoforms in all tumor samples, but genes related to mitotic arrest only in responder models. Moreover, tumors with high expression of genes involved in cell adhesion/angiogenesis as well as of wild-type TP53 were more likely to be resistant to Sagopilone therapy. As suggested by these findings, Sagopilone was combined with Bevacizumab and Sorafenib, drugs targeting vascular endothelial growth factor signaling, in Sagopilone-resistant models and, indeed, antitumor activity could be restored.

Conclusion: Analyses provided here show how preclinical studies can provide hypotheses for the identification of patients who more likely will benefit from new drugs as well as a rationale for combination therapies to be tested in clinical trials. Clin Cancer Res; 16(5); 1452–65
Association of TGF-β1 Genetic Variants with HPV16-positive Oropharyngeal Cancer
Authors: Guan Xiaoxiang , Sturgis Erich M. , Lei Dapeng , Liu Zhensheng , Dahlstrom Kristina R. , Wei Qingyi , Li Guojun
Published: February 2010

Purpose: Transforming growth factor-β1 (TGF-β1) plays an important role in inflammation and immune responses, which control the human papillomavirus (HPV) clearance and escape of immune surveillance, and may contribute to genetic susceptibility to HPV16 infection.

Experimental Design: In this case series study, we analyzed the HPV16 status in tumor specimens and genotyped three TGF-β1 polymorphisms using genomic DNA from the blood of 200 squamous cell carcinoma of the oropharynx (SCCOP) cases. We calculated odds ratio (OR) and 95% confidence intervals (95% CI) in univariate and multivariable logistic regression models to examine the association between the TGF-β1 polymorphisms and HPV16 status in SCCOP.

Results: Compared with those with the common homozygous genotype, the TGF-β1 T869C variant genotypes were significantly associated with HPV16-positive tumor status among patients with SCCOP (OR, 1.97; 95% CI, 1.03-3.76), but no significant association was observed for the TGF-β1 C509T or G915C polymorphism. When all variant genotypes were combined, however, SCCOP patients carrying genotypes with any of these TGF-β1 variants were more than twice as likely to have an HPV16-positive tumor (OR, 2.28; 95% CI, 1.16-4.50) as patients with no variant genotypes. The stratified analysis showed that those under 54 years of age, non-Hispanic white patients, never smokers, and never drinkers with any variant TGF-β1 genotypes were also more likely to have HPV16-positive tumors.

Conclusions: TGF-β1 polymorphisms may serve as a susceptibility marker for tumor HPV16 status among SCCOP patients, particularly those who were never smokers and never drinkers. Large studies are needed to validate our findings. Clin Cancer Res; 16(5); 1416–22
Development of Immunohistochemistry Assays to Assess GALNT14 and FUT3/6 in Clinical Trials of Dulanermin and Drozitumab
Authors: Stern Howard M. , Padilla Mary , Wagner Klaus , Amler Lukas , Ashkenazi Avi
Published: February 2010

Purpose: In vitro sensitivity to the proapoptotic receptor agonists dulanermin (rhApo2L/TRAIL) and drozitumab (DR5-agonist antibody) is strongly predicted by the expression of the O-glycosylation enzymes GALNT14 in non–small cell lung cancer (NSCLC) cell lines (among others) and of FUT3/6 in colorectal cancer (CRC) cell lines. We developed immunohistochemistry (IHC) assays that measure GALNT14 and FUT3/6 levels in archival formalin-fixed, paraffin-embedded human tumor tissue to determine marker prevalence in NSCLC and CRC tissue and to enable the future examination of these markers in clinical trials.

Experimental Design: GALNT14 or FUT3/6 ELISA-positive hybridoma clones were screened through IHC on cell pellets with known mRNA levels. The specificity of staining was examined in cell lines, normal tissue, and tumor tissue.

Results: GALNT14 and FUT3/6 IHC exhibited a golgi staining pattern and correlated with GALNT14 and FUT3/6 (but not GALNT2 and FUT4) mRNA expression levels in cell lines and normal tissues, suggesting specificity. GALNT14 and FUT3/6 H-scores were significantly higher in cell lines sensitive to dulanermin (P = 0.01 and P = 0.0004, respectively) and drozitumab (P = 0.03 and P < 0.0001, respectively) versus resistant cell lines. GALNT14 and FUT3/6 H-scores varied widely, with ∼45% of NSCLC samples exhibiting weak to moderate GALNT14 staining (H-score of at least 25) and 70% of CRC samples exhibiting moderate to strong FUT3/6 staining (H-score of at least 125).

Conclusions: GALNT14 and FUT3/6 expression can be assessed in human tumors using sensitive and specific IHC assays. Both assays are being deployed in ongoing clinical trials of dulanermin and drozitumab to assess potential utility for patient selection. Clin Cancer Res; 16(5); 1587–96
American Ginseng Suppresses Colitis through p53-Mediated Apoptosis of Inflammatory Cells
Authors: Jin Yu , Hofseth Anne B. , Cui Xiangli , Windust Anthony J. , Poudyal Deepak , Chumanevich Alex A. , Matesic Lydia E. , Singh Narendra P. , Nagarkatti Mitzi , Nagarkatti Prakash S. , Hofseth Lorne J.
Published: February 2010

Ulcerative colitis is a dynamic, chronic inflammatory condition associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism regulating ulcerative colitis. American ginseng (AG) is a putative antioxidant that can suppress hyperactive immune cells. We have recently shown that AG can prevent and treat mouse colitis. Because p53 levels are elevated in inflammatory cells in both mouse and human colitis, we tested the hypothesis that AG protects from colitis by driving inflammatory cell apoptosis through a p53 mechanism. We used isogenic p53+/+ and p53−/− inflammatory cell lines as well as primary CD4+/CD25− effector T cells from p53+/+ and p53−/− mice to show that AG drives apoptosis in a p53-dependent manner. Moreover, we used a dextran sulfate sodium (DSS) model of colitis in C57BL/6 p53+/+ and p53−/− mice to test whether the protective effect of AG against colitis is p53 dependent. Data indicate that AG induces apoptosis in p53+/+ but not in isogenic p53−/− cells in vitro. In vivo, C57BL/6 p53+/+ mice are responsive to the protective effects of AG against DSS-induced colitis, whereas AG fails to protect from colitis in p53−/− mice. Furthermore, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling of inflammatory cells within the colonic mesenteric lymph nodes is elevated in p53+/+ mice consuming DSS + AG but not in p53−/− mice consuming DSS + AG. Results are consistent with our in vitro data and with the hypothesis that AG drives inflammatory cell apoptosis in vivo, providing a mechanism by which AG protects from colitis in this DSS mouse model. Cancer Prev Res; 3(3); 339–47
Adaptor Proteins as Targets for Cancer Prevention
Authors: Yee Douglas
Published: February 2010

This perspective on the report by McCampbell et al. in this issue of the journal (beginning on page 290) addresses the role of insulin receptor substrate (IRS) proteins in cancer progression. The IRS proteins link many cell-surface receptors to signal transduction pathways. Activation of the phosphoinositide-3 kinase/Akt/mammalian target of rapamycin axis normally results in serine phosphorylation and subsequent downregulation of these adaptor proteins. The authors show that changes in the negative feedback regulation of IRS proteins is associated with the progression of endometrial epithelial cells to hyperplasia and cancer. Therefore, understanding the function of adaptor proteins could provide additional strategies for cancer prevention and treatment. Cancer Prev Res; 3(3); 263–5
Predicting Pilots’ Risk-Taking Behavior Through an Implicit Association Test
Authors: Molesworth Brett R. C. , Chang Betty
Published: February 2010

Objective: The Implicit Association Test (IAT), in combination with a battery of additional psychometric tests, was employed to examine the accuracy with which it predicts pilots’ risk-taking behavior. Background: Risk management is an integral part of piloting. Many factors affect pilots’ risk management, including individual differences. Therefore, employing a unique methodology from social cognition, the present study examined the influence of attitude, as measured implicitly through the IAT, personality, and flight experience variables on pilots’ risk-taking behavior. Method: In addition to a simulated flight on a computer-based flight simulator, 35 pilots completed a battery of psychometric tests. Results: Among the 6 risk perception variables, 10 risk attitude variables, and 2 experience variables, only 2 variables were found to be significantly related with in-flight risk-taking behavior: everyday risk (risk perception) and the IAT effect (attitude). Of these, the IAT effect was the strongest predictor of flight behavior. Conclusion: The results indicate that implicit attitudinal measures, such as the IAT, provide a more accurate forecast of pilot behavior than do the more traditional explicit attitudinal or personality measures. Application: An implicit attitudinal measure can be proactively employed to identify pilots who are potentially more likely to engage in high-risk activities, hence permitting a more strategic approach to pilot training.
The Economic Cost of Harboring Terrorism
Authors: Benmelech Efraim , Berrebi Claude , Klor Esteban F.
Published: February 2010

The literature on conflict and terrorism has paid little attention to the economic costs of terrorism for the perpetrators. This article aims to fill that gap by examining the economic costs of harboring suicide terror attacks. Using data covering the universe of Palestinian suicide terrorists during the second Palestinian uprising, combined with data from the Palestinian Labor Force Survey, the authors identify and quantify the impact of a successful attack on unemployment and wages. They find robust evidence that terror attacks have important economic costs. The results suggest that a successful attack causes an increase of 5.3 percent in unemployment, increases the likelihood that the district’s average wages fall in the quarter following an attack by more than 20.0 percent, and reduces the number of Palestinians working in Israel by 6.7 percent relative to its mean. Importantly, these effects are persistent and last for at least six months after the attack.
Learning the Meaning of Verbs: Insights from Quechua
Authors: Courtney Ellen H.
Published: February 2010

Largely based on observations of English-speaking children, investigators have proposed constraints on verb learning, e.g., syntactic bootstrapping, the principle of uniqueness, and innate semantic-conceptual categories. Children produce overgeneralization errors as they acquire verb meaning, and data from some languages reveal an intriguing asymmetry: children use intransitive verbs transitively, while seldom using causative-transitive verbs intransitively. This study presents experimental evidence corroborating the author’s earlier finding that Quechua-speaking children’s overgeneralization errors observe the same asymmetry. The transitive variants of change-of-state verbs were elicited from 30 Peruvian children, aged 2;8—4;11. The ensuing discussion considers how Quechua-speaking children recover from this pattern of overgeneralization in light of constraints that have been proposed for children acquiring English, which is typologically very different from Quechua.
Hebrew Adjectives in Later Language Text Production
Authors: Ravid Dorit , Levie Ronit
Published: February 2010

The study investigates the distribution and use of adjectives in 252 texts produced by 63 Hebrew-speaking children, adolescents, and adults who were asked to tell and write a story about a personal fight or a quarrel, and to present a talk and write an expository text on the topic of school violence. All adjective types and tokens in each text were identified, counted, classified, and analyzed using semantic, morphological, and syntactic criteria. Findings show that the adjective class grows larger, richer, and more diverse with age and schooling — in lexicon, morpho-semantics, and syntax. Also, adjectives configure by text genres and modalities in ways that provide independent support for text type classification from spoken narratives, on the one hand, to written expositories, on the other. Finally, gender effects point in the direction of Hebrew-speaking girls and women employing a richer and more diverse adjective lexicon than boys and men in this study.
The Attractive Female Body Weight and Female Body Dissatisfaction in 26 Countries Across 10 World Regions: Results of the International Body Project I
Authors: Swami Viren , Frederick David A. , Aavik Toivo , Alcalay Lidia , Allik Jüri , Anderson Donna , Andrianto Sonny , Arora Arvind , Brännström Åke , Cunningham John , Danel Dariusz , Doroszewicz Krystyna , Forbes Gordon B. , Furnham Adrian , Greven Corina U. , Halberstadt Jamin , Shuang Hao  , Haubner Tanja , Choon Sup Hwang  , Inman Mary , Laile Jaafar Jas , Johansson Jacob , Jung Jaehee , Keser Aşkın , Kretzschmar Uta , Lachenicht Lance , Li Norman P. , Locke Kenneth , Lönnqvist Jan-Erik , Lopez Christy , Loutzenhiser Lynn , Maisel Natalya C. , McCabe Marita P. , McCreary Donald R. , McKibbin William F. , Mussap Alex , Neto Félix , Nowell Carly , Peña Alampay Liane , Pillai Subash K. , Pokrajac-Bulian Alessandra , Proyer René T. , Quintelier Katinka , Ricciardelli Lina A. , Rozmus-Wrzesinska Malgorzata , Ruch Willibald , Russo Timothy , Schütz Astrid , Shackelford Todd K. , Shashidharan Sheeba , Simonetti Franco , Sinniah Dhachayani , Swami Mira , Vandermassen Griet , van Duynslaeger Marijke , Verkasalo Markku , Voracek Martin , Yee Curtis K. , Xian Zhang Echo , Xiaoying Zhang  , Zivcic-Becirevic Ivanka
Published: February 2010

This study reports results from the first International Body Project (IBP-I), which surveyed 7,434 individuals in 10 major world regions about body weight ideals and body dissatisfaction. Participants completed the female Contour Drawing Figure Rating Scale (CDFRS) and self-reported their exposure to Western and local media. Results indicated there were significant cross-regional differences in the ideal female figure and body dissatisfaction, but effect sizes were small across high-socioeconomic-status (SES) sites. Within cultures, heavier bodies were preferred in low-SES sites compared to high-SES sites in Malaysia and South Africa ( ds = 1.94-2.49) but not in Austria. Participant age, body mass index (BMI), and Western media exposure predicted body weight ideals. BMI and Western media exposure predicted body dissatisfaction among women. Our results show that body dissatisfaction and desire for thinness is commonplace in high-SES settings across world regions, highlighting the need for international attention to this problem.