bluuebunny/crossref_metadata_2025 huggingface dataset:
Arrhythmogenic consequences of intracellular calcium waves
Authors: Xie Lai-Hua , Weiss James N.
Published: June 2009

Intracellular Ca2+ (Cai2+) waves are known to cause delayed afterdepolarizations (DADs), which have been associated with arrhythmias in cardiac disease states such as heart failure, catecholaminergic polymorphic ventricular tachycardia, and digitalis toxicity. Here we show that, in addition to DADs, Cai2+ waves also have other consequences relevant to arrhythmogenesis, including subcellular spatially discordant alternans (SDA, in which the amplitude of the local Cai2+ transient alternates out of phase in different regions of the same cell), sudden repolarization changes promoting the dispersion of refractoriness, and early afterdepolarizations (EADs). Cai2+ was imaged using a charge-coupled device-based system in fluo-4 AM-loaded isolated rabbit ventricular myocytes paced at constant or incrementally increasing rates, using either field stimulation, current clamp, or action potential (AP) clamp. Cai2+ waves were induced by Bay K 8644 (50 nM) + isoproterenol (100 nM), or low temperature. When pacing was initiated during a spontaneous Cai2+ wave, SDA occurred abruptly and persisted during pacing. Similarly, during rapid pacing, SDA typically arose suddenly from spatially concordant alternans, due to an abrupt phase reversal of the subcellular Cai2+ transient in a region of the myocyte. Cai2+ waves could be visualized interspersed with AP-triggered Cai2+ transients, producing a rich variety of subcellular Cai2+ transient patterns. With free-running APs, complex Cai2+ release patterns were associated with DADs, EADs, and sudden changes in AP duration. These findings link Cai2+ waves directly to a variety of arrhythmogenic phenomena relevant to the intact heart.
Novel strategy for measuring creatine kinase reaction rate in the in vivo heart
Authors: Xiong Qiang , Li Qinglu , Mansoor Abdul , Jameel Mohammad Nurulqadr , Du Fei , Chen Wei , Zhang Jianyi
Published: June 2009

In the heart, the creatine kinase (CK) system plays an important role in the cascade of ATP production, transportation, and utilization. The forward pseudo-first-order rate constant for the CK reaction can be measured noninvasively by the31P-magnetic resonance (MR) spectroscopy magnetization saturation transfer (MST) techniques. However, the measurement of MST in the in vivo heart is limited by the lengthy data acquisition time, especially for studies requiring spatial localization. This technical report presents a new method for measuring ATP production rate via CK that can reduce the MST data acquisition time by 82%. This method is validated using an in vivo pig model to evaluate the forward pseudo-first-order rate constant of myocardial CK reaction noninvasively.
Apolipoprotein A-I mimetic peptide treatment inhibits inflammatory responses and improves survival in septic rats
Authors: Zhang Zhenghao , Datta Geeta , Zhang Yun , Miller Andrew P. , Mochon Paulina , Chen Yiu-Fai , Chatham John , Anantharamaiah G. M. , White C. Roger
Published: June 2009

Systemic inflammation induces a multiple organ dysfunction syndrome that contributes to morbidity and mortality in septic patients. Since increasing plasma apolipoprotein A-I (apoA-I) and HDL may reduce the complications of sepsis, we tested the hypothesis that the apoA-I mimetic peptide 4F confers similar protective effects in rats undergoing cecal ligation and puncture (CLP) injury. Male Sprague-Dawley rats were randomized to undergo CLP or sham surgery. IL-6 levels were significantly elevated in plasma by 6 h after CLP surgery compared with shams. In subsequent studies, CLP rats were further subdivided to receive vehicle or 4F (10 mg/kg) by intraperitoneal injection, 6 h after sepsis induction. Sham-operated rats received saline. Echocardiographic studies showed a reduction in left ventricular end-diastolic volume, stroke volume, and cardiac output (CO) 24 h after CLP surgery. These changes were associated with reduced blood volume and left ventricular filling pressure. 4F treatment improved blood volume status, increased CO, and reduced plasma IL-6 in CLP rats. Total cholesterol (TC) and HDL were 79 ± 5 and 61 ± 4 mg/dl, respectively, in sham rats. TC was significantly reduced in CLP rats (54 ± 3 mg/dl) due to a reduction in HDL (26 ± 3 mg/dl). 4F administration to CLP rats attenuated the reduction in TC (69 ± 4 mg/dl) and HDL (41 ± 3 mg/dl) and prevented sepsis-induced changes in HDL protein composition. Increased plasma HDL in 4F-treated CLP rats was associated with an improvement in CO and reduced mortality. It is proposed that protective effects of 4F are related to its ability to prevent the sepsis-induced reduction in plasma HDL.
Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development
Authors: Segawa Hiroko , Onitsuka Akemi , Furutani Junya , Kaneko Ichiro , Aranami Fumito , Matsumoto Natsuki , Tomoe Yuka , Kuwahata Masashi , Ito Mikiko , Matsumoto Mitsuru , Li Minqi , Amizuka Norio , Miyamoto Ken-ichi
Published: July 2009

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessively inherited disorder, characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH is caused by a defect in the sodium-dependent phosphate transporter (NaPi-IIc/Npt2c/NPT2c), which was thought to have only a minor role in renal phosphate (Pi) reabsorption in adult mice. In fact, mice that are null for Npt2c (Npt2c−/−) show no evidence for renal phosphate wasting when maintained on a diet with a normal phosphate content. To obtain insights and the relative importance of Npt2a and Npt2c, we now studied Npt2a−/−Npt2c+/+, Npt2a+/−Npt2c−/−, and Npt2a−/−Npt2c−/− double-knockout (DKO). DKO mice exhibited severe hypophosphatemia, hypercalciuria, and rickets. These findings are different from those in Npt2a KO mice that show only a mild phosphate and bone phenotype that improve over time and from the findings in Npt2c KO mice that show no apparent abnormality in the regulation of phosphate homeostasis. Because of the nonreddundant roles of Npt2a and Npt2c, DKO animals showed a more pronounced reduction in Pi transport activity in the brush-border membrane of renal tubular cells than that in the mice with the single-gene ablations. A high-Pi diet after weaning rescued plasma phosphate levels and the bone phenotype in DKO mice. Our findings thus showed in mice that Npt2a and Npt2c have independent roles in the regulation of plasma Pi and bone mineralization.
Principal Cell Spiking, Postsynaptic Excitation, and Oxygen Consumption in the Rat Cerebellar Cortex
Authors: Thomsen Kirsten , Piilgaard Henning , Gjedde Albert , Bonvento Gilles , Lauritzen Martin
Published: July 2009

One contention within the field of neuroimaging concerns the character of the depicted activity: Does it represent neuronal action potential generation (i.e., spiking) or postsynaptic excitation? This question is related to the metabolic costs of different aspects of neurosignaling. The cerebellar cortex is well suited for addressing this problem because synaptic input to and spiking of the principal cell, the Purkinje cell (PC), are spatially segregated. Also, PCs are pacemakers, able to generate spikes endogenously. We examined the contributions to cerebellar cortical oxygen consumption (CMRO2) of postsynaptic excitation and PC spiking during evoked and ongoing neuronal activity in the rat. By inhibiting excitatory synaptic input using ionotropic glutamate receptor blockers, we found that the increase in CMRO2 evoked by parallel fiber (PF) stimulation depended entirely on postsynaptic excitation. In contrast, PC spiking was largely responsible for the increase in CMRO2 when ongoing neuronal activity was increased by γ-aminobutyric acid type A receptor blockade. In this case, CMRO2 increased equally during PC spiking with excitatory synaptic activity as during PC pacemaker spiking without excitatory synaptic input. Subsequent inhibition of action potential propagation and neurotransmission by blocking voltage-gated Na+-channels eliminated the increases in CMRO2 due to PF stimulation and increased PC spiking, but left a large fraction of CMRO2, i.e., basal CMRO2, intact. In conclusion, whereas basal CMRO2 in anesthetized animals did not seem to be related to neurosignaling, increases in CMRO2 could be induced by all aspects of neurosignaling. Our findings imply that CMRO2 responses cannot a priori be assigned to specific neuronal activities.
Negative energy balance alters global gene expression and immune responses in the uterus of postpartum dairy cows
Authors: Wathes D. Claire , Cheng Zhangrui , Chowdhury Waliul , Fenwick Mark A. , Fitzpatrick Richard , Morris Dermot G. , Patton Joe , Murphy John J.
Published: July 2009

Most dairy cows suffer uterine microbial contamination postpartum. Persistent endometritis often develops, associated with reduced fertility. We used a model of differential feeding and milking regimes to produce cows in differing negative energy balance status in early lactation (mild or severe, MNEB or SNEB). Blood hematology was assessed preslaughter at 2 wk postpartum. RNA expression in endometrial samples was compared using bovine Affymetrix arrays. Data were mapped using Ingenuity Pathway Analysis. Circulating concentrations of IGF-I remained lower in the SNEB group, whereas blood nonesterified fatty acid and β-hydroxybutyrate concentrations were raised. White blood cell count and lymphocyte number were reduced in SNEB cows. Array analysis of endometrial samples identified 274 differentially expressed probes representing 197 recognized genes between the energy balance groups. The main canonical pathways affected related to immunological and inflammatory disease and connective tissue disorders. Inflammatory response genes with major upregulation in SNEB cows included matrix metalloproteinases, chemokines, cytokines, and calgranulins. Expression of several interferon-inducible genes including ISG20, IFIH1, MX1, and MX2 were also significantly increased in the SNEB cows. These results provide evidence that cows in SNEB were still undergoing an active uterine inflammatory response 2 wk postpartum, whereas MNEB cows had more fully recovered from their energy deficit, with their endometrium reaching a more advanced stage of repair. SNEB may therefore prevent cows from mounting an effective immune response to the microbial challenge experienced after calving, prolonging the time required for uterine recovery and compromising subsequent fertility.
Nonlinear Conjugate Gradient Methods with Sufficient Descent Condition for Large‐Scale Unconstrained Optimization
Authors: Zhang Jianguo , Xiao Yunhai , Wei Zengxin
Published: July 2009

Two nonlinear conjugate gradient‐type methods for solving unconstrained optimization problems are proposed. An attractive property of the methods, is that, without any line search,
the generated directions always descend. Under some mild conditions, global convergence results for
both methods are established. Preliminary numerical results show that these proposed methods are
promising, and competitive with the well‐known PRP method.
On the Solutions of the System of Difference Equations xn+1 = max{A/xn, yn/xn}, yn+1 = max{A/yn, xn/yn}
Authors: Simsek Dağistan , Demir Bilal , Cinar Cengiz
Published: July 2009

We study the behavior of the solutions of the following system
of difference equations xn+1 = max {A/xn, yn/xn}, yn+1 = max {A/yn, xn/yn} where the constant A and the initial conditions are positive real numbers.
A Fatal Waterborne Outbreak of Pesticide Poisoning Caused by Damaged Pipelines, Sindhikela, Bolangir, Orissa, India, 2008
Authors: Panda Manjubala , Hutin Yvan J. , Ramachandran Vidya , Murhekar Manoj
Published: July 2009

Introduction. We investigated a cluster of pesticide poisoning in Orissa.Methods. We searched the village for cases of vomiting and sweating on 2 February 2008. We described the outbreak by time, place, and person. We compared cases with controls.Results. We identified 65 cases (two deaths; attack rate: 12 per 1000; case fatality: 3%). The epidemic curve suggested a point source outbreak, and cases clustered close to a roadside eatery. Consumption of water from a specific source (odds ratio [OR]: 35, confidence interval [CI]: 13–93) and eating in the eatery (OR: 2.3, CI: 1.1–4.7) was associated with illness. On 31 January 2008, villagers had used pesticides to kill street dogs and had discarded leftovers in the drains. Damaged pipelines located beneath and supplying water may have aspirated the pesticide during the nocturnal negative pressure phase and rinsed it off the next morning in the water supply.Conclusions. Innapropriate use of pesticides contaminated the water supply and caused this outbreak. Education programs and regulations need to be combined to ensure a safer use of pesticides in India.
Estimation of Cachexia among Cancer Patients Based on Four Definitions
Authors: Fox Kathleen M. , Brooks John M. , Gandra Shravanthi R. , Markus Richard , Chiou Chiun-Fang
Published: July 2009

Objectives. Estimate and compare the proportion of cancer patients with cachexia using different definitions from available clinical data.Methods. Electronic medical records were examined to estimate the proportion of cancer patients with cachexia using 4 definitions: (1) ICD-9 diagnostic code of 799.4 (cachexia), (2) ICD-9 diagnosis of cachexia, anorexia, abnormal weight loss, or feeding difficulties, (3) prescription for megestrol acetate, oxandrolone, somatropin, or dronabinol, and (4) 5% weight loss. Patients with cancer of the stomach, pancreas, lung, colon/rectum, head/neck, esophagus, prostate, breast, or liver diagnosed between 1999 and 2004 were followed for cachexia.Results. Of 8541 cancer patients (60% men and 55% Caucasian), cachexia was observed in 2.4% of patients using the cachexia diagnostic code, 5.5% expanded diagnoses, 6.4% prescription medication definition, and 14.7% with 5% weight loss.Conclusions. The proportion of patients with cachexia varied considerably depending upon the definition employed, indicating that a standard operational definition is needed.
In-Network Adaptation of Video Streams Using Network Processors
Authors: Shorfuzzaman Mohammad , Eskicioglu Rasit , Graham Peter
Published: July 2009

The increasing variety of networks and end systems, especially wireless devices, pose new challenges in communication support for, particularly, multicast-based collaborative applications. In traditional multicasting, the sender transmits video at the same rate and resolution to all receivers independent of their network characteristics, end system equipment, and users' preferences about video quality and significance. Such an approach results in resources being wasted and may also result in some receivers having their quality expectations unsatisfied. This problem can be addressed, near the network edge, by applying dynamic, in-network adaptation (e.g., transcoding) of video streams to meet available connection bandwidth, machine characteristics, and client preferences. In this paper, we extrapolate from earlier work of Shorfuzzaman et al. 2006 in which we implemented and assessed an MPEG-1 transcoding system on the Intel IXP1200 network processor to consider the feasibility of in-network transcoding for other video formats and network processor architectures. The use of “on-the-fly” video adaptation near the edge of the network offers the promise of simpler support for a wide range of end devices with different display, and so forth, characteristics that can be used in different types of environments.
A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer
Authors: DiMeo Theresa A. , Anderson Kristen , Phadke Pushkar , Feng Chang , Perou Charles M. , Naber Steven , Kuperwasser Charlotte
Published: July 2009

The establishment of metastasis depends on the ability of cancer cells to acquire a migratory phenotype combined with their capacity to recreate a secondary tumor in a distant tissue. In epithelial cancers, such as those of the breast, the epithelial-mesenchymal transition (EMT) is associated with basal-like breast cancers, generates cells with stem-like properties, and enables cancer cell dissemination and metastasis. However, the molecular mechanism(s) that connects stem cell–like characteristics with EMT has yet to be defined. Using an orthotopic model of human breast cancer metastasis to lung, we identified a poor prognosis gene signature, in which several components of the wnt signaling pathway were overexpressed in early lung metastases. The wnt genes identified in this signature were strongly associated with human basal-like breast cancers. We found that inhibiting wnt signaling through LRP6 reduced the capacity of cancer cells to self-renew and seed tumors in vivo. Furthermore, inhibition of wnt signaling resulted in the reexpression of breast epithelial differentiation markers and repression of EMT transcription factors SLUG and TWIST. Collectively, these results provide a molecular link between self-renewal, EMT, and metastasis in basal-like breast cancers. [Cancer Res 2009;69(13):5364–73]
Antitumor Activity of Gemcitabine and Oxaliplatin Is Augmented by Thymoquinone in Pancreatic Cancer
Authors: Banerjee Sanjeev , Kaseb Ahmed O. , Wang Zhiwei , Kong Deujan , Mohammad Mussop , Padhye Subhash , Sarkar Fazlul H. , Mohammad Ramzi M.
Published: July 2009

Previous studies have shown biological activity of thymoquinone, an active compound extracted from Nigella sativa, in pancreatic cancer cells; however, preclinical animal studies are lacking. Here, we report, for the first time, the chemosensitizing effect of thymoquinone to conventional chemotherapeutic agents both in vitro and in vivo using an orthotopic model of pancreatic cancer. In vitro studies revealed that preexposure of cells with thymoquinone (25 μmol/L) for 48 h followed by gemcitabine or oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when gemcitabine or oxaliplatin was used alone. Moreover, we found that thymoquinone could potentiate the killing of pancreatic cancer cells induced by chemotherapeutic agents by down-regulation of nuclear factor-κB (NF-κB), Bcl-2 family, and NF-κB-dependent antiapoptotic genes (X-linked inhibitors of apoptosis, survivin, and cyclooxygenase-2). As shown previously by our laboratory, NF-κB gets activated on exposure of pancreatic cancer cells to conventional chemotherapeutic agents; interestingly, thymoquinone was able to down-regulate NF-κB in vitro, resulting in chemosensitization. In addition to in vitro results, here we show for the first time, that thymoquinone in combination with gemcitabine and/or oxaliplatin is much more effective as an antitumor agent compared with either agent alone. Most importantly, our data also showed that a specific target, such as NF-κB, was inactivated in animal tumors pretreated with thymoquinone followed by gemcitabine and/or oxaliplatin. These results provide strong in vivo molecular evidence in support of our hypothesis that thymoquinone could abrogate gemcitabine- or oxaliplatin-induced activation of NF-κB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics. [Cancer Res 2009;69(13):5575–83]
Spleen Tyrosine Kinase Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia
Authors: Buchner Maike , Fuchs Simon , Prinz Gabriele , Pfeifer Dietmar , Bartholomé Kilian , Burger Meike , Chevalier Nina , Vallat Laurent , Timmer Jens , Gribben John G. , Jumaa Hassan , Veelken Hendrik , Dierks Christine , Zirlik Katja
Published: July 2009

B-cell receptor signaling contributes to apoptosis resistance in chronic lymphocytic leukemia (CLL), limiting the efficacy of current therapeutic approaches. In this study, we investigated the expression of spleen tyrosine kinase (SYK), a key component of the B-cell receptor signaling pathway, in CLL and its role in apoptosis. Gene expression profiling identified enhanced expression of SYK and downstream pathways in CLL compared with healthy B cells. Immunoblotting showed increased expression and phosphorylation of SYK, PLCγ2, signal transducers and activators of transcription 3, and extracellular signal regulated kinase 1/2 in CLL compared with healthy B cells, suggesting enhanced activation of these mediators in CLL. SYK inhibitors reduced phosphorylation of SYK downstream targets and induced apoptosis in primary CLL cells. With respect to prognostic factors, SYK inhibitors exerted stronger cytotoxic effects in unmutated and ZAP70+ cases. Cytotoxic effects of SYK inhibitors also associated with SYK protein expression, potentially predicting response to therapy. Combination of fludarabine with SYK Inhibitor II or R406 increased cytotoxicity compared with fludarabine therapy alone. We observed no stroma-contact–mediated drug resistance for SYK inhibitors as described for fludarabine treatment. CD40 ligation further enhanced efficacy of SYK inhibition. Our data provide mechanistic insight into the recently observed therapeutic effects of the SYK inhibitor R406 in CLL. Combination of SYK inhibitors with fludarabine might be a novel treatment option particularly for CLL patients with poor prognosis and should be further evaluated in clinical trials. [Cancer Res 2009;69(13):5424–32]
Secretion of Tumor-Specific Antigen by Myeloma Cells Is Required for Cancer Immunosurveillance by CD4+ T Cells
Authors: Corthay Alexandre , Lundin Katrin U. , Lorvik Kristina Berg , Hofgaard Peter O. , Bogen Bjarne
Published: July 2009

Tumor-specific CD4+ T cells orchestrate the adaptive immune responses against cancer. We have previously shown that CD4+ T cells recognize MHC class II–negative myeloma cells indirectly by collaborating with tumor-infiltrating macrophages. We, here, hypothesize that this critical step may be dependent on secretion of tumor-specific antigens by cancer cells. This was investigated using T-cell receptor–transgenic mice, in which CD4+ T cells mediate rejection of syngeneic MOPC315 myeloma cells. We analyzed the immune response against myeloma cell variants, which either secrete or retain intracellularly a tumor-specific idiotypic (Id) antigen. Our results reveal that CD4+ T cells helped by macrophages are capable of detecting nonsecreted tumor antigens from MHC class II–negative cancer cells. However, Id secretion was required for successful myeloma immunosurveillance. Antigen secretion resulted in stronger priming of naive myeloma-specific CD4+ T cells in tumor-draining lymph nodes. Secretion of antigen by at least some cancer cells within a tumor was shown to facilitate immunosurveillance. Treatment by local injection of purified tumor-specific antigen successfully enhanced immunity against nonsecreting myeloma cells. Collectively, the data indicate that antigen concentration within the tumor extracellular matrix must reach a certain threshold to allow successful cancer immunosurveillance by CD4+ T cells. [Cancer Res 2009;69(14):5901–7]
Therapeutics by Cytotoxic Metabolite Accumulation: Pemetrexed Causes ZMP Accumulation, AMPK Activation, and Mammalian Target of Rapamycin Inhibition
Authors: Racanelli Alexandra C. , Rothbart Scott B. , Heyer Cortney L. , Moran Richard G.
Published: July 2009

Pemetrexed represents the first antifolate cancer drug to be approved by the Food and Drug Administration in 20 years; it is currently in widespread use for first line therapy of mesothelioma and non–small cell lung cancer. Pemetrexed has more than one site of action; the primary site is thymidylate synthase. We now report that the secondary target is the downstream folate-dependent enzyme in de novo purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The substrate of the AICART reaction, ZMP, accumulated in intact pemetrexed-inhibited tumor cells, identifying AICART as the step in purine synthesis that becomes rate-limiting after drug treatment. The accumulating ZMP causes an activation of AMP-activated protein kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and hypophosphorylation of the downstream targets of mTOR that control initiation of protein synthesis and cell growth. We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP. [Cancer Res 2009;69(13):5467–74]
Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma
Authors: Kadariya Yuwaraj , Yin Bu , Tang Baiqing , Shinton Susan A. , Quinlivan Eoin P. , Hua Xiang , Klein-Szanto Andres , Al-Saleem Tahseen I. , Bassing Craig H. , Hardy Richard R. , Kruger Warren D.
Published: July 2009

Large homozygous deletions of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers. The role for CDKN2A and ARF in tumorigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear. MTAP encodes the enzyme methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway. To determine if loss of MTAP plays a functional role in tumorigenesis, we have created an MTAP-knockout mouse. Mice homozygous for a MTAP null allele (MtaplacZ) have an embryonic lethal phenotype dying around day 8 postconception. Mtap/MtaplacZ heterozygotes are born at Mendelian frequencies and appear indistinguishable from wild-type mice during the first year of life, but they tend to die prematurely with a median survival of 585 days. Autopsies on these animals reveal that they have greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers, consistent with lymphoma. Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin. Lymphoma-infiltrated tissues tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methyldeoxycytidine. These studies show that Mtap is a tumor suppressor gene independent of CDKN2A and ARF. [Cancer Res 2009;69(14):OF5961–8]
Evaluation of the 8q24 Prostate Cancer Risk Locus and MYC Expression
Authors: Pomerantz Mark M. , Beckwith Christine A. , Regan Meredith M. , Wyman Stacia K. , Petrovics Gyorgy , Chen Yongmei , Hawksworth Dorota J. , Schumacher Fredrick R. , Mucci Lorelei , Penney Kathryn L. , Stampfer Meir J. , Chan Jennifer A. , Ardlie Kristin G. , Fritz Brian R. , Parkin Rachael K. , Lin Daniel W. , Dyke Michelle , Herman Paula , Lee Steve , Oh William K. , Kantoff Philip W. , Tewari Muneesh , McLeod David G. , Srivastava Shiv , Freedman Matthew L.
Published: July 2009

Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus. [Cancer Res 2009;69(13):5568–74]
Compartment-Specific Roles of ATP-Binding Cassette Transporters Define Differential Topotecan Distribution in Brain Parenchyma and Cerebrospinal Fluid
Authors: Shen Jun , Carcaboso Angel M. , Hubbard K. Elaine , Tagen Michael , Wynn Henry G. , Panetta John C. , Waters Christopher M. , Elmeliegy Mohamed A. , Stewart Clinton F.
Published: July 2009

Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves. The mean ± SD ratios for wild-type, Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice were 3.07 ± 0.09, 2.57 ± 0.17, 1.63 ± 0.12, and 0.86 ± 0.05, respectively. In contrast, the ECF-to-plasma ratios for wild-type, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice were 0.36 ± 0.06, 0.42 ± 0.06, and 0.88 ± 0.07. Topotecan lactone was below detectable limits in the ECF of Mdr1a/b−/− mice. When gefitinib (200 mg/kg) was preadministered to inhibit Bcrp1 and P-gp, the vCSF-to-plasma ratio decreased to 1.29 ± 0.09 in wild-type mice and increased to 1.13 ± 0.13 in Mdr1a/b−/−Bcrp1−/− mice, whereas the ECF-to-plasma ratio increased to 0.74 ± 0.14 in wild-type and 1.07 ± 0.03 in Mdr1a/b−/−Bcrp1−/− mice. Preferential active transport of topotecan lactone over topotecan carboxylate was shown in vivo by vCSF lactone-to-carboxylate area under the curve ratios for wild-type, Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice of 5.69 ± 0.83, 3.85 ± 0.64, 3.61 ± 0.46, and 0.78 ± 0.19, respectively. Our results suggest that Bcrp1 and P-gp transport topotecan into vCSF and out of brain parenchyma through the blood-brain barrier. These findings may help to improve pharmacologic strategies to treat brain tumors. [Cancer Res 2009;69(14):5885–92]
Aneuploidy: Cancer's Fatal Flaw?
Authors: Williams Bret R. , Amon Angelika
Published: July 2009

Aneuploidy is a characteristic of cancer, with greater than 90% of all solid tumors in humans carrying an aberrant karyotype. Yet, whether or how this condition contributes to tumorigenesis is not understood. Here we summarize our recent findings on the effects of aneuploidy on cell physiology and proliferation. These studies suggest that aneuploidy puts significant stress on the cell, which responds to this condition in what can be viewed as an aneuploidy stress response. We will discuss how our results may bear on our understanding of the role of this condition in tumorigenesis and how they may provide new opportunities for treatment of the disease. [Cancer Res 2009;69(13):5289–91]
Mediators of Glioblastoma Resistance and Invasion during Antivascular Endothelial Growth Factor Therapy
Authors: Lucio-Eterovic Agda K. , Piao Yuji , de Groot John F.
Published: July 2009

Purpose: Vascular endothelial growth factor (VEGF) has been identified as a critical regulator of angiogenesis. Currently, several different strategies are being used to target the VEGF-VEGF receptor signal transduction pathway in glioblastoma. Although anti-VEGF therapy seems be effective in normalizing abnormal tumor vasculature, leading to an enhanced response to radiation and chemotherapy, tumors eventually become resistant to the therapy and adopt a highly infiltrative and invasive phenotype.

Experimental Design: In the present study, we evaluated the effects of anti-VEGF therapy (bevacizumab) on glioblastoma invasion both in vitro and in vivo and evaluated the angiogenesis- and invasion-related mediators of developed resistance to this therapy.

Results: We found that glioblastoma tumors escaped from antiangiogenic treatment by (a) reactivating angiogenesis through up-regulation of other proangiogenic factors and (b) invading normal brain areas, which was seen in association with up-regulation of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12; secreted protein, acidic, cysteine-rich; and tissue inhibitor of metalloproteinase 1. In addition to the paracrine effects of VEGF on endothelial cells, autocrine VEGF signaling seemed to regulate glioblastoma invasion because anti-VEGF therapy increased tumor invasiveness in vitro.

Conclusions: Collectively, these findings reinforce the importance of VEGF in regulating tumor invasion and identify potential mediators of resistance to targeted VEGF therapy. These results will be important for developing novel combination therapies to overcome this resistance phenotype.
An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells
Authors: Kwong Joseph , Kulbe Hagen , Wong Donald , Chakravarty Probir , Balkwill Fran
Published: July 2009

The chemokine receptor CXCR4 is expressed by malignant cells in ovarian cancer and is implicated in their growth and spread. We report here a unique mechanism of action of a small peptide antagonist of CXCR4 on ovarian cancer cells: induction of cell death by mitotic catastrophe. CTCE-9908 inhibited ovarian cancer cell migration to CXCL12, but on longer incubation, caused cell death in CXCR4-positive cells. CTCE-9908 did not cause apoptosis or cellular senescence, but induced multinucleation, G2-M arrest, and abnormal mitosis in ovarian cancer cells. This suggests that cell death was caused by mitotic catastrophe. Using microarray and Western blot analysis, we showed that CTCE-9908 deregulated DNA damage checkpoint proteins and spindle assembly checkpoint proteins at G2-M phases of the cell cycle. Combination treatment of CTCE-9908 and the drug paclitaxel led to an additive cytotoxicity that also involved mitotic catastrophe. We conclude that CTCE-9908 has a unique mechanism of action in ovarian cancer cells that seems to be CXCR4 specific. [Mol Cancer Ther 2009;8(7):1893–905]
Gene expression profiling of imatinib and PD166326-resistant CML cell lines identifies Fyn as a gene associated with resistance to BCR-ABL inhibitors
Authors: Grosso Sébastien , Puissant Alexandre , Dufies Maeva , Colosetti Pascal , Jacquel Arnaud , Lebrigand Kevin , Barbry Pascal , Deckert Marcel , Cassuto Jill Patrice , Mari Bernard , Auberger Patrick
Published: July 2009

Imatinib is used to treat chronic myelogenous leukemia (CML), but resistance develops in all phases of this disease. The purpose of the present study was to identify the mode of resistance of newly derived imatinib-resistant (IM-R) and PD166326-resistant (PD-R) CML cells. IM-R and PD-R clones exhibited an increase in viability and a decrease in caspase activation in response to various doses of imatinib and PD166326, respectively, as compared with parental K562 cells. Resistance involved neither mutations in BCR-ABL nor increased BCR-ABL, MDR1 or Lyn expression, all known modes of resistance. To gain insight into the resistance mechanisms, we used pangenomic microarrays and identified 281 genes modulated in parental versus IM-R and PD-R cells. The gene signature was similar for IM-R and PD-R cells, accordingly with the cross-sensitivity observed for both inhibitors. These genes were functionally associated with pathways linked to development, cell adhesion, cell growth, and the JAK-STAT cascade. Especially relevant were the increased expression of the tyrosine kinases AXL and Fyn as well as CD44 and HMGA2. Small interfering RNA experiments and pharmacologic approaches identified FYN as a candidate for resistance to imatinib. Our findings provide a comprehensive picture of the transcriptional events associated with imatinib and PD166326 resistance and identify Fyn as a new potential target for therapeutic intervention in CML. [Mol Cancer Ther 2009;8(7):1924–33]
Testing for Differential Item Functioning With Measures of Partial Association
Authors: Woods Carol M.
Published: July 2009

Differential item functioning (DIF) occurs when an item on a test or questionnaire has different measurement properties for one group of people versus another, irrespective of mean differences on the construct. There are many methods available for DIF assessment. The present article is focused on indices of partial association. A family of average conditional ordinal association measures described by Quade is described and empirically compared to the Mantel-Haenszel (MH) test, the partial Pearson correlation pr, and the Spearman rank correlation prs. Because coefficients of linear association are not meaningful for the binary and ordinal variables usually used in DIF applications, practitioners are urged to seek alternatives to pr and prs. Some of the Quade-family measures are viable alternatives and performed as well as, or better than, the established MH test. Computer code for calculating the average conditional ordinal measures using the free R program is given.
Parental Psychological Control, Psychological Autonomy, and Acceptance as Predictors of Self-Esteem in Latino Adolescents
Authors: Bean Roy A. , Northrup Jason C.
Published: July 2009

This study examines several key parenting variables (psychological control, psychological autonomy, and acceptance) in predicting self-esteem among Latino adolescents using structural equation modeling analyses. Nested models are tested and parental acceptance variables are omitted from the model and group gender comparisons are examined. Two variables, maternal psychological autonomy and paternal psychological control, are found to be significant predictors of Latino boys’ self-esteem, whereas psychological autonomy and control (paternal and maternal) are all significantly related to self-esteem among Latino girls. Cultural factors that may have influenced these results are discussed.
Vibration therapy in multiple sclerosis: a pilot study exploring its effects on tone, muscle force, sensation and functional performance
Authors: Schyns F. , Paul L. , Finlay K. , Ferguson C. , Noble E.
Published: June 2009

Objective: To examine the effectiveness of whole body vibration (WBV) on tone, muscle force, sensation and functional performance in people with multiple sclerosis.

Design: A randomized cross-over pilot study.

Setting: Revive MS Support Therapy Centre. Glasgow, UK.

Subjects: Sixteen people with multiple sclerosis were randomly allocated to one of two groups.

Intervention: Group 1 received four weeks of whole body vibration plus exercise three times per week, two weeks of no intervention and then four weeks of exercise alone three times per week. Group 2 were given the two treatment interventions in the reverse order to group 1.

Main measures: Ten-metre walk, Timed Up and Go Test, Modified Ashworth Scale, Multiple Sclerosis Spasticity Scale (MSSS-88), lower limb muscle force, Nottingham Sensory Assessment and Multiple Sclerosis Impact Scale (MSIS-29) were used before and after intervention.

Results: The exercise programme had positive effects on muscle force and well-being, but there was insufficient evidence that the addition of whole body vibration provided any further benefit. The Modified Ashworth Scale was generally unaffected by either intervention, although, for each group, results from the MSSS-88 showed whole body vibration and exercises reduced muscle spasms (P = 0.02). Although results for the 10-m walk and Timed Up and Go Test improved, this did not reach statistical significance (P = 0.56; P = 0.70, respectively). For most subjects sensation was unaffected by whole body vibration.

Conclusion: Exercise may be beneficial to those with multiple sclerosis, but there is limited evidence that the addition of whole body vibration provides any additional improvements. Further larger scale studies into the effects of whole body vibration in people with multiple sclerosis are essential.
The effect of an intensive exercise programme on leg function in chronic stroke patients: a pilot study with one-year follow-up
Authors: Stock Roland , Mork Paul Jarle
Published: June 2009

Objective: To investigate the effect of two weeks of intensive exercise on leg function in chronic stroke patients and to evaluate the feasibility of an intensive exercise programme in a group setting.

Design: Pilot study with one-group pre-test post-test design with two pre-tests and one-year follow-up.

Setting: Inpatient rehabilitation hospital.

Subjects: Twelve hemiparetic patients completed the intervention. Ten patients participated at one-year follow-up.

Intervention: Six hours of daily intensive exercise for two weeks with focus on weight-shifting towards the affected side and increased use of the affected extremity during functional activities. An insole with nubs in the shoe of the non-paretic limb was used to reinforce weight-shift toward the affected side.

Main measures: Timed Up and Go, Four Square Step Test, gait velocity, gait symmetry and muscle strength in knee and ankle muscles.

Results: Maximal gait velocity (P = 0.002) and performance time (seconds) on Timed Up and Go (mean, SD; 12.2, 3.8 vs. 9.4, 3.2) and Four Square Step Test improved from pre- to post-test (P = 0.005). Improvements remained significant at follow-up. Preferred gait velocity and gait symmetry remained unchanged. Knee extensor (P<50.009) and flexor (P<50.001) strength increased bilaterally from pre- to post-test but only knee flexor strength remained significant at follow-up. Ankle dorsi flexor (P = 0.02) and plantar flexor (P<0.001) strength increased on paretic side only (not tested at follow-up).

Conclusion: Intensive exercise for lower extremity is feasible in a group setting and was effective in improving ambulatory function, maximal gait velocity and muscle strength in chronic stroke patients. Most improvements persisted at the one-year follow-up.
Planning Long Dynamically Feasible Maneuvers for Autonomous Vehicles
Authors: Likhachev Maxim , Ferguson Dave
Published: June 2009

In this paper, we present an algorithm for generating complex dynamically feasible maneuvers for autonomous vehicles traveling at high speeds over large distances. Our approach is based on performing anytime incremental search on a multi-resolution, dynamically feasible lattice state space. The resulting planner provides real-time performance and guarantees on and control of the suboptimality of its solution. We provide theoretical properties and experimental results from an implementation on an autonomous passenger vehicle that competed in, and won, the Urban Challenge competition.
‘Posh music should equal posh dress’: an investigation into the concert dress and physical appearance of female soloists
Authors: Griffiths Noola K.
Published: June 2009

This study investigates the effects of concert dress and physical appearance on perceptions of female classical soloists’ musical abilities over a range of genres. Four female violinists were recorded playing three pieces, in four styles of dress of varying formality. Each combination of performer, piece and dress was recorded twice, once as the performer’s own interpretation and again with a master-track dubbed over the top. The master-track provided a constant musical soundtrack and allowed the investigation of observer perceptions based on changes in visual information alone. The clips were rated by 15 male and 15 female observers (age range 18—28) in terms of technical proficiency, musicality, appropriateness of dress and attractiveness of performer on six-point Likert scales. Significant effects of dress, performer and piece suggest that (1) observers have a strong concept of appropriate dress by genre of music; (2) inappropriate and body-focused dress may have a detrimental effect on perceptions of performers’ musical abilities; and (3) performers’ body movement style may also affect perceptions of their abilities.
A generative model of teachers’ thinking on musical creativity
Authors: Odena Oscar , Welch Graham
Published: June 2009

This article draws on and extends a four-year investigation of creativity in music education with particular reference to the perceptions of six secondary school teachers (Odena & Welch, 2007; Odena, Plummeridge, & Welch, 2005). A comprehensive review of recent literature in musical creativity is provided, which complements and reinforces the theoretical framework of the original study. A qualitative approach was used for data gathering, including a video elicitation interview technique and Musical Career Path questionnaires. Transcripts were subsequently categorized using NVivo. Taking into account other recent studies, previously unpublished data is examined and a generative model of how the teachers’ thinking about creativity might develop over time is suggested: the teachers’ past in-and out-of-school experiences and their daily classroom teaching shape their perceptions of musical creativity; this occurs as a continuing interaction that has the potential to modify the teachers’ perceptions over time. Educational implications are considered in the conclusion.
A comparison of modes of communication between members of a string quartet and a jazz sextet
Authors: Seddon Frederick , Biasutti Michele
Published: June 2009

This study revealed the modes of communication employed between the members of a professional string quartet during rehearsal and performance. Results of this study enabled comparison with modes of communication employed by a student jazz sextet revealed in a previous study by the first author. Six modes of communication were revealed in both studies (i.e., verbal and non-verbal, instruction/cooperation/ collaboration). Results indicated that the modes of communication employed by both groups of musicians (i.e., the string quartet and the jazz sextet) were the same, although, at times, the content of the communication differed based on the presence of a pre-composed score and conventions of the musical genre. Participants in both studies confirmed researcher interpretations of the modes of communication during member checks. Results also indicated that when playing from a pre-composed score the string quartet were able to become empathetically attuned and produce ‘spontaneous musical variations’ during performance. The authors propose that these spontaneous musical variations are examples of ‘empathetic creativity’.
Criminal Profiling as a Plotting Activity Based on Abductive Processes
Authors: Verde Alfredo , Nurra Antonio
Published: June 2009

In this article the authors analyze the nature and aims of criminal profiling from a theoretical point of view. The need to become increasingly “scientific” has given rise to the modern approaches of profiling, which have been particularly successful in cases of serial homicides and sex crimes, given that compulsive (perverse) acts, because of their ritual nature, have been described as being more easily foreseeable and presumably linkable to the psychological and even personal characteristics of a given criminal. On this basis, the authors analyze profiling from an epistemological point of view and show how, in the concrete activity of profiling, profilers depart from the “certainty” of the scientific models (those that are based on deductive—inductive processes); the epistemological basis of reasoning changes as there is no longer an induction—deduction model but rather an abductive model (as conceived and explained by Peirce) in which the importance of plotting (the weaving of a narrative) becomes greater.