bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving pre-operative medicines reconciliation
Authors: Brunswicker Annemarie , Yogarajah Amieth
Published: August 2014

An audit of 143 surgical admissions showed that only 30% of general surgery and urology patients have complete medication charts on the day of surgery prior to going to theatre, compared to 94% of orthopaedic patients. This was despite having been seen previously in the pre-operative assessment clinic (POAC). These patients went to the wards post-operatively, where many then missed doses of their life-sustaining medications. Orthopaedic patients see a prescribing pharmacist in POAC who undertakes medicines reconciliation; this is performed by junior doctors for surgical patients.

We designed three interventions to improve drug chart completion by junior doctors, and gathered prospective data for 22 weeks in the POAC. We also recorded attendance of junior doctors in the POAC and reasons for absence. Daily and weekly percentages of drug chart completion were plotted on a run chart.

The baseline completion rate was 43%. This rose to 45% after the first and second interventions, and 51% after the third intervention. However, the completion rate remained markedly below our target of 94%. Junior doctors attended only 44% of POACs. They reported being "too busy to attend" 41% of the time, and could not be contacted on 11% of occasions.

Junior doctors reported that they were unable to attend to both unwell inpatients and the POAC, the latter seeming less of a priority. This was despite a rota allocating doctors to attend POAC sessions free from clinical or teaching commitments.

We were unable to increase the rate of drug chart completion with the resources available. We therefore recommend the employment of prescribing pharmacists in the POAC for general surgery and urology patients.
Evaluating vehicular emissions with an integrated mesoscopic and microscopic traffic simulation
Authors: Sider Timothy M.N. , Alam Ahsan , Farrell William , Hatzopoulou Marianne , Eluru Naveen
Published: August 2014

This paper demonstrates the implementation of a traffic simulation linked with instantaneous emissions modelling and is used to evaluate the effects of street closures and area-wide pedestrianization on vehicle-induced greenhouse gas emissions. The study is set in Montreal, Canada where traffic in a dense borough (8656 links) is simulated in a dynamic traffic assignment mode to generate second-by-second speed profiles along every link in the 7–8 AM period. Instantaneous speeds are then used to estimate link-level and intersection-level emissions. The traffic demand at the borough boundaries is simulated using a mesoscopic traffic assignment model developed for the Montreal metropolitan region (127 217 links). Street closures and area-wide pedestrianization schemes are modelled within the microscopic as well as the mesoscopic models to evaluate their effects on greenhouse gas emissions, both while accounting for changes in demand and under constant demand. In all cases, we observe an increase in borough-level greenhouse gas emissions compared to the base-case scenario indicating that such schemes do not lead to a reduction in emissions even when accounting for changes in demand. We also compare emissions calculated using the microscopic models (traffic and emissions) and those obtained from the mesoscopic assignment (traffic and average-speed emissions) and observe that the regional model is much less sensitive to local-level changes mostly due to the incapacity of simulating accelerations and decelerations and therefore underestimating the changes in borough-level emissions compared to the base-case scenario. This indicates the importance of adopting instantaneous emissions models for the evaluation of changes to street configuration.
Forecasting breaks in cast iron water mains in the city of Kingston with an artificial neural network model
Authors: Nishiyama Michael , Filion Yves
Published: August 2014

Predictive water main break models can assist municipalities in prioritizing the replacement and rehabilitation of water mains. The aim of the paper is to develop an artificial neural network (ANN) model to forecast water main breaks in the water distribution network of the City of Kingston, Ontario, Canada. The ANN model includes variables of diameter, age, length, and soil type to forecast breaks. Historical break data from the 1998 to 2011 period is used to develop the ANN model and forecast pipe breaks over a 5 year planning period. The mean square error, receiver operating characteristics curves, and a confusion matrix are used to evaluate the ANN model training and testing. The trained neural network correctly classified 85% of the data set at the training, validation, and testing stages. Model forecasts showed lower pipe break rates in Kingston West, Kingston Central, and Kingston East. The reduction in break rate in the Kingston system was attributed to the removal of old pipes, and the favourable performance of pipes that are in the usage phase of their life cycle. The ANN model provided Utilities Kingston with a tool to assist them in the planning and management of their water main rehabilitation program.
Beneficial effects of platelet-derived growth factor on hemorrhagic shock in rats and the underlying mechanisms
Authors: Liu Liangming , Zhang Jie , Zhu Yu , Xiao Xudong , Peng Xiaoyong , Yang Guangming , Zang Jiatao , Liu Shangqing , Li Tao
Published: August 2014

Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1–15 μg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+sensitivity, whereas it did not interfere with the intracellular Ca2+concentration in hypoxia-treated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis.
Verapamil reduces incidence of reentry during ventricular fibrillation in pigs
Authors: Jin Qi , Dosdall Derek J. , Li Li , Rogers Jack M. , Ideker Raymond E. , Huang Jian
Published: August 2014

The characteristics of reentrant circuits during short duration ventricular fibrillation (SDVF; 20 s in duration) and the role of Ca++and rapid-activating delayed rectifier potassium currents during long duration ventricular fibrillation (LDVF; up to 10 min in duration) were investigated using verapamil and sotalol. Activation mapping of the LV epicardium with a 21 × 24 electrode plaque was performed in 12 open-chest pigs. Pigs were given either verapamil (0.136 mg/kg) or sotalol (1.5 mg/kg) and verapamil. Reentry patterns were quantified for SDVF, and, for LDVF, activation patterns were compared with our previously reported control LDVF data. Verapamil significantly increased conduction velocity around the reentrant core by 10% and reduced the reentrant cycle length by 15%, with a net reduction in reentry incidence of 70%. Sotolol had an opposite effect of decreasing the conduction velocity around the core by 6% but increasing the reentrant cycle length by 13%, with a net reduction of reentry incidence of 50%. After 200 s of VF, verapamil significantly slowed wavefront conduction velocity and activation rate compared with control data. Verapamil decreased the incidence of reentry in SDVF by accelerating conduction velocity to increase the likelihood of conduction block, possibly through increased sympathetic tone. The drug slowed activation rate and conduction velocity after 200 s of VF, suggesting that L-type Ca++channels remain active and may be important in the maintenance of LDVF. Sotalol in addition to verapamil caused no additional antiarrhythmic effect.
BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo
Authors: Lai Michael H. , Wu Yuejin , Gao Zhan , Anderson Mark E. , Dalziel Julie E. , Meredith Andrea L.
Published: August 2014

Large-conductance Ca2+- and voltage-activated K+ (BK) channels play prominent roles in shaping muscle and neuronal excitability. In the cardiovascular system, BK channels promote vascular relaxation and protect against ischemic injury. Recently, inhibition of BK channels has been shown to lower heart rate in intact rodents and isolated hearts, suggesting a novel role in heart function. However, the underlying mechanism is unclear. In the present study, we recorded ECGs from mice injected with paxilline (PAX), a membrane-permeable BK channel antagonist, and examined changes in cardiac conduction. ECGs revealed a 19 ± 4% PAX-induced reduction in heart rate in wild-type but not BK channel knockout ( Kcnma1−/−) mice. The heart rate decrease was associated with slowed cardiac pacing due to elongation of the sinus interval. Action potential firing recorded from isolated sinoatrial node cells (SANCs) was reduced by 55 ± 15% and 28 ± 9% by application of PAX (3 μM) and iberiotoxin (230 nM), respectively. Furthermore, baseline firing rates from Kcnma1−/− SANCs were 33% lower than wild-type SANCs. The slowed firing upon BK current inhibition or genetic deletion was due to lengthening of the diastolic depolarization phase of the SANC action potential. Finally, BK channel immunoreactivity and PAX-sensitive currents were identified in SANCs with HCN4 expression and pacemaker current, respectively, and BK channels cloned from SANCs recapitulated similar activation as the PAX-sensitive current. Together, these data localize BK channels to SANCs and demonstrate that loss of BK current decreases SANC automaticity, consistent with slowed sinus pacing after PAX injection in vivo. Furthermore, these findings suggest BK channels are potential therapeutic targets for disorders of heart rate.
Early life exposure to air pollution induces adult cardiac dysfunction
Authors: Gorr Matthew W. , Velten Markus , Nelin Timothy D. , Youtz Dane J. , Sun Qinghua , Wold Loren E.
Published: August 2014

Exposure to ambient air pollution contributes to the progression of cardiovascular disease, particularly in susceptible populations. The objective of the present study was to determine whether early life exposure to air pollution causes persistent cardiovascular consequences measured at adulthood. Pregnant FVB mice were exposed to filtered (FA) or concentrated ambient particulate matter (PM2.5) during gestation and nursing. Mice were exposed to PM2.5at an average concentration of 51.69 μg/m3from the Columbus, OH region for 6 h/day, 7 days/wk in utero until weaning at 3 wk of age. Birth weight was reduced in PM2.5pups compared with FA (1.36 ± 0.12 g FA, n = 42 mice; 1.30 ± 0.15 g PM2.5, n = 67 P = 0.012). At adulthood, mice exposed to perinatal PM2.5had reduced left ventricular fractional shortening compared with FA-exposed mice (43.6 ± 2.1% FA, 33.2 ± 1.6% PM2.5, P = 0.001) with greater left ventricular end systolic diameter. Pressure-volume loops showed reduced ejection fraction (79.1 ± 3.5% FA, 35.5 ± 9.5% PM2.5, P = 0.005), increased end-systolic volume (10.4 ± 2.5 μl FA, 39.5 ± 3.8 μl PM2.5, P = 0.001), and reduced dP/d t maximum (11,605 ± 200 μl/s FA, 9,569 ± 800 μl/s PM2.5, P = 0.05) and minimum (−9,203 ± 235 μl/s FA, −7,045 ± 189 μl/s PM2.5, P = 0.0005) in PM2.5-exposed mice. Isolated cardiomyocytes from the hearts of PM2.5-exposed mice had reduced peak shortening (%PS, 8.53 ± 2.82% FA, 6.82 ± 2.04% PM2.5, P = 0.003), slower calcium reuptake (τ, 0.22 ± 0.09 s FA, 0.26 ± 0.07 s PM2.5, P = 0.048), and reduced response to β-adrenergic stimulation compared with cardiomyocytes isolated from mice that were exposed to FA. Histological analyses revealed greater picro-sirius red-positive-stained areas in the PM2.5vs. FA group, indicative of increased collagen deposition. We concluded that these data demonstrate the detrimental role of early life exposure to ambient particulate air pollution in programming of adult cardiovascular diseases and the potential for PM2.5to induce persistent cardiac dysfunction at adulthood.
Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels
Authors: Oguri Gaku , Nakajima Toshiaki , Yamamoto Yumiko , Takano Nami , Tanaka Tomofumi , Kikuchi Hironobu , Morita Toshihiro , Nakamura Fumitaka , Yamasoba Tatsuya , Komuro Issei
Published: August 2014

Cardiac fibroblasts contribute to the pathogenesis of cardiac remodeling. Methylglyoxal (MG) is an endogenous carbonyl compound produced under hyperglycemic conditions, which may play a role in the development of pathophysiological conditions including diabetic cardiomyopathy. However, the mechanism by which this occurs and the molecular targets of MG are unclear. We investigated the effects of MG on Ca2+signals, its underlying mechanism, and cell cycle progression/cell differentiation in human cardiac fibroblasts. The conventional and quantitative real-time RT-PCR, Western blot, immunocytochemical analysis, and intracellular Ca2+concentration [Ca2+]i measurement were applied. Cell cycle progression was assessed using the fluorescence activated cell sorting. MG induced Ca2+entry concentration dependently. Ruthenium red (RR), a general cation channel blocker, and HC030031 , a selective transient receptor potential ankyrin 1 (TRPA1) antagonist, inhibited MG-induced Ca2+entry. Treatment with aminoguanidine, a MG scavenger, also inhibited it. Allyl isothiocyanate, a selective TRPA1 agonist, increased Ca2+entry. The use of small interfering RNA to knock down TRPA1 reduced the MG-induced Ca2+entry as well as TRPA1 mRNA expression. The quantitative real-time RT-PCR analysis showed the prominent existence of TRPA1 mRNA. Expression of TRPA1 protein was confirmed by Western blotting and immunocytochemical analyses. MG promoted cell cycle progression from G0/G1 to S/G2/M, which was suppressed by HC030031 or RR. MG also enhanced α-smooth muscle actin expression. The present results suggest that methylglyoxal activates TRPA1 and promotes cell cycle progression and differentiation in human cardiac fibroblasts. MG might participate the development of pathophysiological conditions including diabetic cardiomyopathy via activation of TRPA1.
Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency
Authors: Chen Zaixing , Zhao Runzhen , Zhao Meimi , Liang Xinrong , Bhattarai Deepa , Dhiman Rohan , Shetty Sreerama , Idell Steven , Ji Hong-Long
Published: August 2014

Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na+flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na+-K+-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA−/−mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na+-K+-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function.
MicroRNA-96 inhibits FoxO3a function in IPF fibroblasts on type I collagen matrix
Authors: Nho Richard Seonghun , Im Jintaek , Ho Yen-Yi , Hergert Polla
Published: August 2014

Idiopathic pulmonary fibrosis (IPF) is a lethal and progressive lung disease characterized by persistent (myo)fibroblasts and the relentless accumulation of collagen matrix. Unlike normal lung fibroblasts, IPF lung fibroblasts have suppressed forkhead box O3a (FoxO3a) activity, which allows them to expand in this diseased environment. microRNA-96 (miR-96) has recently been found to directly bind to the 3′-untranslated region of FoxO3a mRNA, which subsequently inhibits its function. We examined whether aberrantly low FoxO3a expression is in part due to increased miR-96 levels in IPF fibroblasts on polymerized collagen, thereby causing IPF fibroblasts to maintain their pathological properties. miR-96 expression was upregulated in IPF fibroblasts compared with control fibroblasts when cultured on collagen. In contrast, FoxO3a mRNA levels were reduced in most IPF fibroblasts. However, when miR-96 function was inhibited, FoxO3a mRNA and protein expression were increased, suppressing IPF fibroblast proliferation and promoting their cell death in a dose-dependent fashion. Likewise, FoxO3a and its target proteins p21, p27, and Bim expression was also increased in the presence of a miR-96 inhibitor in IPF fibroblasts. However, when control fibroblasts were treated with miR-96 mimic, FoxO3a, p27, p21, and Bim mRNA and protein levels were decreased. In situ hybridization analysis further revealed the presence of enhanced miR-96 expression in cells within the fibroblastic foci of IPF lung tissue. Our results suggest that when IPF fibroblasts interact with collagen-rich matrix, pathologically altered miR-96 expression inhibits FoxO3a function, causing IPF fibroblasts to maintain their pathological phenotype, which may contribute to the progression of IPF.
Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow
Authors: Konrad Franziska M. , Braun Stefan , Ngamsri Kristian-Christos , Vollmer Irene , Reutershan Jörg
Published: August 2014

Recruiting polymorphonuclear neutrophil granulocytes (PMNs) from circulation and bone marrow to the site of inflammation is one of the pivotal mechanisms of the innate immune system. During inflammation, the enzyme heme oxygenase 1 (HO-1) has been shown to reduce PMN migration. Although these effects have been described in various models, underlying mechanisms remain elusive. Recent studies revealed an influence of HO-1 on different cells of the bone marrow. We investigated the particular role of the bone marrow in terms of HO-1-dependent pulmonary inflammation. In a murine model of LPS inhalation, stimulation of HO-1 by cobalt (III) protoporphyrin-IX-chloride (CoPP) resulted in reduced segmented PMN migration into the alveolar space. In the CoPP group, segmented PMNs were also decreased intravascularly, and concordantly, mature and immature PMN populations were higher in the bone marrow. Inhibition of the enzyme by tin protoporphyrin-IX increased segmented and banded PMN migration into the bronchoalveolar lavage fluid with enhanced PMN release from the bone marrow and aggravated parameters of tissue inflammation. Oxidative burst activity was significantly higher in immature compared with mature PMNs. The chemokine stromal-derived factor-1 (SDF-1), which mediates homing of leukocytes into the bone marrow and is decreased in inflammation, was increased by CoPP. When SDF-1 was blocked by the specific antagonist AMD3100, HO-1 activation was no longer effective in curbing PMN trafficking to the inflamed lungs. In conclusion, we show evidence that the anti-inflammatory effects of HO-1 are largely mediated by inhibiting the release of segmented PMNs from the bone marrow rather than direct effects within the lung.
Humphry Davy, nitrous oxide, the Pneumatic Institution, and the Royal Institution
Authors: West John B.
Published: August 2014

Humphry Davy (1778–1829) has an interesting place in the history of respiratory gases because the Pneumatic Institution in which he did much of his early work signaled the end of an era of discovery. The previous 40 years had seen essentially all of the important respiratory gases described, and the Institution was formed to exploit their possible value in medical treatment. Davy himself is well known for producing nitrous oxide and demonstrating that its inhalation could cause euphoria and heightened imagination. His thinking influenced the poets Samuel Taylor Coleridge and William Wordsworth, and perhaps we can claim that our discipline colored the poetry of the Romantic Movement. Davy was also the first person to measure the residual volume of the lung. The Pneumatic Institution was the brainchild of Thomas Beddoes, who had trained in Edinburgh under Joseph Black, who discovered carbon dioxide. Later Davy moved to the Royal Institution in London formed, in part, to diffuse the knowledge of scientific discoveries to the general public. Davy was a brilliant lecturer and developed an enthusiastic following. In addition he exploited the newly described electric battery to discover several new elements. He also invented the safety lamp in response to a series of devastating explosions in coal mines. Ultimately Davy became president of the Royal Society, a remarkable honor for somebody with such humble origins. Another of his important contributions was to introduce Michael Faraday (1791–1867) to science. Faraday became one of the most illustrious British scientists of all time.
Liver growth factor treatment reverses emphysema previously established in a cigarette smoke exposure mouse model
Authors: Pérez-Rial Sandra , del Puerto-Nevado Laura , Girón-Martínez Álvaro , Terrón-Expósito Raúl , Díaz-Gil Juan J. , González-Mangado Nicolás , Peces-Barba Germán
Published: August 2014

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease largely associated with cigarette smoke exposure (CSE) and characterized by pulmonary and extrapulmonary manifestations, including systemic inflammation. Liver growth factor (LGF) is an albumin-bilirubin complex with demonstrated antifibrotic, antioxidant, and antihypertensive actions even at extrahepatic sites. We aimed to determine whether short LGF treatment (1.7 μg/mouse ip; 2 times, 2 wk), once the lung damage was established through the chronic CSE, contributes to improvement of the regeneration of damaged lung tissue, reducing systemic inflammation. We studied AKR/J mice, divided into three groups: control (air-exposed), CSE (chronic CSE), and CSE + LGF (LGF-treated CSE mice). We assessed pulmonary function, morphometric data, and levels of various systemic inflammatory markers to test the LGF regenerative capacity in this system. Our results revealed that the lungs of the CSE animals showed pulmonary emphysema and inflammation, characterized by increased lung compliance, enlargement of alveolar airspaces, systemic inflammation (circulating leukocytes and serum TNF-α level), and in vivo lung matrix metalloproteinase activity. LGF treatment was able to reverse all these parameters, decreasing total cell count in bronchoalveolar lavage fluid and T-lymphocyte infiltration in peripheral blood observed in emphysematous mice and reversing the decrease in monocytes observed in chronic CSE mice, and tends to reduce the neutrophil population and serum TNF-α level. In conclusion, LGF treatment normalizes the physiological and morphological parameters and levels of various systemic inflammatory biomarkers in a chronic CSE AKR/J model, which may have important pathophysiological and therapeutic implications for subjects with stable COPD.
CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment
Authors: Flister Michael J. , Endres Bradley T. , Rudemiller Nathan , Sarkis Allison B. , Santarriaga Stephanie , Roy Ishan , Lemke Angela , Geurts Aron M. , Moreno Carol , Ran Sophia , Tsaih Shirng-Wern , De Pons Jeffery , Carlson Daniel F. , Tan Wenfang , Fahrenkrug Scott C. , Lazarova Zelmira , Lazar Jozef , North Paula E. , LaViolette Peter S. , Dwinell Michael B. , Shull James D. , Jacob Howard J.
Published: August 2014

The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous, and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that affect only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the nonmalignant microenvironment. Using CXM, we defined genetic variants on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3IL2Rγ consomic model compared with the SSIL2Rγ parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3IL2Rγ background. Through comparative mapping and whole-genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment that underlie differences in breast cancer risk. Cancer Res; 74(22); 6419–29. ©2014 AACR.
Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer
Authors: Pal Anupama , Young Matthew A. , Donato Nicholas J.
Published: August 2014

The ubiquitin–proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor–mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. Cancer Res; 74(18); 4955–66. ©2014 AACR.
Sonic Hedgehog Signaling in Basal Cell Nevus Syndrome
Authors: Athar Mohammad , Li Changzhao , Kim Arianna L. , Spiegelman Vladimir S. , Bickers David R.
Published: August 2014

The hedgehog (Hh) signaling pathway is considered to be a major signal transduction pathway during embryonic development, but it usually shuts down after birth. Aberrant Sonic hedgehog (Shh) activation during adulthood leads to neoplastic growth. Basal cell carcinoma (BCC) of the skin is driven by this pathway. Here, we summarize information related to the pathogenesis of this neoplasm, discuss pathways that crosstalk with Shh signaling, and the importance of the primary cilium in this neoplastic process. The identification of the basic/translational components of Shh signaling has led to the discovery of potential mechanism-driven druggable targets and subsequent clinical trials have confirmed their remarkable efficacy in treating BCCs, particularly in patients with nevoid BCC syndrome (NBCCS), an autosomal dominant disorder in which patients inherit a germline mutation in the tumor-suppressor gene Patched (Ptch). Patients with NBCCS develop dozens to hundreds of BCCs due to derepression of the downstream G-protein–coupled receptor Smoothened (SMO). Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expression of transcription factors Glis that drive cell proliferation and tumor growth. Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in patients with NBCCS, which finally led to its FDA approval in 2012. Cancer Res; 74(18); 4967–75. ©2014 AACR.
A Prospective Cohort Study of Body Size and Risk of Head and Neck Cancers in the NIH–AARP Diet and Health Study
Authors: Etemadi Arash , O'Doherty Mark G. , Freedman Neal D. , Hollenbeck Albert R. , Dawsey Sanford M. , Abnet Christian C.
Published: August 2014

Background: The association between body size and head and neck cancers (HNCA) is unclear, partly because of the biases in case–control studies.

Methods: In the prospective NIH–AARP cohort study, 218,854 participants (132,288 men and 86,566 women), aged 50 to 71 years, were cancer free at baseline (1995 and 1996), and had valid anthropometric data. Cox proportional hazards regression was used to examine the associations between body size and HNCA, adjusted for current and past smoking habits, alcohol intake, education, race, and fruit and vegetable consumption, and reported as HR and 95% confidence intervals (CI).

Results: Until December 31, 2006, 779 incident HNCAs occurred: 342 in the oral cavity, 120 in the oro- and hypopharynx, 265 in the larynx, 12 in the nasopharynx, and 40 at overlapping sites. There was an inverse association between HNCA and body mass index, which was almost exclusively among current smokers (HR = 0.76 per each 5 U increase; 95% CI, 0.63–0.93), and diminished as initial years of follow-up were excluded. We observed a direct association with waist-to-hip ratio (HR = 1.16 per 0.1 U increase; 95% CI, 1.03–1.31), particularly for cancers of the oral cavity (HR, 1.40; 95% CI, 1.17–1.67). Height was also directly associated with total HNCAs (P = 0.02), and oro- and hypopharyngeal cancers (P < 0.01).

Conclusions: The risk of HNCAs was associated inversely with leanness among current smokers, and directly with abdominal obesity and height.

Impact: Our study provides evidence that the association between leanness and risk of HNCAs may be due to effect modification by smoking. Cancer Epidemiol Biomarkers Prev; 23(11); 2422–9. ©2014 AACR.
Gene Signature–Guided Dasatinib Therapy in Metastatic Breast Cancer
Authors: Pusztai Lajos , Moulder Stacy , Altan Mehmet , Kwiatkowski Danielle , Valero Vicente , Ueno Naoto T. , Esteva Francisco J. , Avritscher Rony , Qi Yuan , Strauss Lewis , Hortobagyi Gabriel N. , Hatzis Christos , Symmans W. Fraser
Published: August 2014

Purpose: Dasatinib has limited single-agent activity in unselected patients with metastatic breast cancer. Several gene signatures predictive of dasatinib response in vitro have been reported. The purpose of this three-arm, phase II study was to prospectively assess the utility of three previously published gene signatures to select patients with clinical benefit from dasatinib.

Experimental Design: Patients with metastatic breast cancer underwent biopsy for gene expression profiling in an academic CLIA laboratory; those who were positive for any one of three predictive gene signatures (dasatinib sensitivity signature, SRC pathway activity signature, and dasatinib target index) received dasatinib 100 mg orally daily. The three marker-defined cohorts were analyzed separately, using early stopping rules for futility.

Results: Ninety-seven patients were enrolled, 93 underwent biopsy, and 80% of the biopsies were sufficient for molecular testing. Thirty patients were positive for at least one signature and received treatment. Only 1 patient experienced clinical benefit and had stable disease over 300 days. All three arms were closed early for futility. There was one serious biopsy-related adverse event (hematoma and pain following a liver biopsy). There were no unexpected toxicities from dasatinib.

Conclusion: None of the three predictive gene signatures, although supported by preclinical evidence, defined tumors clinically sensitive to dasatinib as a single agent. Clin Cancer Res; 20(20); 5265–71. ©2014 AACR.
Targeted Silencing of MLL5β Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers
Authors: Nin Dawn Sijin , Yew Chow Wenn , Tay Sun Kuie , Deng Lih-Wen
Published: August 2014

We previously identified a novel MLL5 isoform, MLL5β, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAi-mediated silencing of MLL5β through the use of MLL5β-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5β silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model. This corresponded with the enhanced antitumor effects of MLL5β-siRNA compared with E6- or E7-siRNA single treatments. Significant reduction in tumor size after MLLβ-siRNA treatment in the HeLa xenograft tumor model further emphasized the importance of MLL5β in HPV16/18-associated tumor growth and the potential of RNAi therapeutics that target MLL5β. We also identified MLL5β as a modulator of gamma-irradiation (IR) sensitization properties of cisplatin. We observed that while MLL5β silencing alone was enough to evoke cisplatin-like IR sensitization in tumor cells in vitro, overexpression of MLL5β inhibited the ability of cisplatin to sensitize HeLa cells to IR-induced cytotoxicity. MLL5β-siRNA-IR cotreatment was also observed to enhance tumor growth inhibition in vivo. Taken together, our findings highlight the potential of targeted silencing of MLL5β via the use of MLL5β-siRNA as a novel therapeutic strategy and propose that MLL5β-siRNA could be a viable alternative for cisplatin in the current cisplatin-based chemotherapeutics for HPV16/18-associated cervical cancers. Mol Cancer Ther; 13(11); 2572–82. ©2014 AACR.
Delineating the mTOR Kinase Pathway Using a Dual TORC1/2 Inhibitor, AZD8055, in Multiple Myeloma
Authors: Cirstea Diana , Santo Loredana , Hideshima Teru , Eda Homare , Mishima Yuko , Nemani Neeharika , Mahindra Anuj , Yee Andrew , Gorgun Gullu , Hu Yiguo , Ohguchi Hiroto , Suzuki Rikio , Cottini Francesca , Guichard Sylvie M. , Anderson Kenneth C. , Raje Noopur
Published: August 2014

Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor 1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055. We evaluated p-mTOR S2481 as the readout for mTORC2/Akt activity in multiple myeloma cells in the context of mTOR inhibition via AZD8055 or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in multiple myeloma cells alone or in culture with bone marrow stroma cells and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of multiple myeloma cells. AZD8055 treatment, however, induced upregulation of IGF1R phosphorylation in p-Akt S473–expressing multiple myeloma cell lines. Furthermore, exposure of AZD8055-treated cells to IGF1 induced p-Akt S473 and rescued multiple myeloma cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF1R-blocking agents is a promising strategy in multiple myeloma with potential IGF1R/Akt signaling–mediated survival. Mol Cancer Ther; 13(11); 2489–500. ©2014 AACR.
On the Relationship between Birds and Spirits of the Dead
Authors: Moreman Christopher M.
Published: August 2014

Birds have an ambiguous symbolic significance across cultures throughout human history, ubiquitously relating to both life and death. Birds are routinely seen as portents of impending calamity and death, while they are also often thought to bear away or steal spirits of the dead, sometimes even embodying those very spirits themselves. On the other hand, birds are also commonly associated with life, fertility, and longevity. This paper brings together cross-cultural evidence for the practically universal associations between birds and both life and death. This paper offers an explanation for this association as an expression of the deep-seated human ambivalence to mortality. As a form of Jungian archetype, birds reflect a fundamental aspect of human nature—the denial of death as finality through a desire for renewal, transformation, and rebirth.
An Examination of the Possible Benefits for Well-Being Arising from the Social Interactions that Occur while Dog Walking
Authors: Duvall Antonacopoulos Nikolina M. , Pychyl Timothy A.
Published: August 2014

Although researchers have established that companion animals act as social catalysts by promoting interaction between people, they have not examined the possible beneficial effects for well-being arising from the social interactions that occur while dog walking. The present study examined the relations between dog walkers’ social interactions and two components of psychological well-being. A sample of 987 Canadian dog walkers (18-84 years old) completed an online survey. Results of hierarchical regression analyses revealed that dog walkers who conversed with the people they encountered while dog walking were less lonely, but not less stressed, than those who did not converse with the people they encountered. Findings from closed- and open-ended questions provided insight into the positive benefits dog walkers received from their social interactions while dog walking. This study provides preliminary evidence that the social interactions that occur through dog walking are related to aspects of psychological well-being.
Constructing the Biotech Nonhuman Animal: Instrumentalism and Ambivalence
Authors: Ung-Lanki Sari
Published: August 2014

This article was designed to give insight into the role of biotechnology in redefining the complex human-animal relations of our times. In particular, it is used to examine accounts of nonhuman animals and animal usage in the context of biotechnology, as covered in the leading scientific journalNature Biotechnology. Data consist of editorials, commentaries, and research news for four years (N= 104), and has been analyzed using discourse analysis. The journal constructs a consistent, yet one-sided, view on animals as they are represented through physico-material, technical and biomedical discourses, as well as discourses on human benefits and manageable risks. The biotechnological epistemology of the animal is positioned at the far end of the subjectification-instrumentalization continuum in our treatment of other animals. It also clashes with simultaneous discussions on animal mind, subjectivity, and moral status. These developments are likely to further intensify the discrepancies in human-animal relations in science and society.
Animal Publics: Accounting for Heterogeneity in Political Life
Authors: Blue Gwendolyn , Rock Melanie
Published: August 2014

To what extent do non-human animals participate in that particular political configuration known as a public? While conventional wisdom about publics is predicated on a vision of political agency that privileges discursive and deliberative processes, recent scholarship situated in the material turn in the social sciences and humanities challenges the notion that publics are purely human and constituted exclusively through language. With these theorizations as a backdrop, this paper takes into consideration the multiple species that are implicated in political life and that play a role in constituting publics. Placing material definitions of publics in line with central concerns raised by human-animal studies, it is argued that animality is significant to publics in ways that have yet to be sufficiently theorized. The intent of this research is to invite further investigation of the myriad ways in which animal bodies and lives influence public formations in a manner that accounts for and also exceeds human capacity for symbolic communication.
Cross-reactivity of insulin analogues with three insulin assays
Authors: Dayaldasani A , Rodríguez Espinosa M , Ocón Sánchez P , Pérez Valero V
Published: August 2014

Background

Immunometric assays have recently shown higher specificity in the detection of human insulin than radioimmunoassays with almost no cross-reaction with proinsulin or C peptide. The introduction of the new insulin analogues on the market, however, has raised the need to define their cross-reactivity in these assays. Several studies have been published in this regard with different results.

Methods

The analogues studied were insulins lispro, aspart, glargine, detemir, and glulisine. Insulin concentrations were measured in Immulite® 2000 and Advia Centaur® XP (Siemens Healthcare Diagnostics), and Elecsys® Modular Analytics E170 (Roche). All samples were processed 15 times in the same analytical run following a random sequence. Those samples which showed statistically and clinically significant changes in insulin concentration were reprocessed using increasing concentrations of analogue, and this was done twice, using two different serum pools, one with a low concentration of insulin and one with a high concentration of insulin.

Results

In the Elecsys® E170 analyser, glargine showed statistical changes (comparison of mean concentrations with p < 0.05) and clinically significant changes in measured insulin (percentage difference 986.2% > reference change value: 59.8%), and the interference increased with increasing concentrations of analogue; the differences were not significant in the case of the other analogues. In the Advia Centaur® and Immulite® 2000 only the results for glulisine did not present significance (percentage difference 44.7% < reference change value 103.5%). Increasing concentrations of aspart, glargine, and lispro showed increased interference in Immulite® 2000.

Conclusions

In the Elecsys® E170 assay, relevant cross-reactivity was only detected with insulin glargine, whereas in the other analysers all analogues except glulisine showed significant interference.
Collinear Latent Variables in Multilevel Confirmatory Factor Analysis
Authors: Can Seda , van de Schoot Rens , Hox Joop
Published: August 2014

Because variables may be correlated in the social and behavioral sciences, multicollinearity might be problematic. This study investigates the effect of collinearity manipulated in within and between levels of a two-level confirmatory factor analysis by Monte Carlo simulation. Furthermore, the influence of the size of the intraclass correlation coefficient (ICC) and estimation method; maximum likelihood estimation with robust chi-squares and standard errors and Bayesian estimation, on the convergence rate are investigated. The other variables of interest were rate of inadmissible solutions and the relative parameter and standard error bias on the between level. The results showed that inadmissible solutions were obtained when there was between level collinearity and the estimation method was maximum likelihood. In the within level multicollinearity condition, all of the solutions were admissible but the bias values were higher compared with the between level collinearity condition. Bayesian estimation appeared to be robust in obtaining admissible parameters but the relative bias was higher than for maximum likelihood estimation. Finally, as expected, high ICC produced less biased results compared to medium ICC conditions.
Educating consumers in self-testing: The development of an online decision aid
Authors: Ickenroth Martine HP , Grispen Janaica EJ , Ronda Gaby , Dinant Geert-Jan , de Vries Nanne K , van der Weijden Trudy
Published: August 2014

Context and objective:

Diagnostic self-tests have become available worldwide. The most frequently performed self-tests in the Netherlands are tests to detect high cholesterol and diabetes. Since these tests can be performed without professional guidance, potential consumers need to receive independent information on the pros and cons of self-testing. The aim of this study was to develop a decision aid (DA) on cholesterol and glucose self-testing to encourage informed choice and to meet consumers’ needs and expectations.

Methods:

A DA was developed based on previous research and medical practice guidelines. The first prototype was assessed for content by means of semi-structured interviews with experts ( n = 13), followed by usability tests with users ( n = 10), leading to improvements to the DA in an iterative process.

Results:

Comments of the experts were grouped into four categories: general comments, textual remarks, technical errors and lay-out. User comments were mainly consistent with the experts’ opinions. Important considerations that were identified concerned the safety of providing this information without direct professional counselling, whether a ranking of available tests should be provided and how strong a warning about self-testing should be.

Conclusion:

Important considerations on how to inform consumers about self-testing were discussed, and led to important changes in the DA. Future research will have to assess the actual use of the DA once it is accessible to the general public, as well as its effects on knowledge and attitude towards self-testing.
China, architecture and Ghana’s spaces: Concrete signs of a soft Chinese imperium?
Authors: Amoah Lloyd G. Adu
Published: August 2014

Africa’s interaction with China is beginning to be marked tellingly by Chinese architectural inscriptions on the African cityscape which need to be deconstructed. The furore in the African press and academia that greeted the building and handing over by China of the African Union headquarters in Addis Ababa makes such an interrogation imperative. This study will attempt to offer some understanding of this nascent phenomenon using the Accra cityscape as an exemplary point of reference. In this regard this work seeks to locate the meaning of fortifications within contemporary global and local discourses on power, architecture, symbols, interests and international relations.