bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Control Strategy to Reduce Steering Torque Without Perceptible Vibration for Vehicles Equipped With Electric Power Steering
Authors: Kurishige Masahiko , Nishihara Osamu , Kumamoto Hiromitsu
Published: September 2010

This paper proposes a new electric power steering control strategy, which significantly reduces the effort needed to change the steering direction of stationary vehicles. Previous attempts to reduce undesirable steering vibration have failed to reduce the steering torque because high-assist gains tend to produce oscillation or increase noise sensitivity. Herein, to eliminate this vibration, a new control strategy was developed based on pinion angular velocity control using a newly developed observer based on a simplified steering model. Tests yielded excellent estimations of the pinion angular velocity, and this made it possible to eliminate vibration at all steering wheel rotation speeds. Experiments with a test vehicle confirmed significant steering torque reduction, over a wide range of steering wheel speeds, without vibration transmission to the driver. The proposed control strategy allowed use of an assist gain more than three times higher than is conventional. Additionally, the proposed control strategy does not require supplemental sensors.
A Novel Translational Total Body Irradiation Technique
Authors: Brown Derek W. , Knibutat Kurt , Edmonds Nathan , Tom Daniel , Moriarty Leo , Hanson Peter , Udowicz Mona , Hussain Amjad , Villarreal-Barajas Jose Eduardo , Hudson Alana
Published: September 2010

A novel translating bed total body irradiation treatment delivery technique that employs dynamically shaped beams is presented. The patient is translated along the floor on a moving bed through a stationary radiation beam and the shape of the radiation beam is changed dynamically as the patient is moved through it, enabling compensation for local variations in patient thickness and tissue density. We demonstrate that the use of dynamically shaped beams results in greatly improved dose homogeneity compared with standard techniques, which use a single static beam shape. Along a representative dose profile through the lungs of a mock-human body, the maximum range of dose deviation from the average is 5.6% (from +2.7% to −2.9%) for the dynamic beam technique compared with 12.8% (from +3.6% to −9.2%) for the static beam technique. A novel, dual-interlock system that prevents bed motion when the radiation beam is stopped and stops the radiation beam when the bed motor is stopped has also been developed. The dual-interlock not only enhances the safety of the treatment but also ensures accuracy in the delivery of the treatment.
Design Improvements and In Vitro Testing of an Implantable Muscle Energy Converter for Powering Pulsatile Cardiac Assist Devices
Authors: Trumble Dennis R. , Norris Marshall , Melvin Alan
Published: September 2010

Harnessing skeletal muscle for circulatory support would improve on current blood pump technologies by eliminating infection-prone drivelines and cumbersome transcutaneous energy transmission systems. Toward that end, we have built and tested an implantable muscle energy converter (MEC) designed to transmit the contractile energy of the latissimus dorsi muscle in hydraulic form. The MEC weighs less than 300 g and comprises a metallic bellows formed from AM350 stainless steel actuated by a rotary cam (440C) attached to a titanium rocker arm (Ti–6Al–4V). The rocker arm is fixed to the humeral insertion of the muscle via a looped artificial tendon developed specifically for this purpose. The device housing (Ti–6Al–4V) is anchored to the ribcage using a perforated mounting ring and a wire suture. Lessons learned through seven previous design iterations have produced an eighth-generation pump with excellent durability, energy transfer efficiency, anatomic fit, and tissue interface characteristics. This report describes recent improvements in MEC design and summarizes results from in silico and in vitro testing. Long-term implant studies will be needed to confirm these findings prior to clinical testing.
Preliminary Development and Engineering Evaluation of a Novel Cricothyrotomy Device
Authors: Carey Jason P. , Gwin Morgan , Kan Andrew , Toogood Roger , Finegan Barry
Published: September 2010

Cricothyrotomy is one of the procedures used to ventilate patients with upper airway blockage. This paper examines the most regularly used and preferred cricothyrotomy devices on the market, suggests critical design specifications for improving cricothyrotomy devices, introduces a new cricothyrotomy device, and performs an engineering evaluation of the device’s critical components. Through a review of literature, manufacturer products, and patents, four principal cricothyrotomy devices currently in clinical use were identified. From the review, the Cook™ Melker device is the preferred method of clinicians but the device has acknowledged problems. A new emergency needle cricothyrotomy device (ENCD) was developed to address all design specifications identified in literature. Engineering, theoretical, and experimental assessments were performed. In situ evaluations of a prototype of the new device using porcine specimens to assess insertion, extraction, and cyclic force capabilities were performed. The device was very successful in its evaluation. Further discussion focuses on these aspects and a comparison of the new device with established devices. The proposed emergency needle cricothyrotomy device performed very well. Further work will be pursued in the future with in-vitro and in-vivo with canine models demonstrates the capabilities of the ENCD.
Application of Neural Networks and Finite Element Computation for Multiscale Simulation of Bone Remodeling
Authors: Hambli Ridha
Published: September 2010

In this paper, a novel multiscale hierarchical model based on finite element analysis and neural network computation was developed to link mesoscopic and macroscopic scales to simulate the bone remodeling process. The finite element calculation is performed at the macroscopic level, and trained neural networks are employed as numerical devices for substituting the finite element computation needed for the mesoscale prediction. Based on a set of mesoscale simulations of representative volume elements of bones taken from different bone sites, a neural network is trained to approximate the responses at the meso level and transferred at the macro level.
Tau Reduction Prevents Aβ-Induced Defects in Axonal Transport
Authors: Vossel Keith A. , Zhang Kai , Brodbeck Jens , Daub Aaron C. , Sharma Punita , Finkbeiner Steven , Cui Bianxiao , Mucke Lennart
Published: September 2010

A mechanism for the protective effects of tau reduction in mouse models of Alzheimer’s disease.
Systematic review and meta-analysis of psychomotor effects of mobile phone electromagnetic fields
Authors: Valentini Elia , Ferrara Michele , Presaghi Fabio , Gennaro Luigi De , Curcio Giuseppe
Published: September 2010

Objectives

Over the past 10 years there has been increasing concern about the possible behavioural effects of mobile phone use. This systematic review and meta-analysis focuses on studies published since 1999 on the human cognitive and performance effects of mobile phone-related electromagnetic fields (EMF).

Methods

PubMed, Biomed, Medline, Biological Sciences, PsychInfo, PsycARTICLES, Environmental Sciences and Pollution Management, Neurosciences Abstracts and Web of Science professional databases were searched and 24 studies selected for meta-analysis. Each study had to have at least one psychomotor measurement result as a main outcome. Data were analysed using standardised mean difference (SMD) as the effect size measure.

Results

Only three tasks (2-back, 3-back and simple reaction time (SRT)) displayed significant heterogeneity, but after studies with extreme SMD were excluded using sensitivity analysis, the statistical significance disappeared (χ2(7)=1.63, p=0.20; χ2(6)=1.00, p=0.32; χ2(10)=14.04, p=0.17, respectively). Following sensitivity analysis, the effect of sponsorship and publication bias were assessed. Meta-regression indicated a significant effect (b1/40.12, p<0.05) only for the 2-back task with mixed funding (industry and public/charity). Funnel plot inspection revealed a significant publication bias only for two cognitive tasks: SRT (Begg's rank correlation r=0.443; Egger's test b=−0.652) and the subtraction task (Egger's test b=−0.687).

Conclusions

Mobile phone-like EMF do not seem to induce cognitive and psychomotor effects. Nonetheless, the existence of sponsorship and publication biases should encourage WHO intervention to develop official research standards and guidelines. In addition, future research should address critical and neglected issues such as investigation of repeated, intensive and chronic exposures, especially in highly sensitive populations such as children.
Morphology and origin of erosion surfaces in the Cardium Formation (Upper Cretaceous, Western Interior Seaway, Alberta) and their implications for rapid sea level fluctuations
Authors: Wadsworth Jennifer A. , Walker Roger G.
Published: September 2010

The morphology of three basin-wide erosion surfaces has been defined using 7869 resistivity well logs, over an area of about 50 000 km2. The lowest of these, designated E6, is topographically smooth, and has no incised steps or low areas. It cuts into marine mudstones, and indicates either an uninterrupted erosive transgression following a major lowering of relative sea level, or wave scouring of the substrate following a very minor lowering of sea level. Erosion surface E6.5 also cuts into marine mudstones, but its overall morphology is less well understood owing to subsequent dissection by surface E7. This surface (E7) is characterized by three strike-parallel linear low areas that die out northwestward. These linear lows are up to 40 km wide, 36 m deep, and have irregular to symmetrical cross-sectional profiles. They cut into, and are filled with, marine mudstones, and their origin is enigmatic. The differences in the morphologies of the surfaces suggest the interplay of several controlling parameters: (i) steady transgression versus transgression interrupted by stillstands; (ii) absolute depth of erosion during transgression, which in turn controls the preservation or erosion of incised river valleys; (iii) wave scouring of substrate in response to minor lowerings of sea level; and (iv) availability of coarse sediment and river gradients steep enough for its transport to the shoreline. The average time span between erosion surfaces is 300 000 – 350 000 years. This timing is hard to explain tectonically, or in terms of global eustacy, suggesting the possibility of glacio-eustatic control of fluctuations in relative sea level.
Silurian (Llandovery) graptolites from the Bay of Exploits, north-central Newfoundland, and their geological significance
Authors: Williams S. Henry , O'Brien Brian H.
Published: September 2010

Only one specimen of a Silurian graptolite has ever been recorded from Newfoundland, and it was not identifiable below generic level. The graptolite assemblage discussed and figured here, from a sequence of turbidites on Upper Black Island, north-central Newfoundland, includes the first positively identified Silurian taxa from the province, and provides the first unequivocal evidence of Silurian oceanic sedimentation in the Dunnage Zone. The graptolite taxa include Rastrites peregrinus (Barrande), Coronograptus? sp. cf. C. gregarius (Lapworth), Monograptus austerus sequens Hutt?, Orthograptus insectiformis (Nicholson), Monograptus spp. indet., "Climacograptus"? sp., and Glyptograptus? sp. This assemblage demonstrates that the strata, previously assigned to the Middle Ordovician Lawrence Harbour Formation, are actually Aeronian (middle Llandovery) in age and that the turbidites considerably postdate both the Lawrence Harbour and Point Leamington formations of the Exploits Subzone. Furthermore, the graptolite fauna is similar to that found in coeval sediments in the United Kingdom and Scandinavia but unlike any assemblages known from elsewhere in North America. This suggests the presence of open oceanic conditions, or deep marginal basins during the Llandovery hosting graptolites with European affinities, and raises the possibility that at least part of the Iapetus Ocean was still open in central Newfoundland during Early Silurian times.
Preconsolidation pressures in the Battleford Formation, southern Saskatchewan, Canada
Authors: Sauer E. Karl , Christiansen E. A.
Published: September 2010

Soft, surficial, unoxidized till of the Battleford Formation overlies hard, oxidized and unoxidized till of the Floral Formation. The difference in hardness between these two formations is the result of preconsolidation pressures that range from 1500 to 2200 kPa in the Floral Formation and from 350 to 750 kPa in the lower till unit of the Battleford Formation. The upper till and clay unit of the Battleford Formation, which represents a conformable contact between this formation and the overlying glaciolacustrine clay, is normally consolidated. Preconsolidation of the Floral Formation apparently took place upglacier where the potentiometric surface for subglacial beds was 170–240 m below the ice surface. The lower till unit of the Battleford Formation was deposited from and consolidated under stagnant ice. The upper normally consolidated till and clay unit of the Battleford Formation was let down upon the lower till unit by ablation. The calculated minimum stagnant ice thickness required for consolidation of the lower till unit of the Battleford Formation ranges from 51 to 81 m. The calculated time required for consolidation is less than 100 years.
Metamorphism of the Kisseynew gneisses and related rocks of the Reindeer Zone, Trans-Hudson Orogen, northern Saskatchewan
Authors: Perkins Dexter
Published: September 2010

In the Reindeer Zone of Saskatchewan, the mostly metasedimentary Kisseynew gneiss crops out in a 300 km wide belt extending from the Tabbernor Fault to the Manitoba border. Metamorphic grade varies from middle amphibolite to granulite facies. Associated with the main Kisseynew gneiss are metasedimentary rocks of the Glennie Domain, Attitti Block, and Hanson Lake Block. Sillimanite is the common aluminosilicate in most parts of the four domains. Andalusite occurs at several places within the southern Glennie Domain, in the southern Hanson Lake Block, and in the northern Flin Flon Belt. Kyanite, appearing relict in many samples, is found in a 10 km × 50 km zone adjacent to the Flin Flon Belt.Most of the regional variation in metamorphic P–T can be explained by postmetamorphic folding and uplift. Peak T varied from less than 600 °C (in the Glennie Domain) to 725 °C. The highest temperatures were recorded near enderbite occurrences at Chicken Lake, 10 km east of Sandy Bay, and along a thermal anticline, extending east-northeast from the Hanson Lake Block, across the Attitti Block. Metamorphic P ranged from less than 4.5 kbar to 10 kbar (1 kbar = 100 MPa). Highest pressures were associated with the uplifted Hanson Lake and Attitti blocks.The Precambrian geology of the Reindeer Zone is characterized by stacked thrust sheets, many of which are separated by originally subhorizontal shear zones. The sheet including the Kisseynew sediments was carried to approximately 20–30 km depth by continental thickening due to the thrusting. Metamorphism did not take place on a normal geotherm: heat for metamorphism was augmented by plutonic heat sources. Late, northeast-plunging folds postdated peak metamorphism and were followed by uplift. If the Kisseynew sediments are metamorphosed equivalents of the Flin Flon Amisk and Missi Groups, a transect from the Flin Flon Belt to the Attitti Block may represent a deformed 20 km section.
MODELING AND QUERYING UNCERTAIN RELATIONAL DATABASES: A SURVEY OF APPROACHES BASED ON THE POSSIBLE WORLDS SEMANTICS
Authors: BOSC PATRICK , PIVERT OLIVIER
Published: September 2010

In this paper, we give an overview of the most representative approaches aimed at querying databases containing ill-known data, starting from the pioneering works by Codd and Lipski and up to very recent proposals. This study focuses on approaches with a clear and sound semantics, based on the notion of possible worlds. Three types of queries are considered: (i) those about attribute values (in an algebraic or SQL-like framework), (ii) those about the properties satisfied by a given set of worlds (i.e., a set of instances of an imprecise database), and (iii) those about the representation of uncertain data. For the first two types, it is emphasized that a trade-off has to be found between expressivity (of the model) and tractability (of the queries in the context of a given model).
Evolution of the Levant margin and western Arabia platform since the Mesozoic: introduction
Authors: Homberg Catherine , Bachmann Martina
Published: September 2010

The Levant area comprises the offshore Levant Basin (LB) (eastern corner of the Eastern Mediterranean) as well as the adjacent continental slopes and platforms of the African and Arabian plates. This area experienced major events of the geodynamical evolution of the Middle East, such as the Late Palaeozoic–Early Mesozoic Pangea break up, the Late Cretaceous–Cenozoic closure of the Neo-Tethys and individualization of the Arabian plate, as well as a set of external factors like global sea-level and climate changes. This volume combines original data from the offshore and onshore Levant in various fields, including sedimentology, palaeontology, sequence stratigraphy, geochemistry, structural geology, stress reconstitution and geophysics (seismic lines, palaeomagnetism). All together, these multidisciplinary approaches allow the review of the development of the LB and gain a better insight on the later geological history and deformation processes of the Levant provinces.
Tethyan rifting in the Levant Region and its role in Early Mesozoic crustal evolution
Authors: Gardosh Michael A. , Garfunkel Zvi , Druckman Yehezkel , Buchbinder Binyamin
Published: September 2010

At the time of the opening of the Tethys Ocean the northern edge of Gondwana was affected by several rifting events. In this study, we used data from deep exploration wells, seismic profiles, and seismic depth maps to reconstruct the pattern of Tethyan rifting in the Levant region and to investigate its effects on the evolution of the Levant crust.

The results show a several hundred kilometre wide deformation zone, comprised of graben and horst structures that extend from the inner part of the Levant to the marine basin offshore Israel. The structures are dominated by sets of NE–SW and NNE–SSW oriented normal faults with vertical offsets in the range of 1–8 km. Rifting was associated with a NW–SE direction of extension, approximately perpendicular to the present-day Mediterranean coast. Faulting activity progressed over a period of 120 Ma and took place in three main pulses: Late Palaeozoic (Carboniferous to Permian); Middle to Late Triassic; and Early to Middle Jurassic. The last, and the most intense, tectonic phase post-dates the activity in other rifted margins of northern Gondwana.

Rifting was associated with the modification and stretching of the Levant crust. Our results demonstrate an extension discrepancy between the brittle deformation in the upper crust and the amount of total crustal thinning. Seismic reflection data shows that the Levant Basin lacks the characteristics of typical rifted margins, either volcanic or non-volcanic. The evolution of the basin may be explained by depth-dependant stretching, associated with the upwelling of divergent mantle flow and removal of lower crustal layers by decoupling along deep detachment faults.
Mechanism of hypoxia-inducible factor 1α-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium
Authors: Bhattacharyya Asima , Chattopadhyay Ranajoy , Hall Emily H. , Mebrahtu Semret T. , Ernst Peter B. , Crowe Sheila E.
Published: September 2010

Hypoxia-inducible factor 1 (HIF1) consists of a hypoxia-inducible α subunit and a constitutively expressed β subunit. Reactive oxygen species (ROS) induced by Helicobacter pylori stabilize HIF1α in the human gastric epithelium in normoxia. HIF1α plays crucial role in carcinogenesis and has been associated with malignant progression of gastric cancer. Several genes contain functional hypoxia-response elements (HREs) in their promoters including Bcl2 family member, Mcl1. Cellular ratios of antiapoptotic oncogenic protein, Mcl1, and tumor suppressor proapoptotic protein, Noxa, determine cell fate by regulating normal cellular growth, cell death and oncogenic processes. The aim of the present study was to examine the mechanism of HIF1α induction in the H. pylori -infected gastric epithelium to better understand disease pathogenesis by H. pylori relevant to gastric carcinogenesis. Our data showed that the dose-dependent increase in HIF1α in H. pylori -infected gastric epithelia is mediated by induction of a ROS-inducible protein, apurinic/apyrimidinic endonuclease 1 (APE1), and an enhanced interaction of APE1 with the transcriptional coactivator p300. Surprisingly, with accumulation of HIF1α, further transcriptional activation of mcl1 was not observed. We identified a HIF-binding site (HBS) in the hif1α promoter and showed that increased HIF1α expression, whether H. pylori -induced or hypoxia-mimetic agent, CoCl2-induced, resulted in enhanced HIF1α binding to its own promoter. This resulted in a transcriptionally inactive hif1α promoter since hif1α HBS lacks HIF ancillary sequence (HAS) required for HIF1 transcriptional activity. We conclude that enhanced binding of “nonfunctional” HIF1α to hif1α promoter and limiting availability of p300 in the cell serves as checkpoints for uncontrolled HIF1α activity.
Appendiceal Mucocele Presenting as a Right Adnexal Mass: A Case Report
Authors: Gortchev Grigor , Tomov Slavcho , Dimitrov Dobromir , Nanev Vasil , Betova Tatyana
Published: September 2010

A 68‐year‐old female presented to the Gynecologic Oncology Clinic with a right‐lower quadrant abdominal mass 3 × 4 cm in diameter palpable on pelvic examination. Her routine laboratory tests were normal. Transvaginal ultrasonography revealed a cystic mass in the right adnexa 3.9 cm in diameter, which was thought to arise in the ovary. At the time of laparoscopy, a 3 × 4 cm tumor arising from the distal end of the appendix was noted. A laparoscopic appendectomy with tumor removal was performed. Histologic examination of the surgical specimen revealed a mucocele of the appendix (AM). Although rare, this tumor should be considered in the differential diagnosis of a right adnexal mass. These tumors can be identified laparoscopically and removed by minimally invasive surgery.
A Case of HELLP Syndrome in a Patient with Immune Thrombocytopenic Purpura
Authors: Ben Sebastián , Rodríguez Fabián , Severo Carlos , Debat Natalia
Published: September 2010

We will describe the clinical case of a pregnant patient with chronic Immune Thrombocytopenic Purpura who develops preeclampsia syndrome with HELLP syndrome. These concomitant and independent conditions become complex, resulting in thrombocytopenia which creates diagnostic, prognostic and therapeutic inconveniences.
Tai Chi Enhances the Effects of Endurance Training in the Rehabilitation of Elderly Patients with Chronic Heart Failure
Authors: Caminiti Giuseppe , Volterrani Maurizio , Marazzi Giuseppe , Cerrito Anna , Massaro Rosalba , Arisi Arianna , Franchini Alessio , Sposato Barbara , Rosano Giuseppe
Published: September 2010

Purpose. To assess if Tai Chi added to endurance training (ET) is more effective than ET alone in improving exercise tolerance and quality of life (QOL) of elderly patients with chronic heart failure (CHF).Design. Sixty CHF patients, age years, M/F 51/9, were enlisted. Thirty pts were randomized to combined training (CT) performing Tai Chi +ET and 30 patients to ET (ET only).Methods. At baseline and after 12 weeks all patients underwent 6-minute walking test (6MWT), assessment of amino terminal probrain natriuretic peptide (NT-pro BNP), quadriceps maximal voluntary contraction (MVC) and peak torque (PT), QOL questionnaire (MacNewQLMI), blood pressure (BP), and heart rate (HR). All patients performed 4 sessions of exercise/week.Results. Distance at 6mwt improved in both groups with significant between-groups differences (). Systolic BP and NT-proBNP decreased significant in the CT group compared to ET () and ), resp.). CT group had a greater significant improvement in physical perception () and a significant increase of PT compared to ET group.Conclusions. The association of Tai Chi and ET improves exercise tolerance and QOL of patients with CHF more efficiently than ET.
PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity
Authors: Zhang Cathy C. , Yan Zhengming , Zhang Qin , Kuszpit Kyle , Zasadny Kenneth , Qiu Ming , Painter Cory L. , Wong Anthony , Kraynov Eugenia , Arango Maria E. , Mehta Pramod P. , Popoff Ian , Casperson Gerald F. , Los Gerrit , Bender Steve , Anderes Kenna , Christensen James G. , VanArsdale Todd
Published: September 2010

Purpose: P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models.

Experimental Design: The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated.

Results: PF-03732010 selectively inhibits P-cadherin–mediated cell adhesion and aggregation in vitro. In the P-cadherin–overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3′-[18F]fluoro-3′-deoxythymidine–positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane β-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3′-[18F]fluoro-3′-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts.

Conclusions: These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials. Clin Cancer Res; 16(21); 5177–88. ©2010 AACR.
Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer
Authors: Lockman Paul R. , Mittapalli Rajendar K. , Taskar Kunal S. , Rudraraju Vinay , Gril Brunilde , Bohn Kaci A. , Adkins Chris E. , Roberts Amanda , Thorsheim Helen R. , Gaasch Julie A. , Huang Suyun , Palmieri Diane , Steeg Patricia S. , Smith Quentin R.
Published: September 2010

Purpose: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood–tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain.

Experimental Design:Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy.

Results: Analysis of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C-paclitaxel and 14C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (∼10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with overexpression of the pericyte protein desmin.

Conclusions: This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. Clin Cancer Res; 16(23); 5664–78. ©2010 AACR.
A MicroRNA Screen to Identify Modulators of Sensitivity to BCL2 Inhibitor ABT-263 (Navitoclax)
Authors: Lam Lloyd T. , Lu Xin , Zhang Haichao , Lesniewski Rick , Rosenberg Saul , Semizarov Dimitri
Published: September 2010

Evasion of apoptosis is a known feature of cancer cells. One mechanism of deregulating the apoptotic pathway is through overexpression of antiapoptotic BCL2 family members. ABT-263 (navitoclax) is a first-in-class BCL2 family inhibitor that restores the ability of cancer cells to undergo apoptosis. However, many cancer cells are resistant to ABT-263 due to high levels of a BCL2 family member, MCL1, which is not targeted by the drug. MCL1 expression is regulated transcriptionally, translationally, and through proteasome-mediated degradation. Recently, MCL1 expression was shown to be affected by microRNAs (miRNA). To identify miRNAs that modulate the sensitivity of cancer cells to ABT-263, we screened a library of 810 human miRNA mimics in HCT-116 cells in the presence of ABT-263. The screen revealed 19 miRNAs that sensitize HCT-116 cells to ABT-263. Fifteen of these miRNAs were also shown to sensitize CHL1 melanoma cells to the same agent. We further evaluated 12 of the strongest sensitizers in these cell lines. We found that these sensitizers induced apoptosis only in the presence of ABT-263. In addition, whereas all 12 of these miRNAs reduced MCL1 protein expression, only 10 of them targeted MCL1 through direct binding to the 3′-untranslated region of the gene, raising the possibility that other resistance regulators of MCL1 expression may be identified using our method. Finally, because sensitizing miRNA expression is lower in tumors compared with normal tissues, our data can facilitate the design of miRNA replacement therapies to increase sensitivity to BCL2 antagonists. Mol Cancer Ther; 9(11); 2943–50. ©2010 AACR.
The Dual Role of Saliva in Oral Carcinogenesis
Authors: Nagler Rafael , Dayan Dan
Published: September 2010

Oral squamous cell carcinoma (OSCC), the most common head and neck malignancy, represents a serious public health problem. Exposure to cigarette smoke (CS)/tobacco is considered responsible for up to 90% of cases of this cancer worldwide. Free radicals, which often originate in CS and reactive nitrogen species, are frequently considered to be the reagents capable of triggering the process leading to malignant transformation. Initially dysplastic lesions of the mucosa are transformed into in situ carcinoma lesions, eventually resulting in a full-blown infiltrating and metastasizing OSCC. A synergistic, deleterious interaction between CS and saliva has been reported, which may result in the rapid destruction of biological macromolecules such as enzymes and proteins, giving it a possible pivotal role in the pathogenesis of OSCC. This lethal synergistic effect of CS and saliva is probably based on the reaction between redox-active metals in saliva and low reactive free radicals in CS. This is a novel concept recognizing that when exposed to CS, salivary behavior is reversed and saliva loses its antioxidant capacity, becoming a potent pro-oxidant milieu.
Pathophysiology of Dyslipidemia in Cushing’s Syndrome
Authors: Arnaldi Giorgio , Scandali Valerio Mattia , Trementino Laura , Cardinaletti Marina , Appolloni Gloria , Boscaro Marco
Published: September 2010

Dyslipidemia seems to be less frequent than other metabolic comorbidities in human Cushing’s syndrome. Nevertheless, it plays an important role in determining the global cardiovascular risk in overt and subclinical Cushing’s syndrome. In Cushing’s syndrome, there is an increase of triglyceride and total cholesterol levels whereas HDL can be at variable levels. Overt and subclinical Cushing’s syndrome share many features with metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia. The pathogenetic mechanisms are multifactorial, including direct and indirect cortisol action on lipolysis, free fatty acid production and turnover, very-low-density lipoprotein synthesis and fatty accumulation in the liver. AMP-activated protein kinase mediates many of glucocorticoid-induced metabolic changes. Insulin resistance plays a key role in determining lipid abnormalities. Other hormonal changes are involved including growth hormone, testosterone in men and estrogen in women, catecholamines and cytokines. In vitro, cortisol increases lipoprotein lipase in adipose tissues and particularly in visceral fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing’s syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk.
Medical Treatment of Cushing’s Syndrome: Adrenal-Blocking Drugs and Ketaconazole
Authors: Feelders Richard A. , Hofland Leo J. , de Herder Wouter W.
Published: September 2010

Cushing’s syndrome is associated with serious morbidity and increased mortality. Irrespective of its cause, i.e. a pituitary adenoma, ectopic ACTH production or an adrenal neoplasia, Cushing’s syndrome is primarily treated surgically. However, when surgery is unsuccessful or contraindicated, medical therapy is needed to treat hypercortisolism. The spectrum of available drugs includes adrenal-blocking agents, neuromodulatory drugs and glucocorticoid receptor antagonists. Adrenal blocking drugs suppress adrenal cortisol production via inhibition of steroidogenic enzymes. Ketoconazole and metyrapone are most frequently used for this purpose, but chronic treatment with these drugs can be limited by side effects like hepatotoxicity (ketoconazole) and increased androgen and mineralocorticoid production (metyrapone). Etomidate can be used to rapidly reverse cortisol excess in patients with acute complications of (severe) hypercortisolism like psychosis. In Cushing’s disease, combination therapy with drugs that target the corticotropic adenoma, i.e. the universal somatostatin analogue pasireotide and/or the dopamine agonist cabergoline, and low-dose ketoconazole seems a rational approach to achieve biochemical control.
Coagulopathy in Cushing’s Syndrome
Authors: Trementino Laura , Arnaldi Giorgio , Appolloni Gloria , Daidone Viviana , Scaroni Carla , Casonato Alessandra , Boscaro Marco
Published: September 2010

A hypercoagulable state and its consequent increased incidence of thromboembolic complications are reported in patients with Cushing’s syndrome (CS). These alterations are related to cortisol excess that induces prothrombotic changes in blood by several and complex mechanisms including increased levels of clotting factors, mainly factor VIII and von Willebrand factor (VWF) and impaired fibrinolytic capacity. However, it has recently been observed that the increase in VWF levels is not a constant feature of CS and that VWF response to glucocorticoids is genetically determined and depends on the presence of particular polymorphisms in the VWF gene promoter. The risk of venous thromboembolism is moreover enhanced in patients with CS by additional endogenous and exogenous risk factors such as obesity, bed rest, surgery and invasive diagnostic procedures like inferior petrosal sinus (IPS) sampling. In line with all these data, patients with active CS should be treated as having a prothrombotic disorder and undergo antithrombotic prophylaxis during IPS sampling. Special care should be taken in the immediate perioperative period in order to avoid thromboembolic events. In the absence of prospective randomized trials, preventive antithrombotic treatment (best with heparin) during IPS sampling and low-dose heparin treatment early after surgery should be suggested.
Clinical Use of Polihexanide on Acute and Chronic Wounds for Antisepsis and Decontamination
Authors: Eberlein T. , Assadian O.
Published: September 2010

Polihexanide is an antimicrobial compound suitable for clinical use in critically colonized or infected acute and chronic wounds. Its beneficial characteristic is attributable particularly to its broad antimicrobial spectrum, good cell and tissue tolerability, ability to bind to the organic matrix, low risk of contact sensitization, and wound healing promoting effect. In addition, no development of microorganism resistance during polihexanide use has been detected to date, nor does this risk appear imminent. The aim of therapy using polihexanide is to reduce the pathogen burden in a critically colonized or infected acute or chronic wound. An increasing number of articles on the subject of wound antisepsis with polihexanide can be found in the medical literature. However, there is still little published information on the practical use of polihexanide-containing wound antiseptics. The purpose of this review article is to describe the handling and the different possibilities of use of polihexanide-containing preparations, including the currently approved indications, contraindications and reservations. The use of polihexanide is not the only therapeutic option in management of wounds; therefore, priority is also given to prior surgical debridement and clarification of the cause of the underlying disease, including appropriate therapy.
No Influence of DTNBP1 Polymorphisms on the Response to Aripiprazole
Authors: Pae Chi-Un , Chiesa Alberto , Mandelli Laura , Serretti Alessandro
Published: September 2010

Aims: The aim of the present study was to investigate pos- sible influences of a panel of markers in the dysbindin gene DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761 and rs2619522) on the clinical outcome and side effects associated to the treatment with aripiprazole in schizophrenic patients. Methods: Efficacy was assessed at baseline and weeks 1, 2, 4, 6 and 8 using the Clinical Global Impression Severity and Improvement Scales, the Brief Psychiatric Rating Scale and the Schedule for the Assessment of Negative Symptoms. Side effects were evaluated by the Simpson-Angus, Barnes Akathisia and Abnormal Involuntary Movement Scales. Multivariate analysis of covariance was used to test possible influences of single nucleotide polymorphisms on clinical and safety scores. Analysis of haplotypes was also performed. Results: No relevant association between DTNBP1 variants and clinical or safety scores was observed. Additionally, haplotype analysis did not reveal any significant association with clinical and safety scores at any time as well. Conclusion: Our data suggest no association between the investigated alleles and genotypes in DTNBP1 and the response to aripiprazole. However, because several limitations characterize the present study, further investigations are required.
Cognitive-Behavioral Self-Help Treatment for Nightmares: A Randomized Controlled Trial
Authors: Lancee Jaap , Spoormaker Victor I. , van den Bout Jan
Published: September 2010

Background: Several cognitive-behavioral techniques are effective in reducing nightmare frequency, but the therapeutic factor (e.g. cognitive restructuring, systematic desensitization) remains unclear. The aim of this study was to compare the nightmare treatments imagery rehearsal therapy (IRT), exposure, and recording (keeping a diary) – in a self-help format – with a waiting list. Methods: Participants were recruited through a Dutch nightmare website. After completion of the baseline questionnaires, 399 participants were randomly assigned to a condition, received a 6-week self-help treatment (or were placed on the waiting list), and filled out the post-treatment measurements 11 weeks after baseline. Results: Compared to the waiting list, IRT and exposure were effective in ameliorating nightmare frequency and distress, subjective sleep quality, anxiety (after imagery rehearsal), and depression (after exposure; Δd = 0.25–0.56). Compared to recording, IRT reduced nightmare frequency while exposure reduced nightmare distress (Δd = 0.20–0.30; p < 0.05). The recording condition was more effective compared to the waiting list in ameliorating nightmare frequency, nightmare distress, and subjective sleep quality (Δd = 0.19–0.28; p < 0.05). IRT had a more rapid reduction on the diary compared to exposure and recording. Conclusions: IRT and exposure appear equally effective in ameliorating nightmare complaints. Exposure to nightmare imagery may function as the crucial therapeutic factor; however, cognitive restructuring may be a useful addition to increase immediate effects.
Increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and colorectal adenocarcinoma determined by a newly developed ELISA using a specific monoclonal antibody
Authors: Ordóñez Adriana , Yélamos Jose , Pedersen Shona , Miñano Antonia , Conesa-Zamora Pablo , Kristensen Soren R. , Stender Mogens T. , Thorlacius-Ussing Ole , Martínez-Martínez Irene , Vicente Vicente , Corral Javier
Published: September 2010

Citrullination is a post-translational modification that plays essential roles in both physiological processes and disease. Recent studies have found increased levels of citrullinated antithrombin in patients with rheumatoid arthritis and in different malignant tumours. Antithrombin, the main haemostatic serpin, loses its anticoagulant function via citrullination, which might contribute to the pathogenesis or thrombotic side effects of these disorders. We have developed a specific monoclonal antibody against citrullinated antithrombin. We determined the levels of citrullinated antithrombin and anti-FXa activity in plasma from 66 donors, 17 patients with rheumatoid arthritis and 77 patients with colorectal adenocarcinoma (42 suffering from venous thrombosis). Healthy subjects had negligible amounts of citrullinated antithrombin in plasma (7.9 ± 22.1 ng/ml), while it significantly increased in patients with rheumatoid arthritis or adenocarcinoma (159.7 ± 237.6 ng/ml and 36.8 ± 66.1 ng/ml), levels that, however, did not modify the plasma anticoagulant activity. Moreover, we did not find association between citrullinated antithrombin and the thrombotic risk in patients with adenocarcinoma. In conclusion, we have developed an antibody specific for citrullinated antithrombin that allows its quantification in biological samples, offering a new tool for the analysis of citrullination in different diseases. We confirm increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and adenocarcinoma. This modification, probably local, could have pathological consequences in both disorders, but only affects a minor fraction of plasma antithrombin, resulting in no significant reduction of global anticoagulant activity. This result explains the absence of association of this marker with an increased risk of thrombosis in patients with colorectal adenocarcinoma.
The Relationship Between Plasma Angiopoietin-like Protein 4 Levels, Angiopoietin-like Protein 4 Genotype, and Coronary Heart Disease Risk
Authors: Smart-Halajko Melissa C. , Robciuc Marius R. , Cooper Jackie A. , Jauhiainen Matti , Kumari Meena , Kivimaki Mika , Khaw Kay-Tee , Boekholdt S. Matthijs , Wareham Nicholas J. , Gaunt Tom R. , Day Ian N. , Braund Peter S. , Nelson Christopher P. , Hall Alistair S. , Samani Nilesh J. , Humphries Steve E. , Ehnholm Christian , Talmud Philippa J.
Published: September 2010

Objective—

To investigate the relationship between angiopoietin-like protein 4 (Angptl4) levels, coronary heart disease (CHD) biomarkers, and
ANGPTL4
variants.

Methods and Results—

Plasma Angptl4 was quantified in 666 subjects of the Northwick Park Heart Study II using a validated ELISA. Seven
ANGPTL4
single-nucleotide polymorphisms were genotyped, and CHD biomarkers were assessed in the whole cohort (N=2775). Weighted mean±SD plasma Angptl4 levels were 10.0±11.0 ng/mL. Plasma Angptl4 concentration correlated positively with age (
r
=0.15,
P
<0.001) and body fat mass (
r
=0.19,
P
=0.003) but negatively with plasma high-density lipoprotein cholesterol (
r
=−0.13,
P
=0.01). No correlation with triglycerides (TGs) was observed. T266M was independently associated with plasma Angptl4 levels (
P
<0.001) but was not associated with TGs or CHD risk in the meta-analysis of 5 studies (4061 cases/15 395 controls). E40K showed no independent association with plasma Angptl4 levels. In human embryonic kidney 293 and human hepatoma 7 cells compared with wild type, E40K and T266M showed significantly altered synthesis and secretion, respectively.

Conclusion—

Circulating Angptl4 levels may not influence TG levels or CHD risk for the following reasons: (1) Angptl4 levels were not correlated with TGs; (2) T266M, although associated with Angptl4 levels, showed no association with plasma TGs; and (3) TG-lowering E40K did not influence Angptl4 levels. These results provide new insights into the role of Angptl4 in TG metabolism.