bluuebunny/crossref_metadata_2025 huggingface dataset:
Appropriate clinical use of blood in Uganda
Authors: Kajja I.
Published: May 2013

The Uganda Blood Transfusion Services, in line with the requirements for the minimum health care package of Uganda, has made tremendous strides in improving the adequacy and quality on blood supply to hospitals and health center that administer blood. This is mainly due to the extensive technical and financial support to the procurement and processing components of the transfusion chain. Unfortunately these efforts have not been reciprocated at the in‐hospital setting. This is characterized by underdeveloped administrative structures catering for blood transfusion like lack of a hospital transfusion policy which has lead to paucity of instructive procedures, monitoring and evaluation as well as defined persons responsible for in‐hospital transfusion quality assurance. Additionally, documentation of what is to be or what has been done is still under‐developed.

As a way of improvement, a step‐by‐step quality improvement strategy should be developed. First, a small working group of clinicians, laboratory technicians and administrators should be created to design the policy and strategies (blood transfusion plan) for clinical use of blood. Second, start creating Hospital Transfusion Committees with appropriate terms of reference. These should be supported by the hospital high authority. Third, design simple education materials for the three major in‐hospital transfusion processes and identified procedures, with their respective standard operating procedures (SOPs) and related outcome documents like a Blood Request Form (ordering, component selection and administration). Disseminate these materials through continuous professional trainings for in‐service staff and curriculum reviews for medical and paramedical schools. Fifth, embark on updating the National Transfusion Policy to embrace and support the development of National clinical standards and guidelines. These steps will be achieved when the concept of quality assurance is formally and philosophically incorporated into the structure and functioning of Uganda's health systems, consistently implemented, and supported by a culture of quality, as reflected in organizational values and policies that advocate quality of care.
The Effectiveness of Coxiella burnetii Vaccines in Occupationally Exposed Populations: A Systematic Review and Meta‐Analysis
Authors: O'Neill T. J. , Sargeant J. M. , Poljak Z.
Published: May 2013

To estimate the effect of vaccination in preventing acute Q fever in individuals occupationally exposed to Coxiella burnetii, a systematic review and meta‐analysis were undertaken in controlled trials and observational studies. Publications were obtained through a scoping study of English and non‐English articles, and those reporting a commercially licensed or licensable vaccine compared with an unvaccinated or placebo control group were included in the review. Two authors performed independent assessment of risk of systematic error and data extraction. One controlled trial and five cohort publications met the inclusion criteria. All trials used a Henzerling phase I vaccine. A random‐effects meta‐analysis estimated significant protection in abattoir workers (RR = 0.07; 95% confidence interval [CI] 0.02–0.22) compared with the control individuals. In individuals with rare or sporadic contact with the abattoir, a significant benefit of vaccination was also found (RR = 0.06; 95% CI 0–0.93). Overall, the vaccine effectively prevented acute Q fever in individuals responsible for handling animals or their products and those working in the abattoir but not directly exposed to animals (RR = 0.06; 95% CI 0.02–0.18). Caution must be taken when interpreting the effect of C. burnetii vaccination as significant heterogeneity amongst publications was observed. A meta‐regression found no significant univariate associations. This may reflect the uncertainty provided by reported data in the cohort publications. Potential systematic biases were present in the publications, and evidence included may not be sufficiently robust to extrapolate the effect of vaccination on occupationally exposed groups beyond the population of abattoir employees in Australia where all included studies occurred.
Numerical Stability Analysis of Linear Incommensurate Fractional Order Systems
Authors: Das Sambit , Chatterjee Anindya
Published: May 2013

We present a method for detecting right half plane (RHP) roots of fractional order polynomials. It is based on a Nyquist-like criterion with a system-dependent contour which includes all RHP roots. We numerically count the number of origin encirclements of the mapped contour to determine the number of RHP roots. The method is implemented in Matlab, and a simple code is given. For validation, we use a Galerkin based strategy, which numerically computes system eigenvalues (Matlab code is given). We discuss how, unlike integer order polynomials, fractional order polynomials can sometimes have exponentially large roots. For computing such roots we suggest using asymptotics, which provide intuition but require human inputs (several examples are given).
Microscopic Matrix Remodeling Precedes Endothelial Morphological Changes During Capillary Morphogenesis
Authors: McLeod Claire , Higgins John , Miroshnikova Yekaterina , Liu Rachel , Garrett Aliesha , Sarang-Sieminski Alisha L.
Published: May 2013

The formation of microvascular networks (MVNs) is influenced by many aspects of the microenvironment, including soluble and insoluble biochemical factors and the biophysical properties of the surrounding matrix. It has also become clear that a dynamic and reciprocal interaction between the matrix and cells influences cell behavior. In particular, local matrix remodeling may play a role in driving cellular behaviors, such as MVN formation. In order to explore the role of matrix remodeling, an in vitro model of MVN formation involving suspending human umbilical vein endothelial cells within collagen hydrogels was used. The resulting cell and matrix morphology were microscopically observed and quantitative metrics of MVN formation and collagen gathering were applied to the resulting images. The macroscopic compaction of collagen gels correlates with the extent of MVN formation in gels of different stiffness values, with compaction preceding elongation leading to MVN formation. Furthermore, the microscopic analysis of collagen between cells at early timepoints demonstrates the alignment and gathering of collagen between individual adjacent cells. The results presented are consistent with the hypothesis that endothelial cells need to gather and align collagen between them as an early step in MVN formation.
Global Bifurcations of Mean Electric Field in Plasma L–H Transition Under External Bounded Noise Excitation
Authors: Nono Dueyou Buckjohn C. , Siewe Siewe M. , Tchawoua C. , Kofane T. C.
Published: May 2013

In this paper, global bifurcations and chaotic dynamics under bounded noise perturbation for the nonlinear normalized radial electric field near plasma are investigated using the Melnikov method. From this analysis, we get criteria that could be useful for designing the model parameters so that the appearance of chaos could be induced (when heating particles) or run out for quiescent H-mode appearance. For this purpose, we use a test of chaos to verify our prediction. We find that, chaos could be enhanced by noise amplitude growing. The results of numerical simulations also reveal that noise intensity modifies the attractor size through power spectra, correlation function, and Poincaré map. The criterion from the Melnikov method which is used to analytically predict the existence of chaotic behavior of the normalized radial electric field in plasma could be a valid tool for predicting harmful parameters values involved in experiment on Tokamak L–H transition.
Mechanics and Validation of an in Vivo Device to Apply Torsional Loading to Caudal Vertebrae
Authors: Rizza Robert , Liu XueCheng
Published: May 2013

Axial loading of vertebral bodies has been shown to modulate growth. Longitudinal growth of the vertebral body is impaired by compressive forces while growth is stimulated by distraction. Investigations of torsional loading on the growth plate in the literature are few. The purposes of this study were two-fold: (1) to develop a torque device to apply torsional loads on caudal vertebrae and (2) investigate numerically and in vivo the feasibility of the application of the torque on the growth plate. A controllable torque device was developed and validated in the laboratory. A finite element study was implemented to examine mechanically the deformation of the growth plate and disk. A rat tail model was used with six 5-week-old male Sprague-Dawley rats. Three rats received a static torsional load, and three rats received no torque and served as sham control rats. A histological study was undertaken to investigate possible morphological changes in the growth plate, disk, and caudal bone. The device successfully applied a controlled torsional load to the caudal vertebrae. The limited study using finite element analysis (FEA) and histology demonstrated that applied torque increased lateral disk height and increased disk width. The study also found that the growth plate height increased, and the width decreased as well as a curved displacement of the growth plate. No significant changes were observed from the in vivo study in the bone. The torsional device does apply controlled torque and is well tolerated by the animal. This study with limited samples appears to result in morphological changes in the growth plate and disk. The use of this device to further investigate changes in the disk and growth plate is feasible.
Patterns of Femoral Cartilage Thickness are Different in Asymptomatic and Osteoarthritic Knees and Can be Used to Detect Disease-Related Differences Between Samples
Authors: Favre Julien , Scanlan Sean F. , Erhart-Hledik Jenifer C. , Blazek Katerina , Andriacchi Thomas P.
Published: May 2013

Measures of mean cartilage thickness over predefined regions in the femoral plate using magnetic resonance imaging have provided important insights into the characteristics of knee osteoarthritis (OA), however, this quantification method suffers from the limited ability to detect OA-related differences between knees and loses potentially important information regarding spatial variations in cartilage thickness. The objectives of this study were to develop a new method for analyzing patterns of femoral cartilage thickness and to test the following hypotheses: (1) asymptomatic knees have similar thickness patterns, (2) thickness patterns differ with knee OA, and (3) thickness patterns are more sensitive than mean thicknesses to differences between OA conditions. Bi-orthogonal thickness patterns were extracted from thickness maps of segmented magnetic resonance images in the medial, lateral, and trochlea compartments. Fifty asymptomatic knees were used to develop the method and establish reference asymptomatic patterns. Another subgroup of 20 asymptomatic knees and three subgroups of 20 OA knees each with a Kellgren/Lawrence grade (KLG) of 1, 2, and 3, respectively, were selected for hypotheses testing. The thickness patterns were similar between asymptomatic knees (coefficient of multiple determination between 0.8 and 0.9). The thickness pattern alterations, i.e., the differences between the thickness patterns of an individual knee and reference asymptomatic thickness patterns, increased with increasing OA severity (Kendall correlation between 0.23 and 0.47) and KLG 2 and 3 knees had significantly larger thickness pattern alterations than asymptomatic knees in the three compartments. On average, the number of significant differences detected between the four subgroups was 4.5 times greater with thickness pattern alterations than mean thicknesses. The increase was particularly marked in the medial compartment, where the number of significant differences between subgroups was 10 times greater with thickness pattern alterations than mean thickness measurements. Asymptomatic knees had characteristic regional thickness patterns and these patterns were different in medial OA knees. Assessing the thickness patterns, which account for the spatial variations in cartilage thickness and capture both cartilage thinning and swelling, could enhance the capacity to detect OA-related differences between knees.
Rapid Sliding Contact in Three-Dimensional by an Ellipsoidal Die on Transversely Isotropic Half-Spaces With Surfaces on Different Principal Planes
Authors: Brock L. M.
Published: May 2013

A rigid ellipsoidal die slides on the surfaces of transversely isotropic half-spaces. In one case the material symmetry axis coincides with the half-space surface normal. In the other, the axis lies in the plane of the surface. In both cases sliding proceeds with constant sub-critical speed along a straight path at an arbitrary angle to the principal material axes. A three-dimensional dynamic steady state is considered, i.e., the contact zone surface must conform to the die profile and contact zone traction remains constant in the frame of the die. Exact solutions for contact zone traction are derived in analytic form, as well as formulas for contact zone geometry. Symmetry need not be assumed in the solution process. Anisotropy is found to largely determine zone shape at low sliding speed, but the direction of sliding can become a major influence at higher sliding speeds. Cartesian coordinates are used in the analysis, but introduction of quasi-polar coordinates allows problem reduction to a Cauchy singular integral equation.
Solving the Mascon Mystery
Authors: Montesi Laurent G. J.
Published: May 2013

Modeling the formation of regions of mass concentration may lead to new estimates of early heat flux in the Moon.

[Also see Report by

Melosh
et al.

]
Direct Imaging of Covalent Bond Structure in Single-Molecule Chemical Reactions
Authors: de Oteyza Dimas G. , Gorman Patrick , Chen Yen-Chia , Wickenburg Sebastian , Riss Alexander , Mowbray Duncan J. , Etkin Grisha , Pedramrazi Zahra , Tsai Hsin-Zon , Rubio Angel , Crommie Michael F. , Fischer Felix R.
Published: May 2013

Watching Organic Reactions

Single-molecule studies can overcome the difficulty of inferring the various outcomes of reactions in ensemble measurements.

De Oteyza
et al.

(p.
1434
, published online 30 May; see the Perspective by

Giessibl

) used a variation of noncontact atomic force microscopy in which the imaging tip was derivatized with a single CO molecule to obtain subnanometer-resolution images of conjugated organic molecules undergoing reaction on a silver surface. Different thermally induced cyclization reactions of oligo- (phenylene-1,2-ethynylenes) were observed.
Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies
Authors: Weiskopf Kipp , Ring Aaron M. , Ho Chia Chi M. , Volkmer Jens-Peter , Levin Aron M. , Volkmer Anne Kathrin , Özkan Engin , Fernhoff Nathaniel B. , van de Rijn Matt , Weissman Irving L. , Garcia K. Christopher
Published: May 2013

Immunotherapy Packs a One-Two Punch

Despite the immune system's best efforts, cancer always seems to be one step ahead. One example of this is that tumor cells express CD47 on their cell surface. CD47 acts as a “don't eat me” signal to phagocytic macrophages. A potential therapeutic strategy could thus be to block this signal.

Weiskopf
et al.

(p.
88
, published online 30 May; see the Perspective by

Kershaw and Smyth

) created variants of the CD47 receptor, SIRPα, that could act as high-affinity antagonists of CD47. Although the antagonists blocked CD47 effectively in tumor-bearing mice, on their own they did not induce macrophages to phagocytose the tumor cells. When paired with a variety of therapeutic antitumor antibodies, however, the CD47 antagonists were very effective in treating several mouse tumor models.
Draft Genome Sequence of Dematiaceous Coelomycete
Pyrenochaeta
sp. Strain UM 256, Isolated from Skin Scraping
Authors: Yew Su Mei , Chan Chai Ling , Soo-Hoo Tuck Soon , Na Shiang Ling , Ong Seong Siang , Hassan Hamimah , Ngeow Yun Fong , Hoh Chee Choong , Lee Kok Wei , Yee Wai Yan , Ng Kee Peng
Published: May 2013

Pyrenochaeta
, classified under the order
Pleosporales
, is known to cause diseases in plants and humans. Here, we report a draft genome sequence of a
Pyrenochaeta
sp. isolated from a skin scraping, with an estimated genome size of 39.4 Mb. Genes associated with the synthesis of proteases, toxins, plant cell wall degradation, and multidrug resistance were found.
Complete Genome Sequence of
Pseudomonas denitrificans
ATCC 13867
Authors: Ainala Satish Kumar , Somasundar Ashok , Park Sunghoon
Published: May 2013

Pseudomonas denitrificans
ATCC 13867, a Gram-negative facultative anaerobic bacterium, is known to produce vitamin B
12
under aerobic conditions. This paper reports the annotated whole-genome sequence of the circular chromosome of this organism.
Draft Genome Sequence of an Escherichia coli O157:H43 Strain Isolated from Cattle
Authors: Sváb Domonkos , Horváth Balázs , Szűcs Attila , Maróti Gergely , Tóth István
Published: May 2013

Here we report the draft genome sequence of an
Escherichia coli
O157:H43 strain, designated T22, with an atypical virulence gene profile and isolated from healthy cattle. T22 produces cytolethal distending toxin V (CDT-V) and belongs to phylogenetic group B1 and sequence type 155 (ST155).
Draft Genome Sequence of a Thermophilic Member of the
Bacillaceae
, Anoxybacillus flavithermus Strain Kn10, Isolated from the Kan-nawa Hot Spring in Japan
Authors: Matsutani Minenosuke , Shirakihara Yasuo , Imada Katsumi , Yakushi Toshiharu , Matsushita Kazunobu
Published: May 2013

Here, we report the draft genome sequence of the
Anoxybacillus flavithermus
Kn10 strain (NBRC 109594), isolated from a water drain of the Kan-nawa Hot Spring in Japan. The draft genome sequence is composed of 90 contigs for 2,772,624 bp with 41.6% G+C content and contains 2,883 protein-coding genes and 80 tRNA genes.
Characteristics of central lesions in patients with dizziness determined by diffusion MRI in the emergency department
Authors: Lee Dong Hwan , Kim Won Young , Shim Byoung Soo , Kim Tae Su , Ahn Joong Ho , Chung Jong Woo , Yoon Tae Hyun , Park Hong Ju
Published: May 2013

Background

To describe the rate and risk factors of central lesions among patients with dizziness in the emergency department based on diffusion-weighted MRI, which otologists consulted for evaluation of patients with dizziness need to know.

Methods

902 Consecutive patients who presented with dizziness symptoms as a chief complaint in the emergency department (ED) of our tertiary referral centre between January 2011 and June 2011 were studied. Central lesions were confirmed by diffusion-weighted MRI. Univariate and multivariate analyses were used for factors predictive of central lesions.

Results

Of 645 patients who underwent MRI, 23 (3.6%) had acute central lesions (22 infarcts/1 haemorrhage). Univariate analyses revealed that older age, hypertension, atrial fibrillation, non-whirling type of dizziness symptoms and combined neurological symptoms were significantly associated with the development of central lesions (p<0.05). The incidence of central lesions in patients aged in their 40s, 50s, 60s, 70s and ≥80s was 0, 3.9%, 3.4%, 7.4% and 16.7%. Multivariate analyses showed that hypertension (p=0.01, OR=3.42), symptoms of non-whirling type (p=0.03, OR=3.12) and combined neurological symptoms (p<0.01, OR=16.72) were independent predictors of central lesions.

Conclusions

Although dizziness in the ED is generally benign, the prevalence of acute central lesions was 3.6% among 645 patients with dizziness who underwent MRI. Old age (>50 years), hypertension, non-whirling type of dizziness symptoms and associated neurological symptoms were significant risk factors for central lesions.
Correlation between the expression of Id-1 and hyperthermia-associated molecules in oral squamous cell carcinoma
Authors: Zhao Jun , Wang Shengzhi , Liu Na , Tang Xiufa
Published: May 2013

Objective

To investigate the expression of inhibitor of differentiation/DNA binding (Id-1), phosphatidylinositol-3-kinase/protein kinase B pathway proteins and hyperthermia-associated protein and their association with various clinicopathological factors in oral squamous cell cancer (OSCC), and explore the relationship among them in OSCC.

Methods

Id-1, phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase 3β (p-GSK3β) and phosphorylated heat shock factor 1 (p-HSF1) expression were assessed immunohistochemically in 76 OSCC.

Results

Id-1 (73.8%), p-Akt (65.8%), p-GSK3β (60.5%) and p-HSF1 (75%) were found to be overexpressed in most of the oral cancer samples tested, and the expressions of them are correlated with advanced clinical stage, metastasis and recurrence (p<0.01), but there is no apparent relationship with gender, age, differentiation and habits (p>0.05). Survival curves show that the survival of patients with high Id-1, p-Akt, p-GSK3β and p-HSF1 expression was significantly worse than those with low Id-1, p-Akt, p-GSK3β and p-HSF1 expression (p=0.000). Id-1 expression was significantly higher in cases with high expression of p-Akt, p-GSK3β and p-HSF1 than in those with low expression (p=0.002, p=0.003, p=0.001).

Conclusions

This study revealed that there was a positive correlation between Id-1 expression and the expression of p-Akt, p-GSK3β and p-HSF1. The inhibition of Id-1 expression can improve the efficacy of hyperthermia in OSCC.
THE ENTANGLED QUANTUM HEAT ENGINE IN THE VARIOUS HEISENBERG MODELS FOR A TWO-QUBIT SYSTEM
Authors: ALBAYRAK ERHAN
Published: May 2013

The four-level entangled quantum heat engine (QHE) is analyzed in the various Heisenberg models for a two-qubit. The QHE is examined for the XX, XXX and XXZ Heisenberg models by introducing a parameter x which controls the strength of the exchange parameter Jz = xJ along the z-axis with respect to the ones along the x- and y-axes, i.e. Jx = Jy = J, respectively. It is assumed that the two-qubit is entangled and in contact with two heat reservoirs at different temperatures and under the effect of a constant magnetic field. The concurrences (C) are used as a measure of entanglement and then the expressions for the amount of heat transferred, the work performed and the efficiency of the QHE are derived. The contour, i.e. the isoline maps, and some two-dimensional plots of the above mentioned thermodynamic quantities are calculated and some interesting features are found.
MY IDEA IS OUR IDEA! SUPPORTING USER-DRIVEN INNOVATION ACTIVITIES IN CROWDSOURCING COMMUNITIES
Authors: KOSONEN MIIA , GAN CHUNMEI , OLANDER HEIDI , BLOMQVIST KIRSIMARJA
Published: May 2013

There is a growing stream of research unraveling individual motivations to participate in idea crowdsourcing and online user communities. While the current research has largely focused on individual user characteristics and overlooked the features of surrounding communities, our research turns the focus onto the actual community where knowledge is shared and created. We investigate the relationships between perceived support from a crowdsourcing community, and the users' intentions to share knowledge. Our research is based on a survey of 241 Chinese users of IdeasProject and shows that (1) for community trust, trust in the hosting firm has a significant effect on knowledge-sharing intentions, while collaborative norms do not; (2) for community support, both technology-based support and knowledge-based support have an effect on knowledge-sharing intentions. From a community management viewpoint, our results demonstrate the importance of providing continued support for knowledge integration, such as more opportunities for user-to-user interaction and features for providing constructive feedback.
Influence of source materials and fractionating assemblage on magmatism along the Aegean Arc, and implications for crustal growth
Authors: Elburg Marlina A. , Smet Ingrid , De Pelsmaeker Elien
Published: May 2013

Volcanic products from Methana, Santorini and Nisyros show mineralogical and geochemical characteristics that can be linked to their differentiation at different crustal levels, and varying sources of subducted sediments. The products from Methana, in the western part of the arc, where the overriding plate is thicker, are affected by amphibole fractionation and crustal contamination. Santorini volcano, in the central part of the arc, is located on an extensively thinned section of the overriding plate; it shows high Y-contents, a-typical for average continental crust. Crustal contamination is minor, similar to Nisyros volcano. Products of the latter, easternmost volcanic centre have been variably affected by amphibole fractionation. Its sub-arc magma source is different from the central and western part of the arc, reflecting sedimentary input from the Nile.

Amphibole fractionation, caused by crystallization at greater depths, seems necessary to lower Y-contents and yield volcanic products that resemble average continental crust in this respect. In detail, however, none of the magmatic products of the Aegean Arc displays MREE–HREE patterns or levels of compatible elements that are an exact match for average continental crust. Garnet stability and mixing processes appear crucial to obtain the REE and compatible element characteristics of continental crust.
Impact of stent mis-sizing and mis-positioning on coronary fluid wall shear and intramural stress
Authors: Chen Henry Y. , Koo Bon-Kwon , Bhatt Deepak L. , Kassab Ghassan S.
Published: May 2013

Stent deployments with geographical miss (GM) are associated with increased risk of target-vessel revascularization and periprocedural myocardial infarction. The aim of the current study was to investigate the underlying biomechanical mechanisms for adverse events with GM. The hypothesis is that stent deployment with GM [longitudinal GM, or LGM (i.e., stent not centered on the lesion); or radial GM, RGM (i.e., stent oversizing)] results in unfavorable fluid wall shear stress (WSS), WSS gradient (WSSG), oscillatory shear index (OSI), and intramural circumferential wall stress (CWS). Three-dimensional computational models of stents and plaque were created using a computer-assisted design package. The models were then solved with validated finite element and computational fluid dynamic packages. The dynamic process of large deformation stent deployment was modeled to expand the stent to the desired vessel size. Stent deployed with GM resulted in a 45% increase in vessel CWS compared with stents that were centered and fully covered the lesion. A 20% oversized stent resulted in 72% higher CWS than a correct sized stent. The linkages between the struts had much higher stress than the main struts (i.e., 180 MPa vs. 80 MPa). Additionally, LGM and RGM reduced endothelial WSS and increased WSSG and OSI. The simulations suggest that both LGM and RGM adversely reduce WSS but increase WSSG, OSI, and CWS. These findings highlight the potential mechanical mechanism of the higher adverse events and underscore the importance of stent positioning and sizing for improved clinical outcome.
Obesity accentuates circadian variability in breathing during sleep in mice but does not predispose to apnea
Authors: Davis Eric M. , Locke Landon W. , McDowell Angela L. , Strollo Patrick J. , O'Donnell Christopher P.
Published: May 2013

Obesity is a primary risk factor for the development of obstructive sleep apnea in humans, but the impact of obesity on central sleep apnea is less clear. Given the comorbidities associated with obesity in humans, we developed techniques for long-term recording of diaphragmatic EMG activity and polysomnography in obese mice to assess breathing patterns during sleep and to determine the effect of obesity on apnea generation. We hypothesized that genetically obese ob/ob mice would exhibit less variability in breathing across the 24-h circadian cycle, be more prone to central apneas, and be more likely to exhibit patterns of increased diaphragm muscle activity consistent with obstructive apneas compared with lean mice. Unexpectedly, we found that obese mice exhibited a greater circadian impact on respiratory rate and diaphragmatic burst amplitude than lean mice, particularly during rapid eye movement (REM) sleep. Central apneas were more common in REM sleep (42 ± 17 h−1) than non-REM (NREM) sleep (14 ± 5 h−1) in obese mice ( P < 0.05), but rates were not different between lean and obese mice in either sleep state. Even after experimentally enhancing central apnea generation by acute withdrawal of hypoxic chemoreceptor activation during sleep, central apnea rates remained comparable between lean and obese mice. Last, we were unable to detect patterns of diaphragmatic burst activity suggestive of obstructive apnea events in obese mice. In summary, obesity does not predispose mice to increased occurrence of central or obstructive apneas during sleep, but does lead to a more pronounced circadian variability in respiration.
Novel Recombinant Human B7-H4 Antibodies Overcome Tumoral Immune Escape to Potentiate T-Cell Antitumor Responses
Authors: Dangaj Denarda , Lanitis Evripidis , Zhao Aizhi , Joshi Shree , Cheng Yi , Sandaltzopoulos Raphael , Ra Hyun-Jeong , Danet-Desnoyers Gwenn , Powell Daniel J. , Scholler Nathalie
Published: May 2013

B7-H4 (VTCN1, B7x, B7s) is a ligand for inhibitory coreceptors on T cells implicated in antigenic tolerization. B7-H4 is expressed by tumor cells and tumor-associated macrophages (TAM), but its potential contributions to tumoral immune escape and therapeutic targeting have been less studied. To interrogate B7-H4 expression on tumor cells, we analyzed fresh primary ovarian cancer cells collected from patient ascites and solid tumors, and established cell lines before and after in vivo passaging. B7-H4 expression was detected on the surface of all fresh primary human tumors and tumor xenotransplants, but not on most established cell lines, and B7-H4 was lost rapidly by tumor xenograft cells after short-term in vitro culture. These results indicated an in vivo requirement for B7-H4 induction and defined conditions for targeting studies. To generate anti-B7-H4–targeting reagents, we isolated antibodies by differential cell screening of a yeast-display single-chain fragments variable (scFv) library derived from patients with ovarian cancer. We identified anti-B7-H4 scFv that reversed in vitro inhibition of CD3-stimulated T cells by B7-H4 protein. Notably, these reagents rescued tumor antigen-specific T-cell activation, which was otherwise inhibited by coculture with antigen-loaded B7-H4+ APCs, B7-H4+ tumor cells, or B7-H4- tumor cells mixed with B7-H4+ TAMs; peritoneal administration of anti-B7-H4 scFv delayed the growth of established tumors. Together, our findings showed that cell surface expression of B7-H4 occurs only in tumors in vivo and that antibody binding of B7-H4 could restore antitumor T-cell responses. We suggest that blocking of B7-H4/B7-H4 ligand interactions may represent a feasible therapeutic strategy for ovarian cancer. Cancer Res; 73(15); 4820–9. ©2013 AACR.
PML-RARα and Its Phosphorylation Regulate PML Oligomerization and HIPK2 Stability
Authors: Shima Yutaka , Honma Yuki , Kitabayashi Issay
Published: May 2013

The PML gene is frequently fused to the retinoic acid receptor α (RARα) gene in acute promyelocytic leukemia (APL), generating a characteristic PML-RARα oncogenic chimera. PML-RARα disrupts the discrete nuclear speckles termed nuclear bodies, which are formed in PML, suggesting that nuclear body disruption is involved in leukemogenesis. Nuclear body formation that relies upon PML oligomerization and its stabilization of the hypoxia-inducible protein kinase (HIPK)-2 is disrupted by expression of the PML-RARα chimera. Here, we report that disruption of nuclear bodies is also mediated by PML-RARα inhibition of PML oligomerization. PKA-mediated phosphorylation of PML-RARα blocked its ability to inhibit PML oligomerization and destabilize HIPK2. Our results establish that both PML oligomerization and HIPK2 stabilization at nuclear bodies are important for APL cell differentiation, offering insights into the basis for the most common prodifferentiation therapies of APL used clinically. Cancer Res; 73(14); 4278–88. ©2013 AACR.
HMGA2 Is a Driver of Tumor Metastasis
Authors: Morishita Asahiro , Zaidi M. Raza , Mitoro Akira , Sankarasharma Devipriya , Szabolcs Matthias , Okada Yasunori , D'Armiento Jeanine , Chada Kiran
Published: May 2013

The non-histone chromatin-binding protein HMGA2 is expressed predominantly in the mesenchyme before its differentiation, but it is also expressed in tumors of epithelial origin. Ectopic expression of HMGA2 in epithelial cells induces epithelial–mesenchymal transition (EMT), which has been implicated in the acquisition of metastatic characters in tumor cells. However, little is known about in vivo modulation of HMGA2 and its effector functions in tumor metastasis. Here, we report that HMGA2 loss of function in a mouse model of cancer reduces tumor multiplicity. HMGA2-positive cells were identified at the invasive front of human and mouse tumors. In addition, in a mouse allograft model, HMGA2 overexpression converted nonmetastatic 4TO7 breast cancer cells to metastatic cells that homed specifically to liver. Interestingly, expression of HMGA2 enhanced TGFβ signaling by activating expression of the TGFβ type II receptor, which also localized to the invasive front of tumors. Together our results argued that HMGA2 plays a critical role in EMT by activating the TGFβ signaling pathway, thereby inducing invasion and metastasis of human epithelial cancers. Cancer Res; 73(14); 4289–99. ©2013 AACR.
Antitumor Activity of a Humanized, Bivalent Immunotoxin Targeting Fn14-Positive Solid Tumors
Authors: Zhou Hong , Hittelman Walter N. , Yagita Hideo , Cheung Lawrence H. , Martin Stuart S. , Winkles Jeffrey A. , Rosenblum Michael G.
Published: May 2013

The TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) receptor Fn14 (TNFRSF12A) is expressed at low levels in normal tissues but frequently highly expressed in a wide range of tumor types such as lung, melanoma, and breast, and therefore it is a potentially unique therapeutic target for these diverse tumor types. We have generated a recombinant protein containing a humanized, dimeric single-chain anti–fibroblast growth factor-inducible 14-kDa protein (Fn14) antibody fused to recombinant gelonin toxin as a potential therapeutic agent (designated hSGZ). The hSGZ immunotoxin is a highly potent and selective agent that kills Fn14-positive (Fn14+) tumor cells in vitro. Treatment of cells expressing the MDR protein MDR1 (ABCB1B) showed no cross-resistance to hSGZ. Induced overexpression of Fn14 levels in MCF7 cells through HER2 (ERBB2) signaling translated to an improved therapeutic index of hSGZ treatment. In combination with trastuzumab, hSGZ showed an additive or synergistic cytotoxic effect on HER2+/Fn14+ breast cancer cell lines. Also, hSGZ treatment inhibited Erb3/Akt signaling in HER2-overexpressing breast cancer cells. Pharmacokinetic studies in mice revealed that hSGZ exhibited a biexponential clearance from plasma with a rapid initial clearance (t1/2α = 1.26 hours) followed by a seven-fold longer plasma half-life (t1/2β = 7.29 hours). At 24, 48, and 72 hours after injection, uptake of the hSGZ into tumors was 5.1, 4.8, and 4.7%ID/g, with a tumor-to-muscle ratio of 5.6, 6.2, and 9.0, respectively. Therapeutic efficacy studies showed significant tumor inhibition effects using an MDA-MB-231/Luc breast cancer xenograft model. Our findings show that hSGZ is an effective anticancer agent and a potential candidate for clinical studies. Cancer Res; 73(14); 4439–50. ©2013 AACR.
TRAF6 Upregulates Expression of HIF-1α and Promotes Tumor Angiogenesis
Authors: Sun Heng , Li Xue-Bing , Meng Ya , Fan Li , Li Min , Fang Jing
Published: May 2013

TNF receptor (TNFR)–associated factor TRAF6 is a key activator of NF-κB, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses. TRAF6 interactions determine receptor-induced cell death versus survival. TRAF6 has been implicated in cancer but its contributions have not been investigated deeply. In this study, we show that TRAF6 upregulates expression of hypoxia-inducible factor (HIF)–1α. TRAF6 affects HIF-1α protein levels but has little effect on mRNA level. TRAF6 increases HIF-1α protein independent of oxygen. We found that TRAF6 binds HIF-1α and mediates its K63-linked polyubiquitination. The E3 ligase activity of TRAF6 was required to increase HIF-1α protein levels. Finally, we showed that TRAF6 promoted tumor angiogenesis and growth. Our results reveal how TRAF6 functions to upregulate HIF-1α expression and promote tumor angiogenesis. Cancer Res; 73(15); 4950–9. ©2013 AACR.
Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma
Authors: Rao Jyotsna U. , Engelke Udo F.H. , Rodenburg Richard J.T. , Wevers Ron A. , Pacak Karel , Eisenhofer Graeme , Qin Nan , Kusters Benno , Goudswaard Angelina G. , Lenders Jacques W.M. , Hermus Ad R.M.M. , Mensenkamp Arjen R. , Kunst Henricus P.M. , Sweep Fred C.G.J. , Timmers Henri J.L.M.
Published: May 2013

Purpose: Pheochromocytomas and paragangliomas (PGL) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. This study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors.

Experimental Design: Respiratory chain enzyme assays and 1H-nuclear magnetic resonance (NMR) spectroscopy at 500 MHz were conducted on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in succinate dehydrogenase subunits B and D (SDHB, SDHD), succinate dehydrogenase assembly factor 2, von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and myc-associated factor X.

Results: In SDHx-related PGLs, a significant decrease in complex II activity (P < 0.0001) and a significant increase in complex I, III, and IV enzyme activities were observed when compared to sporadic, RET, and NF1 tumors. Also, a significant increase in citrate synthase (P < 0.0001) enzyme activity was observed in SDHx-related PGLs when compared to sporadic-, VHL-, RET-, and NF1-related tumors. An increase in succinate accumulation (P < 0.001) and decrease in ATP/ADP/AMP accumulation (P < 0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (P < 0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues.

Conclusions: This study for the first time establishes a relationship between determinants of energy metabolism, like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in PGL tumors. Also, this study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with an SDHx mutation. Clin Cancer Res; 19(14); 3787–95. ©2013 AACR.
HMGB1 in Cancer: Good, Bad, or Both?
Authors: Kang Rui , Zhang Qiuhong , Zeh Herbert J. , Lotze Michael T. , Tang Daolin
Published: May 2013

Forty years ago, high mobility group box 1 (HMGB1) was discovered in calf thymus and named according to its electrophoretic mobility in polyacrylamide gels. Now, we know that HMGB1 performs dual functions. Inside the cell, HMGB1 is a highly conserved chromosomal protein acting as a DNA chaperone. Outside of the cell, HMGB1 is a prototypical damage-associated molecular pattern, acting with cytokines, chemokines, and growth factors. During tumor development and in cancer therapy, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways, including inflammation, immunity, genome stability, proliferation, metastasis, metabolism, apoptosis, and autophagy. Here, we review the current knowledge of both HMGB1′s oncogenic and tumor-suppressive roles and the potential strategies that target HMGB1 for the prevention and treatment of cancer. Clin Cancer Res; 19(15); 4046–57. ©2013 AACR.
Correlation between Levels of Circulating Adipokines and Adiponectin/Resistin Index with Carotid Intima-Media Thickness in Hypertensive Type 2 Diabetic Patients
Authors: Rubio-Guerra Alberto F. , Cabrera-Miranda Luis J. , Vargas-Robles Hilda , Maceda-Serrano Alberto , Lozano-Nuevo José J. , Escalante-Acosta Bruno A.
Published: May 2013

Background: Hypoadiponectinemia and hyperresistinemia are associated with cardiovascular disease. The increase in the carotid intima-media thickness (CIMT) assessed by B-mode ultrasound has been directly associated with increased risk of myocardial infarction and stroke. Objective: To evaluate the correlation between adipokine levels with CIMT in hypertensive type 2 diabetic patients. Methods: Serum levels of adiponectin and resistin levels were measured by ELISA in 30 type 2 diabetic patients with never-treated hypertension and in age-matched healthy controls. The CIMT (B-mode color imaging of extracranial carotid arteries using high-resolution ultrasound) was also obtained. The relationship between adipokine levels and the adiponectin/resistin index with the CIMT was assessed by the Pearson correlation coefficient test. Results: Adiponectin was lower (p < 0.05), and resistin higher (p < 0.01) in patients than in controls, CIMT correlated positively with resistin (R = 0.45, p < 0.02) and the adiponectin/resistin index (R = 0.58, p < 0.001), but not with adiponectin levels (r = -0.11, p > 0.1) in patients. Whereas only adiponectin levels correlated - negatively - with CIMT (r = -0.39, p < 0.02) in controls. Conclusion: Our results shown that the adiponectin/resistin index seems to be more strongly associated with atherosclerosis than adipokine levels, and may be used as a reliable marker of cardiovascular risk in type 2 diabetic hypertensive patients.
Sublingual Microvascular Glycocalyx Dimensions in Lacunar Stroke Patients
Authors: Martens Remy J.H. , Vink Hans , van Oostenbrugge Robert J. , Staals Julie
Published: May 2013

Background: Cerebral small vessel disease is thought to result from endothelial dysfunction. The glycocalyx, lining the endothelium, is a major determinant of endothelial function. The glycocalyx is partially accessible to flowing red blood cells at its luminal side, called the perfused boundary region (PBR). Glycocalyx damage results in increased PBR, which can be measured in the sublingual microvasculature. We tested whether PBR is increased in patients with cerebral small vessel disease, i.e. lacunar stroke patients, and further distinguished patients with presence of white matter lesions as a sign of extensive cerebral small vessel disease. Methods: We used sidestream dark field imaging of the sublingual microcirculation in 31 lacunar stroke patients (6 with and 25 without white matter lesions) and 19 healthy controls. In each subject, automatic image analyzing software analyzed PBR in more than 3,000 vessel segments and the average dimension of glycocalyx PBR was determined in vessel segments with a diameter of 5-25 μm. Results: PBR did not differ between lacunar stroke patients and healthy controls (2.10 ± 0.25 vs. 2.08 ± 0.24 μm, p = 0.8). However, lacunar stroke patients with white matter lesions had an increased PBR compared with both healthy controls (2.35 ± 0.23 vs. 2.08 ± 0.24 μm, p = 0.03) and patients without white matter lesions (2.04 ± 0.22 μm, p = 0.004). Conclusions: White matter lesions are associated with an increase in the red blood cell permeable part of the sublingual microvascular glycocalyx in lacunar stroke patients. This implicates compromised glycocalyx barrier properties, which is consistent with impaired endothelial function in lacunar stroke patients with white matter lesions.
Common Hemodynamic Problems in the Neonate
Authors: Barrington Keith J.
Published: May 2013

Hemodynamic problems are common in neonatal intensive care. They occur in the context of incomplete myocardial and vascular development and in cardiovascular responses to interventions which are, as a result, limited and often uncertain and unpredictable. In this review, I outline the hemodynamic features of 4 neonatal conditions which often require intervention: (1) persistent pulmonary hypertension of the newborn, (2) cardiogenic shock (most commonly in the context of hypoxic ischemic injury), (3) sepsis and (4) low blood pressure in the transitional period of the extremely preterm infant. I also look at the evidence which exists for effective interventions and the most important research questions for the future.
Oxygen Targets for Preterm Infants
Authors: Stenson Ben J.
Published: May 2013

Retinopathy of prematurity (ROP) was first observed soon after the widespread introduction of oxygen therapy into neonatal care. Early trials suggested that restricting oxygen supplementation could reduce ROP without other consequences, but when oxygen restriction became widespread, increased mortality was observed. These observations were made before continuous monitoring of oxygenation was possible. New trial evidence from masked randomized controlled trials of different pulse oximeter oxygen saturation (SpO2) target ranges now shows that targeting lower SpO2 levels reduces ROP but is associated with significantly increased mortality. These results illustrate the importance of randomized trials because, prior to these recent studies, trends in practice based on observational data were favouring lower SpO2. Follow-up data may yet further inform clinical practice.
Optimization of Airway Medications in the Infant
Authors: Shinwell Eric S.
Published: May 2013

Airway medications are frequently used in the care of the sick neonate. The most prominent airway medication, surfactant for respiratory distress syndrome, will be discussed elsewhere in this issue of Neonatology. Other indications for airway medications have included the prevention and treatment of bronchopulmonary dysplasia, pulmonary hypertension, persistent atelectasis, transient tachypnea of the newborn and upper airway edema. Indications such as the prevention of bronchopulmonary dysplasia are currently the focus of a large multicenter international trial. Other indications require further study.