bluuebunny/crossref_metadata_2025 huggingface dataset:
Draft Genome Sequences of
Geomicrobium
sp. Strains JCM 19037, JCM 19038, JCM 19039, and JCM 19055, Isolated from Aquatic Samples
Authors: Kudo Toshiaki , Nakahara Tomomi , Zhang Xiaochi , Taniyama Shigeto , Arakawa Osamu , Murase Shinji , Nakata Hideaki , Oshima Kenshiro , Suda Wataru , Kitamura Keiko , Iida Toshiya , Oshida Yumi , Inoue Tetsushi , Hongoh Yuichi , Hattori Masahira , Ohkuma Moriya
Published: June 2014

Haloalkaliphilic strains JCM 19037, JCM 19038, JCM 19039, and JCM 19055, closely related to
Geomicrobium sediminis
, were isolated from aquatic samples, and their draft genome sequences were determined. The genome information of these four strains will be useful for studies of their physiology and ecology.
Draft Genome Sequence of Bacillus amyloliquefaciens B-1895
Authors: Karlyshev Andrey V. , Melnikov Vyacheslav G. , Chistyakov Vladimir A.
Published: June 2014

In this report, we present a draft genome sequence of
Bacillus amyloliquefaciens
strain B-1895. Comparison with the genome of a reference strain demonstrated similar overall organization, as well as differences involving large gene clusters.
Draft Genome Sequence of
Penicillium expansum
Strain R19, Which Causes Postharvest Decay of Apple Fruit
Authors: Yu Jiujiang , Jurick Wayne M. , Cao Huansheng , Yin Yanbin , Gaskins Verneta L. , Losada Liliana , Zafar Nikhat , Kim Maria , Bennett Joan W. , Nierman William C.
Published: June 2014

Among the species that cause blue mold, isolates of
Penicillium expansum
are the most prevalent and virulent species, causing more than 50 percent of postharvest decay. We report the draft genome sequence of
P. expansum
R19 in order to identify fungal virulence factors and to understand the mechanism of infection.
Differences in socioeconomic position, lifestyle and health-related pregnancy characteristics between Pakistani and White British women in the Born in Bradford prospective cohort study: the influence of the woman's, her partner's and their parents’ place of birth
Authors: West J , Lawlor D A , Fairley L , Wright J
Published: June 2014

Objective

To examine differences between Pakistani and White British women in relation to socioeconomic position, lifestyle and health-related pregnancy characteristics, and to determine whether these differences vary depending on the woman's, her partner's and both of their parents’ place of birth.

Design

Prospective cohort study.

Setting

Bradford, UK

Participants

3656 Pakistani and 3503 White British women recruited to the Born in Bradford study.

Main outcome measures

Socioeconomic position (employment status; level of education; receipt of benefits; housing tenure), lifestyle characteristics (body mass index (BMI) at the start of pregnancy; smoking during pregnancy) and health-related pregnancy characteristics (hypertensive disorders of pregnancy; gestational diabetes; fasting glucose, postload glucose and fasting insulin at ∼27 weeks gestation).

Results

Fewer Pakistani women were employed (OR 0.17, 95% CI 0.15 to 0.19), the difference being markedly less for UK born women. UK born Pakistani women were more likely, and South Asian born less likely, to be educated post 16 than White British women. Smoking was uncommon among Pakistani women, though the difference comparing UK born Pakistani women to White British women was less than for other groups. BMI was lower among Pakistani compared to White British women (adjusted mean difference −1.12, 95% CI −1.43 to −0.81), the difference being greatest when partners were UK born irrespective of the woman’s place of birth. Pakistani women had higher fasting and postload glucose (mean difference 0.20 mmol/L, 95% CI 0.17 to 0.24; 0.37, 95% CI 0.28 to 0.45), higher fasting insulin and were more likely to have gestational diabetes (GDM).

Conclusions

Our results suggest that some socioeconomic, lifestyle and pregnancy characteristics could be beginning to change in response to migration to the UK, with generally beneficial changes, that is, improving education and employment prospects, lower BMI and no evidence that being UK born has further increased the risk of GDM, but some negative, that is, slight increases in smoking.
Epidemiology of injuries in hurling: a prospective study 2007–2011
Authors: Blake Catherine , O'Malley Edwenia , Gissane Conor , Murphy John C
Published: June 2014

Objectives

Hurling is a stick handling game which, although native to Ireland, has international reach and presence. The aim of this study was to report incidence and type of injuries incurred by elite male hurling players over five consecutive playing seasons.

Design

Prospective cohort study.

Setting

Male intercounty elite sports teams participating in the National GAA Injury Database, 2007–2011.

Participants

A total of 856 players in 25 county teams were enrolled.

Primary and secondary outcomes

Incidence, nature and mechanism of injury were recorded by team physicians or physiotherapists to a secure online data collection portal. Time-loss injury rates per 1000 training and match play hours were calculated and injury proportions were expressed.

Results

In total 1030 injuries were registered, giving a rate of 1.2 injuries per player. These were sustained by 71% (n=608) of players. Injury incidence rate was 2.99 (95% CI 2.68 to 3.30) per 1000 training hours and 61.75 (56.75 to 66.75) per 1000 match hours. Direct player-to-player contact was recorded in 38.6% injuries, with sprinting (24.5%) and landing (13.7%) the next most commonly reported injury mechanisms. Median duration of time absent from training or games, where the player was able to return in the same season, was 12 days (range 2–127 days). The majority (68.3%) of injuries occurred in the lower limbs, with 18.6% in the upper limbs. The trunk and head/neck regions accounted for 8.6% and 4.1% injuries, respectively. The distribution of injury type was significantly different (p<0.001) between upper and lower extremities: fractures (upper 36.1%, lower 1.5%), muscle strain (upper 5.2%, lower 45.8%).

Conclusions

These data provide stable, multiannual data on injury patterns in hurling, identifying the most common injury problems. This is the first step in applying a systematic, theory-driven injury prevention model in the sport.
Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland
Authors: Ruokoniemi Päivi , Sund Reijo , Arffman Martti , Helin-Salmivaara Arja , Huupponen Risto , Keskimäki Ilmo , Vehko Tuulikki , Korhonen Maarit Jaana
Published: June 2014

Objective

To assess the representativeness of the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) for incident statin users.

Design

A population-based analysis with linked register data.

Setting

Finland.

Population

56 963 patients with diabetes initiating statin use from 2005 to 2008.

Main outcome measures

We determined the proportions of real-world patients who fulfilled the eligibility criteria for HPS and CARDS trials and assessed the cardiovascular disease (CVD) event rates, assumed to reflect the background CVD risk, for those eligible and ineligible. We used descriptive statistics to identify the patient characteristics, lipid-lowering interventions and adherence to statin therapy.

Results

Of the real-world patients, 57% (N=32 582) fulfilled the eligibility criteria for HPS (DM) and 49% (N=20 499) of those without CVD for CARDS. The patients ineligible for HPS (DM) had a higher cumulative risk for CVD events than those eligible, whereas regarding CARDS the cumulative risks were of similar magnitude. The overall CVD event rates seemed to be comparable to those in the reviewed trials. Both trials were under-representative of women and users of antihypertensive agents and metformin. 27% and 29% of real-world patients had an initial statin dose corresponding to <20 mg of simvastatin. The proportions of patients who were deemed adherent were 57% in the real world and 85% in both trials.

Conclusions

Only half of the real-world patients would have qualified for the HPS (DM) and CARDS, limiting their representativeness for clinical practice. Women and users of antihypertensive agents and metformin were under-represented in both trials. These deviations reflect the changes in diabetes treatment over the years and are not expected to modify the average treatment effects of statins on CVD. Prescribing of lower statin doses in clinical practice than used in the trials and lower adherence may, however, attenuate the benefits in the real world.
Analgesic use, pain and daytime sedation in people with and without dementia in aged care facilities: a cross-sectional, multisite, epidemiological study protocol
Authors: Tan Edwin C K , Visvanathan Renuka , Hilmer Sarah N , Vitry Agnes I , Quirke Tara , Emery Tina , Robson Leonie , Shortt Terry , Sheldrick Simon , Lee Sunny (Soon Won) , Clothier Robyn , Reeve Emily , Gnjidic Danijela , Ilomäki Jenni , Bell J Simon
Published: June 2014

Introduction

People living with dementia may experience and express pain in different ways to people without dementia. People with dementia are typically prescribed fewer analgesics than people without dementia indicating a potential difference in how pain is identified and treated in these populations. The objectives of this study are to (1) investigate the prevalence of analgesic load, pain and daytime sedation in people with and without dementia in Australian residential aged care facilities (RACFs), and (2) investigate the clinical and diagnostic associations between analgesic load, pain and daytime sedation in people with and without dementia in Australian RACFs.

Methods/analysis

This will be a cross-sectional study of 300 permanent residents of up to 10 low-level and high-level RACFs in South Australia with and without dementia. Trained study nurses will administer validated and dementia-specific assessments of self-reported and clinician-observed pain, sedation and other clinical and humanistic outcomes. Medicine-use data will be extracted directly from each resident's medication administration chart. Binary and multinominal logistic regression will be used to compute unadjusted and adjusted ORs and 95% CIs for factors associated with pain, analgesic load and daytime sedation. These factors will include dementia severity, behavioural and psychological symptoms, quality of life, resident satisfaction, attitudes towards medicines, activities of daily living and nutritional status.

Ethics and dissemination

Institutional ethics approval has been granted. The findings will be disseminated through public lectures, professional and scientific conferences and in peer-reviewed journal articles. The findings of this study will allow for a better understanding of the prevalence and factors associated with analgesic use, pain and other outcomes in residential care. The findings of this study will be used to inform the development and implementation of strategies to improve the quality of life of people with dementia.
OH-initiated AOPs degradation mechanism of ibuprofen in aqueous environments
Authors: He Lin , Sun Xiaomin , Sun Xuefei , Gao Jun , Zhang Chenxi , Cao Haijie , Wang Shuguang
Published: June 2014

As a common pharmaceutical and personal care product, ibuprofen (IBP) is regarded as an important pollutant in aqueous environments. In this paper, the OH-initiated advanced oxidation processes (AOPs) degradation mechanism and its subsequent reaction mechanism with IBP were studied at the M06-2x/6-311++G(2d, p)//M06-2x/6-31+G(d,p) level. The frontier electron density and bond dissociation energy were analyzed. In addition, profiles of the potential energy surface were constructed, and all the possible pathways were discussed. H-atom abstraction is the most important mechanism. The dominant products were IBAP, 2-[4-(1-hydroxyisobutyl)phenyl]propionic acid, and 1-(4-isobutylphenyl)-1-ethanol, which is in good agreement with the experimental results.
Distribution of the foliar fungal endophyte Phialocephala scopiformis and its toxin in the crown of a mature white spruce tree as revealed by chemical and qPCR analyses
Authors: Frasz Samantha L. , Walker Allison K. , Nsiama Tienabe K. , Adams Gregory W. , Miller J. David
Published: June 2014

Phialocephala scopiformis Kowalski & Kehr is a foliar fungal endophyte of white spruce (Picea glauca (Moench) Voss) that produces the anti-insect compound rugulosin and other compounds in lower amounts. Seedlings inoculated with this and other toxigenic endophytes have increased tolerance to the spruce budworm Choristoneura fumiferana (Clemens, 1865). The presence of rugulosin in the diet and in needles infected by P. scopiformis reduces the growth rate of the insect. One of 300 white spruce trees inoculated as a seedling in 2001 was chosen to investigate the distribution of P. scopiformis and its principal toxin rugulosin throughout the crown. To facilitate the detection of the fungus in small samples, a qPCR assay was developed based on the ITS region of fungal ribosomal DNA targeting a genetic polymorphism unique to P. scopiformis. The assay was specific, with a method limit of detection 100 ng mycelium per gram needle sample with high reproducibility and accuracy. We found that 11 years after inoculation, P. scopiformis DAOM 229536 and its toxin were detectable in needle samples distributed throughout the crown. Of the 109 samples tested, 100% of the rugulosin-positive samples also tested positive for P. scopiformis DAOM 229536 DNA in the qPCR assay. The mean and median needle rugulosin concentrations were >2 times that required to reduce the growth of spruce budworm.
Architecture-Based Planning of Software Evolution
Authors: Kang Sungwon , Garlan David
Published: June 2014

Software architecture allows us to make many decisions about a software system and analyze it even before it has been implemented, so as to make planned development possible. Similarly, architecture-based software evolution planning makes planned evolution possible by allowing us to make many decisions about the evolution of a software system and to analyze its evolution at the level of architecture design before software evolution is realized. In this paper, we develop a framework for architecture-based software evolution planning. It is done by defining various foundational terms and concepts, providing a taxonomy of software evolution plans, and then showing how to calculate values for various types of plans. By identifying and defining constituent foundational concepts, this conceptual framework makes precise the notion of "architecture-based software planning". By developing a value-calculation framework for software evolution plans, it also provides a basis for concrete methods for designing and evaluating evolution plans.
BIOMIMETIC STRUCTURE DESIGN OF DRAGONFLY WING VENATION USING TOPOLOGY OPTIMIZATION METHOD
Authors: SUN JIYU , LING MINGZE , PAN CHUNXIANG , CHEN DONGHUI , TONG JIN , LI XIN
Published: June 2014

Scientists have carried out research for various biomimetic applications based on the dragonfly wings because of the superb flying skills and lightsome posture. The wings of dragonflies are mainly composed of veins and membranes, which give rise to the special characteristics of their wings that make dragonflies being supremely versatile, maneuverable fliers. Mimicking the dragonfly wing motion is of great technological interest from application's point of view. However, the major challenge is the biomimetic fabrication to replicate the wing motion due to the very complex nature of the wing venation of dragonfly wings. In this regard, the topology optimization method (TOM) is useful to simplify object's structure while retaining its mechanical properties. In this paper, TOM is employed to simplify and optimize the venation structure of dragonfly (Pantala flavescens Fabricius) wing that is captured by a 3D scanner and numerical reconfiguration. Combined with the material parameters obtained from nanoindentation testing, the quantitative models are established based on a finite element (FE) analysis and discussed in static range. The quantitative models are then compared with the square frame, staggered grid frame and hexagonal frame to examine the potentials of the biomimetic structure design for the fabrication of greenhouse roof.
High-precision U–Pb zircon CA-ID-TIMS dates from western European late Viséan bentonites
Authors: Pointon Michael A. , Chew David M. , Ovtcharova Maria , Sevastopulo George D. , Delcambre Bernard
Published: June 2014

Three new U–Pb zircon chemical abrasion isotope dilution thermal ionization mass spectrometry dates obtained from late Viséan Belgian bentonites are reported and are used to estimate the periodicity of early Warnantian shallowing-upwards carbonate parasequences that are interbedded with the dated bentonites. Early Warnantian parasequences exhibit mean cycle periodicity values that are consistent with the
c
. 100 ka Milankovitch cycle, which is the dominant Milankovitch frequency recognized from recent Pleistocene glacial records, and thus strengthen the arguments for (1) these sedimentary cycles being of glacio-eustatic origin and (2) the initiation of the main phase of late Palaeozoic glaciation before the start of or during earliest Warnantian times. The new dates also provide additional high-precision age constraints for the improved calibration of the Mississippian time scale. Using the new dates, the stratigraphical age of the Clyde Plateau Volcanic Formation, Midland Valley of Scotland, is revised from Holkerian to early Asbian.

Supplementary material:

U–Pb zircon CA-ID-TIMS data tables and the method of the mean cycle periodicity calculations are available at
www.geolsoc.org.uk/SUP18747
.
Open source, open heart
Authors: Beach Jesse
Published: June 2014

Creativity requires technical training, personal development, and the freedom to take risks regardless of your gender.
In search of diverse students
Authors: Berg Tobias , Apel Rebecca , Leicht-Scholten Carmen
Published: June 2014

In Germany, the IGaDtools4MINT research project aims to integrate gender and diversity in STEM subjects.
Hackers!
Authors: Jeong Sarah , McSwiggen Colin
Published: June 2014

From the early 1980s to the present day, the tech industry, the law, and media representations have evolved in tandem, all hypnotized by the myth of "The Hacker"---an ideal coder, stereotyped as an exceptional young white man.
The prerequisites and privilege of autodidacticism
Authors: Aufrichtig Aliza
Published: June 2014

The proliferation of free, high-quality online courses has been heralded as a means to democratize education. The real innovations in online learning will be programs that teach the critical thinking required to learn more.
The Revealing Flashlight
Authors: Ridel Brett , Reuter Patrick , Laviole Jeremy , Mellado Nicolas , Couture Nadine , Granier Xavier
Published: June 2014

Cultural heritage artifacts often contain details that are difficult to distinguish due to aging effects such as erosion. We propose the
revealing flashlight
, a new interaction and visualization technique in spatial augmented reality that helps to reveal the detail of such artifacts. We locally and interactively augment a physical artifact by projecting an expressive 3D visualization that highlights its features, based on an analysis of its previously acquired geometry at multiple scales. Our novel interaction technique simulates and improves the behavior of a flashlight: according to 6-degree-of-freedom input, we adjust the numerous parameters involved in the expressive visualization—in addition to specifying the location to be augmented. This makes advanced 3D analysis accessible to the greater public with an everyday gesture, by naturally combining the inspection of the real object and the virtual object in a colocated interaction and visualization space.

The
revealing flashlight
can be used by archeologists, for example, to help decipher inscriptions in eroded stones, or by museums to let visitors interactively discover the geometric details and meta-information of cultural artifacts. We confirm its effectiveness, ease of use, and ease of learning in an initial preliminary user study and by the feedback of two public exhibitions.
Efficient Matching for Column Intersection Graphs
Authors: Auer B. O. Fagginger , Bisseling R. H.
Published: June 2014

To improve the quality and efficiency of hypergraph-based matrix partitioners, we investigate high-quality matchings in column intersection graphs of large sparse binary matrices. We show that such algorithms have a natural decomposition in an integer-weighted graph-matching function and a neighbor-finding function and study the performance of 16 combinations of these functions. We improve upon the original matching algorithm of the Mondriaan matrix partitioner: by using PGA’, we improve the average matching quality from 95.3% to 97.4% of the optimum value; by using our new neighbor-finding heuristic, we obtain comparable quality and speedups of up to a factor of 19.6.
Quality Software Costs Money - Heartbleed Was Free
Authors: Kamp Poul-Henning
Published: June 2014

The world runs on free and open-source software, FOSS for short, and to some degree it has predictably infiltrated just about any software-based product anywhere in the world.
Cortisol is not the primary mediator for augmented CXCR4 expression on natural killer cells after acute exercise
Authors: Okutsu Mitsuharu , Ishii Kenji , Niu Kaijun , Nagatomi Ryoichi
Published: June 2014

CXC-chemokine receptor 4 (CXCR4) and its ligand, stromal-derived factor 1α (SDF-1α; also known as CXCL12), are crucial for the redistribution of immune cells after acute exercise. We investigated the relationships between acute exercise and CXCR4 expression on natural killer (NK) cells. Peripheral blood mononuclear cells (PBMCs) were cultured with cortisol and analyzed for CXCR4 expression on CD3−/CD56+NK cells and NK cell migration activity. To determine the effect of exercise, we isolated PBMCs from subjects before and after a 90-min exercise at 70% peak O2uptake (V̇o2peak) and determined the changes in CXCR4 expression on NK cells after exercise. We cultured PBMCs with plasma obtained before and after exercise and with the glucocorticoid antagonist RU-486 to determine NK cell migration activity and the effects of cortisol on CXCR4 expression in vitro. Cortisol treatment increased CXCR4 expression ( P < 0.05) and migration activity ( P < 0.05) of NK cells. Exercise did not affect CXCR4 expression on NK cells, whereas incubating them with postexercise plasma significantly increased CXCR4 expression ( P < 0.05) and migration activity ( P < 0.05). RU-486 blocked cortisol-induced CXCR4 upregulation on NK cells, but only partially blocked (7%) CXCR4 upregulation when PMBCs were incubated with postexercise plasma. Thus acute exercise increases CXCR4 expression on NK cells and their migration activity and may contribute to NK cell redistribution after acute exercise; however, cortisol did not appear to be the primary mediator of augmented CXCR4 expression.
Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle
Authors: Kavazis Andreas N. , Smuder Ashley J. , Powers Scott K.
Published: June 2014

Doxorubicin (DOX) is a potent antitumor agent used in cancer treatment. Unfortunately, DOX can induce myopathy in both cardiac and skeletal muscle, which limits its clinical use. Importantly, exercise training has been shown to protect against DOX-mediated cardiac and skeletal muscle myopathy. However, the mechanisms responsible for this exercise-induced muscle protection remain elusive. These experiments tested the hypothesis that short-term exercise training protects against acute DOX-induced muscle toxicity, in part, due to decreased forkhead-box O (FoxO) transcription of atrophy genes. Rats ( n = 6 per group) were assigned to sedentary or endurance exercise-trained groups and paired with either placebo or DOX treatment. Gene expression and protein abundance were measured in both cardiac and skeletal muscles to determine the impact of DOX and exercise on FoxO gene targets. Our data demonstrate that DOX administration amplified FoxO1 and FoxO3 mRNA expression and increased transcription of FoxO target genes [i.e., atrogin-1/muscle atrophy F-box (MaFbx), muscle ring finger-1 (MuRF-1), and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] in heart and soleus muscles. Importantly, exercise training protected against DOX-induced increases of FoxO1 and MuRF-1 in cardiac muscle and also prevented the rise of FoxO3, MuRF-1, and BNIP3 in soleus muscle. Furthermore, our results indicate that exercise increased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in both the heart and soleus muscles. This is important because increased PGC-1α expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes. Together, these results are consistent with the hypothesis that exercise training protects against DOX-induced myopathy in both heart (FoxO1 and MuRF-1) and skeletal muscles (FoxO3, MuRF-1, and BNIP3).
Role of VPAC2 receptor in monocrotaline-induced pulmonary hypertension in rats
Authors: Koga Motokazu , Mizuno Yusuke , Watanabe Itaru , Kawakami Hiromasa , Goto Takahisa
Published: June 2014

Pulmonary hypertension (PH) is associated with significant morbidity and mortality. Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) have pulmonary vasodilatory and positive inotropic effects via receptors VPAC1 and VPAC2, which possess a similar affinity for both peptides, and PAC1, a PACAP-preferring receptor. VIP is a promising option for PH treatment; however, various physiological effects of VIP have limited its clinical use. We investigated the effects of VPAC1 and VPAC2 selective agonists VIP and PACAP to explore more appropriate means of treatment for PH. We examined hemodynamic changes in right ventricular systolic pressure (RVSP), systemic blood pressure (SBP), total pulmonary resistance index (TPRI), total systemic resistance index, and cardiac index (CI) in response to their agonists with monocrotaline (MCT)-induced PH and explored involvement of VIP/PACAP expression and receptors in PH. Sprague-Dawley rats were divided into the MCT group (administered MCT 60 mg/kg) and control group. In MCT-induced PH, decreased VIP and PACAP were associated with upregulation of VPAC1, VPAC2, and PAC1 in lung tissues. Intravenous injection of VPAC2-selective agonist BAY 55–9837 and VIP, but not [Ala11,22,28]VIP, improved the CI. The decrease in SBP with VPAC2 agonist was significantly less than that in the control. Although they decreased SBP, these agonists hardly affected RVSP in the control. Activation of VPAC2 receptor with BAY 55–9837 effectively improved RVSP, TPRI, and CI in MCT-induced PH, suggesting a VPAC2 agonist as a possible promising treatment for PH.
Effects of elevated oxygen and carbon dioxide partial pressures on respiratory function and cognitive performance
Authors: Gill Matthew , Natoli Michael J. , Vacchiano Charles , MacLeod David B. , Ikeda Keita , Qin Michael , Pollock Neal W. , Moon Richard E. , Pieper Carl , Vann Richard D.
Published: June 2014

Hyperoxia during diving has been suggested to exacerbate hypercapnic narcosis and promote unconsciousness. We tested this hypothesis in male volunteers (12 at rest, 10 at 75 W cycle ergometer exercise) breathing each of four gases in a hyperbaric chamber. Inspired Po2 (PiO2) was 0.21 and 1.3 atmospheres (atm) without or with an individual subject's maximum tolerable inspired CO2 (PiO2 = 0.055–0.085 atm). Measurements included end-tidal CO2 partial pressure (PetCO2), rating of perceived discomfort (RPD), expired minute ventilation (V̇e), and cognitive function assessed by auditory n-back test. The most prominent finding was, irrespective of PetCO2, that minute ventilation was 8–9 l/min greater for rest or exercise with a PiO2 of 1.3 atm compared with 0.21 atm ( P < 0.0001). For hyperoxic gases, PetCO2 was consistently less than for normoxic gases ( P < 0.01). For hyperoxic hypercapnic gases, n-back scores were higher than for normoxic gases ( P < 0.01), and RPD was lower for exercise but not rest ( P < 0.02). Subjects completed 66 hyperoxic hypercapnic trials without incident, but five stopped prematurely because of serious symptoms (tunnel vision, vision loss, dizziness, panic, exhaustion, or near syncope) during 69 normoxic hypercapnic trials ( P = 0.0582). Serious symptoms during hypercapnic trials occurred only during normoxia. We conclude serious symptoms with hyperoxic hypercapnia were absent because of decreased PetCO2 consequent to increased ventilation.
Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle
Authors: Fealy Ciaran E. , Mulya Anny , Lai Nicola , Kirwan John P.
Published: June 2014

Defects in mitochondrial dynamics, the processes of fission, fusion, and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Dynamin-related protein-1 (Drp1) is a GTPase protein that plays a central role in mitochondrial fission. We hypothesized that aerobic exercise training would decrease Drp1 Ser616phosphorylation and increase fat oxidation and insulin sensitivity in obese (body mass index: 34.6 ± 0.8 kg/m2) insulin-resistant adults. Seventeen subjects performed supervised exercise for 60 min/day, 5 days/wk at 80–85% of maximal heart rate for 12 wk. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and fat oxidation was determined by indirect calorimetry. Skeletal muscle biopsies were obtained from the vastus lateralis muscle before and after the 12-wk program. The exercise intervention increased insulin sensitivity 2.1 ± 0.2-fold ( P < 0.01) and fat oxidation 1.3 ± 0.3-fold ( P < 0.01). Phosphorylation of Drp1 at Ser616was decreased (pre vs. post: 0.81 ± 0.15 vs. 0.58 ± 0.14 arbitrary units; P < 0.05) following the intervention. Furthermore, reductions in Drp1 Ser616phosphorylation were negatively correlated with increases in fat oxidation ( r = −0.58; P < 0.05) and insulin sensitivity (rho = −0.52; P < 0.05). We also examined expression of genes related to mitochondrial dynamics. Dynamin1-like protein (DNM1L; P < 0.01), the gene that codes for Drp1, and Optic atrophy 1 (OPA1; P = 0.05) were significantly upregulated following the intervention, while there was a trend towards an increase in expression of both mitofusin protein MFN1 ( P = 0.08) and MFN2 ( P = 0.07). These are the first data to suggest that lifestyle-mediated improvements in substrate metabolism and insulin sensitivity in obese insulin-resistant adults may be regulated through decreased activation of the mitochondrial fission protein Drp1.
PBX1 Is a Favorable Prognostic Biomarker as It Modulates 13-cis Retinoic Acid–Mediated Differentiation in Neuroblastoma
Authors: Shah Nilay , Wang Jianjun , Selich-Anderson Julia , Graham Garrett , Siddiqui Hasan , Li Xin , Khan Javed , Toretsky Jeffrey
Published: June 2014

Purpose: Neuroblastoma is an embryonic childhood cancer with high mortality. 13-cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance and the normal differentiation pathway are poorly understood. Three–amino-acid loop extension (TALE) family genes are master regulators of differentiation. Because retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma.

Experimental Design: We evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13-cisRA treatment, identifying genes whose expression correlates with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by qRT-PCR, and three independent clinical cohort microarray datasets.

Results: We confirmed that induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in neuroblastoma cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA-dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histologic neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts.

Conclusions: PBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors. Clin Cancer Res; 20(16); 4400–12. ©2014 AACR.
Association of EGFR Expression Level and Cetuximab Activity in Patient-Derived Xenograft Models of Human Non–Small Cell Lung Cancer
Authors: Amendt Christiane , Staub Eike , Friese-Hamim Manja , Störkel Stephan , Stroh Christopher
Published: June 2014

Purpose: To explore in a panel of patient-derived xenograft models of human non–small cell lung cancer (NSCLC) whether high EGFR expression, was associated with cetuximab activity.

Experimental Design: NSCLC patient-derived xenograft models (n = 45) were implanted subcutaneously into panels of nude mice and randomization cohorts were treated with either cetuximab, cisplatin, cisplatin plus cetuximab, vehicle control, or else were left untreated. Responses according to treatment were assessed at week 3 by analyzing the relative change in tumor volume and an experimental analogue of the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. An EGFR IHC score was calculated for each patient-derived xenograft model and response was assessed according to EGFR expression level.

Results: When tumors were stratified into high and low EGFR expression groups (IHC score threshold 200; scale 0–300), a stronger antitumor activity was seen in the high EGFR expression group compared with the low EGFR expression group in both the cetuximab monotherapy and cisplatin plus cetuximab combination therapy settings. For tumors treated with cisplatin plus cetuximab, the objective response rate was significantly higher in the high EGFR expression group compared with the low EGFR expression group (68% vs. 29%). Objective response rates were similar in high and low expression groups for tumors treated with cisplatin alone (27% vs. 24%, respectively).

Conclusion: Cetuximab activity in NSCLC patient-derived xenograft models was demonstrated clearly only in tumors that expressed high levels of EGFR, as defined by an IHC score of ≥200. Clin Cancer Res; 20(17); 4478–87. ©2014 AACR.
Sonic Hedgehog Paracrine Signaling Activates Stromal Cells to Promote Perineural Invasion in Pancreatic Cancer
Authors: Li Xuqi , Wang Zheng , Ma Qingyong , Xu Qinhong , Liu Han , Duan Wanxing , Lei Jianjun , Ma Jiguang , Wang Xiu , Lv Shifang , Han Liang , Li Wei , Guo Jian , Guo Kun , Zhang Dong , Wu Erxi , Xie Keping
Published: June 2014

Purpose: Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression.

Experimental Design: In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression.

Results: We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models.

Conclusions: These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI-associated molecules to promote PNI in pancreatic cancer. Clin Cancer Res; 20(16); 4326–38. ©2014 AACR.
Screening for Cardiac Dysfunction in Anthracycline-Exposed Childhood Cancer Survivors
Authors: Armenian Saro H. , Gelehrter Sarah K. , Vase Tabitha , Venkatramani Rajkumar , Landier Wendy , Wilson Karla D. , Herrera Claudia , Reichman Leah , Menteer John-David , Mascarenhas Leo , Freyer David R. , Venkataraman Kalyanasundaram , Bhatia Smita
Published: June 2014

Purpose: To examine the utility and reliability of obtaining early echocardiographic measurements of left ventricular (LV) remodeling as well as blood biomarkers of cardiac injury in asymptomatic childhood cancer survivors at risk for LV dysfunction and congestive heart failure due to past exposure to anthracycline chemotherapy.

Experimental Design: Using a cross-sectional design, anthracycline-exposed childhood cancer survivors with preserved ejection fraction (EF; ≥50%) were evaluated using early echocardiographic indices and blood biomarkers of LV dysfunction. Survivors treated with ≥300 mg/m2 anthracyclines [high risk (HR): n = 100] were compared with those treated with <300 mg/m2 anthracyclines [low risk (LR): n = 50] and matched healthy controls (HC: n = 50). All echocardiograms were interpreted by an institutional cardiologist and a study cardiologist blinded to risk status.

Results: Time from diagnosis was comparable for HR (12.0 years) and LR (13.2 years, P = 0.8) survivors. Echocardiograms: HR had lower LV thickness-dimension ratio (Z-score: HR: −0.62, LR: −0.03, HC: −0.02; P < 0.001), increased LV wall stress (HR: 66.7 g/cm2, LR: 56.6 g/cm2, HC: 54.2 g/cm2; P < 0.01), and higher myocardial performance index (HR: 0.51, LR: 0.46, HC: 0.46; P < 0.01). Interobserver correlation (clinical/blinded reading) for all echocardiographic indices was excellent (range: R = 0.76–0.97, P < 0.001). Blood biomarkers: With the exception of NT-proBNP (r = 0.28, P < 0.01), there was no correlation between blood biomarkers (B-type natriuretic peptide, Troponin-T, ST-2, Galectin-3) and LV dysfunction.

Conclusion: Childhood cancer survivors with preserved EF 10+ years from anthracycline exposure had dose-dependent changes in echocardiographic markers of LV dysfunction. Clin Cancer Res; 20(24); 6314–23. ©2014 AACR.
ID1 Promotes Breast Cancer Metastasis by S100A9 Regulation
Authors: Gumireddy Kiranmai , Li Anping , Kossenkov Andrew V. , Cai Kathy Q. , Liu Qin , Yan Jinchun , Xu Hua , Showe Louise , Zhang Lin , Huang Qihong
Published: June 2014

Metastasis is a major factor responsible for mortality in patients with breast cancer. Inhibitor of DNA binding 1 (Id1) has been shown to play an important role in cell differentiation, tumor angiogenesis, cell invasion, and metastasis. Despite the data establishing Id1 as a critical factor for lung metastasis in breast cancer, the pathways and molecular mechanisms of Id1 functions in metastasis remain to be defined. Here, we show that Id1 interacts with TFAP2A to suppress S100A9 expression. We show that expression of Id1 and S100A9 is inversely correlated in both breast cancer cell lines and clinical samples. We also show that the migratory and invasive phenotypes in vitro and metastasis in vivo induced by Id1 expression are rescued by reestablishment of S100A9 expression. S100A9 also suppresses the expression of known metastasis-promoting factor RhoC activated by Id1 expression. Our results suggest that Id1 promotes breast cancer metastasis by the suppression of S100A9 expression.

Implications: Novel pathways by Id1 regulation in metastasis. Mol Cancer Res; 12(9); 1334–43. ©2014 AACR.
Corneal Collagen Crosslinking: A Systematic Review
Authors: Sorkin Nir , Varssano David
Published: June 2014

Keratoconus (KCN) is an ectatic disorder with progressive corneal thinning and a clinical picture of corneal protrusion, progressive irregular astigmatism, corneal fibrosis and visual deterioration. Other ectatic corneal disorders include: post-LASIK ectasia (PLE) and pellucid marginal degeneration (PMD). Corneal crosslinking (CXL) is a procedure whereby riboflavin sensitization with ultraviolet A radiation induces stromal crosslinks. This alters corneal biomechanics, causing an increase in corneal stiffness. In recent years, CXL has been an established treatment for the arrest of KCN, PLE and PMD progression. CXL has also been shown to be effective in the treatment of corneal infections, chemical burns, bullous keratopathy and other forms of corneal edema. This is a current review of CXL - its biomechanical principles, the evolution of CXL protocols in the past, present and future, indications for treatment, treatment efficacy and safety.
Impact of Red Blood Cell Distribution Width on Long-Term Mortality in Patients with ST-Elevation Myocardial Infarction
Authors: Sun Xi-peng , Chen Wen-ming , Sun Zhi-jun , Ding Xiao-song , Gao Xiang-yu , Liang Si-wen , Zhao Hui-qiang , Yao Dao-kuo , Chen Hui , Li Hong-wei , Li Dong-bao
Published: June 2014

Objectives: Recent studies have reported increased red blood cell distribution width (RDW) has been associated with adverse outcomes in heart failure and stable coronary disease. We investigated the association between RDW and risk of all-cause mortality in patients with ST-elevation myocardial infarction (STEMI) who were free of heart failure at baseline. Methods: We enrolled 691 patients with STEMI who were free of heart failure at baseline confirmed by coronary angiography in Beijing Friendship Hospital from January 2007 to December 2008. According to the median RDW at baseline (13.0%) on admission, the patients were divided into two groups: a low-RDW group (RDW <13.0%, n = 329) and a high-RDW group (RDW ≥13.0%, n = 362). All-cause mortality rates were compared between groups. Mean duration of follow-up was 41.8 months. The relation between RDW and clinical outcomes after hospital discharge were tested using Cox regression models, adjusting for clinical variables. At the same time, the sensitivity and specificity of RDW were analyzed by ROC analysis. Results: Forty-seven patients (6.8%) died during follow-up. The cumulative incidence of all-cause death was significantly higher in the high-RDW group than in the low-RDW group (log-rank p = 0.007). Multivariate analysis revealed that high RDW was associated with all-cause mortality (hazard ratio: 3.43; 95% confidence interval: 1.17-8.32; p = 0.025). The area under the ROC curve was 0.562. Conclusion: From the statistical point of view, increased RDW is associated with all-cause and cardiac mortality rates in patients with STEMI who were free of heart failure at baseline. But RDW is a marker with a very low prognostic accuracy that does not seem to be clinically helpful.
Repeated β2-Adrenergic Receptor Agonist Therapy Attenuates the Response to Rescue Bronchodilation in a Hyperoxic Newborn Mouse Model
Authors: Raffay Thomas , Kc Prabha , Reynolds James , Di Fiore Juliann , MacFarlane Peter , Martin Richard J.
Published: June 2014

Background: Preterm infants with neonatal lung injury are prone to wheezing and are often treated with β2-adrenergic receptor (β-AR) agonists although the benefits of β-AR agonists may be lost with chronic use. Objective: To investigate if repeated β-AR agonist exposure downregulates β-ARs in the immature lung resulting in a decreased response to bronchodilator rescue and whether hyperoxic exposure aggravates this response. Methods: Newborn mice were raised for 21 days in 60 or 21% oxygen and received daily aerosols of formoterol or saline. Respiratory system resistance (Rrs) and compliance (Crs) were measured in response to methacholine challenge and rescue bronchodilation with levalbuterol. Western blot analysis quantified the relative amount of lung β-ARs. Results: Hyperoxia increased the airway reactivity to methacholine. Animals raised in hyperoxia that received daily formoterol were most sensitive to methacholine and exhibited a blunted response to levalbuterol bronchodilation. Hyperoxia-exposed animals receiving daily formoterol versus saline showed a significant decrease in the relative amount of lung β-ARs. Conclusions: In this hyperoxia-exposed neonatal mouse model, repeated β-AR agonist treatments increased the airway reactivity and attenuated the response to a rescue bronchodilator. The blunted bronchodilator response could be explained by a reduced quantity of lung β-ARs. Our findings may account for the time-dependent decrease in the therapeutic benefit of β-AR agonists in preterm infants with neonatal lung injury, which may have clinical consequences for patients already prone to airway hyperreactivity.
Genomic Characterization of Acute Leukemias
Authors: Chiaretti Sabina , Gianfelici Valentina , Ceglie Giulia , Foà Robin
Published: June 2014

Over the past two decades, hematologic malignancies have been extensively evaluated due to the introduction of powerful technologies, such as conventional karyotyping, FISH analysis, gene and microRNA expression profiling, array comparative genomic hybridization and SNP arrays, and next-generation sequencing (including whole-exome sequencing and RNA-seq). These analyses have allowed for the refinement of the mechanisms underlying the leukemic transformation in several oncohematologic disorders and, more importantly, they have permitted the definition of novel prognostic algorithms aimed at stratifying patients at the onset of disease and, consequently, treating them in the most appropriate manner. Furthermore, the identification of specific molecular markers is opening the door to targeted and personalized medicine. The most important findings on novel acquisitions in the context of acute lymphoblastic leukemia of both B and T lineage and de novo acute myeloid leukemia are described in this review.
Development of the Cloaca, Hemipenes, and Hemiclitores in the Green Anole, Anolis carolinensis
Authors: Gredler Marissa L. , Sanger Thomas J. , Cohn Martin J.
Published: June 2014

In most amniotes, the intromittent organ is a single phallus; however, squamates (lizards, snakes, and amphisbaenians) have paired hemiphalluses. All amniotes studied to date initiate external genital development with the formation of paired genital swellings. In mammals, archosaurs, and turtles, these swellings merge to form a single genital tubercle, the precursor of the penis and clitoris; however, in squamates, the paired genital buds remain separate, giving rise to the hemiphalluses (hemipenes in males and hemiclitores in females). Although the molecular genetics and sexual differentiation of the genital tubercle have been investigated in mammals and birds, little is known about hemiphallus development. Here we describe development of the cloaca and hemiphallus in the green anole, Anolis carolinensis. Each hemiphallus originates as a protuberance that emerges at the ventral base of the hindlimb bud. Development of the hemipenes resembles penis development; however, differences exist in their tissue composition, morphogenesis, and gene expression patterns. These findings reveal aspects of phallus development that appear to be evolutionarily labile, both within squamates and more broadly among reptiles, and identify features that are conserved across amniotes. Our results, together with parallel studies in other reptilian taxa, suggest potential mechanisms for the diversification of external genital form.