bluuebunny/crossref_metadata_2025 huggingface dataset:
Technical Note: Immunohistochemical evaluation of mouse brain irradiation targeting accuracy with 3D‐printed immobilization device
Authors: Zarghami Niloufar , Jensen Michael D. , Talluri Srikanth , Foster Paula J. , Chambers Ann F. , Dick Frederick A. , Wong Eugene
Published: October 2015

Purpose:

Small animal immobilization devices facilitate positioning of animals for reproducible imaging and accurate focal radiation therapy. In this study, the authors demonstrate the use of three‐dimensional (3D) printing technology to fabricate a custom‐designed mouse head restraint. The authors evaluate the accuracy of this device for the purpose of mouse brain irradiation.

Methods:

A mouse head holder was designed for a microCT couch using cad software and printed in an acrylic based material. Ten mice received half‐brain radiation while positioned in the 3D‐printed head holder. Animal placement was achieved using on‐board image guidance and computerized asymmetric collimators. To evaluate the precision of beam localization for half‐brain irradiation, mice were sacrificed approximately 30 min after treatment and brain sections were stained for γ‐H2AX, a marker for DNA breaks. The distance and angle of the γ‐H2AX radiation beam border to longitudinal fissure were measured on histological samples. Animals were monitored for any possible trauma from the device.

Results:

Visualization of the radiation beam on ex vivo brain sections with γ‐H2AX immunohistochemical staining showed a sharp radiation field within the tissue. Measurements showed a mean irradiation targeting error of 0.14 ± 0.09 mm (standard deviation). Rotation between the beam axis and mouse head was 1.2° ± 1.0° (standard deviation). The immobilization device was easily adjusted to accommodate different sizes of mice. No signs of trauma to the mice were observed from the use of tooth block and ear bars.

Conclusions:

The authors designed and built a novel 3D‐printed mouse head holder with many desired features for accurate and reproducible radiation targeting. The 3D printing technology was found to be practical and economical for producing a small animal imaging and radiation restraint device and allows for customization for study specific needs.
Modeling of Women's 100-m Dash World Record: Wind-Aided or Not?
Authors: Hazelrigg Conner , Waibel Bryson , Baker Blane
Published: October 2015

On July 16, 1988, Florence Griffith Joyner (FGJ) shattered the women's 100-m dash world record (WR) with a time of 10.49 s, breaking the previous mark by an astonishing 0.27 s. By all accounts FGJ dominated the race that day, securing her place as the premiere female sprinter of that era, and possibly all time. In the aftermath of such an extraordinary performance, track officials immediately assumed that her posted time was wind aided—that is, attained under tailwind conditions beyond the legal limit of 2.0 m/s for world records. However, wind-measuring devices at the track site showed zero wind conditions during her WR performance. Before and during FGJ's race, other wind-measuring devices indicated speeds exceeding 4.0 m/s at the site of the triple jump runway, located on the same field as the running track. Video clips of flags placed near the starting line of FGJ's race also revealed tailwind conditions. Using available data from that era, the study here incorporates modeling techniques to compute velocity and position as functions of time for no wind and tailwind conditions. Modeling under no wind conditions produces a 100-m time of 10.70 s, a performance clearly attainable by FGJ during this stage of her sprinting career. Incorporating tailwinds of 4.0 m/s into the computations reduces this time by approximately 0.20 s, in close agreement with FGJ's record-breaking performance. These results strongly suggest that tailwinds of order 4 m/s were present during FGJ's world record race even though wind-measuring devices at the track site did not register these speeds. In spite of such strong evidence to support a wind-aided race on July 16, 1988, FGJ remains one of the top female sprinters in history and would likely hold the WR even today, given that she attained a non-wind-aided 100-m time of 10.61 s on the day following her WR performance.
Re-Cycling
Authors: Brown Robert W. , Covault Corbin E.
Published: October 2015

An old comedy routine on Saturday Night Live by Father Guido Sarducci introduced a “Five-Minute University,” because five minutes is all that's remembered after graduation anyway. In counterpoint, we discuss “cycling,” a teaching method for memory enhancement. Our principal implementation consists of offering a simple version of a given course in the first third of the semester, a deeper and more integrated version in the second third, and the final, targeted version in the last third. We describe the benefits and challenges in this tale from the trenches.
Item-Writing Guidelines for Physics
Authors: Regan Tom
Published: October 2015

A teacher learning how to write test questions (test items) will almost certainly encounter item-writing guidelines—lists of item-writing do's and don'ts. Item-writing guidelines usually are presented as applicable across all assessment settings. Table I shows some guidelines that I believe to be generally applicable and two will be briefly discussed here. The teacher may also encounter some guidelines that are not applicable in all assessment settings, or that can be applied to physics only with care. Two such guidelines, and their limitations, will be discussed as well.
Go-to's: Pedagogical knowledge
Authors: Wester Ken
Published: October 2015

A couple of months ago, I wrote a column that included my “go-to's” when I needed to beef up my content knowledge of a particular physics topic. This month, I turn the focus to the times when you know the material you want to teach, but you cannot figure out the best way to deliver the content to your students. When I encounter this problem, I have a few places that I know will provide great resources to help me. Often, the best source is a seasoned teacher that you know and respect. What if you don't know anyone who can help? What if it's too late to make a phone call? What if you want to figure it out for yourself? Below is a short list of the places that I recommend you use to answer the question, “What is the best method to teach _____?”
Quantum Griffiths singularity of superconductor-metal transition in Ga thin films
Authors: Xing Ying , Zhang Hui-Min , Fu Hai-Long , Liu Haiwen , Sun Yi , Peng Jun-Ping , Wang Fa , Lin Xi , Ma Xu-Cun , Xue Qi-Kun , Wang Jian , Xie X. C.
Published: October 2015

Cooling to see the effects of disorder

In sufficiently strong external magnetic fields, thin superconducting films typically become insulating. The presence of disorder can affect this phase transition. Theorists have proposed that disorder can cause the so-called Griffiths singularity, where the behavior of the system is determined by a small number of superconducting islands that form above the critical magnetic field. Xing
et al.
observed a signature of such a singularity in thin films of gallium by analyzing transport data taken at very low temperatures (see the Perspective by Markovic). In this regime, thermal fluctuations were not strong enough to homogenize the system, which allowed the rare islands to form.

Science
, this issue p.
542
; see also p.
509
Structure of
Tetrahymena
telomerase reveals previously unknown subunits, functions, and interactions
Authors: Jiang Jiansen , Chan Henry , Cash Darian D. , Miracco Edward J. , Ogorzalek Loo Rachel R. , Upton Heather E. , Cascio Duilio , O’Brien Johnson Reid , Collins Kathleen , Loo Joseph A. , Zhou Z. Hong , Feigon Juli
Published: October 2015

Chromosome-capping enzyme complex

Telomeres cap and protect the ends of our chromosomes. The telomerase complex helps maintain the telomere DNA repeat sequences. Telomerase consists of an RNA and a number of protein subunits. Jiang
et al.
used cryo–electron microscopy and x-ray crystallography to determine the structure of the
Tetrahymena
telomerase complex. The telomerase is made up of three subcomplexes, which include two previously unknown protein subunits in addition to the seven known subunits. The structures also reveal the path of the RNA component in the telomerase catalytic core.

Science
, this issue p.
10.1126/science.aab4070
Complete Genome Sequences of Nine Phages Capable of Infecting Paenibacillus larvae, the Causative Agent of American Foulbrood Disease in Honeybees
Authors: Tsourkas Philippos K. , Yost Diane G. , Krohn Andrew , LeBlanc Lucy , Zhang Anna , Stamereilers Casey , Amy Penny S.
Published: October 2015

We present here the complete genome sequences of nine phages that infect
Paenibacillus larvae
, the causative agent of American foulbrood disease in honeybees. The phages were isolated from soil, propolis, and infected bees from three U.S. states. This is the largest number of
P. larvae
phage genomes sequenced in a single publication to date.
Genome Sequence of a Multidrug-Resistant Strain of Stenotrophomonas maltophilia with Carbapenem Resistance, Isolated from King Abdullah Medical City, Makkah, Saudi Arabia
Authors: Abdel-Haleem Alyaa M. , Rchiad Zineb , Khan Babar K. , Abdallah Abdallah M. , Naeem Raeece , Nikhat Sheerin Shalam , Solovyev Victor , Ahmed Abdalla , Pain Arnab
Published: October 2015

The emergence and spread of multidrug-resistant (MDR) bacteria have been regarded as major challenges among health care-associated infections worldwide. Here, we report the draft genome sequence of an MDR
Stenotrophomonas maltophilia
strain isolated in 2014 from King Abdulla Medical City, Makkah, Saudi Arabia.
Complete Genome Sequence of Type 1 Porcine Reproductive and Respiratory Syndrome Virus Strain E38, Isolated from South Korea with a Novel Deletion
Authors: Kim Jeong-Min , Kwon Young-Woo , Choi Eun-Jin , Ouh In-Ohk , Choe Se-Eun , Lee Jienny , Song Jae-Young , Cha Sang-Ho
Published: October 2015

We report the complete genome sequence of the European type 1 porcine reproductive and respiratory syndrome virus E38 strain, isolated from South Korea with a novel deletion. It contains a 61-nucleotide discontinuous deletion of the Nsp2 and Nsp12 regions. This study will aid in understanding the genetic diversity of type 1 PRRSV and in manufacturing a construct based on Korean vaccine candidate development.
Draft Genome Sequence of the Pathogenic Bacterium Vibrio vulnificus V252 Biotype 1, Isolated in Israel
Authors: Efimov Vera , Danin-Poleg Yael , Green Stefan J. , Elgavish Sharona , Kashi Yechezkel
Published: October 2015

We report the genome sequence of the pathogenic
Vibrio vulnificus
biotype 1 clade B, which is suggested to have a common ancestor with biotype 3. This draft genome of the clinical strain V252, isolated in Israel, represents the clonal clade B group that contains both clinical and environmental strains.
Complete Genome Sequence of Citrobacter freundii Myophage Mordin
Authors: Guan Jingwen , Snowden Jeffrey D. , Cahill Jesse L. , Rasche Eric S. , Kuty Everett Gabriel F.
Published: October 2015

Citrobacter freundii
is a Gram-negative opportunistic pathogen that is associated with urinary tract infections. Bacteriophages infecting
C. freundii
can be used as an effective treatment to fight these infections. Here, we announce the complete genome sequence of the
C. freundii
Felix O1-like myophage Mordin and describe its features.
Draft Genome Sequence of Taylorella equigenitalis Strain ERC_G2224 Isolated from the Semen of a Lipizzaner Stallion in South Africa
Authors: May Catherine E. , Schulman Martin L. , Howell Peter G. , Lourens Carina W. , Gouws Johan , Joone Christopher , Monyai Mpho S. , le Grange Misha , Bezuidt Oliver K. I. , Harper Cindy K. , Guthrie Alan J.
Published: October 2015

Taylorella equigenitalis
is the causative agent of contagious equine metritis (CEM), a sexually transmitted infection of horses. We report here the genome sequence of
T. equigenitalis
strain ERC_G2224, isolated in 2015 from a semen sample collected in 1996 from a Lipizzaner stallion in South Africa.
Draft Genome Sequence of Planomicrobium glaciei UCD-HAM (Phylum
Firmicutes
)
Authors: Betts Makayla N. , Jospin Guillaume , Eisen Jonathan A. , Coil David A.
Published: October 2015

Here, we present the draft genome of
Planomicrobium glaciei
, a member of the phylum
Firmicutes
, found at the University of California Davis. Paired-end, 300-bp reads were generated on an Illumina MiSeq. The assembly consists of 3,925,122 bp, contained in 109 contigs, with a G+C content of 46.7%.
Draft Genome Sequence of
Streptomyces
sp. TP-A0890, a Producer of FR-900452 and A-74863a
Authors: Komaki Hisayuki , Ichikawa Natsuko , Hosoyama Akira , Fujita Nobuyuki , Igarashi Yasuhiro
Published: October 2015

Here, we report the draft genome sequence of
Streptomyces
sp. TP-A0890, a producer of FR-900452 and A-74863a. The genome was found to contain at least eight polyketide synthase and nonribosomal peptide synthetase gene clusters. A prediction of gene functions based on the sequence similarity allowed us to assign the biosynthetic gene clusters for FR-900452 and A-74863a.
Draft Genome Sequence of the Polychlorinated Biphenyl-Degrading Bacterium Comamonas testosteroni KF712 (NBRC 110673)
Authors: Hirose Jun , Yamazoe Atsushi , Hosoyama Akira , Kimura Nobutada , Suenaga Hikaru , Watanabe Takahito , Fujihara Hidehiko , Futagami Taiki , Goto Masatoshi , Furukawa Kensuke
Published: October 2015

We present a 5.89-Mb draft genome sequence of
Comamonas testosteroni
KF712 (NBRC 110673), a polychlorinated biphenyl degrader. The genome sequence clarified that KF712 harbors the gene clusters coding for the catabolism of biphenyl and at least seven other aromatic compounds.
Acute bilateral useless hand syndrome: a rare presenting manifestation of vitamin B12deficiency
Authors: Biyani Sumant , Jha Sneh Kumar , Pandey Suchit , Shukla Rakesh
Published: October 2015

We report a case of bilateral useless hand syndrome, a rare presenting manifestation of vitamin B12deficiency. A 38-year-old man, a strict vegetarian and a teacher by occupation, presented with acute onset clumsiness of both hands while performing fine movements. Detailed history-taking, examination of the patient and relevant investigations (complete blood count, serum vitamin B12and MRI of the cervical spinal cord) were carried out. Laboratory analysis was suggestive of vitamin B12deficiency and MRI demonstrated a lesion involving the posterior columns of the cervical cord. The patient was diagnosed as a case of non-compressive cervical myelopathy predominantly involving the posterior column due to vitamin B12deficiency. Acute bilateral useless hand syndrome can be a rare presenting feature of vitamin B12deficiency.
Type B aortic dissection triggered by heart transplantation in a patient with Marfan syndrome
Authors: Audenaert Tjorven , De Pauw Michel , François Katrien , De Backer Julie
Published: October 2015

Heart transplantation in patients with Marfan syndrome is challenging and raises concerns with regards to the haemodynamic and immunosuppressive-induced effects on the inherently fragile aorta. Most aortic events following transplantation reported so far in the literature occurred in patients with pre-existent distal aortic dissection. We report a case of successful orthotopic heart transplantation in a patient with Marfan syndrome that was complicated by late-onset type B dissection in pre-existing mild and stable distal aortic dilation. Serial aortic imaging revealed progressive growth at the level of the descending thoracic aorta. An open thoracoabdominal aortic repair procedure was successfully performed 6 months after the transplantation.
Sinus venosus atrial septal defect presenting with brain abscesses in a 77-year-old immunocompetent patient
Authors: Alhamshari Yaser SM , Punjabi Chitra , Pressman Gregg S , Govil Anita
Published: October 2015

We present a case of 77-year-old immunocompetent patient who initially presented with vertigo, nausea and vomiting, with symptoms later progressing to headaches and increased lethargy. Brain MRI revealed ring-enhancing lesions typical of abscesses in the right cerebellum. Transoesophageal echocardiogram (TEE) was performed to look for the source of his abscesses, and uncovered a sinus venosus type atrial septal defect. Cardiac CT was carried out; the patient was found to have a sinus venosus atrial septal defect with partial anomalous pulmonary venous return. Moreover, dental examination showed multiple dental caries with poor oral hygiene. The patient was started on intravenous empiric antibiotics and steroids. Subsequent brain imaging showed almost complete resolution of the abscesses. The patient's symptoms started to improve, and he was eventually sent to an intensive rehabilitation centre with future plans to surgically correct his congenital heart disease to prevent further complications.
Obstruction and perforation of the small bowel caused by inadvertent ingestion of a blister pill pack in an elderly patient
Authors: Al-Ramahi Ghassan , Mohamed Mohamed , Kennedy Kristin , McCann Michael
Published: October 2015

Perforation of the small bowel due to foreign body ingestion is a rare instance that occurs in less than 1% of all ingestions. Although rare, ingestion of blister pill packaging is becoming more recognised as a causative agent for intestinal perforation, but is very rarely reported to cause intestinal obstruction. This is a report of a 66-year-old woman who presented with intestinal obstruction and underwent laparotomy, revealing small bowel perforation by a piece of blister pill pack foil. The patient was incognisant of the ingestion.
Giving your heart to pathology
Authors: Klaassen Jim
Published: October 2015

Jim KIaassen recently joined Axiom Veterinary Laboratories as a clinical pathologist. During his career, Dr Klaassen has worked in small animal practice, lectured in clinical pathology, undertaken preclinical research and held senior roles in commercial veterinary laboratories in the USA, including as chief medical officer of Antech Diagnostics
Mitigating avian collision with power lines: a proof of concept for installation of line markers via unmanned aerial vehicle
Authors: Lobermeier Scott , Moldenhauer Matthew , Peter Christopher M. , Slominski Luke , Tedesco Richard A. , Ver Meer Marcus , Dwyer James F. , Harness Richard E. , Stewart Andrew H.
Published: October 2015

Avian collisions with overhead power lines are a global conservation concern. Collisions are mitigated primarily through marking power lines to increase their visibility. Line marking is typically accomplished via an expensive and potentially dangerous process of hovering a helicopter within 1 m of a wire and installing line markers by hand. Unmanned Aerial Vehicles (UAVs) may offer a less dangerous, less costly alternative that is also less disturbing to wildlife. Herein we describe equipping a commercially available UAV with an installation arm designed in collaboration with the Colorado State University Department of Mechanical Engineering to install line markers on a power line. The UAV installed line markers within a 30 cm target window on a model power line. The proof of concept described here demonstrates the potential utility of UAVs in mitigating avian collision with overhead power lines.
Constraints Evolve: Context Dependency of Gene Effects Allows Evolution of Pleiotropy
Authors: Pavličev Mihaela , Cheverud James M.
Published: October 2015

Evolutionary constraint due to pleiotropy refers to a situation in which mutations in genes shared among traits generate trait covariance; therefore, traits that are not directly exposed to selective challenge show a correlated response. When such a correlated response is deleterious, it may constrain the trait from evolving. Here, we argue that the idea of absolute constraints draws from the perception that gene effects are inherent to alleles and thus invariant across genetic and environmental backgrounds. However, evidence from studies involving genetic effects on multiple traits, observed across different genetic backgrounds and environments, supports the notion that genes' effects on traits change. Consequently, pleiotropy also varies across backgrounds. We argue for a stronger emphasis on interaction effects when describing a trait's genetic basis and its evolutionary potential. By discussing different cases of trait individuation, we demonstrate how this approach can lead to new insights.
Neurobiology of Monarch Butterfly Migration
Authors: Reppert Steven M. , Guerra Patrick A. , Merlin Christine
Published: October 2015

Studies of the migration of the eastern North American monarch butterfly (Danaus plexippus) have revealed mechanisms behind its navigation. The main orientation mechanism uses a time-compensated sun compass during both the migration south and the remigration north. Daylight cues, such as the sun itself and polarized light, are processed through both eyes and integrated through intricate circuitry in the brain's central complex, the presumed site of the sun compass. Monarch circadian clocks have a distinct molecular mechanism, and those that reside in the antennae provide time compensation. Recent evidence shows that migrants can also use a light-dependent inclination magnetic compass for orientation in the absence of directional daylight cues. The monarch genome has been sequenced, and genetic strategies using nuclease-based technologies have been developed to edit specific genes. The monarch butterfly has emerged as a model system to study the neural, molecular, and genetic basis of long-distance animal migration.
Accelerating Discovery and Functional Analysis of Small RNAs with New Technologies
Authors: Barquist Lars , Vogel Jörg
Published: October 2015

Over the past decade, bacterial small RNAs (sRNAs) have gone from a biological curiosity to being recognized as a major class of regulatory molecules. High-throughput methods for sampling the transcriptional output of bacterial cells demonstrate that sRNAs are universal features of bacterial transcriptomes, are plentiful, and appear to vary extensively over evolutionary time. With ever more bacteria coming under study, the question becomes how can we accelerate the discovery and functional characterization of sRNAs in diverse organisms. New technologies built on high-throughput sequencing are emerging that can rapidly provide global insight into the numbers and functions of sRNAs in bacteria of interest, providing information that can shape hypotheses and guide research. In this review, we describe recent developments in transcriptomics (RNA-seq) and functional genomics that we expect to help us develop an integrated, systems-level view of sRNA biology in bacteria.
Neural Regulatory Pathways of Feeding and Fat in Caenorhabditis elegans
Authors: Lemieux George A. , Ashrafi Kaveh
Published: October 2015

The compact nervous system of Caenorhabditis elegans and its genetic tractability are features that make this organism highly suitable for investigating energy balance in an animal system. Here, we focus on molecular components and organizational principles emerging from the investigation of pathways that largely originate in the nervous system and regulate feeding behavior but also peripheral fat regulation through neuroendocrine signaling. We provide an overview of studies aimed at understanding how C. elegans integrate internal and external cues in feeding behavior. We highlight some of the similarities and differences in energy balance between C. elegans and mammals. We also provide our perspective on unresolved issues, both conceptual and technical, that we believe have hampered critical evaluation of findings relevant to fat regulation in C. elegans.
Syntactic Ergativity: Analysis and Identification
Authors: Deal Amy Rose
Published: October 2015

Some languages showing morphological ergativity in case and/or agreement also show ergative patterns in core syntactic domains—syntactic ergativity. The most-studied type of syntactic ergativity is a ban on the Ā movement of ergative subjects; an additional type concerns the distribution of absolutives in nonfinite clauses. This article first presents the standard view of syntactic ergativity, which is closely connected to the treatment of ergative as an inherent case. Evidence from Shipibo suggests that a ban on ergative Ā extraction does not require inherent ergative. This points to a view of syntactic ergativity centered around morphological case discrimination. One consequence is that pure head-marking languages cannot feature a true ban on ergative extraction, because ergative morphological case is not in use. This conclusion highlights the challenging tasks of diagnosing extraction restrictions in pure head-marking languages, as in the Mayan and Salish families, and of distinguishing extraction restrictions from instances where extraction merely interacts with agreement. A variety of crosslinguistic evidence suggests that agreement/extraction interactions are fully possible in morphologically ergative languages, and not only for ergative arguments. Special morphology in the context of transitive subject extraction is therefore not necessarily evidence of syntactic ergativity.
What Does Genetics Tell Us About Age-Related Macular Degeneration?
Authors: Grassmann Felix , Ach Thomas , Brandl Caroline , Heid Iris M. , Weber Bernhard H.F.
Published: October 2015

Age-related macular degeneration (AMD) is a chronic degenerative disease of the central retina and a major cause of vision impairment and blindness with millions of people affected in the elderly population. In recent years, considerable efforts have been made to understand disease pathology with the long-term goal of designing novel and effective treatment options for this devastating disease. Although striking advances in treating the neovascular stage of late AMD have occurred, no therapy is available for almost half of all AMD patients, specifically those who are affected by the atrophic form of the disease. This review highlights current knowledge on the genetic factors associated with early- and late-stage forms of the disease. It also summarizes the findings regarding the extent to which these factors may play a role in the transition from one disease stage to another, and it emphasizes the need to explore further the underlying mechanisms for both development and progression of this disease as a starting point for designing innovative therapies for it.
Spectral transfer function analysis of respiratory hemodynamic fluctuations predicts end-diastolic stiffness in preserved ejection fraction heart failure
Authors: Abdellatif Mahmoud , Leite Sara , Alaa Mohamed , Oliveira-Pinto José , Tavares-Silva Marta , Fontoura Dulce , Falcão-Pires Inês , Leite-Moreira Adelino F. , Lourenço André P.
Published: October 2015

Preserved ejection fraction heart failure (HFpEF) diagnosis remains controversial, and invasive left ventricular (LV) hemodynamic evaluation and/or exercise testing is advocated by many. The stiffer HFpEF myocardium may show impaired stroke volume (SV) variation induced by fluctuating LV filling pressure during ventilation. Our aim was to investigate spectral transfer function (STF) gain from end-diastolic pressure (EDP) to indexed SV (SVi) in experimental HFpEF. Eighteen-week-old Wistar-Kyoto (WKY) and ZSF1 lean (ZSF1 Ln) and obese rats (ZSF1 Ob) randomly underwent LV open-chest (OC, n = 8 each group) or closed-chest hemodynamic evaluation (CC, n = 6 each group) under halogenate anesthesia and positive-pressure ventilation at constant inspiratory pressure. Beat-to-beat fluctuations in hemodynamic parameters during ventilation were assessed by STF. End-diastolic stiffness (βi) and end-systolic elastance (Eesi) for indexed volumes were obtained by inferior vena cava occlusion in OC (multibeat) or single-beat method estimates in CC. ZSF1 Ob showed higher EDP spectrum ( P < 0.001), higher STF gain between end-diastolic volume and EDP, and impaired STF gain between EDP and SVi compared with both hypertensive ZSF1 Ln and normotensive WKY controls ( P < 0.001). Likewise βi was only higher in ZSF1 Ob while Eesi was raised in both ZSF1 groups. On multivariate analysis βi and not Eesi correlated with impaired STF gain from EDP to SVi ( P < 0.001), and receiver-operating characteristics analysis showed an area under curve of 0.89 for higher βi prediction ( P < 0.001). Results support further clinical testing of STF analysis from right heart catheterization-derived EDP surrogates to noninvasively determined SV as screening/diagnostic tool to assess myocardial stiffness in HFpEF.
The relationship between biventricular myocardial performance and metabolic parameters during incremental exercise and recovery in healthy adolescents
Authors: Pieles Guido E. , Gowing Lucy , Forsey Jonathan , Ramanujam Paramanantham , Miller Felicity , Stuart A Graham , Williams Craig A.
Published: October 2015

Background left ventricular (LV) and right ventricular (RV) myocardial reserve during exercise in adolescents has not been directly characterized. The aim of this study was to quantify myocardial performance response to exercise by using two-dimensional (2-D) speckle tracking echocardiography and describe the relationship between myocardial reserve, respiratory, and metabolic exercise parameters. A total of 23 healthy boys and girls (mean age 13.2 ± 2.7 yr; stature 159.1 ± 16.4 cm; body mass 49.5 ± 16.6 kg; BSA 1.47 ± 0.33 m2) completed an incremental cardiopulmonary exercise test (25 W·3 min increments) with simultaneous acquisition of 2-D transthoracic echocardiography at rest, each exercise stage up to 100 W, and in recovery at 2 min and 10 min. Two-dimensional LV (LV Sl) and RV (RV Sl) longitudinal strain and LV circumferential strain (LV Sc) were analyzed to define the relationship between myocardial performance reserve and metabolic exercise parameters. Participants achieved a peak oxygen uptake (V̇o2peak) of 40.6 ± 8.9 ml·kg−1·min−1 and a work rate of 154 ± 42 W. LV Sl and LV Sc and RV Sl increased significantly across work rates ( P < 0.05). LV Sl during exercise was significantly correlated to resting strain, V̇o2peak, oxygen pulse, and work rate (0.530 ≤ r ≤ 0.784, P < 0.05). This study identifies a positive and moderate relationship between LV and RV myocardial performance and metabolic parameters during exercise by using a novel methodology. Relationships detected present novel data directly describing myocardial adaptation at different stages of exercise and recovery that in the future can help directly assess cardiac reserve in patients with cardiac pathology.
Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle
Authors: Kaur Jasdeep , Machado Tiago M. , Alvarez Alberto , Krishnan Abhinav C. , Hanna Hanna W. , Altamimi Yasir H. , Senador Danielle , Spranger Marty D. , O'Leary Donal S.
Published: October 2015

Metabolite accumulation due to ischemia of active skeletal muscle stimulates group III/IV chemosensitive afferents eliciting reflex increases in arterial blood pressure and sympathetic activity, termed the muscle metaboreflex. We and others have previously demonstrated sympathetically mediated vasoconstriction of coronary, renal, and forelimb vasculatures with muscle metaboreflex activation (MMA). Whether MMA elicits vasoconstriction of the ischemic muscle from which it originates is unknown. We hypothesized that the vasodilation in active skeletal muscle with imposed ischemia becomes progressively restrained by the increasing sympathetic vasoconstriction during MMA. We activated the metaboreflex during mild dynamic exercise in chronically instrumented canines via graded reductions in hindlimb blood flow (HLBF) before and after α1-adrenergic blockade [prazosin (50 μg/kg)], β-adrenergic blockade [propranolol (2 mg/kg)], and α1 + β-blockade. Hindlimb resistance was calculated as femoral arterial pressure/HLBF. During mild exercise, HLBF must be reduced below a threshold level before the reflex is activated. With initial reductions in HLBF, vasodilation occurred with the imposed ischemia. Once the muscle metaboreflex was elicited, hindlimb resistance increased. This increase in hindlimb resistance was abolished by α1-adrenergic blockade and exacerbated after β-adrenergic blockade. We conclude that metaboreflex activation during submaximal dynamic exercise causes sympathetically mediated α-adrenergic vasoconstriction in ischemic skeletal muscle. This limits the ability of the reflex to improve blood flow to the muscle.
Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats
Authors: Brooks Steven D. , DeVallance Evan , d'Audiffret Alexandre C. , Frisbee Stephanie J. , Tabone Lawrence E. , Shrader Carl D. , Frisbee Jefferson C. , Chantler Paul D.
Published: October 2015

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7–8, 12–13, and 16–17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7–8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS.
Protective role of spleen-derived macrophages in lung inflammation, injury, and fibrosis induced by nitrogen mustard
Authors: Venosa Alessandro , Malaviya Rama , Gow Andrew J. , Hall Leroy , Laskin Jeffrey D. , Laskin Debra L.
Published: October 2015

Nitrogen mustard (NM) is a vesicant that causes lung injury and fibrosis, accompanied by a persistent macrophage inflammatory response. In these studies we analyzed the spleen as a source of these cells. Splenectomized (SPX) and sham control rats were treated intratracheally with NM (0.125 mg/kg) or PBS control. Macrophage responses were analyzed 1–7 days later. Splenectomy resulted in an increase in lung macrophages expressing CCR2, but a decrease in ATR-1α+ cells, receptors important in bone marrow and spleen monocyte trafficking, respectively. Splenectomy was also associated with an increase in proinflammatory M1 (iNOS+, CD11b+CD43+) macrophages in lungs of NM-treated rats, as well as greater upregulation of iNOS and COX-2 mRNA expression. Conversely, a decrease in CD11b+CD43− M2 macrophages was observed in SPX rats, with no changes in CD68+, CD163+, CD206+, or YM-1+ M2 macrophages, suggesting distinct origins of M2 subpopulations responding to NM. Macrophage expression of M2 genes including IL-10, ApoE, PTX-2, PTX-3, 5-HT2α, and 5-HT7 was also reduced in NM-treated SPX rats compared with shams, indicating impaired M2 activity. Changes in lung macrophages responding to NM as a consequence of splenectomy were correlated with exacerbated tissue injury and more rapid fibrogenesis. These data demonstrate that the spleen is a source of a subset of M2 macrophages with anti-inflammatory activity; moreover, in their absence, proinflammatory/cytotoxic M1 macrophages predominate in the lung, resulting in heightened pathology. Understanding the origin of macrophages and characterizing their phenotype after vesicant exposure may lead to more targeted therapeutics aimed at reducing toxicity and disease pathogenesis.
Contributions of Subtypes of Non-Hodgkin Lymphoma to Mortality Trends
Authors: Howlader Nadia , Morton Lindsay M. , Feuer Eric J. , Besson Caroline , Engels Eric A.
Published: October 2015

Background: Non-Hodgkin lymphoma (NHL) comprises distinct tumor subtypes. Although mortality from NHL overall has changed dramatically in the United States over time, little is known about trends for subtypes, because death certificates do not record this information.

Methods: Using data from U.S. Surveillance, Epidemiology, and End Results (SEER) areas, we assessed NHL mortality rates and mapped NHL deaths to incident NHL cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific NHL subtypes (incidence-based mortality; IBM). We also describe NHL incidence and survival after NHL diagnosis by calendar year. We used Joinpoint to identify years when IBM and incidence rate trends changed slope.

Results: Overall NHL mortality rates increased during 1975–1997, peaking at 10.9 per 100,000 person-years, then decreased subsequently in 1997–2011. Overall IBM rates mirror this trend during 1990–2011. For B-cell NHL subtypes, IBM rates decreased beginning in the mid-1990s, with yearly declines of −3.0% for diffuse large B-cell lymphoma (DLBCL), −2.7% for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and −5.3% for follicular lymphoma. Incidence rates for these subtypes did not decrease until after 2003. Corresponding 5-year cancer-specific survival increased dramatically over time for DLBCL (from 37%–66%), CLL/SLL (69%–84%), and follicular lymphoma (69%–82%). IBM for peripheral T-cell lymphoma was flat during 2006–2011, although incidence increased.

Conclusions: Mortality due to three common B-cell NHL subtypes has fallen over time in the United States.

Impact: This decline reflects better survival after NHL diagnosis, likely from improved therapies, because the decline in NHL incidence occurred later. Cancer Epidemiol Biomarkers Prev; 25(1); 174–9. ©2015 AACR.
Abstract A02: The art of omission: Low fucose antibodies enhance tumor cell clearance in vivo
Authors: Braster Rens , Visser Remco , Vidarsson Gestur , Egmond Marjolein van
Published: October 2015

The use of monoclonal antibodies (mAbs) in treating cancer patients has become an important addition to chemo- and radiotherapy. Depending on the type of antibody, these mAbs induce a variety of different effector functions, including induction of apoptosis and growth inhibition that can lead to eradication of the tumor. Additionally, tumor targeting mAbs can activate the immune system resulting in induction of complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP) of tumor cells by natural killer cells or myeloid cells (monocyte/macrophages and neutrophils). Currently most clinically used mAbs are primarily chimeric or humanized Immunoglobulin G1 (IgG1) mAbs, which bind to IgG Fc receptors (FcγRs).

Efficient binding to FcγRs requires the IgG-Fc-glycan moieties at position 297. In humans, core-fucosylation of IgG is particularly important for binding to human FcγRIIIa and FcγRIIIb, resulting in enhanced uptake of opsonized particles and enhanced ADCC. These properties are increasingly exploited in the next generation of therapeutic anti-tumor IgG.

In this study we investigated whether removal of the core fucose also enhanced killing of tumor cells by mouse effector cells, and whether this prevented tumor outgrowth in vivo. Therefore a chimeric IgG1 (TA99), targeting gp75 on B16F10 mouse melanoma cells, was generated with- and without core-fucose, and their effect was assessed in both in vitro and in vivo models.

In vitro mouse immune cells were incubated with B16F10-gp75 cells in the presence or absence of wildtype or low fucose TA99 and tumor killing was analyzed. In vivo the effect of the TA99 IgG1 low fucose on tumor outgrowth was assessed by injecting both B16F10-gp75 cells and either TA99 IgG1 wt or low fucose in the peritoneal cavity of mice.

Fourteen days post injection tumor outgrowth was analyzed. Mice treated with TA99 low fucose had significantly less tumors in comparison to the wildtype TA99 IgG1, showing that changing the fucosylation of the Fc domain has a remarkable effect on the effectiveness of an antibody therapy.

These results emphasize that when the core fucose of therapeutic IgG antibodies is removed, efficacy of monoclonal antibody therapies will be enhanced significantly. Additionally, the effect works cross species, suggesting mouse models are also suitable to study this phenomenon and to screen antibodies in vivo for enhanced effector functions. Ultimately, this may lead to improved clinical outcome of cancer patients.

Citation Format: Rens Braster, Remco Visser, Gestur Vidarsson, Marjolein van Egmond. The art of omission: Low fucose antibodies enhance tumor cell clearance in vivo. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A02.
Abstract A25: Immunotherapy using LOAd700 armed with CD40 ligand controls experimental pancreatic cancer and activates immune responses
Authors: Svensson Emma , Moreno Rafael , Milenova Ioanna , Christiansson Lisa , Alemany Ramon , Loskog Angelica
Published: October 2015

The aim of this study was to evaluate the efficacy of LOAd immunotherapy to treat pancreatic cancer in a xenograft model as well as to determine the capacity of LOAds to stimulate the immune system in in vitro models. LOAd viruses are oncolytic adenoviruses (5/35) armed with immunostimulatory genes in order to shift the tumor milieu towards immune activation at the same time providing release and spread of tumor antigens due to oncolysis. In this manner, LOAd virus is an antigen-independent immunotherapy for various solid tumors.

LOAd armed with CD40 ligand (LOAd700) was constructed from the ICOVIR system by changing the virus shaft and knob to that of serotype 35 to broaden virus binding and entry into cells (pending patent EP14163704). Oncolysis in OCOVIRs is restricted to cells with a disrupted Rb pathway. Viruses were produced using A549 cells. The pancreatic cancer cell lines BxPC3, Panc01, MiaPaCa2 and PaCa3 were used for in vitro evaluation and Panc01 was used in the xenograft model in Nu/Nu mice. Human dendritic cells (DCs) were obtained by differentiation of CD14+ monocytes with GM-CSF and IL4 for 7 days.

LOAd viruses infected both the panel of pancreatic tumor cell lines and human DCs with high efficacy and both the cell lines and the DCs expressed the CMV driven transgene/s post transduction. The oncolytic LOAd virus did not kill DCs nor healthy pancreatic cells present in donor islet cell isolation surplus material. In contrast, oncolysis was restricted to the tumor cell lines. The LOAd-transduced DCs increased markers of maturation such as MHC II, CD86, CD70 and CD83 and produced high levels of IL12. LOAd stimulated DCs were able to activate and expand antigen-specific T cells and NK cells as demonstrated in a CMV in vitro system. LOAd viruses could control tumor growth in a xenograft immunodeficient model due to oncolysis alone.

In conclusion, LOAd700 can kill pancreatic tumor cells in vitro and control growing tumor in mice due to oncolysis alone. Further, upon DC transduction, LOAd viruses mature DCs to efficient antigen presenters and stimulators of Th1 effector cells such as T cells and NK cells. LOAd is an interesting new immunotherapy for solid malignancies including pancreatic cancer.

Citation Format: Emma Svensson, Rafael Moreno, Ioanna Milenova, Lisa Christiansson, Ramon Alemany, Angelica Loskog. Immunotherapy using LOAd700 armed with CD40 ligand controls experimental pancreatic cancer and activates immune responses. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A25.
Abstract A35: Genomic characterization of immune escape pathways in gastric cancer
Authors: Wang Kai , Leung Suet Yi
Published: October 2015

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR06) of the Conference Proceedings.

Citation Format: Kai Wang, Suet Yi Leung. Genomic characterization of immune escape pathways in gastric cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A35.
Abstract A36: Novel therapeutic approaches for human malignant mesothelioma
Authors: Yang Haining , Jube Sandro , Carbone Michele
Published: October 2015

Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that has been linked to asbestos and erionite exposure. MM causes about 3,200 deaths per year in the US and more than 100,000 deaths per year worldwide. We previously found that high-mobility group box-1 protein (HMGB1), a prototypic damage-associated molecular pattern (DAMP), plays a critical role in the early events of HM malignant transformation and MM development. More recently we showed that MM cells are “addicted” to HMGB1 that supports the malignant phenotype by promoting proliferation and invasiveness of MM cells. We demonstrated that MM growth is inhibited by targeting HMGB1 using HMGB1 neutralizing antibody or BoxA, a HMGB1 antagonist. Ethyl pyruvate (EP) is the ethyl ester of pyruvic acid, known to suppress oxygen radical formation and HMGB1 secretion. Here we show that EP impaired motility, survival and proliferation of MM cells in vitro. Both BoxA and EP inhibited the activity of the pro-inflammatory transcription factor NF-kappaB, as well as reduced HMGB1 serum levels and the growth of MM xenografts in SCID mice. Taken together, our results provide a preclinical proof-of-principle that inhibition of HMGB1 activity using either HMGB1 antibody, BoxA or EP offers novel therapeutic approaches for MM treatment.

Citation Format: Haining Yang, Sandro Jube, Michele Carbone. Novel therapeutic approaches for human malignant mesothelioma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A36.