bluuebunny/crossref_metadata_2025 huggingface dataset:
Feto‐ and utero‐placental vascular adaptations to chronic maternal hypoxia in the mouse
Authors: Cahill Lindsay S. , Rennie Monique Y. , Hoggarth Johnathan , Yu Lisa X. , Rahman Anum , Kingdom John C. , Seed Mike , Macgowan Christopher K. , Sled John G.
Published: September 2017

Key points

Chronic fetal hypoxia is one of the most common complications of pregnancy and is known to cause fetal growth restriction.

The structural adaptations of the placental vasculature responsible for growth restriction with chronic hypoxia are not well elucidated.

Using a mouse model of chronic maternal hypoxia in combination with micro‐computed tomography and scanning electron microscopy, we found several placental adaptations that were beneficial to fetal growth including capillary expansion, thinning of the interhaemal membrane and increased radial artery diameters, resulting in a large drop in total utero‐placental vascular resistance.

One of the mechanisms used to achieve the rapid increase in capillaries was intussusceptive angiogenesis, a strategy used in human placental development to form terminal gas‐exchanging villi.

These results contribute to our understanding of the structural mechanisms of the placental vasculature responsible for fetal growth restriction and provide a baseline for understanding adaptive physiological responses of the placenta to chronic hypoxia.

The fetus and the placenta in eutherian mammals have a unique set of compensatory mechanisms to respond to several pregnancy complications including chronic maternal hypoxia. This study examined the structural adaptations of the feto‐ and utero‐placental vasculature in an experimental mouse model of chronic maternal hypoxia (11% O2 from embryonic day (E) 14.5–E17.5). While placental weights were unaffected by exposure to chronic hypoxia, using micro‐computed tomography, we found a 44% decrease in the absolute feto‐placental arterial vascular volume and a 30% decrease in total vessel segments in the chronic hypoxia group compared to control group. Scanning electron microscopy imaging showed significant expansion of the capillary network; consequently, the interhaemal membrane was 11% thinner to facilitate maternal–fetal exchange in the chronic hypoxia placentas. One of the mechanisms for the rapid capillary expansion was intussusceptive angiogenesis. Analysis of the utero‐placental arterial tree showed significant increases (24%) in the diameter of the radial arteries, resulting in a decrease in the total utero‐placental resistance by 2.6‐fold in the mice exposed to chronic maternal hypoxia. Together these adaptations acted to preserve placental weight whereas fetal weight was decreased.
Thermal-Hydraulics Program in Support of Canadian SCWR Concept Development
Authors: Leung Laurence K. H. , Nava-Dominguez Armando
Published: September 2017

The thermal-hydraulics program in support of the development of the Canadian supercritical water-cooled reactor (SCWR) concept has undergone several phases. It focused on key parameters such as heat transfer, critical flow, and stability of fluids at supercritical pressures. Heat-transfer experiments were performed with tubes, annuli, and bundles in water, carbon dioxide (CO2), or refrigerant flows. Data from these experiments have led to enhancement in understanding of the phenomena, improved prediction methods, and verified analytical tools. In addition, these experiments facilitated the investigation of separate effects on heat transfer (such as geometry, diameter, spacing device, and transient). Chocking flow characteristics were studied experimentally with sharp-edged nozzles of two different sizes of opening. Experimental data have been applied in improving the critical-flow correlation in support of accident analyses. A one-dimensional (1D) analytical model for instability phenomena has been developed and assessed against the latest experimental data for quantifying the prediction capability and applicability.
Performance Analysis of the Small-Scale α-Type Stirling Engine Using Computational Fluid Dynamics Tools
Authors: Buliński Zbigniew , Szczygieł Ireneusz , Kabaj Adam , Krysiński Tomasz , Gładysz Paweł , Czarnowska Lucyna , Stanek Wojciech
Published: September 2017

This paper presents the computational fluid dynamics (CFD) model of small-scale α-type Stirling engine. The developed mathematical model comprises of unsteady Reynolds averaged Navier–Stokes set of equations, i.e., continuity, momentum, and energy equations; turbulence was modeled using standard κ–ω model. Moreover, presented numerical model covers all modes of heat transfer inside the engine: conduction, convection, and radiation. The model was built in the framework of the commercial CFD software ANSYS fluent. Piston movements were modeled using dynamic mesh capability in ANSYS fluent; their movement kinematics was described based on the crankshaft geometry and it was implemented in the model using user-defined functions written in C programming language and compiled with a core of the ANSYS fluent software. The developed numerical model was used to assess the performance of the analyzed Stirling engine. For this purpose, different performance measures were defined, including coefficient of performance (COP), exergy efficiency, and irreversibility factor. The proposed measures were applied to evaluate the influence of different heating strategies of the small-scale α-type Stirling engine.
Numerical Determinationof Critical Condensate Saturation in Gas Condensate Reservoirs
Authors: Yi Yang , Li Juhua , Ji Lei
Published: September 2017

Critical condensate saturation, Scc, is a key parameter for the evaluation of well deliverability in gas condensate reservoirs. We propose a new method to determine Scc by performing three-phase flow simulations with three-dimensional (3D) pore network model. First, we establish a network model with random fractal methodology. Second, based on the condensation model in the literature of Li and Firoozabadi, we develop a modified condensation model to describe the condensation phenomenon of gas with connate water in the porous medium. The numerical model is verified by experimental measurements in the literature. Then, we investigate the influence of different factors on the critical condensate saturation, including micro pore structure (pore radius and fractal dimension), condensate gas/oil interfacial tension (IFT), and flow rate at different irreducible water saturation, Swi. The simulation results show that Scc decreases with increasing of average pore radius, but increases with increasing of fractal dimension. In the case of the same gas/oil interfacial tension, the higher the connate water saturation, the higher the critical condensate saturation. There is a critical gas/oil interfacial tension, below the critical value, the critical condensate saturation increases drastically with increasing of interfacial tension while it keeps almost unchanged when the interfacial tension is above the critical value. The critical condensate saturation decreases with increasing in the gas flow rate. High capillary number results in low critical condensate saturation. Reasonable increase in producing pressure drop can effectively improve the flow capacity of condensate oil.
Small Changes Yield Large Results at NIST's Net-Zero Energy Residential Test Facility
Authors: Hunter Fanney A. , Healy William , Payne Vance , Kneifel Joshua , Ng Lisa , Dougherty Brian , Ullah Tania , Omar Farhad
Published: September 2017

The Net-Zero Energy Residential Test Facility (NZERTF) was designed to be approximately 60% more energy efficient than homes meeting the 2012 International Energy Conservation Code requirements. The thermal envelope minimizes heat loss/gain through the use of advanced framing and enhanced insulation. A continuous air/moisture barrier resulted in an air exchange rate of 0.6 air changes per hour at 50 Pa. The home incorporates a vast array of extensively monitored renewable and energy efficient technologies including an air-to-air heat pump system with a dedicated dehumidification cycle; a ducted heat-recovery ventilation (HRV) system; a whole house dehumidifier; a photovoltaic system; and a solar domestic hot water system. During its first year of operation, the NZERTF produced an energy surplus of 1023 kWh. Based on observations during the first year, changes were made to determine if further improvements in energy performance could be obtained. The changes consisted of installing a thermostat that incorporated control logic to minimize the use of auxiliary heat, using a whole house dehumidifier in lieu of the heat pump's dedicated dehumidification cycle, and reducing the ventilation rate to a value that met but did not exceed code requirements. During the second year of operation, the NZERTF produced an energy surplus of 2241 kWh. This paper describes the facility, compares the performance data for the 2 years, and quantifies the energy impact of the weather conditions and operational changes.
Draft Genome Sequence of Solibacillus kalamii, Isolated from an Air Filter Aboard the International Space Station
Authors: Seuylemezian Arman , Singh Nitin K. , Vaishampayan Parag , Venkateswaran Kasthuri
Published: September 2017

We report here the draft genome of
Solibacillus kalamii
ISSFR-015, isolated from a high-energy particulate arrestance filter aboard the International Space Station. The draft genome sequence of this strain contains 3,809,180 bp with an estimated G+C content of 38.61%.
Genome Sequences of 30 Escherichia coli O157:H7 Isolates Recovered from a Single Dairy Farm and Its Associated Off-Site Heifer-Raising Facility
Authors: Kim Seon-Woo , Karns Jeffrey S. , Van Kessel Jo Ann S. , Haley Bradd J.
Published: September 2017

Cattle are the primary reservoir of
Escherichia coli
O157:H7, the most frequently isolated serotype of enterohemorrhagic
E. coli
infections among humans in North America. To evaluate the diversity of
E. coli
O157:H7 isolates within a single dairy herd, the genomes of 30 isolates collected over a 7-year period were sequenced.
Draft Genome Sequence of an Obligate Psychrophilic Yeast,
Candida psychrophila
NRRL Y-17665
T
Authors: Brejová Broňa , Lichancová Hana , Brázdovič Filip , Cillingová Andrea , Neboháčová Martina , Tomáška Ľubomír , Vinař Tomáš , Nosek Jozef
Published: September 2017

Candida psychrophila
is an obligate psychrophilic yeast classified into the family
Debaryomycetaceae
(
Saccharomycotina
). Here, we report the draft genome sequence of the type strain, NRRL Y-17665. The genome sequence is 11.2 Mb long and codes for 5,827 predicted proteins.
Draft Genome Sequences of Sphingomonas mucosissima DSM 17494 and Sphingomonas dokdonensis DSM 21029
Authors: Poehlein Anja , Wübbeler Jan Hendrik , Daniel Rolf , Steinbüchel Alexander
Published: September 2017

Sphingomonas mucosissima
and
Sphingomonas dokdonensis
are Gram-negative chemoheterotrophic strictly aerobic rods or cocci. The genomes (3.453 Mb and 3.587 Mb, respectively) contain 3,279 and 3,329 predicted protein-encoding genes, respectively. The genome of
S. dokdonensis
harbors a 90-kb plasmid.
Draft Genome Sequence of
Methanothermobacter
sp. Strain EMTCatA1, Reconstructed from the Metagenome of a Thermophilic Electromethanogenesis-Catalyzing Biocathode
Authors: Kobayashi Hajime , Sun Xiaohan , Fu Qian , Maeda Haruo , Sato Kozo
Published: September 2017

A draft genome of
Methanothermobacter
sp. strain EMTCatA1 was reconstructed from a metagenome of a thermophilic electromethanogenic biocathode. This genome will provide information about methanogens catalyzing methanogenesis at the biocathodes.
Whole-Genome Sequence of Streptococcus agalactiae Strain S13, Isolated from a Fish Eye from a Nile Tilapia Farm in Southern Brazil
Authors: Facimoto César T. , Chideroli Roberta T. , Gonçalves Daniela D. , Carmo Anderson O. do , Kalaphotakis Evanguedes , Pereira Ulisses de Pádua
Published: September 2017

Streptococcus agalactiae
is an important pathogen to world aquaculture due to its high mortality rates in fish farms and consequent economic losses. Our study presents the complete genome sequence of strain S13, isolated from a tilapia farm outbreak in southern Brazil.
A quality improvement approach to cognitive assessment on hospice admission: could we use the 4AT or Short CAM?
Authors: Baird Lucy , Spiller Juliet Anne
Published: September 2017

BackgroundPrevalence studies show that 13%–42% of patients admitted to specialist palliative care inpatient units have delirium. Symptoms of delirium are often subtle and easily missed, or misdiagnosed as fatigue or depression, and so the use of a screening tool could improve early identification and management of delirium and lead to improved outcomes. Patients admitted to hospices are often frail and tired, therefore a quick and easy-to-use method of cognitive assessment is essential.

MethodsA quality improvement (QI) approach (PDSA: Plan, Do, Study, Act) was used to improve screening for delirium on admission to a hospice unit. A baseline measure was taken of the rate of performance of cognitive assessment on admission. Five PDSA cycles were then undertaken which involved implementing change and then evaluating results through auditing case notes and interviewing staff.

ResultsThe first cycle determined staff preference between two cognitive assessment methods: the Short Confusion Assessment Method and the four 'A's Test (4AT). Two further PDSA cycles embedded the 4AT (the preferred tool) into the admission process, establishing it as a usable tool in the hospice setting for up to 92% of admissions. A subsequent cycle showing poor sustainability prompted staff education and changes to admission documentation, resulting in an increase in cognitive assessment being performed, from 50% to 76%.

ConclusionThe 4AT is a usable tool in the hospice inpatient setting to assess patients’ cognitive state on admission and can easily be incorporated into the admission process. The QI approach highlighted the need to link staff awareness of their use of the screening tool with perceived improvements in the treatment of delirium, which prompted the creation and implementation of a ‘Delirium Checklist’. Some initial lack of sustainability was addressed by staff education and changes to the admission paperwork to ensure compliance with the use of the 4AT and sustained improvement in screening for cognitive impairment.
Fewer REBOA complications with smaller devices and partial occlusion: evidence from a multicentre registry in Japan
Authors: Matsumura Yosuke , Matsumoto Junichi , Kondo Hiroshi , Idoguchi Koji , Ishida Tokiya , Kon Yuri , Tomita Keisuke , Ishida Kenichiro , Hirose Tomoya , Umakoshi Kensuke , Funabiki Tomohiro
Published: September 2017

Background

Resuscitative endovascular balloon occlusion of the aorta (REBOA) performed by emergency physicians has been gaining acceptance as a less invasive technique than resuscitative thoracotomy.

Objective

To evaluate access-related complications and duration of occlusions during REBOA.

Methods

Patients with haemorrhagic shock requiring REBOA, from 18 hospitals in Japan, included in the DIRECT-IABO Registry were studied. REBOA-related characteristics were compared between non-survivors and survivors at 24 hours. 24-Hour survivors were categorised into groups with small (≤8 Fr), large (≥9 Fr) or unusual sheaths (oversized or multiple) to assess the relationship between the sheath size and complications. Haemodynamic response, occlusion duration and outcomes were compared between groups with partial and complete REBOA.

Results

Between August 2011 and December 2015, 142 adults undergoing REBOA were analysed. REBOA procedures were predominantly (94%) performed by emergency medicine (EM) physicians. The median duration of the small sheath (n=53) was 19 hours compared with 7.5 hours for the larger sheaths (P=0.025). Smaller sheaths were more likely to be removed using external manual compression (96% vs 45%, P<0.001). One case of a common femoral artery thrombus (large group) and two cases of amputation (unusual group) were identified. Partial REBOA was carried out in more cases (n=78) and resulted in a better haemodynamic response than complete REBOA (improvement in haemodynamics, 92% vs 70%, P=0.004; achievement of stability, 78% vs 51%, P=0.007) and allowed longer occlusion duration (median 58 vs 33 min, P=0.041). No statistically significant difference in 24-hour or 30-day survival was found between partial and complete REBOA.

Conclusion

In Japan, EM physicians undertake the majority of REBOA procedures. Smaller sheaths appear to have fewer complications despite relatively prolonged placement and require external compression on removal. Although REBOA is a rarely performed procedure, partial REBOA, which may extend the occlusion duration without a reduction in survival, is used more commonly in Japan.
Enduring enrolments in West Virginia’s Medicaid programme due to severe injury
Authors: Smith Michael , Miller Ted R , Zaloshnja Eduard
Published: September 2017

Objective

To assess frequency, duration and costs of Medicaid conversions that occur when severe injury causes patients to enrol in Medicaid to pay their hospital bills. Once enrolled, Medicaid pays all their medical bills, not simply their injury bill.

Data sources

2000–2005 West Virginia Medicaid claims data and 2000–2006 eligibility data for new enrollees under the age of 65. To model national costs, published Medicaid conversion rates across 14 states for 2003 and 2008 Healthcare Cost and Utilization Program Nationwide Inpatient Sample data.

Methods

We identified enrollees who had hospital inpatient claims for injury within 30 days of enrolment, then tabulated eligibility duration and payments by year and in aggregate. For those with open-ended eligibility, we assumed future annual claims payments would equal average payments in eligibility years 5–6. We multiplied the mean payments data adjusted to national prices with the estimated conversions nationally.

Results

Overall, 5.4% of hospitalised patients with injury in West Virginia converted to Medicaid, with 17% of conversions on Medicaid 7 years post injury. In 2010 dollars, Medicaid payments averaged $93 900 per conversion for non-injury medical care before the age of 65. Conversions added an estimated $87 in payments for non-injury care to governments’ medical payments per medically treated injury in the USA. They added 14% to governments’ gunshot and assault medical payments, 7.5% to its road crash medical payments and 6% to its total injury medical payments.

Conclusions

These findings increase the rationale for governments to partner in injury prevention efforts.
John Maelor Gittins
Authors: Duncanson Graham
Published: September 2017

John Gittins was a small animal vet who excelled at surgery.
Parallel careers: a parasitologist and a vet
Authors: Wright Ian
Published: September 2017

Ian Wright heads the European Scientific Counsel Companion Animal Parasites (ESCCAP) UK and Ireland, which involves some international travel. He and his wife are also practice owners and they have two children. He admits that work‐life balance can be a challenge
BVA offers support in practice veterinary ethics
Authors: Wensley Sean
Published: September 2017

Sean Wensley, BVA Senior Vice President discusses how the growth of veterinary ethics has prompted the need for additional support and learning for veterinary teams.
The privilege of connecting with your clients
Authors: Mansell Nicky
Published: September 2017

Nicky Mansell, one of the Young Vet Network representatives on BVA Council, reflects on the importance of keeping your clients in mind.
Career advice and practice management support at the London Vet Show
Authors: Davies Zoe
Published: September 2017

Zoe Davies, BVA Marketing Manager, outlines this year's programme for the BVA career stream and financial one‐to‐ones at London Vet Show.
Recent graduate places at Northern Ireland dinner
Authors: Cotton Helena
Published: September 2017

Helena Cotton, BVA Public Affairs Manager, explains how recent graduates can get involved with BVA's annual dinners.
Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer
Authors: Wang Ting , Du Mingxuan , Ji Zhenyu , Ding Cong , Wang Chengbo , Men Yingli , Liu Shimeng , Liang Taotao , Liu Xin , Kang Qiaozhen
Published: September 2017

Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.
Two-step wireline log analysis of overpressure in the Bekapai Field, Lower Kutai Basin, Indonesia
Authors: Ramdhan Agus M. , Goulty Neil R.
Published: September 2017

As part of our effort to improve pore-pressure estimation in diagenetically altered mudstones, we have used wireline logs to estimate disequilibrium compaction and unloading contributions to the hard overpressure encountered in the Bekapai Field, Lower Kutai Basin. The maximum vertical effective stress that the overpressured mudstones have experienced is estimated from the density log using Dutta's relationship between vertical effective stress and void ratio. The sonic–density cross-plot is then used to estimate the sonic reference trend: that is, the expected sonic response if the mudstones were currently at maximum vertical effective stress. Finally, comparison of the sonic log with the sonic reference trend gives the unloading contribution to overpressure using Bowers’ unloading relationship between the vertical effective stress and velocity. In spite of poor data quality, fair results were obtained showing a steady increase in disequilibrium compaction overpressure below the top of the sharp pressure ramp. Immediately below the pressure ramp, the unloading contribution to overpressure dominates, with gas generation being the most likely cause. Our interpretation explains the pressure and wireline log data in this deltaic setting satisfactorily, resolving a debate on overpressure-generation mechanisms in the shelfal area of the basin that has been ongoing for 25 years.
Active Learning for Classification with Maximum Model Change
Authors: Cai Wenbin , Zhang Yexun , Zhang Ya , Zhou Siyuan , Wang Wenquan , Chen Zhuoxiang , Ding Chris
Published: September 2017

Most existing active learning studies focus on designing sample selection algorithms. However, several fundamental problems deserve investigation to provide deep insight into active learning. In this article, we conduct an in-depth investigation on active learning for classification from the perspective of model change. We derive a general active learning framework for classification called
maximum model change
(MMC), which aims at querying the influential examples. The model change is quantified as the difference between the model parameters before and after training with the expanded training set. Inspired by the stochastic gradient update rule, the gradient of the loss with respect to a given candidate example is adopted to approximate the model change. This framework is applied to two popular classifiers: support vector machines and logistic regression. We analyze the convergence property of MMC and theoretically justify it. We explore the connection between MMC and uncertainty-based sampling to provide a uniform view. In addition, we discuss its potential usability to other learning models and show its applicability in a wide range of applications. We validate the MMC strategy on two kinds of benchmark datasets, the UCI repository and ImageNet, and show that it outperforms many state-of-the-art methods.
A Classification of Locality in Network Research
Authors: Stein Michael , Fischer Mathias , Schweizer Immanuel , Mühlhäuser Max
Published: September 2017

Limiting the knowledge of individual nodes is a major concern for the design of distributed algorithms. With the LOCAL model, theoretical research already established a common model of locality that has gained little practical relevance. As a result, practical research de facto lacks any common locality model. The only common denominator among practitioners is that a local algorithm is distributed with a restricted scope of interaction. This article closes the gap by introducing four practically motivated classes of locality that successively weaken the strict requirements of the LOCAL model. These classes are applied to categorize and survey 36 local algorithms from 12 different application domains. A detailed comparison shows the practicality of the classification and provides interesting insights. For example, the majority of algorithms limit the scope of interaction to at most two hops, independent of their locality class. Moreover, the application domain of algorithms tends to influence their degree of locality.
VFI-Based Power Management to Enhance the Lifetime of High-Performance 3D NoCs
Authors: Das Sourav , Lee Dongjin , Choi Wonje , Doppa Janardhan Rao , Pande Partha Pratim , Chakrabarty Krishnendu
Published: September 2017

The emergence of 3D network-on-chip (NoC) has revolutionized the design of high-performance and energy-efficient manycore chips. However, the anticipated performance gain can be compromised due to the degradation and failure of vertical links (VLs). The Through-Silicon-Via (TSV)-enabled VLs may fail due to workload-induced stress; the failure of a VL can affect the neighboring VLs, thereby causing a cascade of failures and reducing the lifetime of the chip. To enhance the reliability of 3D NoC-enabled manycore chips, we propose to incorporate a voltage-frequency island (VFI)-based power management strategy that helps to reduce the energy consumption and hence, the workload-induced stress of the highly utilized VLs. The adopted power-management strategy relies on control decisions about the voltage/frequency (V/F) levels on VLs. We demonstrate that compared to the well-known spare TSV allocation and adaptive routing strategies, power management is more effective in enhancing the reliability of a 3D NoC. VFI-based power management improves the reliability of the 3D NoC by one order of magnitude compared to both adaptive routing and spare allocation while running popular SPLASH-2 and PARSEC benchmarks. The principal benefit of power management is that it is capable of reducing the operating temperature of the system, which in turn enhances the Mean-Time-To-Failure (MTTF) of the VLs and reliability of the overall 3D NoC.
An Adaptive Markov Model for the Timing Analysis of Probabilistic Caches
Authors: Chen Chao , Beltrame Giovanni
Published: September 2017

Accurate timing prediction for real-time embedded software execution is becoming a problem due to the increasing complexity of computer architecture, and the presence of mixed-criticality workloads. Probabilistic caches were proposed to set bounds to Worst Case Execution Time (WCET) estimates and help designers improve real-time embedded system resource use. Static Probabilistic Timing Analysis (SPTA) for probabilistic caches is nevertheless difficult to perform, because cache accesses depend on execution history, and the computational complexity of SPTA makes it intractable for calculation as the number of accesses increases. In this paper, we explore and improve SPTA for caches with evict-on-miss random replacement policy using a state space modeling technique. A nonhomogeneous Markov model is employed for single-path programs in discrete-time finite state space representation. To make this Markov model tractable, we limit the number of states and use an adaptive method for state modification. Experiments show that compared to the state-of-the-art methodology, the proposed adaptive Markov chain approach provides better results at the occurrence probability of 10
−15
: in terms of accuracy, the state-of-the-art SPTA results are more conservative, by 11% more on average. In terms of computation time, our approach is not significantly different from the state-of-the-art SPTA.
Marked for Life: Epigenetic Effects of Endocrine Disrupting Chemicals
Authors: Jacobs Miriam N. , Marczylo Emma L. , Guerrero-Bosagna Carlos , Rüegg Joëlle
Published: September 2017

The presence of human-made chemical contaminants in the environment has increased rapidly during the past 70 years. Harmful effects of such contaminants were first reported in the late 1950s in wildlife and later in humans. These effects are predominantly induced by endocrine disrupting chemicals (EDCs), chemicals that mimic the actions of endogenous hormones and leave marks at several levels of organization in organisms, from physiological outcomes (phenotypes) to molecular alterations, including epigenetic modifications. Epigenetic mechanisms play pivotal roles in the developmental processes that contribute to determining adult phenotypes, through so-called epigenetic programming. While there is increasing evidence that EDC exposure during sensitive periods of development can perturb epigenetic programming, it is unclear whether these changes are truly predictive of adverse outcomes. Understanding the mechanistic links between EDC-induced epigenetic changes and phenotypic endpoints will be critical for providing improved regulatory tools to better protect the environment and human health from exposure to EDCs.
IL-17 in the lung: the good, the bad, and the ugly
Authors: Gurczynski Stephen J. , Moore Bethany B.
Published: September 2017

The IL-17 family of cytokines has emerged over the last two decades as a pleiotropic group of molecules that function in a wide variety of both beneficial and detrimental (pathological) processes, mainly in mucosal barrier tissue. The beneficial effects of IL-17 expression are especially important in the lung, where exposure to foreign agents is abundant. IL-17A plays an important role in protection from both extracellular bacteria and fungi, as well as viruses that infect cells of the mucosal tracts. IL-17 coregulated cytokines, such as IL-22, are involved in maintaining epithelial cell homeostasis and participate in epithelial cell repair/regeneration following inflammatory insults. Thus, the IL-17/IL-22 axis is important in both responding to, and recovering from, pathogens. However, aberrant expression or overexpression of IL-17 cytokines contributes to a number of pathological outcomes, including asthma, pneumonitis, and generation or exacerbation of pulmonary fibrosis. This review covers the good, bad, and ugly aspects of IL-17 in the lung.
Blockade of extracellular heat shock protein 90α by 1G6-D7 attenuates pulmonary fibrosis through inhibiting ERK signaling
Authors: Dong Hangming , Luo Lishan , Zou Mengchen , Huang Chaowen , Wan Xuan , Hu Yahui , Le Yanqing , Zhao Haijin , Li Wei , Zou Fei , Cai Shaoxi
Published: September 2017

Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis. Heat shock protein 90 (Hsp90) participates in organ fibrosis, and extracellular Hsp90α (eHsp90α) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90α monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents a protective effect by inactivating the profibrotic pathway. Our results showed that eHsp90α was increased in mice with BLM-induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-β1 induced eHsp90α secretion, concomitantly promoting HFL-1 activation and ECM synthesis. 1G6-D7-mediated inhibition of eHsp90α significantly blocked these effects, meanwhile inhibiting downstream profibrotic pathways such as ERK, Akt, and P38. Human recombinant (hr)Hsp90α mimicked the effects of TGF-β1, by activating profibrotic pathways and by upregulating LRP-1. Moreover, ERK inhibition effectively blocked the effect of (hr)Hsp90α. In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production, which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis.
Salvianolic Acid A Inhibits OX‐LDL Effects on Exacerbating Choroidal Neovascularization via Downregulating CYLD
Authors: Mao Ke , Shu Wanting , Liu Libin , Gu Qing , Qiu Qinghua , Wu XingWei
Published: September 2017

Backgrounds. Age‐related macular degeneration is closely related to lipid oxidation, while relationship between OX‐LDL and choroidal neovascularization is unclear. Recently, cylindromatosis is proved to regulate angiogenesis. However, its role in CNV progression remained unclear. Salvianolic acid A is widely used in vascular diseases. We investigated the relationship between OX‐LDL and CNV and explore antineovascularization mechanism of Sal A. Methods. C57BL6/J mice were randomized into four groups and injected with PBS or OX‐LDL, together with Sal A for one week. CNV was induced by laser; CNV severity was analyzed by fundus fluorescein angiography, H&E staining, and choroid flat mount after 1 week. In in vitro experiments, ARPE‐19 and HUVECs were cultured with OX‐LDL (with or without Sal A) for 48 hours. Angiogenic proteins, cell junction integrity, and tube formation were measured. CYLD siRNA and specific inhibitors were used to explore mechanisms of CYLD in promoting OX‐LDL‐induced CNV progression. Results. OX‐LDL promoted laser‐induced CNV volume by increasing VEGF, PDGF, and CYLD levels. Sal A antagonized OX‐LDL effects and restrained CNV progression by decreasing VEGF/PDGF/CYLD, increasing antiangiostatin levels, and promoting P62‐CYLD‐TRAF6 interaction. Conclusions. We demonstrated oxidation damage exacerbates CNV progression, and Sal A could be a clinical therapeutic reagent to exudative AMD.
Genetic Ancestry Is not Associated with Breast Cancer Recurrence or Survival in U.S. Latina Women Enrolled in the Kaiser Permanente Pathways Study
Authors: Engmann Natalie J. , Ergas Isaac J. , Yao Song , Kwan Marilyn L. , Roh Janise M. , Ambrosone Christine B. , Kushi Lawrence H. , Fejerman Laura
Published: September 2017

Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival.

Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer–specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years.

Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86–1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77–1.17), or all-cause mortality (HR = 0.93; 95% CI, 0.80–1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations.

Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality.

Impact: Improving health care access and quality may reduce breast cancer disparities among U.S. Latinas. Cancer Epidemiol Biomarkers Prev; 26(9); 1466–9. ©2017 AACR.
No Association of Vitamin D Pathway Genetic Variants with Cancer Risks in a Population-Based Cohort of German Older Adults
Authors: Ordóñez-Mena José Manuel , Schöttker Ben , Saum Kai U. , Holleczek Bernd , Burwinkel Barbara , Wang Thomas J. , Brenner Hermann
Published: September 2017

Background: Several investigations assessed the association of vitamin D receptor (VDR) SNPs with cancer risk. Less is known about the implications of other vitamin D pathway SNPs on cancer risk.

Methods: In a population-based cohort study of 9,949 German older adults, we used Cox regression to assess the association of 6 SNPs in the VDR, vitamin D–binding protein (GC), 7-dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), and vitamin D 24-hydroxylase (CYP24A1) genes with total and site-specific cancer incidence endpoints.

Results: Overall, no association of SNPs with cancer incidence endpoints was observed, except for a genotype score based on SNPs associated with lower 25(OH)D, which was associated with higher lung cancer risk [HR, 1.20; 95% confidence intervals (CI), 1.03–1.39], although this was no longer significant after correcting for multiple testing.

Conclusions: Our data provide little to no evidence of a major influence of vitamin D genetic predisposition on cancer risks.

Impact: Large-scale genetic epidemiology consortia and meta-analysis of smaller published studies are needed to verify a potential modest influence of genetic variation in the association of vitamin D with the risk of cancer. Cancer Epidemiol Biomarkers Prev; 26(9); 1459–61. ©2017 AACR.
Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies
Authors: Siu Lillian L. , Ivy S. Percy , Dixon Erica L. , Gravell Amy E. , Reeves Steven A. , Rosner Gary L.
Published: September 2017

Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era. Clin Cancer Res; 23(17); 4950–8. ©2017 AACR.

See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
NAD Synthesis Pathway Interference Is a Viable Therapeutic Strategy for Chondrosarcoma
Authors: Peterse Elisabeth F.P. , van den Akker Brendy E.W.M. , Niessen Bertine , Oosting Jan , Suijker Johnny , de Jong Yvonne , Danen Erik H.J. , Cleton-Jansen Anne-Marie , Bovée Judith V.M.G.
Published: September 2017

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2-mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored. Eleven chondrosarcoma cell lines were treated with NAMPT inhibitors, in which the effect on cell viability, colony formation, and 3D collagen invasion was assessed. The expression level of NAMPT and NAPRT transcripts in chondrosarcoma cells was determined by qRT-PCR. Methylation of the NAPRT promoter was evaluated using a previously published dataset of genome-wide methylation. In addition, a methylation dataset was used to determine methylation of the NAPRT promoter in 20 IDH1/2-mutated cartilage tumors. Chondrosarcoma cells showed a dose-dependent decrease in cell viability, 3D collagen invasion, and colony formation upon treatment with NAMPT inhibitors, in which nearly half of the cell lines demonstrated absolute IC50s in the low nanomolar range. Increasing IC50s correlated to increasing NAPRT expression levels and decreasing NAPRT promoter methylation. No correlation between IDH1/2 mutation status and sensitivity for NAMPT inhibitors was observed. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. In conclusion, this study identified NAMPT as a potential target for treatment of chondrosarcoma.

Implications: Chondrosarcoma patients, especially those of high histologic grade with lower expression and hypermethylation of NAPRT, may benefit from inhibition of the NAD synthesis pathway. Mol Cancer Res; 15(12); 1714–21. ©2017 AACR.
Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions
Authors: Domchek Susan M.
Published: September 2017

Summary: Reversion mutations associated with PARP inhibitor resistance have been identified in tumors with RAD51C, RAD51D, and PALB2 as well as BRCA1 and BRCA2 mutations. Multiple different reversion mutations can occur in a single patient, and they can be detected by analysis of circulating cell-free DNA. Cancer Discov; 7(9); 937–9. ©2017 AACR.

See related article by Kondrashova et al., p. 984.

See related article by Quigley et al., p. 999.

See related article by Goodall et al., p. 1006.
Relationship between Contrast-Enhanced CT and Clinicopathological Characteristics and Prognosis of Non-Small Cell Lung Cancer
Authors: Yang Hai , Fan Heng-Xin , Song Li-Hong , Xie Ji-Cheng , Fan Shu-Feng
Published: September 2017

Background: This study investigated the relationship between contrast-enhanced computed tomography (CECT) and clinicopathological characteristics and prognosis of non-small cell lung cancer (NSCLC). Methods: A total of 198 NSCLC patients admitted to Enze Hospital from February 2009 to July 2012 underwent pre-surgical CECT to investigate parameters such as tumor size, CECT enhancement, lymph node enlargement, and lymph node size. Chi-square and log-rank tests were used to analyze associations between CECT parameters and pathological features as well as correlations of CECT parameters with prognosis. A Cox proportional hazard model and logistic regression analysis were applied to identify independent risk factors for prognosis. Results: Tumor size, CECT enhancement, and lymph node enlargement and size were related to degree of differentiation, TNM stage, and lymph node metastasis. Tumor size, lymph node enlargement and metastasis, lymph node size, and CECT enhancement were independent risk factors for NSCLC prognosis. Large tumors and lymph nodes, tumor enhancement, and enlarged and metastatic lymph nodes indicated a poor prognosis. Conclusion: Our study indicates that CECT features can be associated with clinicopathological characteristics and can predict the prognosis of patients with NSCLC.
Of Horse-Caterpillars and Homologies: Evolution of the Hippocampus and Its Name
Authors: Butler Ann B.
Published: September 2017

The hippocampus was first named in mammals based on the appearance of its gross morphological features, one end of it being fancied to resemble the head of a horse and the rest of it a silkworm, or caterpillar. A hippocampus, occupying the most medial part of the telencephalic pallium, has subsequently been identified in diverse nonmammalian taxa, but in which the “horse-caterpillar” morphology is lacking. While some strikingly similar functional similarities have been identified, questions of its homology (“sameness”) across these taxa and about the very fundamental relationship of structure to function in central nervous system structures remain open. The hippocampal formation of amniotes participates in allocentric (external landmark) spatial navigation, memory, and attention to novel stimuli, and these functions generally are shared across amniotes despite variation in its morphological features. Substantially greater deviation in its morphology occurs in anamniotes, including amphibians and ray-finned fishes (actinopterygians), but its functions of allocentric spatial navigation and/or memory have been found to be preserved by studies in these taxa. Its shared functional roles cannot be used as evidence of structural homology, but given that other criteria indicate homology of the medial pallial derivative across these clades, the similar functions themselves may be regarded as homologous functions if they are based on the same cellular mechanisms and connections. The question arises as to whether the similar functions are performed by as yet undiscovered, shared morphological features or by different features that accomplish the same results via different mechanisms of neural function.
Are There Place Cells in the Avian Hippocampus?
Authors: Sherry David F. , Grella Stephanie L. , Guigueno Mélanie F. , White David J. , Marrone Diano F.
Published: September 2017

Birds possess a hippocampus that serves many of the same spatial and mnemonic functions as the mammalian hippocampus but achieves these outcomes with a dramatically different neuroanatomical organization. The properties of spatially responsive neurons in birds and mammals are also different. Much of the contemporary interest in the role of the mammalian hippocampus in spatial representation dates to the discovery of place cells in the rat hippocampus. Since that time, cells that respond to head direction and cells that encode a grid-like representation of space have been described in the rat brain. Research with homing pigeons has discovered hippocampal cells, including location cells, path cells, and pattern cells, that share some but not all properties of spatially responsive neurons in the rodent brain. We have recently used patterns of immediate-early gene expression, visualized by the catFISH method, to investigate how neurons in the hippocampus of brood-parasitic brown-headed cowbirds respond to spatial context. We have found cells that discriminate between different spatial environments and are re-activated when the same spatial environment is re-experienced. Given the differences in habitat and behaviour between birds and rodents, it is not surprising that spatially responsive cells in their hippocampus and other brain regions differ. The enormous diversity of avian habitats and behaviour offers the potential for understanding the general principles of neuronal representation of space.