bluuebunny/crossref_metadata_2025 huggingface dataset:
Some prior considerations about dissonance to understand its reduction: Comment on McGrath (2017)
Authors: Vaidis David C. , Bran Alexandre
Published: August 2018

In a recent contribution to this journal, McGrath (2017) provided an overview of the reduction process of cognitive dissonance theory. To discuss the reduction strategy, she reviewed relevant studies and highlighted the means to reduce dissonance as well as factors that promote their use. In the present paper, we would like to raise some points which have not been considered by McGrath. First, we stress the historical development of the theory that orientated the study of attitude change as the major means of reduction. Second, we raise the issue of the term “dissonance” and the different conceptions about its reduction. Last, on the strength of published data, we insist on resistance to change as a central and essential factor to predict the reduction strategy. We consider that these elements, in addition to McGrath's valuable contribution, provide a comprehensive understanding of the current view of the dissonance reduction process.
Expression of the Hippo signalling effectors YAP and TAZ in canine mammary gland hyperplasia and malignant transformation of mammary tumours
Authors: Rico Charlène , Boerboom Derek , Paquet Marilène
Published: August 2018

Canine mammary tumours (CMTs) are common neoplasms in dogs that feature many of the clinical, genetic and molecular characteristics of human breast cancer. Despite their high metastatic potential, few adjuvant chemotherapeutic treatment options exist for malignant CMTs, and the development of novel, targeted pharmacological approaches will require a better understanding of their pathogenesis. As recent evidence suggests that dysregulated Hippo signalling is involved in the development and progression of breast cancer, we sought to determine if this pathway could also play a role in CMT. The expression of the Hippo signalling effectors YAP and TAZ was analysed by immunoblotting and immunohistochemistry in samples including normal mammary gland, lobular hyperplasia, benign tumours and malignant tumours of all grades. We found a significant increase in TAZ (but not YAP) expression occurred in lobular hyperplasia relative to normal mammary gland, suggesting a role for TAZ in non‐neoplastic epithelial proliferation. Nuclear expression of both TAZ and YAP were significantly higher in malignant tumours than in benign ones, suggesting that Hippo dysregulation could play a role in CMT malignant transformation. No differences in YAP or TAZ expression were detected between grades of malignant tumours. Together, our results indicate that alterations in Hippo signalling may play a role in the pathogenesis of CMT, in a manner similar to breast cancer. Hippo pathway components may therefore represent targets for the development of novel chemotherapeutic agents that could be useful for the treatment of both the human and canine diseases.
The current status of avian aspergillosis diagnoses: Veterinary practice to novel research avenues
Authors: Savelieff Masha G. , Pappalardo Lucia , Azmanis Panagiotis
Published: August 2018

Aspergillus fungal infections continue to be a significant cause of morbidity and mortality in birds that can, in part, be attributed to the lack of a diagnostic “gold standard” for Aspergillus infection, and which delays the diagnosis, treatment, and outcome of avian patients. At present, none of the available methods in veterinary care can detect aspergillosis early enough and with the accuracy, precision, and specificity required of an ideal diagnostic tool. Therefore, researching methods of Aspergillus detection is still an active area of inquiry, and novel techniques continue to emerge. This review will provide a brief overview of current clinical methods, with an emphasis on avian care, in addition to a series of techniques in development that could offer distinct advantages over existing methods.
Global reggae and the appropriation of Jamaican Creole
Authors: Gerfer Anika
Published: August 2018

The present study investigates the sociolinguistics of globalisation and performance, focusing on the linguistic appropriation of Jamaican Creole (JC) by white reggae artists in reggae performances and interviews.1By adopting a multi‐faceted approach including a phonetic, morpho‐syntactic, and lexical analysis of the singing and speaking style of seven reggae artists and bands from the USA, Bermuda, and Europe, this study explores the similarities and differences between on‐ and offstage uses of Jamaican Creole, and whether the singers’ access and exposure to this variety as well as the topic of the song has an effect on their language behaviour. The findings provide evidence for the claim that Jamaican Creole has developed into a prestigious linguistic resource in non‐Jamaican artists’ performances of a global reggae persona, both on‐ and offstage.
Investigation of Blood Hormone and Respiratory Parameters in Active and Passive Tolerance Period after Anaerobic Test in Football Players
Authors: Akyol Betül , Şerare Serdar
Published: August 2018

The aim of the study was to determine the changes in blood hormone and respiratory parameters in recovery phases. 28 voluntary men participated in the study, with an average age of 19.75±1.61 years and playing active football during the league season. Wingate Anaerobic Power Test and Respiratory Function Test (RFT) were applied to the subjects who were randomly divided into two groups, active and passive group. Blood samples were collected from and RFT was applied to all subjects before and after the test. Cortisol hormone, Partial Oxygen Pressure (PO2), Partial Carbon Dioxide Pressure (PCO2), lactic acid (LA) values were obtanied with datas taken from blood samples. The forced vital capacity (FVC), forced expiratory volume (FEV1), and rate of 1. Second of forced expiratory volume to the forced vital capacity (FEV1 / FVC) were measured by the PFT test. SPSS 24.0 program was used for statistical evaluation of the data. As a result; both 5-minute active and passive recovery methods did not reduce the cortisol ratio, but continued to increase in minute increments. In terms of PO2, passive recovery was found to be a more effective method than active recovery. 5 minutes of active and passive recovery did not reduce LA level and did not affect each other significantly. FVC and FEV1 values were found to be higher in the active recovery group than in the passive recovery group at the onset of AT recovery. Active recovery was found to have positive effects on vital capacity FVC and FEV1.
Passive heat therapy protects against endothelial cell hypoxia‐reoxygenation via effects of elevations in temperature and circulating factors
Authors: Brunt Vienna E. , Wiedenfeld‐Needham Karen , Comrada Lindan N. , Minson Christopher T.
Published: August 2018

Key Points

Accumulating evidence indicates that passive heat therapy (chronic use of hot tubs or saunas) has widespread physiological benefits, including enhanced resistance against novel stressors (‘stress resistance’).

Using a cell culture model to isolate the key stimuli that are likely to underlie physiological adaptation with heat therapy, we showed that both mild elevations in temperature (to 39°C) and exposure to serum from human subjects who have undergone 8 weeks of heat therapy (i.e. altered circulating factors) independently prevented oxidative and inflammatory stress associated with hypoxia‐reoxygenation in cultured endothelial cells.

Our results elucidate some of the mechanisms (i.e. direct effects of temperature vs. circulating factors) by which heat therapy seems to improve resistance against oxidative and inflammatory stress.

Heat therapy may be a promising intervention for reducing cellular damage following ischaemic events, which has broad implications for patients with cardiovascular diseases and conditions characterized by ‘chronic’ ischaemia (e.g. peripheral artery disease, metabolic diseases, obesity).

Repeated exposure to passive heat stress (‘heat therapy’) has widespread physiological benefits, including cellular protection against novel stressors. Increased heat shock protein (HSP) expression and upregulation of circulating factors may impart this protection. We tested the isolated abilities of mild heat pretreatment and serum from human subjects (n = 10) who had undergone 8 weeks of heat therapy to protect against cellular stress following hypoxia‐reoxygenation (H/R), a model of ischaemic cardiovascular events. Cultured human umbilical vein endothelial cells were incubated for 24 h at 37°C (control), 39°C (heat pretreatment) or 37°C with 10% serum collected before and after 8 weeks of passive heat therapy (four to five times per week to increase rectal temperature to ≥ 38.5°C for 60 min). Cells were then collected before and after incubation at 1% O2 for 16 h (hypoxia; 37°C), followed by 20% O2 for 4 h (reoxygenation; 37°C) and assessed for markers of cell stress. In control cells, H/R increased nuclear NF‐κB p65 protein (i.e. activation) by 106 ± 38%, increased IL‐6 release by 37 ± 8% and increased superoxide production by 272 ± 45%. Both heat pretreatment and exposure to heat therapy serum prevented H/R‐induced NF‐κB activation and attenuated superoxide production; by contrast, only exposure to serum attenuated IL‐6 release. H/R also decreased cytoplasmic haemeoxygenase‐1 (HO‐1) protein (known to suppress NF‐κB), in control cells (−25 ± 8%), whereas HO‐1 protein increased following H/R in cells pretreated with heat or serum‐exposed, providing a possible mechanism of protection against H/R. These data indicate heat therapy is capable of imparting resistance against inflammatory and oxidative stress via direct heat and humoral factors.
Day-to-Day Reliability of Nonlinear Methods to Assess Walking Dynamics
Authors: Raffalt P. C. , Alkjær T. , Brynjólfsson B. , Jørgensen L. , Bartholdy C. , Henriksen M.
Published: August 2018

The present study investigated the day-to-day reliability (quantified by the absolute and relative reliability) of nonlinear methods used to assess human locomotion dynamics. Twenty-four participants of whom twelve were diagnosed with knee osteoarthritis completed 5 min of treadmill walking at self-selected preferred speed on two separate days. Lower limb kinematics were recorded at 100 Hz and hip, knee, and ankle joint angles, three-dimensional (3D) sacrum marker displacement and stride time intervals were extracted for 170 consecutive strides. The largest Lyapunov exponent and correlation dimension were calculated for the joint angle and sacrum displacement data using three different state space reconstruction methods (group average, test-retest average, individual time delay and embedding dimension). Sample entropy and detrended fluctuation analysis (DFA) were applied to the stride time interval time series. Relative reliability was assessed using intraclass correlation coefficients and absolute reliability was determined using measurement error (ME). For both joint angles and sacrum displacement, there was a general pattern that the group average state space reconstruction method provided the highest relative reliability and lowest ME compared to the individual and test-retest average methods. The DFA exhibited good reliability, while the sample entropy showed poor reliability. The results comprise a reference material that can inspire and guide future studies of nonlinear gait dynamics.
Particle behavior and its contribution to film growth in a remote silane plasma
Authors: Kim Yeonwon , Koga Kazunori , Shiratani Masaharu
Published: August 2018

Time-dependent behavior of particles measured using the laser light scattering method in a remote silane plasma has been investigated using both optical emission spectroscopy and quartz crystal microbalance. Laser-scattered particles were observed from 0.3 s after the plasma ignition and scattering increased rapidly until 3.0 s. In the 0–0.3 s region where no particles were observed, SiH and Hβ emission intensity as well as Si/SiH and Hβ/SiH intensity ratios increased rapidly. Laser-scattered particles decreased in number, 3.0 s after plasma discharge, but the deposition rate measured using the quartz crystal microbalance increased linearly. The relationships between time-resolved images of particle movements and their contribution to film deposition as well as plasma characteristics such as SiH and Hβ are presented. The results show that the particles contributing to film growth at the early stage of plasma are much higher in number than those in the stabilized state.
The Complexity of Sport: Universal Challenges and Their Impact on Women in Sport
Authors: Weatherford Gwendolyn M. , Block Betty A. , Wagner Fredrick L.
Published: August 2018

The experiences of women in sport continue to necessitate deliberation, reflection, new ways of thinking, and further discourse in the continued pursuit of opportunity and equality. The subsequent and parallel impact on the roles that women play in sport as athletes and leaders are revealed by identifying the complexities and social realities that are vying and contending for relevance. The notion of complexity offers a novel conceptualization revealing contexts and competing points of view that challenge progress and equality for women in sport. Complexity refers to the state of the world assailed by increased amounts of data, facts, tasks, evidence, and arguments that yield uncertainty in the current age and unpredictability for the future. Universal challenges characteristic of complexity include globalization; digital technology; interpenetration of the wider society; participation, access, and equal opportunity; marketization; competition; and quality assurance and assessment. As a result, these old and new realities raise questions related to what we know about the current state of sport, sport experiences of women, and the properties of sport that seem difficult to manage. The purpose of this paper is to offer complexity as a theoretical lens by which to examine sport, discuss the universal and formidable challenges that face sport, and, more specifically, discuss the impact they have on women in sport.
Genome mapping of seed-borne allergens and immunoresponsive proteins in wheat
Authors: Juhász Angéla , Belova Tatiana , Florides Chris G. , Maulis Csaba , Fischer Iris , Gell Gyöngyvér , Birinyi Zsófia , Ong Jamie , Keeble-Gagnère Gabriel , Maharajan Amudha , Ma Wujun , Gibson Peter , Jia Jizeng , Lang Daniel , Mayer Klaus F. X. , Spannagl Manuel ,   International Wheat Genome Sequencing Consortium, Tye-Din Jason A. , Appels Rudi , Olsen Odd-Arne
Published: August 2018

We present a comprehensive analysis of variation in genes and gene expression of allergens and immunoresponsive proteins in wheat.
Sequence-programmable covalent bonding of designed DNA assemblies
Authors: Gerling Thomas , Kube Massimo , Kick Benjamin , Dietz Hendrik
Published: August 2018

Site-specific ultraviolet “point welding” makes designed DNA objects much more durable.
Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169)
Authors: Lupien Andréanne , Vocat Anthony , Foo Caroline Shi-Yan , Blattes Emilyne , Gillon Jean-Yves , Makarov Vadim , Cole Stewart T.
Published: August 2018

The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of
Mycobacterium tuberculosis
. Intensive efforts have been made to develop new antibiotics or to repurpose old drugs, and several of these are currently being evaluated in clinical trials for their antitubercular activity.
Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts
Authors: Milev Miroslav P , Graziano Claudio , Karall Daniela , Kuper Willemijn F E , Al-Deri Noraldin , Cordelli Duccio Maria , Haack Tobias B , Danhauser Katharina , Iuso Arcangela , Palombo Flavia , Pippucci Tommaso , Prokisch Holger , Saint-Dic Djenann , Seri Marco , Stanga Daniela , Cenacchi Giovanna , van Gassen Koen L I , Zschocke Johannes , Fauth Christine , Mayr Johannes A , Sacher Michael , van Hasselt Peter M
Published: August 2018

Background

The combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging.

Objective

The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illness-induced encephalopathy and episodes of rhabdomyolysis, followed by developmental arrest, epilepsy and tetraplegia.

Methods

Whole exome sequencing was used to identify pathogenic variants in the two individuals. Biochemical and cell biological analyses were performed on fibroblasts from these individuals and a yeast two-hybrid analysis was used to assess protein-protein interactions.

Results

Probands shared a homozygous TRAPPC2L variant (c.109G>T) resulting in a p.Asp37Tyr missense variant. TRAPPC2L is a component of transport protein particle (TRAPP), a group of multisubunit complexes that function in membrane traffic and autophagy. Studies in patient fibroblasts as well as in a yeast system showed that the p.Asp37Tyr protein was present but not functional and resulted in specific membrane trafficking delays. The human missense mutation and the analogous mutation in the yeast homologue Tca17 ablated the interaction between TRAPPC2L and TRAPPC10/Trs130, a component of the TRAPP II complex. Since TRAPP II activates the GTPase RAB11, we examined the activation state of this protein and found increased levels of the active RAB, correlating with changes in its cellular morphology.

Conclusions

Our study implicates a RAB11 pathway in the aetiology of the TRAPPC2L disorder and has implications for other TRAPP-related disorders with similar phenotypes.
Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome
Authors: Pauli Silke , Altmüller Janine , Schröder Simone , Ohlenbusch Andreas , Dreha-Kulaczewski Steffi , Bergmann Carsten , Nürnberg Peter , Thiele Holger , Li Yun , Wollnik Bernd , Brockmann Knut
Published: August 2018

Background

Joubert syndrome (JBTS) is a rare neurodevelopmental disorder with marked phenotypic variability and genetic heterogeneity. Homozygous or compound heterozygous mutations in the KIAA0586 gene on chromosome 14q23 are known to be associated with JBTS-23. The frameshift variant c.428delG is the most frequent KIAA0586 variant reported in JBTS-23; yet, homozygosity of this variant was observed in two patients with JBTS-23. However, homozygosity of the c.428delG variant was recently reported as well in one healthy individual.

Objective

To clarify whether the frameshift variant c.428delG in KIAA0586 is pathogenic in the homozygous state.

Methods

Whole-exome sequencing as well as RNA analysis were performed.

Results

We identified biallelic mutations, including the variant c.428delG and a splice site variant c.1413–1G>C, in KIAA0586 in two siblings with clinical and MRI features of JBTS. The c.1413–1G>C variant was inherited from the healthy father. The c.428delG variant was found in the healthy mother in a homozygous state in blood lymphocytes, hair root cells and buccal epithelial cells. RNA analysis revealed that the transcript harbouring the c.428delG variant was expressed in blood cells from the healthy mother, indicating that transcripts harbouring this variant elude the mechanism of nonsense-mediated mRNA decay.

Conclusion

Considering this and the high allele frequency of 0.003117 in the gnomAD database, we conclude that c.428delG represents a JBTS disease-causing variant only if present in compound heterozygous state with a more severe KIAA0586 variant, but not in a homozygous situation.
The influence of spatially variable and connected recruitment on complex stock dynamics and its ecological and management implications
Authors: Guan Lisha , Chen Yong , Wilson James A. , Waring Timothy , Kerr Lisa A. , Shan Xiujuan
Published: August 2018

To evaluate the influence of spatially variable and connected recruitments at spawning component scale on complex stock dynamics, a typical agent-based complex stock was modeled based on the Atlantic cod (Gadus morhua) stock in the Gulf of Maine. We simulated three scenarios with different degrees of connectivity (i.e., individual exchange) between the spatially variable recruitments of 36 spawning components within four subpopulations under the stock. Subsequently, the temporal trends were compared for different scenarios in age-1 recruitment, spawning stock biomass, and local depletion proportion of the overall complex stock and the individual subpopulations. Results show that increased recruitment connectivity from 0.1–0.2 to 0.6–0.8 between various components tends to increase the productivity and stability of a complex stock at local and global scales and reduce the proportion of depleted components due to overfishing. Moreover, depletions of less productive components may occur without a substantial reduction in the overall complex stock biomass and recruitment.
Recovery of acidified Sudbury, Ontario, Canada, lakes: a multi-decade synthesis and update
Authors: Keller W. (Bill) , Heneberry Jocelyne , Edwards Brie A.
Published: August 2018

The Sudbury region of northeastern Ontario, Canada, provides one of the world’s best examples of the resilience of aquatic ecosystems after reductions in atmospheric contaminant deposition. Thousands of lakes around the Sudbury metal smelters were badly damaged by acid deposition. Lakes closest to the smelters were also contaminated by metal particulates. However, large reductions in atmospheric SO2and metal emissions starting in the early 1970s have led to widespread chemical improvements in these lakes, and recovery has been observed for various aquatic biota. Studies of Sudbury-area lakes are advancing our understanding of chemical and biological lake recovery; however, recovery is a complicated process and much remains to be learned. Biological recovery has often been slow to follow chemical recovery, and it has become apparent that the recovery of lakes from acidification is closely linked to interactions with other large-scale environmental stressors like climate change and Ca declines. Thus, in our multiple-stressor world, recovery may not bring individual lakes back to their exact former state. However, with time, substantial natural biological recovery toward typical lake communities can be reasonably expected for most but not necessarily all biota. For organisms with limited dispersal ability, particularly fish, human assistance may be necessary to re-establish typical communities. In lakes where food webs have been severely altered, re-establishment of typical diverse fish communities may in fact be an important element aiding the recovery of other important components of aquatic ecosystems including zooplankton and benthic macroinvertebrates. In the lakes closest to the smelters, where historically watersheds as well as lakes were severely damaged, the recovery of aquatic systems will be closely linked to ongoing terrestrial recovery and rehabilitation, particularly through the benefits of increased inputs of terrestrially derived organic matter. The dramatic lake recovery observed in the Sudbury area points to a brighter future for these lakes. However, continued monitoring will be needed to determine future changes and help guide the management and protection of Sudbury-area lakes in this multiple-stressor age.
Structures, elastic, electronic properties and phase stability of Ni–Sc intermetallic compounds from first-principles investigation
Authors: Wu Yali , Guo Xuefeng
Published: August 2018

First-principles method based on density functional theory has been performed to study the lattice structures, elastic properties, Debye temperatures, electronic properties and phase stability of Ni–Sc intermetallic compounds systematically. The calculated lattice parameters are close to available experimental data. The analysis results of formation enthalpies indicate that the Ni–Sc compounds are all thermodynamically stable and NiSc is the most stable. Besides, these compounds are also mechanically stable according to the mechanical stability criterion. The obtained shear modulus G and Young’s modulus E show that Ni5Sc is the stiffest and the most covalent compound. The discussion about G/B (the ratio of shear modulus to bulk modulous), Poisson’s ratio [Formula: see text] and Cauchy pressure demonstrate that all Ni–Sc compounds are ductile and NiSc2 is the most ductile phase, followed by NiSc. The results of Debye temperatures indicate that Ni5Sc has the stronger covalent bonds than others. Finally, the electronic properties are investigated to reveal the underlying mechanical properties.
Electronic properties of armchair graphene nanoribbons under uniaxial strain and electric field
Authors: Jiang Li-Feng , Xu Lei , Zhang Jun
Published: August 2018

The armchair graphene nanoribbons (AGNRs) can be either semiconducting or metallic, depending on their widths. We investigate the electronic properties of AGNRs under uniaxial strain and electric field. We find that the bulk gap decreases gradually with the increase of the electric field for semiconducting case, but it cannot vanish completely in an appropriate range, which is similar to that of a single uniaxial strain. However, a suitable combination of electric field and uniaxial strain can lead to that the energy gap completely vanishes and reopens. For the metallic case, the bulk gap can display the same opening and closing behavior under an electric field and uniaxial strain. Finally, an interesting quantum phenomenon is obtained by applying a perpendicular magnetic field.
Calculations of defect structures and spin Hamiltonian parameters of copper in (70 − x)Bi2O3–xLi2O–30 (ZnO–B2O3) glasses at different compositions
Authors: Zhang Fu , Wu Shao-Yi , Tan Qin-Qin , Zhang Qing , Chen Gui-Jun
Published: August 2018

Defect structures and spin Hamiltonian parameters (SHPs) and the corresponding composition dependencies are quantitatively analyzed for divalent copper in ([Formula: see text])Bi2O3–[Formula: see text]Li2O–30(ZnO–B2O3) ([Formula: see text] mol.%) glasses by means of the relevant perturbation formulas of an octahedral 3d9 cluster with tetragonal elongation distortion. The [CuO6][Formula: see text] groups are subject to the moderate tetragonal elongation distortions of 4% due to the Jahn–Teller effect. The cubic crystal-field (CF) parameter, orbital reduction factor, tetragonal elongation ratio and core polarization constant exhibit respective piecewise linear functions of Li2O composition [Formula: see text], which suitably account for the experimental optical spectra and the SHPs at various compositions. Mechanisms of these composition dependencies for the related quantities can be explained as the variations of immediate CFs strength and copper–oxygen electron cloud admixtures with increasing Li2O composition.
Study of the photoluminescence properties of Eu2+-doped Ca(AlxGa1−x)2S4 solid solutions at high excitation intensity and low temperature
Authors: Asadov E. G. , Tagiev O. B. , Tagiev K. O. , Hadjieva G. S. , Leanenia M. S. , Urmanov B. D. , Babuskin D. I. , Yablonskii G. P. , Dang N. T.
Published: August 2018

The investigation of photoluminescence (PL) properties of Ca(Al[Formula: see text]Ga[Formula: see text]S4:Eu[Formula: see text] solid solutions with [Formula: see text] = 0, 0.1, 0.2 and 0.3 synthesized for the first time was performed in wide temperature and excitation power density ranges. It is shown that PL intensity decreases by only 20–30% for different [Formula: see text] in the temperature range from 10 K to 300 K. The extreme stability of shape and position of the emission spectra was found in the range of excitation power density from [Formula: see text] W/cm2 to [Formula: see text] W/cm2 by nanosecond pulsed radiation. The reversible PL efficiency droop was only above 104 W/cm2 of excitation power density. The PL decay time constant was found to be of about 560 ns to 595 ns for [Formula: see text] ranging between 0.1 and 0.3 at room temperature.
MMP-2: is too low as bad as too high in the cardiovascular system?
Authors: Hardy Eugenio , Hardy-Sosa Anette , Fernandez-Patron Carlos
Published: August 2018

Matrix metalloproteinase (MMP)-2 cleaves a broad spectrum of substrates, including extracellular matrix components (responsible for normal tissue remodeling) and cytokines (modulators of the inflammatory response to physiological insults such as tissue damage). MMP-2 expression is elevated in many cardiovascular pathologies (e.g., myocardial infarction, hypertensive heart disease) where tissue remodeling and inflammatory responses are perturbed. Thus, it has generally been assumed that blockade of MMP-2 activity will yield therapeutic effects. Here, we provide a counterargument to this dogma based on 1) preclinical studies on Mmp2-null ( Mmp2−/−) mice and 2) clinical studies on patients with inactivating MMP2 gene mutations. Furthermore, we put forward the hypothesis that, when MMP-2 activity falls below baseline, the bioavailability of proinflammatory cytokines normally cleaved and inactivated by MMP-2 increases, leading to the production of cytokines and cardiac secretion of phospholipase A2activity into the circulation, which stimulate systemic inflammation that perturbs lipid metabolism in target organs. Finally, we suggest that insufficient understanding of the consequences of MMP-2 deficiency remains a major factor in the failure of MMP-2 inhibitor-based therapeutic approaches. This paucity of knowledge precludes our ability to effectively intervene in cardiovascular and noncardiovascular pathologies at the level of MMP-2.
Effects of placental growth factor deficiency on behavior, neuroanatomy, and cerebrovasculature of mice
Authors: Kay Vanessa R. , Rätsep Matthew T. , Cahill Lindsay S. , Hickman Andrew F. , Zavan Bruno , Newport Margaret E. , Ellegood Jacob , Laliberte Christine L. , Reynolds James N. , Carmeliet Peter , Tayade Chandrakant , Sled John G. , Croy B. Anne
Published: August 2018

Preeclampsia, a hypertensive syndrome occurring in 3–5% of human pregnancies, has lifelong health consequences for fetuses. Cognitive ability throughout life is altered, and adult stroke risk is increased. One potential etiological factor for altered brain development is low concentrations of proangiogenic placental growth factor (PGF). Impaired PGF production may promote an antiangiogenic fetal environment during neural and cerebrovascular development. We previously reported delayed vascularization of the hindbrain, altered retinal vascular organization, and less connectivity in the circle of Willis in Pgf−/− mice. We hypothesized Pgf−/− mice would have impaired cognition and altered brain neuroanatomy in addition to compromised cerebrovasculature. Cognitive behavior was assessed in adult Pgf−/− and Pgf+/+ mice by four paradigms followed by postmortem high-resolution MRI of neuroanatomy. X-ray microcomputed tomography imaging investigated the three-dimensional cerebrovascular geometry in another cohort. Pgf−/− mice exhibited poorer spatial memory, less depressive-like behavior, and superior recognition of novel objects. Significantly smaller volumes of 10 structures were detected in the Pgf−/− compared with Pgf+/+ brain. Pgf−/− brain had more total blood vessel segments in the small-diameter range. Lack of PGF altered cognitive functions, brain neuroanatomy, and cerebrovasculature in mice. Pgf−/− mice may be a preclinical model for the offspring effects of low-PGF preeclampsia gestation.
Abstract A024: Probe Miner: objective, quantitative, data-driven assessment of chemical probes for target validation
Authors: Antolin Albert A. , Tym Joe E. , Komianou Angeliki , Collins Ian , Workman Paul , Al-Lazikani Bissan
Published: August 2018

Chemical probes are important, widely used reagents for understanding biologic systems and for target validation. However, selection of chemical probes is largely subjective and prone to historical and commercial biases. Despite many publications discussing the aspirational properties of chemical probes and the proposal of "fitness factors" to be considered when assessing chemical tools, scientists often select probes through web-based searchers or previous literature that are heavily biased towards older and often flawed probes or use vendor catalogues that do not discriminate between probes. Here, we analyze the scope and quality of published bioactive molecules and uncover large biases and limitations of chemical tools in public databases that need to be urgently addressed and should be always considered when using chemical tools. We also provide the online Probe Miner resource (http://probeminer.icr.ac.uk) capitalizing on the plethora of public pharmacologic data to enable quantitative, unbiased, objective, Big Data-driven assessment of chemical probes and complement expert-curated approaches. We assess >1.8m compounds for their suitability as chemical tools against 2,220 human targets, demonstrating that large-scale public data can contribute to improving chemical probe assessment and prioritization to empower researchers in the selection of chemical tools for biomedical research and target validation.

Citation Format: Albert A. Antolin, Joe E. Tym, Angeliki Komianou, Ian Collins, Paul Workman, Bissan Al-Lazikani. Probe Miner: objective, quantitative, data-driven assessment of chemical probes for target validation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A024.
Abstract A034: Correlating programmed death ligand 1 (PD-L1) expression, mismatch repair deficiency, and outcomes across tumor types: Implications for immunotherapy
Authors: Kim Seung T. , Lim Sung
Published: August 2018

The identification of biomarkers associated with response to therapeutic agents is central to optimizing outcomes. Expression of the immune checkpoint proteins PD-1/L1 and DNA mismatch repair deficiency (dMMR) may be predictive response biomarkers for immunotherapies, but their overlap requires further study. We prospectively conducted PD-L1 and MMR immunohistochemistry (IHC) on 430 consecutive patients with advanced gastrointestinal (GI) cancers, genitourinary (GU) cancers, or rare cancers between June 2012 and March 2016. Correlation between PD-L1 and dMMR was analyzed via t-test and overall survival by the Kaplan-Meier method. Overall, 393/430 (91.4%) patients were evaluable for PD-L1 expression by IHC. The frequency of tumor PD-L1 positivity (PD-L1+) was 16.5% (65/393). Among anatomic tumor sites PD-L1+ was 28.6% in melanoma, 22.2% in GC, 20.9% in CRC, 12.5% in BTC, 7.1% in GU cancer, 6.7% in HCC, 0% in pancreatic cancer, and 0% in sarcoma. Among the 92% evaluable for MLH1/MSH2 expression cases, 18 patients (4.5%) had dMMR tumors. The dMMR was most common in GC (7.1%) followed by 6.7% in HCC, 4.4% in CRC, and 2.7% in sarcoma. Among 365 patients evaluable for both PD-L1 and MLH1/MSH2 expression, there was a significant association between the PD-L1 expression and MLH1/MSH2 loss (P = 0.01), but not with overall survival within tumor types. PD-L1 status and dMMR are overlapping putative reponse biomarkers in immunoncology. Clinical trials with biomarker enrichment for only PD-L1+ or dMMR may be inadequate to completely capture the subset of patients who may benefit. More robust immunotherapy biomarkers and careful clinical trial design are warranted.

Citation Format: Seung T. Kim, Sung Lim. Correlating programmed death ligand 1 (PD-L1) expression, mismatch repair deficiency, and outcomes across tumor types: Implications for immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A034.
Abstract A041: Gene expression alteration in chronic hypoxic PANC-1 pancreatic cancer cell line
Authors: Zihlif Malek A. , Younis Layaly Hisham Younis Hisham , Sharab Ahmad Sharab
Published: August 2018

Background: Cancer cells grow uncontrollably by disregarding the normal rule of cell division; the resulting overcrowding of cancer cells leads to a decrease in oxygen availability, which is known as hypoxia. The role of tumor hypoxia has become a main focus in cancer research since it is a driving force in promoting tumor progression, malignancy, and resistance to therapy. Hypoxia is a prominent feature of the tumor microenvironment of pancreatic tumors. Objective: The main purpose of this study was to identify the changes in gene expression associated with chronic hypoxia in PANC-1 pancreatic cancer cell line. Methodology: Pancreatic cancer cells (PANC-1) were exposed to 8-hour hypoxic episodes (<1% oxygen) three times a week for a total of 40 episodes. The alterations in gene expression were examined using the real-time based PCR array technology after 20 and 40 episodes of hypoxia and compared to normoxic cells. Chemo-resistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay. Cell migration was evaluated using wound healing assay. Results: Noticeable gene expression changes were identified after 20 and 40 episodes of hypoxia. No changes were common in both stages, with most genes rebounding at the level of 40 episodes. Notably, genes HIF1AN, HMOX-1, and PKM have been remarkably upregulated by 6.9, 4.5, and 3.4 fold, respectively, after 20 hypoxic shots. The half-maximal inhibitory concentration (IC50) of doxorubicin in PANC-1 cells has increased by approximately 2.7 fold after 20 episodes of hypoxia and increased by approximately 3.6 fold after 40 episodes compared to normoxic cells. Conclusion: This study provided evidence that exposing cells to prolonged periods of hypoxia (weeks) results in different expression changes than those induced by short-term hypoxia (<72 hours). It also approved induction of chemo-resistance by chronic hypoxia. Finally, it proposed HIF1AN, HMOX-1, and PKM as a potential biomarkers for hypoxia in pancreatic cancer and as main players in the cellular response to chronic hypoxia.

Citation Format: Malek A. Zihlif, Layaly Hisham Younis Hisham Younis, Ahmad Sharab Sharab. Gene expression alteration in chronic hypoxic PANC-1 pancreatic cancer cell line [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A041.
Abstract A043: Identification of a patient enrichment strategy supporting development of a potent and selective dual TTK/CLK2 inhibitor CC-671
Authors: Xu Shuichan , Tran Tam , Shi Tao , Jiang Ning , Zhu Dan , Riggs Jennifer R. , Boylan John
Published: August 2018

CC-671 is a potent and selective TTK1 (Mps1) and CLK2 inhibitor. In support of a phase I proof of concept, we used an image-based, multiplex cell assay to evaluate the antiproliferative impact of CC-671 across a broad panel of cancer cell lines representing tumors from various anatomic origins. CC-671 potently and selectively inhibited proliferation and induced apoptosis. Cell lines representing leukemia, lymphoma, colorectal cancer (CRC), head and neck (H&N), and bladder cancers were uniformly sensitive to CC-671 while the cell lines from other tumor types, such as breast and lung cancers, were differentially sensitive to CC-671. Cell cycle analysis using phospho-histone H3 (pHH3) as a mitosis biomarker suggested that CC-671 had cell line-specific mitotic effects. CC-671 accelerated mitotic exit in 120 cell lines while causing mitotic block in 37 cell lines at concentrations < 1 μM. Custom gene expression signatures correlating with sensitivity or resistance were generated. Mapping these signatures to a gene expression database of clinical tumor samples identified additional CC-671 sensitive tumor types including Wilms tumor, superficial bladder cancer, triple-negative, and luminal Btype breast cancer, and several squamous cell carcinomas (lung, esophageal, cervical, H&N).

To identify a breast cancer patient selection profile, the CC-671 antiproliferative activity was assessed in a panel of 49 breast cancer cell lines. CC-671 potently inhibited the growth of breast cancer cell lines with 50% inhibitory concentrations (IC50 values) < 100 nM in 14 lines and > 10 μM in 21 lines. Triple-negative breast cancer (TNBC) cell lines were significantly more sensitive to CC-671 than non-TNBC (ER+/PR+ and/or HER2+) lines. Within TNBC, the mesenchymal (M) and basal-like 1 (BL1) subtypes were more sensitive to CC-671. In addition, TNBC lines with cancer stem cell (CSC)-like properties were also sensitive, indicating a potential role of TTK1 and CLK2 in cancer stem cells. Interestingly, mutations in several genes (phosphatidylinositol-4,5-bisphosphate 3kinase 110 kDa catalytic subunit alpha [PIK3CA], serine/threonine kinase 11 [STK11], and phosphatase and tensin homolog [PTEN]) in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway tend to associate with CC-671 TNBC sensitivity. These mutational correlates are being confirmed in additional TNBC lines.

Citation Format: Shuichan Xu, Tam Tran, Tao Shi, Ning Jiang, Dan Zhu, Jennifer R. Riggs, John Boylan. Identification of a patient enrichment strategy supporting development of a potent and selective dual TTK/CLK2 inhibitor CC-671 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A043.
Abstract A113: Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures
Authors: Graham Nicholas , Minasyan Aspram , Christofk Heather , Mellinghoff Ingo , Graeber Thomas G.
Published: August 2018

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.

Citation Format: Nicholas Graham, Aspram Minasyan, Heather Christofk, Ingo Mellinghoff, Thomas G. Graeber. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A113.
Abstract A121: Transient increase of tumor perfusion using hypertonic saline
Authors: Patiño Angelica M. , Junqueira Mara S. , Zhang Xiaomeng , Bailey Kate , Ibrahim-Hashim Arig , Gillies Robert J. , Chammas Roger
Published: August 2018

Intravenous administration of hypertonic saline solution (HSS) induces systemic circulatory changes including increases in systemic blood pressure and effective circulating volume, as well as local effects on microvasculature. We analyzed the effects produced by 7.5% HSS administration on tumor hemodynamics through functional imaging studies. Blood velocity assessed by color Doppler ultrasound was increased after HSS injection compared to PBS in B16F10 (p=0.019), SK-MEL-147 (p=0.028), and 4T1 (p=0.015). No statistical differences were observed on the segmental kidney arteries (p=0.476). Dynamic contrast-enhanced ultrasound (CEUS) was used to assess functional blood volume in B16F10, HCT-116, and MDA-MB-231 tumor xenografts, kidney and muscle tissues (n=3 per group). After HSS injection, relative blood volume was increased in B16F10 (p=0.022) and HCT-116 (p=0.039) but not on MDA-MB-231 (p=0.186). There was a mild change that was not statistically significant on the normal tissues (kidney p=0.957; muscle p=0.104). Finally, dynamic contrast-enhanced MRI (DCE-MRI) was performed in B16F10 tumors (n=4) and showed that contrast distribution increases in the HSS group (p=0.002). All statistical tests were two sided. HSS 7.5% is a potential vehicle to transiently increase blood supply in specific tumors, and therefore could be used to enhance intratumoral delivery of different molecules for either tumor diagnosis or treatment. Supported by an UICC Yamagiwa-Yoshida grant and FAPESP (2013/06120-8 and 2015/22814-5).

Citation Format: Angelica M. Patiño, Mara S. Junqueira, Xiaomeng Zhang, Kate Bailey, Arig Ibrahim-Hashim, Robert J. Gillies, Roger Chammas. Transient increase of tumor perfusion using hypertonic saline [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A121.