bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety, hemodynamic effects, and detection of acute xenon inhalation: rationale for banning xenon from sport
Authors: Lawley Justin S. , Gatterer Hannes , Dias Katrin A. , Howden Erin J. , Sarma Satyam , Cornwell William K. , Hearon Christopher M. , Samels Mitchel , Everding Braden , Bruick Richard K. , Hendrix Max , Piper Thomas , Thevis Mario , Levine Benjamin D.
Published: August 2019

This study aimed to quantify the sedative effects, detection rates, and cardiovascular responses to xenon. On 3 occasions, participants breathed xenon (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) in a nonblinded design. Sedation was monitored by a board-certified anesthesiologist. During 70% xenon, participants were also verbally instructed to operate a manual value with time-to-task failure being recorded. Beat-by-beat hemodynamics were measured continuously by ECG, photoplethysmography, and transcranial Doppler. Over 48 h postadministration, xenon was measured in blood and urine by gas chromatography-mass spectrometry. Xenon caused variable levels of sedation and restlessness. Task failure of the self-operating value occurred at 60–90 s in most individuals. Over the first minute, 50% and 70% xenon caused a substantial reduction in total peripheral resistance ( P < 0.05). All dosages caused an increase in cardiac output ( P < 0.05). By the end of xenon inhalation, slight hypertension was observed after all three doses ( P < 0.05), with an increase in middle cerebral artery velocity ( P < 0.05). Xenon was consistently detected, albeit in trace amounts, up to 3 h after all three doses of xenon inhalation in blood and urine with variable results thereafter. Xenon inhalation caused sedation incompatible with self-operation of a breathing apparatus, thus causing a potential life-threatening condition in the absence of an anesthesiologist. Yet, xenon can only be reliably detected in blood and urine up to 3 h postacute dosing.

NEW & NOTEWORTHY Breathing xenon in dosages conceivable for doping purposes (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) causes an initial rapid fall in total peripheral resistance with tachycardia and thereafter a mild hypertension with elevated middle cerebral artery velocity. These dose duration intervals cause sedation that is incompatible with operating a breathing apparatus and can only be detected in blood and urine samples with a high probability for up to ~3 h.
Interrelationships between pulse arrival time and arterial blood pressure during postural transitions before and after spaceflight
Authors: Wood Katelyn N. , Greaves Danielle K. , Hughson Richard L.
Published: August 2019

We tested the hypothesis that acute changes in arterial blood pressure (BP) when astronauts moved between supine and standing posture before and after spaceflight can be tracked by beat-to-beat changes in pulse arrival time (PAT). Nine male crewmembers (45 ± 7 yr of age; mean mission length: 165 ± 13 days) participated in a standardized supine-to-sit-to-stand test (5 min-30 s-3 min) before flight and 1 day following return to Earth with continuous monitoring of ECG and finger arterial BP. PAT was determined from the R-wave of the ECG to the foot of the BP waveform. On average, modest cardiovascular deconditioning was detected by ~10 beats/min increase in heart rate in supine and standing posture after spaceflight ( P < 0.05). When looking across the full data collection period, the r2 values between inverse of PAT (1/PAT) and systolic (SBP) and diastolic BP (DBP) varied considerably between individuals (SBP preflight 0.142 ± 0.186, postflight 0.262 ± 0.243). Individual variability was consistent during periods of transition (SBP preflight 0.284 ± 0.324, postflight 0.297 ± 0.269); however, when SBP dropped >20 mmHg, r2 was significant in 5 of 5 preflight tests and 5 of 7 postflight tests. The standard error of the estimate based on a simple linear model during both pre- and postflight testing was 9–11 mmHg for SBP and 6–7 mmHg for DBP. Overall, the results support the hypothesis that PAT tracked dynamic changes in BP. PAT as a noninvasive, nonintrusive surrogate for changes in BP could be developed as an indicator of risk for syncope on return from spaceflight or other Earth-based applications.

NEW & NOTEWORTHY Astronauts returning to Earth’s gravity are at increased risk of low blood pressure on standing. Arterial pulse arrival time tracked the decrease in arterial blood pressure on moving from supine to upright posture. Nonintrusive technology providing indicators sensitive to acute changes in blood pressure could act as an early warning system to identify risk for hypotension that place astronauts, or people on Earth, at risk of impaired cognitive performance, fainting, and falls.
Influence of priming exercise on oxygen uptake and muscle deoxygenation kinetics during moderate-intensity cycling in type 2 diabetes
Authors: Rocha Joel , Gildea Norita , O’Shea Donal , Green Simon , Egaña Mikel
Published: August 2019

The pulmonary oxygen uptake (V̇o2) kinetics during the transition to moderate-intensity exercise is slowed in individuals with type 2 diabetes (T2D), at least in part because of limitations in O2delivery. The present study tested the hypothesis that a prior heavy-intensity warm-up or “priming” exercise (PE) bout would accelerate V̇o2kinetics in T2D, because of a better matching of O2delivery to utilization. Twelve middle-aged individuals with T2D and 12 healthy controls (ND) completed moderate-intensity constant-load cycling bouts either without (Mod A) or with (Mod B) prior PE. The rates of muscle deoxygenation (i.e., deoxygenated hemoglobin and myoglobin concentration, [HHb+Mb]) and oxygenation (i.e., tissue oxygenation index) were continuously measured by near-infrared spectroscopy at the vastus lateralis muscle. The local matching of O2delivery to O2utilization was assessed by the Δ[HHb+Mb]-to-ΔV̇o2ratio. Both groups demonstrated an accelerated V̇O2kinetics response during Mod B compared with Mod A (T2D, 32 ± 9 vs. 42 ± 12 s; ND, 28 ± 9 vs. 34 ± 8 s; means ± SD) and an elevated muscle oxygenation throughout Mod B, whereas the [HHb+Mb] amplitude was greater during Mod B only in individuals with T2D. The [HHb+Mb] kinetics remained unchanged in both groups. In T2D, Mod B was associated with a decrease in the “overshoot” relative to steady state in the Δ[HHb+Mb]-to-ΔV̇o2ratio (1.17 ± 0.17 vs. 1.05 ± 0.15), whereas no overshoot was observed in the control group before (1.04 ± 0.12) or after (1.01 ± 0.12) PE. Our findings support a favorable priming-induced acceleration of the V̇o2kinetics response in middle-aged individuals with uncomplicated T2D attributed to an enhanced matching of microvascular O2delivery to utilization.

NEW & NOTEWORTHY Heavy-intensity “priming” exercise (PE) elicited faster pulmonary oxygen uptake (V̇o2) kinetics during moderate-intensity cycling exercise in middle-aged individuals with type 2 diabetes (T2D). This was accompanied by greater near-infrared spectroscopy-derived muscle deoxygenation (i.e., deoxygenated hemoglobin and myoglobin concentration, [HHb+Mb]) responses and a reduced Δ[HHb+Mb]-to-ΔV̇o2ratio. This suggests that the PE-induced acceleration in oxidative metabolism in T2D is a result of greater O2extraction and better matching between O2delivery and utilization.
Influence of dietary inorganic nitrate on blood pressure and vascular function in hypertension: prospective implications for adjunctive treatment
Authors: Broxterman Ryan M. , La Salle D. Taylor , Zhao Jia , Reese Van R. , Richardson Russell S. , Trinity Joel D.
Published: August 2019

Dietary inorganic nitrate (nitrate) is a promising adjunctive treatment to reduce blood pressure and improve vascular function in hypertension. However, it remains unknown if the efficacy of nitrate is dependent upon an elevated blood pressure or altered by medication in patients with hypertension. Therefore, blood pressure and vascular function, measured by passive leg movement (PLM) and flow-mediated dilation (FMD), were assessed following 3 days of placebo (nitrate-free beetroot juice) and nitrate (nitrate-rich beetroot juice) administration in 13 patients (age: 53 ± 12 yr) with hypertension taking antihypertensive medications ( study 1) and in 14 patients (49 ± 13 yr) with hypertension not taking antihypertensive medications ( study 2). In study 1, plasma nitrite concentration was greater for nitrate than placebo (341 ± 118 vs. 308 ± 123 nmol/L, P < 0.05), yet blood pressure and vascular function were unaltered. In study 2, plasma nitrite concentration was greater for nitrate than placebo (340 ± 102 vs. 295 ± 93 nmol/L, P < 0.01). Systolic (136 ± 16 vs. 141 ± 19 mmHg), diastolic (84 ± 13 vs. 88 ± 12 mmHg), and mean (101 ± 12 vs. 106 ± 13 mmHg) blood pressures were lower ( P < 0.05), whereas the PLM change in leg vascular conductance (6.0 ± 3.0 vs. 5.1 ± 2.6 mL·min−1·mmHg−1) and FMD (6.1 ± 2.4% vs. 4.1 ± 2.7%) were greater ( P < 0.05) for nitrate than placebo. The changes in systolic blood pressure ( r = −0.60) and FMD ( r = −0.48) induced by nitrate were inversely correlated ( P < 0.05) to the respective baseline values obtained in the placebo condition. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive medication status, per se.

NEW & NOTEWORTHY Dietary nitrate (nitrate) is a promising intervention to improve blood pressure and vascular function in hypertension. We demonstrate that these beneficial effects of nitrate are inversely related to the baseline value in a continuous manner with no distinction between antihypertensive medication status. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive mediation status.
Thermal behavior alleviates thermal discomfort during steady-state exercise without affecting whole body heat loss
Authors: Vargas Nicole T. , Chapman Christopher L. , Johnson Blair D. , Gathercole Rob , Cramer Matthew N. , Schlader Zachary J.
Published: August 2019

We tested the hypothesis that thermal behavior resulting in reductions in mean skin temperature alleviates thermal discomfort and mitigates the rise in core temperature during light-intensity exercise. In a 27 ± 0°C, 48 ± 6% relative humidity environment, 12 healthy subjects (6 men, 6 women) completed 60 min of recumbent cycling. In both trials, subjects wore a water-perfused suit top continually perfusing 34 ± 0°C water. In the behavior trial, subjects maintained their upper body thermally comfortable by pressing a button to perfuse cool water (2.2 ± 0.5°C) through the top for 2 min per button press. Metabolic heat production (control: 404 ± 52 W, behavior: 397 ± 65 W; P = 0.44) was similar between trials. Mean skin temperature was reduced in the behavior trial (by −2.1 ± 1.8°C, P < 0.01) because of voluntary reductions in water-perfused top temperature ( P < 0.01). Whole body ( P = 0.02) and local sweat rates were lower in the behavior trial ( P ≤ 0.05). Absolute core temperature was similar ( P ≥ 0.30); however, the change in core temperature was greater in the behavior trial after 40 min of exercise ( P ≤ 0.03). Partitional calorimetry did not reveal any differences in cumulative heat storage (control: 554 ± 229, behavior: 544 ± 283 kJ; P = 0.90). Thermal behavior alleviated whole body thermal discomfort during exercise (by −1.17 ± 0.40 arbitrary units, P < 0.01). Despite lower evaporative cooling in the behavior trial, similar heat loss was achieved by voluntarily employing convective cooling. Therefore, thermal behavior resulting in large reductions in skin temperature is effective at alleviating thermal discomfort during exercise without affecting whole body heat loss.

NEW & NOTEWORTHY This study aimed to determine the effectiveness of thermal behavior in maintaining thermal comfort during exercise by allowing subjects to voluntarily cool their torso and upper limbs with 2°C water throughout a light-intensity exercise protocol. We show that voluntary cooling of the upper body alleviates thermal discomfort while maintaining heat balance through convective rather than evaporative means of heat loss.
Characterization of a Mixture of Oca (Oxalis tuberosa) and Oat Extrudate Flours: Antioxidant and Physicochemical Attributes
Authors: Castro-Mendoza Marisol P. , Palma-Rodriguez Heidi M. , Heredia-Olea Erick , Hernández-Uribe Juan P. , López-Villegas Edgar O. , Serna-Saldivar Sergio O. , Vargas-Torres Apolonio
Published: August 2019

The oca (Oxalis tuberosa) is a tuber with high starch content and excellent antioxidant properties, which can be used in the production of extruded products; however, starch-rich products can be improved nutritionally through the incorporation of fibers that can result in extrudates with beneficial health properties. The aim of this work was to develop a mixture of oca (Oxalis tuberosa) and oat extrudate flours and evaluate the antioxidant and physicochemical attributes. The results showed that a higher moisture content increased the hardness, water absorption index, and density of the extrudates; however, the solubility and expansion indexes showed an inverse pattern. The addition of oat fiber had the opposite effect from moisture content on the physicochemical properties mentioned above. The cellular antioxidant activity (CAA) of the extrudates decreased when the oat fiber increased. An inverse pattern was observed when the moisture concentration was increased. The starch hydrolysis percentage and glycemic index decreased significantly when the fiber content increased. Oat fiber contributed 67.29% and 65.04% to these parameters, respectively. Oat fiber exerted a greater effect than moisture on the collets extruded in this study according to factor contributions.
Strength and Pore Structure Development of High‐Plasticity Clay Treated with MK‐Blended Cement
Authors: Guo Qian , Wei Mingli , Xue Haochen , Gao Changhui , Du Guangyin
Published: August 2019

This paper focuses on the strength development and pore structure evolution of high‐plasticity clay mixtures treated with metakaolin‐ (MK‐) blended ordinary Portland cement (OPC). The unconfined compressive strength (fcu) of treated soil mixtures is measured to study the effect of MK replacement. The microstructural study is carried out by mercury intrusion porosimetry (MIP), scanning electron microscopy (SEM), and X‐ray diffraction (XRD). The results showed that the MK replacement led to the decrease of unconfined compressive strength of OPC‐treated soil mixture cured for 28 days, but the influence on 7 days strength was negligible. However, the MK addition also enhanced the unconfined compressive strength significantly. The MK addition provided more cementitious products by secondary hydration and pozzolanic reaction, which would give rise to a notable filling effect by turning the large pores (1 to 10 μm) into smaller ones (0.1 to 1 μm). However, the MK replacement led to a decrease of cementitious products due to the lack of calcium hydroxide (CH) in soil mixture, and thus the effect on pore structure refinement was reduced. Nevertheless, the presence of MK enhanced the unconfined compressive strength cured for 7 days, due to the high reactivity of MK with CH.
Ketamine Administration Reverses Corticosterone-Induced Alterations in Excitatory and Inhibitory Transmission in the Rat Dorsal Raphe Nucleus
Authors: Sowa Joanna , Kusek Magdalena , Bobula Bartosz , Hess Grzegorz , Tokarski Krzysztof
Published: August 2019

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in human patients and ameliorates depressive-like behavioral effects of chronic stress in animal models. Chronic stress and elevated corticosterone levels have been shown to modify serotonin (5-HT) neurotransmission, and ketamine’s antidepressant-like activity involves a 5-HT-dependent mechanism. However, it is not known if and how ketamine affects the electrophysiological characteristics of neurons and synaptic transmission within the dorsal raphe nucleus (DRN), the main source of 5-HT forebrain projections. Our study was aimed at investigating the effects of a single ketamine administration on excitatory and inhibitory transmission in the DRN of rats which had previously been administered corticosterone twice daily for 7 days. Spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were then recorded from DRN projection cells in ex vivo slice preparations obtained 24 h after ketamine injection. Repeated corticosterone administration increased sEPSC frequency and decreased sIPSC frequency in DRN projection cells. There were no changes either in the amplitude of postsynaptic currents or in the excitability of these cells. In slices prepared from rats with ketamine administered after the end of corticosterone treatment, the frequencies of sEPSCs and sIPSCs were similar to those in control preparations. These data indicate that a single administration of ketamine reversed the effects of corticosterone on excitatory and inhibitory transmission in the DRN.
Experimental Study on Variation Law and Mechanism of Soil Shear Strength Parameters along the Slope
Authors: Wang Yanhai , Li Jianlin , Jiang Qiao , Huang Yisheng , Li Xinzhe
Published: August 2019

Under the action of rainwater seepage, geological origin, and human activities, the soil shear strength parameters will have spatial variability along the slope direction. After collecting samples of silty clay at a slope in the Three Gorges Reservoir area as the research object, not only the large‐scale direct shear test was carried out on the site but also the direct shear test, water content test, density test, and particle grading analysis test were carried out in the laboratory with the undisturbed soil. The variation law and mechanism of soil shear strength parameters along slope were studied. The results indicate the following: (1) The coefficient of variation of shear strength parameters along the slope is relatively large. With the decrease of the elevation of the test location, the cohesion value tends to be strengthened, while the friction angle tends to degrade. (2) The mechanism of the variation law of soil shear strength parameters along the slope, which is mainly due to the decrease of the elevation, the decrease of the edges and angles between the particles, and the increase of the clay content is determined. (3) The variation model of shear strength parameters along the slope is proposed, which can provide a reference for relevant projects.
Spatialtemporal Characteristics of Tunnel Traffic Accidents in China from 2001 to Present
Authors: Sun Hao , Wang Qiuping , Zhang Peng , Zhong Yujian , Yue Xiabing
Published: August 2019

There are often greater risks in the process of tunnel construction, and because of the unpredictable tunnel features, the risks during tunnel operation are also great. Due to the substantial growth of TTAs during the recent years, the safety issues of the tunnel traffic accidents (TTAs) have become a widely discussed topic in China. This study examined 2703 TTAs that occurred in the expressway tunnels of China, from 2001 to the present. The datasets from these accidents were analyzed in detail to determine the temporal and spatial characteristics of the traffic accidents as well as the source of the traffic accident distributions in the expressway tunnels. According to the analysis results, 58% of TTAs took place in the entrance and exit zones, and the rear end accident is the most common accident. In addition, the special festivals are liable to traffic accidents, especially during the Chinese Spring Festival. In order to reduce the accidents, special traffic service needs to be taken in key periods, the expressway tunnel operation departments should improve the management rules, and all the drivers should be educated to be more careful when they enter the tunnel.
Numerical Simulation Study on Flow and Fracture of Granular Materials
Authors: Liu Mingqing , Liu Jun , Liu Guangkun , Shan Peng , Xiao Zhimin , Zhao Futian
Published: August 2019

Flow and fracture of granular materials under external loads is a complex mechanical process, and the research on its law is still in the exploratory stage. In this paper, the flow and fracture law of granular materials is taken as the research object, and numerical algorithm compilation and program development are combined to study. Taking full advantage of the existing algorithms and developing new ones based on the existing DEM theory, a numerical simulation program for the flow and fracture of granular materials is developed. The flow and fracture process of concrete spherical granular system with diameter of 4 cm under loading rate of 70 mm/min and end of loading of 50 kN is taken as an example to verify the simulation program. At the same time, the loading experiment of the concrete spherical particle system under the same simulation conditions was also carried out. The simulation results are compared with the experimental results in three aspects: the generation location of the particle system, the relationship between the whole load and displacement, and the degree of particle breakage. The results show that the numerical simulation is in good agreement with the experimental results, which verifies the reliability of the numerical algorithm and the simulation program, and can provide support for the study of the flow and fracture process of granular materials.
Experimental Research on the Performance of the Macromolecule Colloid Fire-Extinguishing Material for Coal Seam Spontaneous Combustion
Authors: Fan Shixing , Wen Hu , Zhang Duo , Yu Zhijin
Published: August 2019

Coal resources are rich in China. They are mainly concentrated in the northwest region. But these resources also make the situation of spontaneous coal combustion hazards most serious in this area. Affected by the arid and semiarid climate, the water resource in this area is relatively scarce. In order to improve the utilization rate of water, a macromolecule colloid for coal mine fire fighting was developed in this research. The main components of the macromolecule colloid and the principle of gel formation were analyzed. The physical and chemical properties of the macromolecule colloid were analyzed by the time of gelation and the water loss. The water content of the macromolecule colloid was as high as 99%. The inhibition performance of the macromolecule colloid on coal fire was studied by the programmed heating device. The experimental results show that the macromolecule colloid has a significant inhibitory effect on the heating rate, oxygen consumption rate, and gas production rate. It inhibits the coal-oxygen composite by increasing the activation energy (Ea) of coal, which also has the effect of wrapping coal to isolate oxygen. The inhibition performance of the macromolecule colloid on coal fire disasters is better than that of water, water glass, loess compound colloids, and other traditional fire-extinguishing materials.
miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells
Authors: Mukohyama Junko , Isobe Taichi , Hu Qingjiang , Hayashi Takanori , Watanabe Takashi , Maeda Masao , Yanagi Hisano , Qian Xin , Yamashita Kimihiro , Minami Hironobu , Mimori Koshi , Sahoo Debashis , Kakeji Yoshihiro , Suzuki Akira , Dalerba Piero , Shimono Yohei
Published: August 2019

miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the “cancer stem cell” (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221–reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer.

Significance:

These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.
Curatopes Melanoma: A Database of Predicted T-cell Epitopes from Overly Expressed Proteins in Metastatic Cutaneous Melanoma
Authors: Lischer Christopher , Eberhardt Martin , Jaitly Tanushree , Schinzel Cornelia , Schaft Niels , Dörrie Jan , Schuler Gerold , Vera Julio
Published: August 2019

Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at https://www.curatopes.com.

Significance:

A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.
Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma
Authors: Li Xiaolong , Martinez-Ledesma Emmanuel , Zhang Chen , Gao Feng , Zheng Siyuan , Ding Jie , Wu Shaofang , Nguyen Nghi , Clifford Stephan C. , Wen Patrick Y. , Ligon Keith L. , Yung W.K. Alfred , Koul Dimpy
Published: August 2019

PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy.

Significance:

These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.
Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression
Authors: Wettersten Hiromi I. , Weis Sara M. , Pathria Paulina , Von Schalscha Tami , Minami Toshiyuki , Varner Judith A. , Cheresh David A.
Published: August 2019

Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the coenrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 “don't eat me” signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers.

Significance:

Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvβ3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.
Precision Therapy for Aggressive Endometrial Cancer by Reactivation of Protein Phosphatase 2A
Authors: Haines Kaitlin , Huang Gloria S.
Published: August 2019

Critically important to reducing uterine cancer mortality is the development of more effective therapy for aggressive endometrial cancers, including uterine serous cancer and uterine carcinosarcoma, which together account for over half of deaths due to endometrial cancer. About one-third of these aggressive endometrial cancers harbor mutations in the protein phosphatase 2A (PP2A) Aα scaffold subunit encoded by PPP2R1A. In this issue, the study by Taylor and colleagues elucidates the role of a highly recurrent PP2A-Aα–subunit mutation PPP2R1A P179R as a biological driver of aggressive endometrial cancer. Compelling data demonstrate that the P179R mutation alters PP2A-Aα protein conformation, impairing holoenzyme formation and reducing PP2A phosphatase activity to promote endometrial cancer progression. Restoration of wild-type PPP2R1A in P179R-mutant endometrial cancer cells increases phosphatase activity and inhibits tumor growth in vivo. Furthermore, a small-molecule activator of PP2A (SMAP) phenocopies restoration of wild-type PPP2R1A to suppress tumor growth. These promising results are an important advance toward effective precision therapy for aggressive endometrial cancer.

See related article by Taylor et al., p. 4242
Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer
Authors: Farago Anna F. , Yeap Beow Y. , Stanzione Marcello , Hung Yin P. , Heist Rebecca S. , Marcoux J. Paul , Zhong Jun , Rangachari Deepa , Barbie David A. , Phat Sarah , Myers David T. , Morris Robert , Kem Marina , Dubash Taronish D. , Kennedy Elizabeth A. , Digumarthy Subba R. , Sequist Lecia V. , Hata Aaron N. , Maheswaran Shyamala , Haber Daniel A. , Lawrence Michael S. , Shaw Alice T. , Mino-Kenudson Mari , Dyson Nicholas J. , Drapkin Benjamin J.
Published: August 2019

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m2 daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients. The confirmed overall response rate was 41.7% (20/48 evaluable); median progression-free survival was 4.2 months [95% confidence interval (CI), 2.8–5.7]; and median overall survival was 8.5 months (95% CI, 5.1–11.3). Patient-derived xenografts (PDX) from trial patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial. This revealed a correlation between low basal expression of inflammatory-response genes and cross-resistance to both OT and standard first-line chemotherapy (etoposide/platinum). These results demonstrate a promising new therapeutic strategy in SCLC and uncover a molecular signature of those tumors most likely to respond.

Significance:

We demonstrate substantial clinical activity of combination olaparib/temozolomide in relapsed SCLC, revealing a promising new therapeutic strategy for this highly recalcitrant malignancy. Through an integrated coclinical trial in PDXs, we then identify a molecular signature predictive of response to OT, and describe the common molecular features of cross-resistant SCLC.

See related commentary by Pacheco and Byers, p. 1340.

This article is highlighted in the In This Issue feature, p. 1325
Sahamalaza Sportive Lemur, Lepilemur sahamalaza, Vocal Communication: Call Use, Context and Gradation
Authors: Mandl Isabella , Schwitzer Christoph , Holderied Marc
Published: August 2019

Stereotypical vocalisations can facilitate long-distance communication in dense and, thus, sound-degrading forest habitats. Despite this, primate vocal repertoires often also include gradations between different call types that are used in social interactions. Because many nocturnal primates show a solitary social structure, it has been difficult to assess the role vocalisations play in mediating their social encounters. Here we aim to expand on the call types of Sahamalaza sportive lemurs, Lepilemur sahamalaza, as well as investigate their variability and use in social contexts. Through long-term behavioural observations with concurrent recording of vocalisations of known and unknown individuals between 2015 and 2016, we described three previously unrecorded calls and expanded the vocal repertoire to 12 different call types that were used in both targeted social and broadcast solitary contexts. Linear discriminant function and cluster analysis supported initial observations that vocalisations within call types were variable and that at least two call types can be classified as “graded,” contrary to expectations. Despite variations in call-context connections, no clear patterns of call use could be established. However, measurable differences in vocal behaviour between the seasons and the sexes indicate that calling is used in a reproductive context, similar to other nocturnal and diurnal primates.
The Future of Gene-Guided Neuroscience Research in Non-Traditional Model Organisms
Authors: Juntti Scott
Published: August 2019

Natural variations across animals in form, function, and behavior have long been sources of inspiration to scientists. Despite this, experimentalists focusing on the neural bases of behavior have increasingly focused on a select few model species. This consolidation is motivated primarily by the availability of resources and technologies for manipulation in these species. Recent years have witnessed a proliferation of experimental approaches that were developed primarily in traditional model species, but that may in principle be readily applied to any species. High-throughput sequencing, CRISPR gene editing, transgenesis, and other technologies have enabled new insights through their deployment in non-traditional model species. The availability of such approaches changes the calculation of which species to study, particularly when a trait of interest is most readily observed in a non-traditional model organism. If these technologies are widely adopted in many new species, it promises to revolutionize the field of neuroethology.
Commercial Rodents in America: Standard Animals, Model Animals, and Biological Diversity
Authors: Logan Cheryl A.
Published: August 2019

Rodents as standardized test animals were developed for commercial distribution in the USA between 1910 and the 1930s. The selective breeding of rats (Rattus norvegicus) and pure-bred mice (Mus musculus) at the Wistar Institute and the Jackson Memorial Laboratories eventually led to a decline in the diversity of species used in American medical and life sciences. The early driving figures, science administrator Milton Greenman and the scientists Henry Donaldson and Clarence Little, sought to standardize animals to render science and its application to humanity more precise. But their efforts were exaggerated in the USA through an expanding industrial and engineering ideal, culminating in a preference for Big Science. I explore the nineteenth century origins of this ideal in Emil Du Bois-Reymond’s neurophysiology. This foundation later merged with increasing standardization, American commercialism, and the success of Big Science to transform animal laboratory “standards” into “model animals.” Recent accounts of research with commercially bred mice reveal how findings can be co-constructed using human clinical data, as animal research is applied to humans. The neglect of evolutionary perspectives and the dominance of “models” may even have begun with the government’s post-war emphasis on funding greater species access for large-scale biomedical research.
Spatial Dependence of Stimulus Competition in the Avian Nucleus Isthmi Pars Magnocellularis
Authors: Schryver Hannah M. , Mysore Shreesh P.
Published: August 2019

The nucleus isthmi pars magnocellularis (Imc) is a group of specialized inhibitory neurons in the midbrain tegmentum, thought to be conserved across vertebrate classes. Past anatomical work in reptiles has suggested a role for it in stimulus selection, which has been supported by recent studies in avians. Additionally, focal inactivation of Imc neurons is known to abolish all competitive interactions in the optic tectum (OT; SC in mammals), a midbrain sensorimotor hub that is critical for the control of spatial attention, thereby revealing a key role for Imc in stimulus selection. However, the functional properties of Imc neurons are not well understood. Here, with electrophysiological experiments in the barn owl Imc, we show that Imc neurons themselves exhibit signatures of stimulus competition. Distant competing stimuli outside the spatial receptive field (RF) suppressed powerfully, and divisively, the responses of Imc neurons to stimuli inside the RF, and did so from all tested locations along the elevation as well as azimuth. Notably, this held true even for locations encoded by the opposite side of the brain from the one containing the recording site. This global divisive inhibition operated independently of the sensory modality of the competing stimulus. Thus, the Imc not only supplies inhibition to the OT to support competition there, but may itself be an active site of stimulus competition. These results from experiments in the barn owl shed light on the functional properties of a vital node in the vertebrate midbrain selection network.
Critique of Pure Marmoset
Authors: Preuss Todd M.
Published: August 2019

The common marmoset, a New World (platyrrhine) monkey, is currently being fast-tracked as a non-human primate model species, especially for genetic modification but also as a general-purpose model for research on the brain and behavior bearing on the human condition. Compared to the currently dominant primate model, the catarrhine macaque monkey, marmosets are notable for certain evolutionary specializations, including their propensity for twin births, their very small size (a result of phyletic dwarfism), and features related to their small size (rapid development and relatively short lifespan), which result in these animals yielding experimental results more rapidly and at lower cost. Macaques, however, have their own advantages. Importantly, macaques are more closely related to humans (which are also catarrhine primates) than are marmosets, sharing approximately 20 million more years of common descent, and are demonstrably more similar to humans in a variety of genomic, molecular, and neurobiological characteristics. Furthermore, the very specializations of marmosets that make them attractive as experimental subjects, such as their rapid development and short lifespan, are ways in which marmosets differ from humans and in which macaques more closely resemble humans. These facts warrant careful consideration of the trade-offs between convenience and cost, on the one hand, and biological realism, on the other, in choosing between non-human primate models of human biology. Notwithstanding the advantages marmosets offer as models, prudence requires continued commitment to research on macaques and other primate species.
ApoER2 (Apolipoprotein E Receptor-2) Deficiency Accelerates Smooth Muscle Cell Senescence via Cytokinesis Impairment and Promotes Fibrotic Neointima After Vascular Injury
Authors: Komaravolu Ravi K. , Waltmann Meaghan D. , Konaniah Eddy , Jaeschke Anja , Hui David Y.
Published: August 2019

Objective:

Genome-wide studies showed that mutation in apoER2 (apolipoprotein E receptor-2) is additive with ε4 polymorphism in the
APOE
gene on cardiovascular disease risk in humans. ApoE or apoER2 deficiency also accelerates atherosclerosis lesion necrosis in hypercholesterolemic mice and promotes neointima formation after vascular injury. This study tests the hypothesis that apoE and apoER2 modulate vascular occlusive diseases through distinct mechanisms.

Approach and Results:

Carotid endothelial denudation induced robust neointima formation in both
apoE
−/−
and apoER2-deficient
Lrp8
−/−
mice. The intima in
apoE
−/−
mice was rich in smooth muscle cells, but the intima in
Lrp8
−/−
mice was cell-poor and rich in extracellular matrix. Vascular smooth muscle cells isolated from
apoE
−/−
mice were hyperplastic whereas
Lrp8
−/−
smooth muscle cells showed reduced proliferation but responded robustly to TGF (transforming growth factor)-β–induced fibronectin synthesis indicative of a senescence-associated secretory phenotype, which was confirmed by increased β-galactosidase activity, p16
INK4a
immunofluorescence, and number of multinucleated cells. Western blot analysis of cell cycle-associated proteins showed that apoER2 deficiency promotes cell cycle arrest at the metaphase/anaphase. Coimmunoprecipitation experiments revealed that apoER2 interacts with the catalytic subunit of protein phosphatase 2A. In the absence of apoER2, PP2A-C (protein phosphatase 2A catalytic subunit) failed to interact with CDC20 (cell-division cycle protein 20) thus resulting in inactive anaphase-promoting complex and impaired cell cycle exit.

Conclusions:

This study showed that apoER2 participates in APC (anaphase-promoting complex)/CDC20 complex formation during mitosis, and its absence impedes cytokinesis abscission thereby accelerating premature cell senescence and vascular disease. This mechanism is distinct from apoE deficiency, which causes smooth muscle cell hyperplasia to accelerate vascular disease.
Serum apoA1 (Apolipoprotein A-1), Insulin Resistance, and the Risk of Gestational Diabetes Mellitus in Human Pregnancy—Brief Report
Authors: Retnakaran Ravi , Ye Chang , Connelly Philip W. , Hanley Anthony J. , Sermer Mathew , Zinman Bernard
Published: August 2019

Objective:

apoA1 (apolipoprotein A-1) is the main lipoprotein associated with HDL (high-density lipoprotein) cholesterol. It was recently reported that intravenous infusion of apoA1 could lower insulin resistance in pregnant rats, leading to the suggestion that apoA1 could provide a target for reducing pregnancy-induced insulin resistance and the risk of gestational diabetes mellitus (GDM) in humans. However, the effects of apoA1 on insulin resistance and risk of GDM in human pregnancy are not known. Thus, we sought to systematically evaluate the relationships of apoA1 with glucose homeostasis and metabolic function in pregnant women.

Approach and Results:

In this study, 870 pregnant women were recruited in late second trimester and underwent metabolic characterization, including an oral glucose tolerance test on which 214 were diagnosed with GDM. Metabolic characterization included assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance), pancreatic β-cell function, lipids (LDL [low-density lipoprotein] cholesterol, HDL cholesterol, triglycerides, apoB [apolipoprotein B], and apoA1), CRP (C-reactive protein), and adiponectin. Serum apoA1 was strongly correlated with HDL (r=0.79,
P
<0.0001) and weakly so with adiponectin (r=0.12,
P
=0.0004) but showed no association with measures of insulin sensitivity/resistance, β-cell function, glycemia, or CRP. There were no significant differences across apoA1 tertiles in mean adjusted Matsuda index (
P
=0.24), homeostasis model assessment of insulin resistance (
P
=0.08), or area under the glucose curve on the oral glucose tolerance test (
P
=0.96). Moreover, there were no differences in risk of GDM across tertiles of apoA1, both before (
P
=0.67) and after covariate adjustment (
P
=0.78).

Conclusions:

Serum apoA1 is not associated with insulin resistance or the risk of GDM in human pregnancy.
Regional Variability in Longitudinal Strain Across Vendors in Patients With Cardiomyopathy Due to Increased Left Ventricular Wall Thickness
Authors: Sperry Brett W. , Sato Kimi , Phelan Dermot , Grimm Richard , Desai Milind Y. , Hanna Mazen , Jaber Wael A. , Popović Zoran B
Published: August 2019

Background:

Cardiomyopathies with increased left ventricular wall thickness such as cardiac amyloidosis, septal hypertrophic cardiomyopathy (HCM), and apical HCM exhibit characteristic regional longitudinal strain (LS) patterns. However, between-vendor agreement of segmental and regional LS has not been tested in these diseases. We sought to assess LS values among vendors in specific cardiomyopathies that exhibit regional strain variation: cardiac amyloidosis, septal HCM, and apical HCM.

Methods:

This was a prospective, cross-sectional study of 69 patients (18 amyloidosis, 30 septal HCM, 6 apical HCM, and 15 controls) who underwent clinically indicated outpatient echocardiography at the Cleveland Clinic. Peak systolic segmental, regional (basal, mid, and apical), and global LS were evaluated using GE (EchoPAC), Siemens (Velocity Vector Imaging), and Phillips (QLab) systems in the same imaging session. Between-vendor, differences were analyzed using correlation coefficients, Bland Altman plots, and a mixed model.

Results:

Global LS was highly correlated among the 3 software packages and most abnormal in patients with amyloidosis (
P
<0.001). Regional LS analysis demonstrated that QLab software tended to produce more negative LS values, driven by differences in apical strains. EchoPAC had the greatest ability to discriminate patients with amyloidosis using regional strain values (area under the curve, 0.932) as compared with Velocity Vector Imaging and QLab (
P
<0.001).

Conclusions:

Global and regional variations in LS exist between-vendors in patients with cardiomyopathies with increased left ventricular wall thickness (amyloidosis, septal HCM, and apical HCM). It is important to be aware of these differences for diagnosis, prognosis, and serial examinations in these conditions.