bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance of osteosarcoma cells to the proapoptotic effects of carfilzomib involves activation of mitogen activated protein kinase pathways
Authors: Lei Li , Zhang Yuchen , Jian Qiang , Lei Lei , Lv Nan , Williamson Ramone A. , Chen Ping , Zhang Dan , Hu Jinsong 
Published: December 2020

New Findings

What is the central question of this study?
Carfilzomib, a second‐generation proteasome inhibitor approved for the treatment of multiple myeloma, shows efficacy against osteosarcoma. However, drug resistance remains a major challenge. What is the role of carfilzomib‐induced changes in mitogen‐activated protein kinase (MAPK) pathways in the sensitivity of osteosarcoma cells to the proapoptotic effects of the drug?

What is the main finding and its importance?
The dose‐dependent antiapoptotic effects in osteosarcoma are associated with activation of MAPK signalling. Combinational targeting of MAPK signalling pathways can synergistically enhance carfilzomib‐induced cell apoptosis, suggesting that MAPK inhibitors in combination with proteasome inhibitors can serve as a novel therapeutic tool for osteosarcoma.

AbstractOsteosarcoma is the most common primary bone malignancy. Despite efforts to improve outcomes, the overall survival rates for osteosarcoma have remained unchanged over the past three decades. In this study, we assessed the proapoptotic effects of the second‐generation proteasome inhibitor carfilzomib on osteosarcoma and investigated the potential mechanisms underlying the synergistic proapoptotic action when combined with mitogen‐activated protein kinase (MAPK) inhibitors. We found that carfilzomib alone significantly inhibited cell proliferation and induced apoptosis in a dose‐dependent manner, characterized by the induction of cleaved caspase 3 and poly (ADP‐ribose) polymerase. More importantly, focusing on the changes of antiapoptotic B‐cell lymphoma 2 (Bcl‐2) family members and signalling pathways, we found a striking induction of myeloid cell leukaemia 1 (Mcl‐1) and the activation of MAPK pathways. Furthermore, we observed that combinational targeting of the MAPK pathways using the specific inhibitors U0126, SP600125 or SB203580 synergistically enhanced carfilzomib‐induced cell apoptosis. Notably, we found that the combinational inhibition of extracellular signal‐regulated kinase or c‐Jun N‐terminal kinase MAPK pathways significantly decreased the expression of the three antiapoptotic Bcl‐2 family proteins, and in particular this reversed induction of Mcl‐1 by carfilzomib. Collectively, our findings show that activation of the MAPK pathways contributes to the mechanisms of drug resistance to carfilzomib. In addition, the synergistic proapoptotic action of MAPK and proteasome inhibitors in osteosarcoma cells suggests that combinational therapy with both drug types may serve as a novel strategy for the clinical management of osteosarcoma.
Dose‐dependent sensorimotor impairment in human ocular tracking after acute low‐dose alcohol administration
Authors: Tyson Terence L. , Feick Nathan H. , Cravalho Patrick F. , Flynn‐Evans Erin E. , Stone Leland S. 
Published: December 2020

Key points
Oculomotor behaviours are commonly used to evaluate sensorimotor disruption due to ethanol (EtOH).
The current study demonstrates the dose‐dependent impairment in oculomotor and ocular behaviours across a range of ultra‐low BACs (<0.035%).
Processing of target speed and direction, as well as pursuit eye movements, are significantly impaired at 0.015% BAC, suggesting impaired neural activity within brain regions associated with the visual processing of motion.
Catch‐up saccades during steady visual tracking of the moving target compensate for the reduced vigour of smooth eye movements that occurs with the ingestion of low‐dose alcohol.
Saccade dynamics start to become ‘sluggish’ at as low as 0.035% BAC.
Pupillary light responses appear unaffected at BAC levels up to 0.065%.
AbstractChanges in oculomotor behaviours are often used as metrics of sensorimotor disruption due to ethanol (EtOH); however, previous studies have focused on deficits at blood‐alcohol concentrations (BACs) above about 0.04%. We investigated the dose dependence of the impairment in oculomotor and ocular behaviours caused by EtOH administration across a range of ultra‐low BACs (≤0.035%). We took repeated measures of oculomotor and ocular performance from sixteen participants, both pre‐ and post‐EtOH administration. To assess the neurological impacts across a wide range of brain areas and pathways, our protocol measured 21 largely independent performance metrics extracted from a range of behavioural responses ranging from ocular tracking of radial step‐ramp stimuli, to eccentric gaze holding, to pupillary responses evoked by light flashes. Our results show significant impairment of pursuit and visual motion processing at 0.015% BAC, reflecting degraded neural processing within extrastriate cortical pathways. However, catch‐up saccades largely compensate for the tracking displacement shortfall caused by low pursuit gain, although there still is significant residual retinal slip and thus degraded dynamic acuity. Furthermore, although saccades are more frequent, their dynamics are more sluggish (i.e. show lower peak velocities) starting at BAC levels as low as 0.035%. Small effects in eccentric gaze holding and no effect in pupillary response dynamics were observed at levels below 0.07%, showing the higher sensitivity of the pursuit response to very low levels of blood alcohol, under the conditions of our study.
Active Detection of Small Imperfections in Structures With Cyclic Symmetry
Authors: Baruch Eyal , Vered Yoav , Plat Harel , Bucher Izhak 
Published: December 2020

Abstract
Structures possessing cyclic symmetry such as turbine bladed disks, ultrasonic motors, and toothed gear wheels can experience elevated vibration levels when small deviations from circumferential periodicity exist. Detection of these perturbations via classical system identification approaches is time-consuming, indirect, and exhibits low sensitivity to defects, and is affected by measurement noise. The present work utilizes low-level forces that automatically lock onto a weighted rotating projection of the system modes at resonance frequency to enhance the detectability of small structural imperfections. The spatial localization of defects is exploited to identify multiple, localized, isolated defects’ locations. The defects’ severities are estimated based on the deviation from the circular structure's analytical mode shapes. The fast and enhanced precision of defect identification is obtained by employing the modal-filtered autoresonance technique. To validate the presented method, an experimental system consisting of a ring of coupled Helmholtz acoustic resonators was developed. Experimental results show good agreement with numerical simulations, verifying the method's capabilities to identify the location and severity of multiple defects. Thus, the implementation of the suggested method provides fast and precise structural health monitoring of cyclic-symmetric systems.
Dynamic Characteristic Analysis of Rotating Blade With Transverse Crack—Part II: A Comparison Study of Different Crack Models
Authors: Yang Lai-Hao , Yang Zhe-Shuai , Mao Zhu , Wu Shu-Ming , Chen Xue-Feng , Yan Ru-Qiang 
Published: December 2020

Abstract
This study aims at the comparative analysis and improvement of different analytical crack models for rotating blade. Part II of this study focuses on the comparative analysis of dynamic characteristics based on modified models mentioned in Part I. A nonlinear damage indicator (NDI) and an equivalent energy indicator (EEI) are introduced to characterize the nonlinear effect of crack from different perspectives. EEI offers a physical mechanism explanation of crack closing behavior, which is invisible. Meanwhile, NDI offers an observable indicator to quantify the nonlinearity of crack. It is demonstrated through the numerical study that the variation of NDI and EEI varies the same with each other, which cross-verified the validity of NDI and EEI for quantifying the nonlinear effect of crack. Comparative investigations are performed to analyze the effects of load amplitude, crack depth, and crack location on the nonlinear dynamics of cracked blade, and both NDI and EEI are utilized to quantify the nonlinear effects of crack. The comparative results suggest that NDI of the second-order super-harmonic component increases with the increasing crack depth and excitation load amplitude and decreases with the increasing crack locations, while the variation of EEI follows the variation of NDI. This phenomenon indicates that the crack, which is deeper and closer to blade root under a larger load will be more dangerous. This study’s comparative results may provide some guidance for choosing the analytical crack models when analyzing the nonlinear dynamics of rotating cracked blade and blade health monitoring.
Damping Frame Vibrations Using Anechoic Stubs: Analysis Using an Exact Wave-Based Approach
Authors: Lv Hangyuan , Leamy Michael J. 
Published: December 2020

Abstract
This paper explores the addition of small stubs with anechoic terminations (termed herein “anechoic stubs”) as a means of damping and/or removing vibration modes from planar frame structures. Due to the difficulties associated with representing anechoic boundary conditions in more traditional analysis approaches (e.g., analytical, finite element, finite difference, and finite volume), the paper employs and further develops an exact wave-based approach, incorporating Timoshenko beams, in which ideal and non-ideal anechoic terminations are simply represented by a reflection matrix. Several numerically evaluated examples are presented documenting novel effects anechoic stubs have on the vibration modes of a two-story frame, such as eliminated, inserted, and exchanged mode shapes. Modal damping ratios are also computed as a function of the location and number of anechoic stubs, illustrating optimal locations and optimal reflection ratios as a function of mode number. Forced vibration studies are then carried out, demonstrating reduced, eliminated, and inserted resonance response.
Stretching is Superior to Brisk Walking for Reducing Blood Pressure in People With High–Normal Blood Pressure or Stage I Hypertension
Authors: Ko Jongbum , Deprez Dalton , Shaw Keely , Alcorn Jane , Hadjistavropoulos Thomas , Tomczak Corey , Foulds Heather , Chilibeck Philip D. 
Published: December 2020

Background: Aerobic exercise is recommended for reducing blood pressure; however, recent studies indicate that stretching may also be effective. The authors compared 8 weeks of stretching versus walking exercise in men and women with high–normal blood pressure or stage 1 hypertension (ie, 130/85–159/99 mm Hg). Methods: Forty men and women (61.6 y) were randomized to a stretching or brisk walking exercise program (30 min/d, 5 d/wk for 8 wk). Blood pressure was assessed during sitting and supine positions and for 24 hours using a portable monitor before and after the training programs. Results: The stretching program elicited greater reductions than the walking program (P < .05) for sitting systolic (146 [9] to 140 [12] vs 139 [9] to 142 [12] mm Hg), supine diastolic (85 [7] to 78 [8] vs 81 [7] to 82 [7] mm Hg), and nighttime diastolic (67 [8] to 65 [10] vs 68 [8] to 73 [12] mm Hg) blood pressures. The stretching program elicited greater reductions than the walking program (P < .05) for mean arterial pressure assessed in sitting (108 [7] to 103 [6] vs 105 [6] vs 105 [8] mm Hg), supine (102 [9] to 96 [9] vs 99 [6] to 99 [7] mm Hg), and at night (86 [9] to 83 [10] vs 88 [9] to 93 [12] mm Hg). Conclusions: An 8-week stretching program was superior to brisk walking for reducing blood pressure in individuals with high–normal blood pressure or stage 1 hypertension.
Leucine metabolites do not induce changes in phase angle, bioimpedance vector analysis patterns, and strength in resistance trained men
Authors: Campa F. , Matias C.N. , Teixeira F.J. , Reis J.F. , Valamatos M.J. , Toselli S. , Monteiro C.P. 
Published: December 2020

We aimed to assess the effects of off-the-shelf leucine metabolite supplements on phase angle (PhA), bioimpedance vector analysis (BIVA) patterns and strength during an 8-week resistance training protocol. Fifty-three male participants were allocated into 4 groups: α-hydroxyisocaproic acid (n = 12, age = 30.9 ± 9.3 years), β-hydroxy-β-methylbutyrate free acid (n = 12, age = 31.0 ± 9.3 years), calcium β-hydroxy-β-methylbutyrate (n = 15, age = 32.1 ± 5.2 years) or placebo (n = 14, age = 28.9 ± 6.6 years). Bioimpedance parameters and 1-repetition maximum (1RM) for back squat and bench press were assessed at baseline and at the end of weeks 4 and 8. Additionally, fat-free mass and fat mass were evaluated by dual-energy X-ray absorptiometry. No statistically group by time interactions were found, even adjusting for age. PhA and vector did not change over the training period, while time-dependent increases were observed for 1RM back squat and 1RM bench press. A direct association was observed between PhA and 1RM bench press changes (whole sample), while PhA and strength were correlated throughout the study, even when adjusting for fat-free mass and percentage of fat mass. Leucine metabolites have no effect on PhA, BIVA patterns or strength during an 8-week resistance training program, in resistance trained subjects. The trial was registered at ClincicalTrials.gov: NCT03511092. Novelty: Supplementation with leucine metabolites is not a supplementation strategy that improves bioelectrical phase angle, cellular health, and strength after an 8-week resistance training program. When consuming a high protein diet, none of the α-hydroxyisocaproic acid, β-hydroxy-β-methylbutyrate free acid, and calcium β-hydroxy-β-methylbutyrate metabolites resulted in an ergogenic effect in resistance trained men.
Abstract A25: Activating alterations of p110 subunits determine PI3K isoform selectivity in prostate cancer
Authors: Zhang Zeda , Mao Ninghui , Lee Young Sun , Li Dan , Rosen Neal , Sawyers Charles , Carver Brett 
Published: December 2020

Abstract
Oncogenic activity of PI3K mutated tumors is often dependent on different PI3K isoforms. In breast cancer PI3Kα activating mutations are dominant drivers, whereas in PTEN-deficient prostate cancer such activity is thought to be driven by PI3Kβ. In particular, loss of PTEN function is seen in 40% of metastatic prostate cancer patients, which remains a challenging clinical problem. Recent success of selectively targeting PI3Kα or PI3Kβ to treat disease caused by hyperactivation of PI3K pathway sheds light on further developing such agents to a boarder disease spectrum. Yet relatively little is known about how different PI3K isoforms are selected as dominant drivers in different genetic and pathologic contexts. Here we use multiple prostate cancer cell lines and organoid models to study the mechanisms of PI3K isoform dependency in prostate cancer. We found PI3K isoform dependency is not always correlated with PTEN status across a panel of prostate cancer models in which different levels of PI3K signaling are observed. However, such dependency can be shifted towards either PI3Kα or PI3Kβ in the presence of its corresponding activating alteration, regardless of its original isoform dependency. Interestingly, such PI3K isoform activating alteration is able to further enhance PI3K signal in the setting of PTEN loss. PI3Kα mutant models are more sensitive to the α selective inhibitor BYL719 while PI3Kβ mutant models are more sensitive to the β selective inhibitor AZD8186. Besides, we found that PI3Kα mutant prostate tumors are sensitive to PI3Ksy inhibition by AZD8186 at a high dosage both in vitro and in vivo. High dose of AZD8186 also inhibits PI3K signaling in PI3Kα mutant breast cancer models. These data raise the possibility that the PI3Kβ selective inhibitor AZD8186 can also target PI3Kα at a high dose. In an ongoing clinical trial at MSK, a prostate cancer patient with PI3Kα mutation also responded to PI3Kβ inhibition. This finding reveals a new mechanism of how PI3K activating mutations determine PI3K isoform selectivity regardless of PTEN status. Results from this study also present new opportunities to treat cancer patients with PI3Kα or PI3Kβ inhibition.
Citation Format: Zeda Zhang, Ninghui Mao, Young Sun Lee, Dan Li, Neal Rosen, Charles Sawyers, Brett Carver. Activating alterations of p110 subunits determine PI3K isoform selectivity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A25.
Abstract B29: Targeting EZH2 and PI3K/mTOR for a novel combination therapeutic strategy in aggressive variant prostate cancer
Authors: Morel Katherine L. , Sweeney Christopher J. , Ellis Leigh 
Published: December 2020

Abstract
Androgen-deprivation therapy (ADT) is the current standard of care for metastatic prostate cancer; however, ADT fails to provide a durable response in 90% of patients due to acquired resistance and progression to castration-resistance prostate cancer. Aggressive-variant prostate cancer (AVPC) is a lethal phenotype that arises upon treatment with ADT, resulting in a lineage switch to a neuroendocrine morphology and the acquisition of molecular alterations that enable the cells to survive independent of AR signaling. Our work, and the work of others, has established that combinatorial loss/mutation of tumor suppressor genes—PTEN, TP53 and RB1—drive lineage plasticity and therapeutic resistance to ADT. Further, epigenetic regulators, including EZH2, are indicated as driver effectors of lineage plasticity downstream of these key combinatorial genetic events. With the known activation PI3K/AKT/mTOR signaling due to PTEN loss and the data supporting epigenetic targeting of EZH2, it remains to be determined if co-inhibition of PI3K/AKT/mTOR and EZH2 will provide a significant response in AVPC patients. GEMMs and GEMM-derived 3D organoid models representing either prostate-specific PTEN and RB1 loss (PbCre4:Ptenfl/fl:Rb1fl/fl), or PTEN and P53 loss (PbCre4:Ptenfl/fl:p53fl/fl), were used to determine if inhibition of PI3K/AKT/mTOR and EZH2 provides lineage reversal and novel therapeutic directions to treat AVPC phenotypes. Tumor organoids were treated in vitro and in vivo with PI3K/AKT/mTOR and EZH2 inhibitors as 1) a monotherapy, 2) each in combination with ADT, and 3) both in combination with ADT. Tumors were interrogated in either androgen-sensitive or androgen-resistant conditions to identify if the combination-therapy approach is more beneficial to prevent progression to AVPC and ADT-resistance or to reverse the AVPC phenotype and restore hormone sensitivity. Quantitative determination of therapeutic response was carried out in vitro in 3D using fluorescent cytotoxicity and proliferation assays. In vivo, tumor response will be assessed by histologic analysis and RNA sequencing. Protein and mRNA expression was measured by qPCR, IHC and Western blot. Despite recent progress in the field, men with AVPC still face a terminal prognosis, and no current therapy provides durable response. The results of this research will help pave the way for early-phase clinical trials testing the efficacy of EZH2 inhibitors in combination with enzalutamide and/or PI3K/AKT/mTOR inhibitors.
Citation Format: Katherine L. Morel, Christopher J. Sweeney, Leigh Ellis. Targeting EZH2 and PI3K/mTOR for a novel combination therapeutic strategy in aggressive variant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B29.
Klotho Deficiency Causes Heart Aging via Impairing the Nrf2-GR Pathway
Authors: Chen Kai , Wang Shirley , Sun Qiwei Wilton , Zhang Bo , Ullah Mujib , Sun Zhongjie 
Published: December 2020

Rationale:
Cardiac aging is an important contributing factor for heart failure, which affects a large population but remains poorly understood.

Objective:
The purpose of this study is to investigate whether Klotho plays a role in cardiac aging.

Methods and Results:

Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size, and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that
Klotho
gene mutation (KL−/−) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (−/−) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (−/−) mice. Serum phosphate levels in KL (−/−) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed GR (glutathione reductase) expression and activity in the heart via inhibition of transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2). Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (−/−) mice.

Conclusions:
Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.
Reconstructing Brutus’ De Virtute: Consolation and Antiochean Fundamentalism
Authors: Osorio Peter 
Published: December 2020

Abstract
Brutus’ De virtute, a lost work that had important but overlooked influence on Cicero’s ethical dialogues, is more dependent on Antiochus’ ethics than has been recognized. In reviewing the sources for De virtute (collected in an appendix), I arrive at a conception of Brutus’ work as a consolation written in a fundamentalist—rather than ecumenical—mode that focalizes its arguments and commonplaces from the perspective of Antiochus’ philosophical system. This conception is supported by the only other testimony for Brutus’ consolatory writing.
School Bullying Among Peers, Human Rights and the State’s Duty to Protect: The Case of Spain
Authors: Casla Koldo 
Published: December 2020

Abstract
Bullying among peers prevents children from enjoying their human rights in schools without the threat of aggression, harassment and discrimination. However, the States’ duty to protect children from bullying remains loudly unexplored both in academia and in human rights practice. This article begins to fill a gap by articulating the States’ duty to protect children from physical, psychological or relational aggression caused by other children in an educational setting beyond a punitive or individualistic perspective. This is the first study to operationalise the States’ duty to protect children from bullying by examining the reliability of reporting mechanisms, the accuracy and disaggregation of data, and the quality of training for education professionals and future teachers in a country, in this case, Spain. The analysis relies on rigorous empirical research with focus groups and semi-structured interviews with 139 people in three Spanish regions, including parents, children, academics, bullying survivors and education professionals.