bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Success and Struggles of Physical Education Teachers While Teaching Online During the COVID-19 Pandemic
Authors: Centeio Erin , Mercier Kevin , Garn Alex , Erwin Heather , Marttinen Risto , Foley John 
Published: June 2021

The purpose of this study was to investigate physical education teachers’ perceptions of implementing online physical education during the COVID-19 pandemic as well as to explore their needs with regard to support for future teaching experiences. A total of 4,302 teachers completed four open-ended questions as part of a larger survey. Deductive and inductive qualitative analysis led to three themes: (a) Teachers’ Proud Moments, (b) Help! So Many Obstacles, and (c) Future Challenges. Teachers stated many successes and challenges that they experienced through the COVID-19 pandemic. Many items specifically focused on use and access to technology, student participation, and meeting students’ needs in various ways. Results can provide guidance for how to address the essential components of physical education in the online environment. In addition, results may provide insight to those who educate, train, and prepare teachers to teach in a virtual and/or physically distanced environment.
Impact of the national home safety equipment scheme ‘Safe At Home’ on hospital admissions for unintentional injury in children under 5: a controlled interrupted time series analysis
Authors: Hill Trevor , Coupland Carol , Kendrick Denise , Jones Matthew , Akbari Ashley , Rodgers Sarah , Watson Michael Craig , Tyrrell Edward , Merrill Sheila , Orton Elizabeth 
Published: June 2021

BackgroundUnintentional home injuries are a leading cause of preventable death in young children. Safety education and equipment provision improve home safety practices, but their impact on injuries is less clear. Between 2009 and 2011, a national home safety equipment scheme was implemented in England (Safe At Home), targeting high-injury-rate areas and socioeconomically disadvantaged families with children under 5. This provided a ‘natural experiment’ for evaluating the scheme’s impact on hospital admissions for unintentional injuries.MethodsControlled interrupted time series analysis of unintentional injury hospital admission rates in small areas (Lower Layer Super Output Areas (LSOAs)) in England where the scheme was implemented (intervention areas, n=9466) and matched with LSOAs in England and Wales where it was not implemented (control areas, n=9466), with subgroup analyses by density of equipment provision.Results57 656 homes receiving safety equipment were included in the analysis. In the 2 years after the scheme ended, monthly admission rates declined in intervention areas (−0.33% (−0.47% to −0.18%)) but did not decline in control areas (0.04% (−0.11%–0.19%), p value for difference in trend=0.001). Greater reductions in admission rates were seen as equipment provision density increased. Effects were not maintained beyond 2 years after the scheme ended.ConclusionsA national home safety equipment scheme was associated with a reduction in injury-related hospital admissions in children under 5 in the 2 years after the scheme ended. Providing a higher number of items of safety equipment appears to be more effective in reducing injury rates than providing fewer items.
On Representing Resilience Requirements of Microservice Architecture Systems
Authors: Yin Kanglin , Du Qingfeng 
Published: June 2021

Together with the spread of DevOps practices and container technologies, Microservice Architecture has become a mainstream architecture style in recent years. Resilience is a key characteristic in Microservice Architecture (MSA) Systems, and it shows the ability to cope with various kinds of system disturbances which cause degradations of services. However, due to lack of consensus definition of resilience in the software field, although a lot of work has been done on resilience for MSA Systems, developers still do not have a clear idea on how resilient an MSA System should be, and what resilience mechanisms are needed. In this paper, by referring to existing systematic studies on resilience in other scientific areas, the definition of microservice resilience is provided and a Microservice Resilience Measurement Model is proposed to measure service resilience. And a requirement model to represent resilience requirements of MSA Systems is given. The requirement model uses elements in KAOS to represent notions in the measurement model, and decompose service resilience goals into system behaviors that can be executed by system components. As a proof of concept, a case study is conducted on an MSA System to illustrate how the proposed models are applied.
Trøndelag Platform and Halten–Dønna Terraces Composite Tectono-Sedimentary Element, Norwegian Rifted Margin, Norwegian Sea
Authors: Bunkholt Halvor S. S. , Oftedal Bjørn Terje , Hansen John Are , Løseth Helge , Kløvjan Oddbjørn Sivert 
Published: June 2021

Abstract
The Trøndelag Platform and Halten–Dønna Terraces occupy a central part of the Norwegian Sea rifted continental margin off the mid-Norway coast. The margin is expected to hold 4500 Mboe of undiscovered oil equivalents and represents an economically important Arctic province. The geological evolution of the area is closely linked to processes involving the Caledonian Orogeny and subsequent plate tectonic reorganizations, multiphase rifting, continental drift and glaciations across the northern hemisphere. In this chapter we review the geology of the Trøndelag Platform and Halten–Dønna Terraces Composite Tectono-Sedimentary Element based on published data and results of Equinor ASA in-house studies. Three new structural elements are defined for the first time: the Leka fault complex, the Vikna high and the Sula basin.
Treatment with HIV-Protease Inhibitor Nelfinavir Identifies Membrane Lipid Composition and Fluidity as a Therapeutic Target in Advanced Multiple Myeloma
Authors: Besse Lenka , Besse Andrej , Stolze Sara C. , Sobh Amin , Zaal Esther A. , van der Ham Alwin J. , Ruiz Mario , Phuyal Santosh , Büchler Lorina , Sathianathan Marc , Florea Bogdan I. , Borén Jan , Ståhlman Marcus , Huber Julia , Bolomsky Arnold , Ludwig Heinz , Hannich J. Thomas , Loguinov Alex , Everts Bart , Berkers Celia R. , Pilon Marc , Farhan Hesso , Vulpe Christopher D. , Overkleeft Herman S. , Driessen Christoph 
Published: June 2021

Abstract

The HIV-protease inhibitor nelfinavir has shown broad anticancer activity in various preclinical and clinical contexts. In patients with advanced, proteasome inhibitor (PI)–refractory multiple myeloma, nelfinavir-based therapy resulted in 65% partial response or better, suggesting that this may be a highly active chemotherapeutic option in this setting. The broad anticancer mechanism of action of nelfinavir implies that it interferes with fundamental aspects of cancer cell biology. We combined proteome-wide affinity-purification of nelfinavir-interacting proteins with genome-wide CRISPR/Cas9–based screening to identify protein partners that interact with nelfinavir in an activity-dependent manner alongside candidate genetic contributors affecting nelfinavir cytotoxicity. Nelfinavir had multiple activity-specific binding partners embedded in lipid bilayers of mitochondria and the endoplasmic reticulum. Nelfinavir affected the fluidity and composition of lipid-rich membranes, disrupted mitochondrial respiration, blocked vesicular transport, and affected the function of membrane-embedded drug efflux transporter ABCB1, triggering the integrated stress response. Sensitivity to nelfinavir was dependent on ADIPOR2, which maintains membrane fluidity by promoting fatty acid desaturation and incorporation into phospholipids. Supplementation with fatty acids prevented the nelfinavir-induced effect on mitochondrial metabolism, drug-efflux transporters, and stress-response activation. Conversely, depletion of fatty acids/cholesterol pools by the FDA-approved drug ezetimibe showed a synergistic anticancer activity with nelfinavir in vitro. These results identify the modification of lipid-rich membranes by nelfinavir as a novel mechanism of action to achieve broad anticancer activity, which may be suitable for the treatment of PI–refractory multiple myeloma.

Significance:
Nelfinavir induces lipid bilayer stress in cellular organelles that disrupts mitochondrial respiration and transmembrane protein transport, resulting in broad anticancer activity via metabolic rewiring and activation of the unfolded protein response.
MAP3K7-IKK Inflammatory Signaling Modulates AR Protein Degradation and Prostate Cancer Progression
Authors: Huang Zhenlin , Tang Bo , Yang Yinhui , Yang Zhaogang , Shi Lei , Bai Yang , Yan Binyuan , Karnes R. Jeffrey , Zhang Jun , Jimenez Rafael , Wang Liguo , Wei Qiang , Yang Jinjian , Xu Wanhai , Jia Zhankui , Huang Haojie 
Published: June 2021

Abstract

Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase β (IKKβ) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKβ by TNFα induced phosphorylation and TRCP1/2 E3 ligase–mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7–IKKβ axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer.

Significance:
This study identifies that MAP3K7–IKKβ signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.
5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study
Authors: Ascierto Paolo A. , Dréno Brigitte , Larkin James , Ribas Antoni , Liszkay Gabriella , Maio Michele , Mandalà Mario , Demidov Lev , Stroyakovskiy Daniil , Thomas Luc , de la Cruz-Merino Luis , Atkinson Victoria , Dutriaux Caroline , Garbe Claus , Hsu Jessie , Jones Surai , Li Haocheng , McKenna Edward , Voulgari Athina , McArthur Grant A. 
Published: June 2021

Abstract

Purpose:
The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation–positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.

Patients and Methods:
Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1–21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).

Results:
495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3–28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0–19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5–14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6–7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.

Conclusions:
Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation–positive advanced melanoma.
Effective Killing of Acute Myeloid Leukemia by TIM-3 Targeted Chimeric Antigen Receptor T Cells
Authors: Lee Wen-Hsin Sandy , Ye Zhiyong , Cheung Alice M.S. , Goh Y.P. Sharon , Oh Hsueh Ling Janice , Rajarethinam Ravisankar , Yeo Siok Ping , Soh Mun Kuen , Chan Esther Hian Li , Tan Lip Kun , Tan Soo-Yong , Chuah Charles , Chng Wee Joo , Connolly John E. , Wang Cheng-I 
Published: June 2021

Abstract
Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis. Effective treatment strategies for long-term remission are lacking, as it has been difficult to eliminate LSCs with conventional therapy. Here, we proposed a new approach based on the chimeric antigen receptor (CAR)-directed T lymphocytes, targeting T-cell immunoglobulin, and mucin domain 3 (TIM-3) to treat MRD in patients with AML. TIM-3 is selected as the target because it is highly expressed on AML blasts and LSCs in most subtypes regardless of the patient's genetic characteristics and treatment course. Moreover, it is absent in the normal hematopoietic stem cells, granulocytes, naïve lymphocytes, and most normal nonhematopoietic tissues. Using a naïve human Fab phage display library, we isolated an anti-human TIM-3 antibody and designed a second-generation anti–TIM-3. Our anti–TIM-3 CAR T cells exhibit potent antileukemic activity against AML cell lines and primary AML blasts, and in the mouse models. More importantly, we demonstrate efficient killing of the primary LSCs directly isolated from the patients. Hence, eradication of the LSCs present in the MRD by anti–TIM-3 CAR T-cell therapy following the first-line treatment may improve the clinical outcomes of patients with AML.
PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer
Authors: Wu Cheng , Peng Shan , Pilié Patrick G. , Geng Chuandong , Park Sanghee , Manyam Ganiraju C. , Lu Yungang , Yang Guang , Tang Zhe , Kondraganti Shakuntala , Wang Daoqi , Hudgens Courtney W. , Ledesma Debora A. , Marques-Piubelli Mario L. , Torres-Cabala Carlos A. , Curry Jonathan L. , Troncoso Patricia , Corn Paul G. , Broom Bradley M. , Thompson Timothy C. 
Published: June 2021

Abstract
We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1–E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic BCL-2 family members (BCL-2 and MCL-1), CDK1, and neuroendocrine differentiation (NED) markers in vitro and in vivo. In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment–induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment–induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including CDK1 and NED proteins, leading to growth inhibition and increased apoptosis in vitro and in vivo. Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.
SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naïve ALK-, ROS1-, or EGFR-altered Non–small Cell Lung Cancer
Authors: Kano Hirohisa , Ichihara Eiki , Watanabe Hiromi , Nishii Kazuya , Ando Chihiro , Nakasuka Takamasa , Ninomiya Kiichiro , Kato Yuka , Kubo Toshio , Rai Kammei , Ohashi Kadoaki , Hotta Katsuyuki , Tabata Masahiro , Maeda Yoshinobu , Kiura Katsuyuki 
Published: June 2021

Abstract
After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain–containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non–small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo. Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.
Targeting TfR1 with the ch128.1/IgG1 Antibody Inhibits EBV-driven Lymphomagenesis in Immunosuppressed Mice Bearing EBV+ Human Primary B-cells
Authors: Martínez Laura E. , Daniels-Wells Tracy R. , Guo Yu , Magpantay Larry I. , Candelaria Pierre V. , Penichet Manuel L. , Martínez-Maza Otoniel , Epeldegui Marta 
Published: June 2021

AbstractEpstein–Barr virus (EBV) is a human gammaherpesvirus associated with the development of hematopoietic cancers of B-lymphocyte origin, including AIDS-related non-Hodgkin lymphoma (AIDS-NHL). Primary infection of B-cells with EBV results in their polyclonal activation and immortalization. The transferrin receptor 1 (TfR1), also known as CD71, is important for iron uptake and regulation of cellular proliferation. TfR1 is highly expressed in proliferating cells, including activated lymphocytes and malignant cells. We developed a mouse/human chimeric antibody targeting TfR1 (ch128.1/IgG1) that has previously shown significant antitumor activity in immunosuppressed mouse models bearing human malignant B-cells, including multiple myeloma and AIDS-NHL cells. In this article, we examined the effect of targeting TfR1 to inhibit EBV-driven activation and growth of human B-cells in vivo using an immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ [NOD/SCID gamma (NSG)] mouse model. Mice were implanted with T-cell–depleted, human peripheral blood mononuclear cells (PBMCs), either without EBV (EBV−), or exposed to EBV in vitro (EBV+), intravenously via the tail vein. Mice implanted with EBV+ cells and treated with an IgG1 control antibody (400 μg/mouse) developed lymphoma-like growths of human B-cell origin that were EBV+, whereas mice implanted with EBV+ cells and treated with ch128.1/IgG1 (400 μg/mouse) showed increased survival and significantly reduced inflammation and B-cell activation. These results indicate that ch128.1/IgG1 is effective at preventing the growth of EBV+ human B-cell tumors in vivo, thus, indicating that there is significant potential for agents targeting TfR1 as therapeutic strategies to prevent the development of EBV-associated B-cell malignancies.Significance:An anti-TfR1 antibody, ch128.1/IgG1, effectively inhibits the activation, growth, and immortalization of EBV+ human B-cells in vivo, as well as the development of these cells into lymphoma-like tumors in immunodeficient mice.
Development of a High-throughput NanoBRET Screening Platform to Identify Modulators of the RAS/RAF Interaction
Authors: Durrant David E. , Smith Emily A. , Goncharova Ekaterina I. , Sharma Nirmala , Alexander Patrick A. , Stephen Andrew G. , Henrich Curtis J. , Morrison Deborah K. 
Published: June 2021

Abstract
Activating mutations in RAS are found in approximately 30% of human cancers, resulting in the delivery of a persistent signal to critical downstream effectors that drive tumorigenesis. RAS-driven malignancies respond poorly to conventional cancer treatments and inhibitors that target RAS directly are limited; therefore, the identification of new strategies and/or drugs to disrupt RAS signaling in tumor cells remains a pressing therapeutic need. Taking advantage of the live-cell bioluminescence resonance energy transfer (BRET) methodology, we describe the development of a NanoBRET screening platform to identify compounds that modulate binding between activated KRAS and the CRAF kinase, an essential effector of RAS that initiates ERK cascade signaling. Using this strategy, libraries containing synthetic compounds, targeted inhibitors, purified natural products, and natural product extracts were evaluated. These efforts resulted in the identification of compounds that inhibit RAS/RAF binding and in turn suppress RAS-driven ERK activation, but also compounds that have the deleterious effect of enhancing the interaction to upregulate pathway signaling. Among the inhibitor hits identified, the majority were compounds derived from natural products, including ones reported to alter KRAS nanoclustering (ophiobolin A), to impact RAF function (HSP90 inhibitors and ROS inducers) as well as some with unknown targets and activities. These findings demonstrate the potential for this screening platform in natural product drug discovery and in the development of new therapeutic agents to target dysregulated RAS signaling in human disease states such as cancer.
Being Theological in a Comparative Manner in Today’s Indonesia
Authors: Laksana Albertus Bagus 
Published: June 2021

Abstract
In today’s Indonesia, public theological discourse is messy, sectarian, superficial, and highly apologetic. While the state philosophy of Pancasila offers an inclusive theological vision of citizenship and nationhood, its inclusiveness and dialogical character suffer from the exclusive use of the combination of the modern world-religion paradigm, European Christian theology, and Islamic parameters. This essay argues that the new comparative theology can serve as a dialogical theological reasoning that is particularly helpful to foster theologically constructive encounters among different religions, and thus able to address public concern, especially identity politics. This essay presents some concrete examples of comparative theological works in the Indonesian context, drawn from the author’s experiments. These highlight the dialogical, confessional, spiritual, and constructive characters of this theological reasoning, and pay attention to the hybrid identity and local cultures that form the richness of the Indonesian reality.