bluuebunny/crossref_metadata_2025_split huggingface dataset:
ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK
Authors: Munck Joanne M. , Berdini Valerio , Bevan Luke , Brothwood Jessica L. , Castro Juan , Courtin Aurélie , East Charlotte , Ferraldeschi Roberta , Heightman Tom D. , Hindley Christopher J. , Kucia-Tran Justyna , Lyons John F. , Martins Vanessa , Muench Sandra , Murray Christopher W. , Norton David , O'Reilly Marc , Reader Michael , Rees David C. , Rich Sharna J. , Richardson Caroline J. , Shah Alpesh D. , Stanczuk Lukas , Thompson Neil T. , Wilsher Nicola E. , Woolford Alison J.-A. , Wallis Nicola G. 
Published: July 2021

Abstract
The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I–II clinical trial in patients with advanced solid tumors (NCT03520075).
Activation of the ABCB1 Amplicon in Docetaxel- and Cabazitaxel-Resistant Prostate Cancer Cells
Authors: Lombard Alan P. , Lou Wei , Armstrong Cameron M. , D'Abronzo Leandro S. , Ning Shu , Evans Christopher P. , Gao Allen C. 
Published: July 2021

Abstract
Docetaxel and cabazitaxel-based taxane chemotherapy are critical components in the management of advanced prostate cancer. However, their efficacy is hindered due to de novo presentation with or the development of resistance. Characterizing models of taxane-resistant prostate cancer will lead to creation of strategies to overcome insensitivity. We have previously characterized docetaxel-resistant C4-2B and DU145 cell line derivatives, TaxR and DU145-DTXR, respectively. In the present study, we characterize cabazitaxel-resistant derivative cell lines created from chronic cabazitaxel exposure of TaxR and DU145-DTXR cells, CabR and CTXR, respectively. We show that CabR and CTXR cells are robustly resistant to both taxanes but retain sensitivity to antiandrogens. Both CabR and CTXR cells possess increased expression of ABCB1, which is shown to mediate resistance to treatment. Interestingly, we also present evidence for coordinated overexpression of additional genes present within the 7q21.12 gene locus where ABCB1 resides. This locus, known as the ABCB1 amplicon, has been demonstrated to be amplified in multidrug-resistant tumor cells, but little is known regarding its role in prostate cancer. We show that two ABCB1-amplicon genes other than ABCB1, RUNDC3B and DBF4, promote cellular viability and treatment resistance in taxane-resistant prostate cancer models. We present evidence that coordinated amplification of ABCB1-amplicon genes is common in a subset of prostate cancer patients. These data together suggest that ABCB1-amplicon activation plays a critical role in taxane resistance.
Nuclear Receptor Nur77 Protects Against Abdominal Aortic Aneurysm by Ameliorating Inflammation Via Suppressing LOX‐1
Authors: Zhang Hengyuan , Geng Na , Sun Lingyue , Che Xinyu , Xiao Qingqing , Tao Zhenyu , Chen Long , Lyu Yuyan , Shao Qin , Pu Jun 
Published: July 2021

Background
Abdominal aortic aneurysm (AAA) is a life‐threatening vascular disorder characterized by chronic inflammation of the aortic wall, which lacks effective pharmacotherapeutic remedies and has an extremely high mortality. Nuclear receptor NR4A1 (Nur77) functions in various chronic inflammatory diseases. However, the influence of Nur77 on AAA has remained unclear. Herein, we sought to determine the effects of Nur77 on the development of AAA.

Methods and Results
We observed that Nur77 expression decreased significantly in human and mice AAA lesions. Deletion of Nur77 accelerated the development of AAA in mice, as evidenced by increased AAA incidence, abdominal aortic diameters, elastin fragmentation, and collagen content. Consistent with genetic manipulation, pharmacological activation of Nur77 by celastrol showed beneficial effects against AAA. Microscopic and molecular analyses indicated that the detrimental effects of Nur77 deficiency were associated with aggravated macrophage infiltration in AAA lesions and increased pro‐inflammatory cytokines secretion and matrix metalloproteinase (MMP‐9) expression. Bioinformatics analyses further revealed that LOX‐1 was upregulated by Nur77 deficiency and consequently increased the expression of cytokines and MMP‐9. Moreover, rescue experiments verified that LOX‐1 notably aggravated inflammatory response, an effect that was blunted by Nur77.

Conclusions
This study firstly demonstrated a crucial role of Nur77 in the formation of AAA by targeting LOX‐1, which implicated Nur77 might be a potential therapeutic target for AAA.
Rewriting Genesis
Authors: Maza Edward 
Published: July 2021

Abstract
Barnett Newman’s abstract paintings are often explicitly linked to biblical narratives by their titles. In particular Newman regularly revisits the Genesis creation story. In the wake of the destruction of the Holocaust, Newman sets out to tell a revitalized story of creation in order to establish a new artistic beginning for the Jewish people (and modernism) in twentieth century New York. Through careful and nuanced visual analysis of Newman’s Genesis paintings, it is possible to construct a detailed mystical retelling of the creation story that is rooted in Jewish scriptures and develops a new receptive tradition. These paintings give Newman the opportunity to recreate the world through proverbial wisdom, Kabalistic mysticism, and Hebrew scriptures in order to create a new and hopeful vision for the future in the wake of tragedy.
UN Efforts to Make isis Accountable for International Crimes: the Challenges Posed by Iraq’s Domestic Law
Authors: Janaby Mohamad Ghazi , Alfatlawi Ahmed Aubais 
Published: July 2021

Abstract
Following the military defeat of isis in Iraq in December 2017, it has become clear that a logical next step would be to hold members of isis accountable for crimes committed during the capture of a number of principal Iraqi cities between 2014–2017. The unsc, accordingly, decided to investigate isis crimes internationally by establishing unitad to document isis violations whilst leaving any proposed prosecutions to be conducted internally by Iraqi courts. The practical implementation of this hybrid international mechanism for prosecuting isis members has generated some legal challenges caused particularly by the national laws of Iraq. Some of these legal issues arise in relation to unitad’s subjective jurisdiction to collect evidence concerning isis terrorist acts that might amount to evidence of war crimes, genocide and crimes against humanity. Others arise in relation to whether unitad’s criminal investigation procedures align or conform with Iraq’s criminal procedure laws. This paper examines these challenges and will propose some appropriate solutions.
Water Diplomacy — The New Modus Operandi of EU Diplomacy? Innovative Methods in Diplomatic Practice
Authors: Tomalová Eliška , Ullrichová Eliška 
Published: July 2021

Summary
This article explores how EU water diplomacy can enrich the current debate on science diplomacy, primarily in the science in diplomacy category. It aims to contribute to the debate on diplomatic instruments and their innovative elements. It focuses on new practices in the field of water diplomacy, including (1) the involvement of a wide range of stakeholders in the diplomatic process from an early stage, (2) a multi-dimensional approach, and (3) multidisciplinary science-based diplomacy. More generally, the article identifies and conceptualises particular diplomatic methods, (1) the internalisation of scientific expertise, (2) cross-cutting lexical understanding across diplomatic agendas, and (3) pluri-disciplinarity, which facilitates the interconnection of science and diplomacy within a diplomatic framework. It thus addresses the commonly acknowledged challenge of interaction between scientists and diplomats and shows that analysis of diplomatic methods may bring more clarity to the peripheral or often neglected science in diplomacy category of science diplomacy.
Why the Global Labor Movement is in Crisis
Authors: van der Linden Marcel 
Published: July 2021

Abstract
One of the great paradoxes of the current era is that the world working class continues to grow, while at the same time many labor movements are experiencing a crisis. How can we explain this paradox? The global simultaneity of the crisis suggests that the failure of individual organizational leaderships is not the main cause, but that more general factors play an important role. The article argues and attemps to partly explain why the first wave of founding workers‘ organizations (mainly in the North, from the 1860s until the 1920s) was not repeated elsewhere after World War ii; and why many movements in the North declined since the 1980s.
Snow-Pit Record from a Coastal Antarctic Site and Its Preservation of Meteorological Features
Authors: Nyamgerel Yalalt , Hong Sang-Bum , Han Yeongcheol , Kim Songyi , Lee Jeonghoon , Hur Soon Do 
Published: July 2021

AbstractPolar snow pits or ice cores preserve valuable information derived from the atmosphere on past climate and environment changes. A 1.57-m snow-pit record from the coastal site (Styx Glacier) in eastern Antarctica covering the period from January 2011 to January 2015 was discussed and compared with meteorological variables. The dominant contribution of the deposition of sea-salt aerosols due to the proximity of the site to the ocean and processes of sea ice formation was revealed in the ionic concentrations. Consistent seasonal peaks in δ18O, δD, MSA, , and indicate the strong enhancement of their source during warm periods, whereas the sea-salt ions (Na+, K+, Mg2+, Ca2+, Cl−, and ) exhibit a distinct distribution. Monthly mean δ18O positively correlates with the air temperature record from an automatic weather station (AWS) located in the main wind direction. Despite the shortness of the record, we suspect that the slight depletion of the isotopic composition and lowering of the snow accumulation could be related to the cooler air temperature with the decrease of open sea area. Consistency with previous studies and the positive correlation of sea-salt ions in the snow pit indicate the relatively good preservation of snow layers with noticeable climate and environmental signals [e.g., changes in sea ice extent (SIE) or sea surface temperature]. We report a new snow-pit record, which would be comparative and supportive to understand similar signals preserved in deeper ice cores in this location.
Co-creating an empowering health education intervention for urological cancer patients
Authors: Petit-Steeghs Violet , Pittens Carina ACM , Oosterman Jurriaan , Broerse Jacqueline EW 
Published: July 2021

Objective: The effectiveness of health education for patients has often been suboptimal. The neglect of a focus on empowerment and the presence of implementation barriers have been put forward as possible explanations for this. This study aimed to gain insight into how to co-create and develop an empowerment theory-based health education intervention for urological cancer patients. Design: Bravo’s empowerment intervention model provided the theoretical foundations for the work undertaken with urological cancer patients in the Netherlands, using a participatory interactive learning and action approach. Method: Insights into needs regarding health education were obtained through semi-structured interviews with patients ( n = 22) and health professionals ( n = 17). Subsequently, eight co-creation sessions ( n = 30) were organised to translate these needs into a health education intervention. Results: An intervention in the form of digital patient information was developed. The information offered provides a view of the different care steps based on clinical guidelines but personalised in different ways. By connecting patients’ empowerment needs to the information provided, and by taking health professionals’ perspectives into account, barriers to health education were made visible and addressed. Conclusion: Patient empowerment theory proved valuable in better aligning a participatory research process with the empowerment needs of urological cancer patients. The programme theory developed may offer a valuable template for the development of future health education interventions.
Brief Cognitive Behavioral Group Therapy and Verbal-Exposure-Augmented Cognitive Behavioral Therapy for Social Anxiety Disorder in University Students: A Randomized Controlled Feasibility Trial
Authors: Singh Preeti , Samantaray Narendra Nath 
Published: July 2021

Background: Considering the need for developing and examining evidenced-based programs using a brief group format for management of social anxiety disorder (SAD) at the community level, we studied theefficacy of two brief versions of cognitive-behavioral therapy (CBT) programs, brief cognitive-behavioral group therapy (bCBGT), and verbal exposure augmented cognitive behavioral therapy (VE-CBT), on social anxiety among university students. Methods: A single-center, randomized, parallel-group design was adopted. We delivered six weekly two-hour group sessions, bCBGT and VE-CBT, to 41 university students diagnosed with SAD. An independent rater assessed participants using the Liebowitz Social Anxiety Scale (LSAS) and Clinical Global Impression scale-Severity (CGI-S) at baseline, postintervention, and two-month follow-up. A patient-rated measure, Social Phobia Inventory (SPIN), was assessed at the same time-points. Results: There was a significant improvement in severity of social anxiety from baseline to posttreatment and baseline to two-month follow-up in both groups. However, the treatment effects in bCBGT were statistically superior to VE-CBT at postintervention (SPIN, P = 0.038; LSAS, P = 0.028; CGI-S, P = 0.036) and follow-up (SPIN, P = 0.006; LSAS, P = 0.01; CGI-S, P = 0.04). Conclusions: Brief CBT treatments, both bCBGT and VE-CBT, are efficacious for SAD among university students. They have the potential to address barriers associated with SAD management. However, we recommend a longer follow-up and replications in diverse settings. Clinical trial registration number: CTRI/2019/11/021954
Digital Capacity and Interest in mHealth Interventions Among Individuals on Opioid Agonist Maintenance Treatment: A Cross-Sectional Community-Based Study
Authors: Ganesh Ragul , Rao Ravindra , Deb Koushik Sinha , Bhad Roshan , Yadav Deepak 
Published: July 2021

Background: Integrating mobile technologies in healthcare (mHealth) is helpful to manage various medical conditions. mHealth applications can bridge the gap in the management of patients with opioid use disorder (OUD). Research evaluating the feasibility of mHealth to address OUD is limited in developing countries. We aimed to assess the digital capacity and interest in mHealth interventions in patients maintained on opioid agonist treatment (OAT). Methods: 150 patients on OAT from a community drug treatment clinic in New Delhi, India, were included. We assessed the participants on their pattern of mobile and Internet use and their willingness to use mHealth technology to access health information and services related to OUD. Results: 88% of participants ( n = 132) owned a mobile phone at assessment; 2.7% ( n = 4) had never used a mobile phone in their lifetime. 70% ( n = 105) participants had Internet access. 80% ( n = 120) of participants showed interest in receiving text messages related to the management of OUD. 60% of participants showed a willingness to download and use applications for monitoring their substance use. Conclusions: In India, there is an interest among people on OAT to use mHealth interventions to manage their substance use. This population also has access to mobile phones and the necessary knowledge to install and run applications needed for various mHealth interventions.
Comparison between acupuncture therapy and gabapentin for chronic pain: a pilot study
Authors: Chen Lucy , Deng Hao , Houle Timothy , Zhang Yi , Ahmed Shihab , Zhang Wei , Sullivan Shelly , Opalacz Arissa , Roth Sarah , Filatava Evgenia Jen , Stabach Kristin , Vo Trang , Malarick Charlene , Kim Hyangin , You Zerong , Shen Shiqian , Mao Jianren 
Published: July 2021

Background: We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST). Methods: We recruited chronic back and neck pain participants who received six sessions (twice weekly) of true electroacupuncture versus sham electroacupuncture or 3 weeks of gabapentin versus placebo treatment. QST profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after three sessions (visit 4) or six sessions (visit 7) of acupuncture or 3 weeks of gabapentin or placebo. Results: A total of 50 participants were analyzed. We found no differences in QST profile changes (p = 0.892), pain reduction (p = 0.222), or functionality (p = 0.254) between the four groups. A major limitation of this pilot study was the limited number of study participants in each group. Conclusion: This pilot study suggests that a large-scale clinical study with an adequate sample size would be warranted to compare acupuncture and medication therapy for chronic pain management. Trial registration number: NCT01678586 (ClinicalTrials.gov).
The impact of spontaneous echo contrast on tunneled dialysis catheter patency
Authors: Özyalçın Sertan , Topçu Hülya 
Published: July 2021

Background: Spontaneous echo contrast (SEC) is an ultrasonographic image of swirling blood flow resembling a dynamic, cigarette smoke-like image. It is mostly observed during the insertion of tunneled dialysis catheters (TDC) into internal jugular veins with ultrasound guidance, often different levels of SEC can be seen. The aim of this study is to investigate the impact of SEC detected during TDC insertion on the patency of the catheter. Methods: Patients who had a TDC insertion in our clinic between January 2015 and December 2020 were prospectively evaluated. The patients were grouped into five groups according to the sec level and followed. Results: A total of 226 patients were examined, among which 107 were male (47.3%). The mean age of all patients was 63.1 ± 9.5 years. SEC grade and catheter occlusion was evaluated, it was observed that higher SEC grades were correlated with faster catheter thrombosis postinsertion. During the follow-up period, it was found that, compared to the SEC 0 group, catheter thrombosis occurred 3.22 times faster in the SEC 1 group, 2.66 times faster in the SEC 2 group, 5.80 times faster in the SEC 3 group, and 26.33 times faster in the SEC 4 group. (HR: 3.22, 2.66, 5.80, 26.33, respectively). Hematological parameters were evaluated by regression analysis, it was observed that hemoglobin, fibrinogen, and platelet count were not risk factors for SEC formation and SEC grade. Conclusion: Significant relationship was found between SEC grade detected during catheter insertion and catheter thrombosis in patients undergoing hemodialysis with a TDC.
Family narratives of lives with persistent physical symptom conditions
Authors: Friedner Kimberley , Solomons Wendy , Flannery Halina , Harrington Jenna 
Published: July 2021

Background Literature reviews revealed no existing research on family narratives of living with multigenerational persistent physical symptom (PPS) conditions. The current study examined the personal and family narratives of one such family, from a relational/systemic perspective. Method This research employed a qualitative research design, specifically using narrative methodologies to explore the experiences of a single family comprising two parents and their three children. All the children and their mother had a diagnosis of Ehlers–Danlos syndrome (EDS) but are specifically afflicted with PPS. The father is in good health. Using narrative inquiry, the family members were interviewed together and then individually. The interviews were audio-recorded, transcribed and analysed using narrative analysis in NVivo. Findings Overarching narratives were stories of loss and sacrifice and stories of family unity. An exploration of the family’s negotiation of roles and identities is presented in the context of stigmatised illness. Discussion Novel findings are presented in the context of the central role of the mother, the importance of family cohesion and the impact to family life resulting from living with stigmatised illness. Lastly, clinical implications and future research ideas are discussed.