The Role of Temperature in Modifying the Risk of Ozone-Attributable Mortality under Future Changes in Climate: A Proof-of-Concept Analysis

2021 ◽  
Author(s):  
Neal Fann ◽  
Evan Coffman ◽  
Melanie Jackson ◽  
Iny Jhun ◽  
Archana P. Lamichhane ◽  
...  
Keyword(s):  
Concept Analysis ◽  
Attributable Mortality ◽  
Proof Of Concept

scholarly journals Retargeting of NK-92 Cells against High-Risk Rhabdomyosarcomas by Means of an ERBB2 (HER2/Neu)-Specific Chimeric Antigen Receptor

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1443
Author(s):  
Leonie D. H. Gossel ◽  
Catrin Heim ◽  
Lisa-Marie Pfeffermann ◽  
Laura M. Moser ◽  
Halvard B. Bönig ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Cells ◽  
Chimeric Antigen Receptor ◽  
Treatment Options ◽  
Antigen Receptor ◽  
Proof Of Concept ◽  
Cell Monolayers ◽  
Novel Treatment ◽  
Dismal Prognosis

The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.

scholarly journals Improving Equine Welfare through Human Habit Formation

Animals ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2156
Author(s):  
Jo White ◽  
Ruth Sims
Keyword(s):  
Management Practices ◽  
Habit Formation ◽  
Positive Impact ◽  
Proof Of Concept ◽  
Mutual Benefit ◽  
Structured Interviews ◽  
Behavioural Research ◽  
Equine Welfare ◽  
Lasting Change

This paper explores the potential for interventions to develop pro-animal welfare habitual behaviours (PAWHBs) in people to improve the lives of animals. Human behavioural research indicates that opportunities exist to deliver lasting change through developing positive habitual behaviours. The routine nature of many equine care and management practices lends itself to habit formation and maintenance. This proof-of-concept paper aims to evaluate a theory-based intervention of developing and maintaining a PAWHB in people caring for equines. Qualitative research methods were used. A 30 day PAWHB intervention (PAWHBInt) of providing enrichment to an equine by scratching them in a consistent context linked to an existing routine behaviour was undertaken. Participants (n = 9) then engaged in semi-structured interviews that were analysed using thematic analysis, where the participants self-reported the outcomes they observed during the intervention. The study findings suggest that the PAWHBInt had a positive impact on human behaviour and habit formation. The research helps to address the dearth of evidence regarding the application of habit theory to equine welfare interventions and emphasised linking a desired new behaviour to an existing routine behaviour when developing PAWHBs. The research also highlights the role of mutual benefit for human and equine, and emotion in providing feedback and potential reward, supporting the link to the cue-routine-reward principle of habit theory.

Automated Treatment Planning System for Uveal Melanomas Treated With Proton Therapy: A Proof-of-Concept Analysis

2018 ◽  
Vol 101 (3) ◽  
pp. 724-731 ◽  
Author(s):  
Fabian Hennings ◽  
Antony Lomax ◽  
Alessia Pica ◽  
Damien Charles Weber ◽  
Jan Hrbacek
Keyword(s):  
Treatment Planning ◽  
Proton Therapy ◽  
Concept Analysis ◽  
Planning System ◽  
Treatment Planning System ◽  
Proof Of Concept ◽  
Uveal Melanomas

scholarly journals cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis

2019 ◽  
Vol 5 (5) ◽  
pp. eaav5562 ◽  
Author(s):  
Ruochan Chen ◽  
Ling Zeng ◽  
Shan Zhu ◽  
Jiao Liu ◽  
Herbert J. Zeh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
Proof Of Concept ◽  
Potential Therapeutic Target ◽  
Camp Metabolism ◽  
Camp Hydrolysis ◽  
Insight Into

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11−/−), or Gsdmd inactivation (GsdmdI105N/I105N) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

scholarly journals Minimal mechanistic component of proteasome activation and prevention of impairment by pathological oligomers

2021 ◽  
Author(s):  
Janelle Chuah ◽  
Tifffany Thibaudeau ◽  
David Smith
Keyword(s):  
Small Molecules ◽  
Conformational Changes ◽  
Bound State ◽  
Proof Of Concept ◽  
Α Subunit ◽  
Gate Opening ◽  
Allosteric Mechanism ◽  
Dependent Mechanism ◽  
Degradation Of Peptides

Abstract Impairment of proteasomal function has been implicated in neurodegenerative diseases, justifying the need to understand how the proteasome is activated for protein degradation. Here, using biochemical and structural (cryo-EM) strategies in both archaeal and mammalian proteasomes, we further determine the HbYX(-motif)-dependent mechanism of proteasomal activation used by multiple proteasome-activating complexes including the 19S Particle. We identify multiple proteasome α subunit residues involved in HbYX-dependent activation, a point mutation that activates the proteasome by partially mimicking a HbYX-bound state, and conformational changes involved in gate-opening with a 2.0A structure. Through an iterative process of peptide synthesis, we successfully design a HbYX-like dipeptide mimetic as a robust tool to elucidate how the motif autonomously activates the proteasome. The mimetic induces near complete gate-opening at saturating concentration, activating mammalian proteasomal degradation of peptides and proteins. Findings using our peptide mimetic suggest the HbYX-dependent mechanism requires cooperative binding in at least two intersubunit pockets of the α ring. Collectively, the results presented here unambiguously demonstrate the lone role of the HbYX tyrosine in the allosteric mechanism of proteasome activation and offer proof of concept for the robust potential of HbYX-like small molecules to activate the proteasome.

scholarly journals A Proof of Concept of the Role of TDM-Based Clinical Pharmacological Advices in Optimizing Antimicrobial Therapy on Real-Time in Different Paediatric Settings

2021 ◽  
Vol 12 ◽  
Author(s):  
Milo Gatti ◽  
Pier Giorgio Cojutti ◽  
Caterina Campoli ◽  
Fabio Caramelli ◽  
Luigi Tommaso Corvaglia ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Real Time ◽  
Antimicrobial Therapy ◽  
Turnaround Time ◽  
Antimicrobial Treatment ◽  
Therapeutic Drug ◽  
Proof Of Concept ◽  
Paediatric Patients ◽  
Dosing Regimens

Introduction: Antimicrobial treatment is quite common among hospitalized children. The dynamic age-associated physiological variations coupled with the pathophysiological alterations caused by underlying illness and potential drug-drug interactions makes the implementation of appropriate antimicrobial dosing extremely challenging among paediatrics. Therapeutic drug monitoring (TDM) may represent a valuable tool for assisting clinicians in optimizing antimicrobial exposure. Clinical pharmacological advice (CPA) is an approach based on the correct interpretation of the TDM result by the MD Clinical Pharmacologist in relation to specific underlying conditions, namely the antimicrobial susceptibility of the clinical isolate, the site of infection, the pathophysiological characteristics of the patient and/or the drug-drug interactions of cotreatments. The aim of this study was to assess the role of TDM-based CPAs in providing useful recommendations for the real-time personalization of antimicrobial dosing regimens in various paediatric settings.Materials and methods: Paediatric patients who were admitted to different settings of the IRCCS Azienda Ospedaliero-Universitaria of Bologna, Italy (paediatric intensive care unit [ICU], paediatric onco-haematology, neonatology, and emergency paediatric ward), between January 2021 and June 2021 and who received TDM-based CPAs on real-time for personalization of antimicrobial therapy were retrospectively assessed. Demographic and clinical features, CPAs delivered in relation to different settings and antimicrobials, and type of dosing adjustments were extracted. Two indicators of performance were identified. The number of dosing adjustments provided over the total number of delivered CPAs. The turnaround time (TAT) of CPAs according to a predefined scale (optimal, <12 h; quasi-optimal, between 12–24 h; acceptable, between 24–48 h; suboptimal, >48 h).Results: Overall, 247 CPAs were delivered to 53 paediatric patients (mean 4.7 ± 3.7 CPAs/patient). Most were delivered to onco-haematological patients (39.6%) and to ICU patients (35.8%), and concerned mainly isavuconazole (19.0%) and voriconazole (17.8%). Overall, CPAs suggested dosing adjustments in 37.7% of cases (24.3% increases and 13.4% decreases). Median TAT was 7.5 h (IQR 6.1–8.8 h). Overall, CPAs TAT was optimal in 91.5% of cases, and suboptimal in only 0.8% of cases.Discussion: Our study provides a proof of concept of the helpful role that TDM-based real-time CPAs may have in optimizing antimicrobial exposure in different challenging paediatric scenarios.

scholarly journals Understanding Screaming Channels: From a Detailed Analysis to Improved Attacks

2020 ◽  
pp. 358-401
Author(s):  
Giovanni Camurati ◽  
Aurélien Francillon ◽  
François-Xavier Standaert
Keyword(s):  
Spatial Diversity ◽  
Low Noise ◽  
Security Evaluation ◽  
The Novel ◽  
Proof Of Concept ◽  
Wireless Devices ◽  
Side Channels ◽  
Security Evaluations ◽  
The One

Recently, some wireless devices have been found vulnerable to a novel class of side-channel attacks, called Screaming Channels. These leaks might appear if the sensitive leaks from the processor are unintentionally broadcast by a radio transmitter placed on the same chip. Previous work focuses on identifying the root causes, and on mounting an attack at a distance considerably larger than the one achievable with conventional electromagnetic side channels, which was demonstrated in the low-noise environment of an anechoic chamber. However, a detailed understanding of the leak, attacks that take full advantage of the novel vector, and security evaluations in more practical scenarios are still missing. In this paper, we conduct a thorough experimental analysis of the peculiar properties of Screaming Channels. For example, we learn about the coexistence of intended and unintended data, the role of distance and other parameters on the strength of the leak, the distortion of the leakmodel, and the portability of the profiles. With such insights, we build better attacks. We profile a device connected via cable with 10000·500 traces. Then, 5 months later, we attack a different instance at 15m in an office environment. We recover the AES-128 key with 5000·1000 traces and key enumeration up to 223. Leveraging spatial diversity, we mount some attacks in the presence of obstacles. As a first example of application to a real system, we show a proof-of-concept attack against the authentication method of Google Eddystone beacons. On the one side, this work lowers the bar for more realistic attacks, highlighting the importance of the novel attack vector. On the other side, it provides a broader security evaluation of the leaks, helping the defender and radio designers to evaluate risk, and the need of countermeasures.

scholarly journals Perfluoroalkyl substances, metabolomic profiling, and alterations in glucose homeostasis among overweight and obese Hispanic children: A proof-of-concept analysis

2019 ◽  
Vol 126 ◽  
pp. 445-453 ◽  
Author(s):  
Tanya L. Alderete ◽  
Ran Jin ◽  
Douglas I. Walker ◽  
Damaskini Valvi ◽  
Zhanghua Chen ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Concept Analysis ◽  
Perfluoroalkyl Substances ◽  
Proof Of Concept ◽  
Hispanic Children ◽  
Metabolomic Profiling

scholarly journals The role of courage on behavioral approach in a fear-eliciting situation: A proof-of-concept pilot study

2009 ◽  
Vol 23 (2) ◽  
pp. 212-217 ◽  
Author(s):  
Peter J. Norton ◽  
Brandon J. Weiss
Keyword(s):  
Pilot Study ◽  
Behavioral Approach ◽  
Proof Of Concept
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