bluuebunny/crossref_metadata_2025 huggingface dataset:
The emerging role of targeted protein degradation to treat and study cancer
Authors: Brodermann Maximillian H , Henderson Elizabeth K , Sellar Rob S
Published: June 2024

The evolution of cancer treatment has provided increasingly targeted strategies both in the upfront and relapsed disease settings. Small‐molecule inhibitors and immunotherapy have risen to prominence with chimeric antigen receptor T‐cells, checkpoint inhibitors, kinase inhibitors, and monoclonal antibody therapies being deployed across a range of solid organ and haematological malignancies. However, novel approaches are required to target transcription factors and oncogenic fusion proteins that are central to cancer biology and have generally eluded successful drug development. Thalidomide analogues causing protein degradation have been a cornerstone of treatment in multiple myeloma, but a lack of in‐depth mechanistic understanding initially limited progress in the field. When the protein cereblon (CRBN) was found to mediate thalidomide analogues' action and CRBN's neo‐targets were identified, existing and novel drug development accelerated, with applications outside multiple myeloma, including non‐Hodgkin's lymphoma, myelodysplastic syndrome, and acute leukaemias. Critically, transcription factors were the first canonical targets described. In addition to broadening the application of protein‐degrading drugs, resistance mechanisms are being overcome and targeted protein degradation is widening the scope of druggable proteins against which existing approaches have been ineffective. Examples of targeted protein degraders include molecular glues and proteolysis targeting chimeras (PROTACs): heterobifunctional molecules that bind to proteins of interest and cause proximity‐induced ubiquitination and proteasomal degradation via a linked E3 ligase. Twenty years since their inception, PROTACs have begun progressing through clinical trials, with early success in targeting the oestrogen receptor and androgen receptor in breast and prostate cancer respectively. This review explores important developments in targeted protein degradation to both treat and study cancer. It also considers the potential advantages and challenges in the translational aspects of developing new treatments. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Dielectric properties of polypropylene blended with copolymers of varying ethylene contents
Authors: Kamarudin Siti Noorhazirah , Lau Kwan Yiew , Ahmad Noor Azlinda , Azrin Nur Azalia , Ching Kuan Yong , Ghani Ahmad Basri Abd , Arifin Nur Amira Nor
Published: June 2024

Polypropylene (PP) has recently been actively investigated as a potential power cable insulation substitute for crosslinked polyethylene (XLPE). This is mainly due to PP's higher thermal withstand capability over XLPE. Notably, PP has much higher stiffness than XLPE and therefore needs to be modified with tougher materials to reduce its overall stiffness while maintaining its desirable dielectric properties. To date, many investigations have been conducted on the mechanical and dielectric effects of PP blended with various copolymers. Nevertheless, systematic investigations on the dielectric effects of PP blended with ethylene‐based copolymers having different ethylene contents are less explored. The current work therefore reports on the impact of different ethylene contents of ethylene‐based copolymers on the breakdown performances of PP. The findings reveal that PP blended with a copolymer having a low ethylene content (68.7 wt%) results in at least 11% higher breakdown performance than PP containing a copolymer having a high ethylene content (77.0 wt%). Specifically, PP containing 10 wt% of copolymers having 68.7 wt% of ethylene content results in comparable breakdown performance to XLPE (325 kV mm−1). These results suggest that ethylene‐based copolymers with an appropriately low ethylene content can be blended with PP to achieve desirable breakdown properties.

Highlights

PP is blended with copolymers of varying amounts and ethylene contents.

PP blended with low amounts of copolymers has good breakdown strength.

PP blended with low ethylene level copolymers has favorable breakdown strength.

PP blended with copolymers of low ethylene contents is desirable.

The breakdown mechanisms are related with the structure and permittivity.
Exploring the Modern Bioactive Peptides (BAPs) Universe: Doors to the Future
Authors: Patil Prasanna J.
Published: June 2024

Because of their wide variety of biological effects, bioactive peptides (BAPs) have recently attracted a lot of attention. BAPs have been observed to be safe, thanks to their widely acknowledged safety status by the United States Food and Drug Administration (USFDA). This has led to their widespread use in various industries, such as food and nutrition, pharmaceuticals, and therapeutics. A considerable amount of research has been devoted to developing cutting‐edge nanomaterials derived from BAPs, which have been utilized in a wide range of industries. In the realm of scientific research, the remarkable ability of BAPs to self‐assemble has been harnessed to develop a wide range of nanoassemblies. These nanoassemblies hold immense potential for the advancement of biomaterials in the future. Research interest continues to focus on the study of the detection of BAPs using artificial intelligence (AI). Over the past few years, there has been a surge of interest in utilizing bio‐inspired strategies to explore new possibilities in the development of advanced energy devices and storage solutions. However, these strategies require scientific attention. This extensive review offers a broad perspective on the applications of BAPs in nanotechnology as well as pharmaceuticals and therapeutics. Moreover, in silico analysis of BAPs, coupled with ‐omics techniques, has been discussed. In the bargain, the next‐generation approaches in BAP research comprising BAP‐based energy devices, as well as BAPs in AI, have been catalogued. There is a considerable emphasis on developing more eco‐friendly energy‐storage technologies that draw inspiration from nature and use BAPs.
OCT for automated conventional welding in the automotive industry
Authors: Dupriez Nataliya Deyneka , Adolph Samuel
Published: June 2024

Similar to laser welding, optical coherence tomography (OCT) simplifies the operation of robot‐guided, automated GMA welding by offering seam tracking capabilities thanks to its industry‐approved, standardized functions and fieldbus communication. Furthermore, OCT can monitor the quality of weld seam online by measuring the seam topography during GMA welding, eliminating the need for time‐consuming and costly off‐line weld inspection.
Quasi‐elastic neutron scattering study on dynamically asymmetric polymer blends
Authors: Mbonu Christopher , Osti Naresh C. , Wu Di , Akcora Pinar
Published: June 2024

Compatibility between polymers with different glass transition temperatures controls the thermomechanical properties of blends. This work explores the segmental dynamics of poly(methyl acrylate) (PMA) chains when they are blended with polymers of different rigidities and miscibility. Inspired by the intriguing dynamic asymmetry of chains within the interfacial layer of nanoparticles, this study aims to understand dynamic heterogeneity in dynamically asymmetric blends of PMA/poly(methyl methacrylate) (PMMA), PMA/polystyrene (PS), and PMA/poly(ethylene oxide) (PEO) using the differential scanning calorimetry (DSC) and quasi‐elastic neutron scattering (QENS) measurements below and above the glass transition temperature of PMMA or PS. Results revealed that the segmental jump distance of PMA increased on blending due to volume enhancement. The reduced effective diffusivity of PMA in PMMA is attributed to PMMA's enhanced flexibility (lower characteristic ratio, ) and superior interaction (lower ) when compared with the PS environment. The results demonstrate that the chain rigidity and miscibility affect the free volume, interchain cooperativity, and segmental dynamics in dynamically asymmetric blends.
The crosslinking and decrosslinking of fluorinated diblock copolymer from RAFT emulsion polymerization toward surface anti‐icing
Authors: Xu Huangbing , Qiu Teng , Tian Xiaoqian , Wu Fengjiao , Guo Longhai , Li Xiaoyu
Published: June 2024

Here, we demonstrate disulfide‐crosslinked polyfluoroacrylate AB block copolymer films with excellent anti‐icing properties. The fluorinated latexes of AB block copolymers were synthesized via two‐step reversible addition‐fragmentation chain‐transfer (RAFT) emulsion polymerization using polyacrylic acid and its sodium salts as the hydrophilic A‐block, and polyhexafluorobutyl acrylate as the hydrophobic B‐block. Diacetone acrylamide was copolymerized in different blocks as a crosslinking anchor. A disulfide‐containing compound dithiodipropionic acid dihydrazide was chosen as the crosslinking agent to form disulfide‐crosslinked fluorinated films to enhance the mechanical properties, surface properties, swelling properties, and anti‐icing properties of the films. It has proved that the crosslinking site has a great impact on the film formation process which in turn affects the film performance. The B‐block crosslinked films showed better resistance to water while the A‐block crosslinked films were more organic solution resistant. The A‐block crosslinked films also possessed better anti‐icing properties due to the high F/O value. Furthermore, decrosslinking experiments were conducted using a reductant tris(2‐carboxyethyl)phosphine hydrochloride to break the disulfide bond. The recycling rate of the B‐block crosslinked films could reach >90% while the recycling rate of the A‐block crosslinked films reached >75%.
Effect of decalcification on immunohistochemical staining of trichorhinophalangeal syndrome type 1
Authors: Miao Chen , Chen Gang , Han Wenli , Hu Ran
Published: June 2024

To evaluate the effect of different decalcification solutions on the immunohistochemical staining of trichorhinophalangeal syndrome type 1 (TRPS1), and to provide a reliable basis for the accurate diagnosis of bone metastasis of breast cancer. Due to the limited biopsy samples of bone metastatic cancer, 20 cases of invasive breast cancer were selected to simulate bone metastatic biopsy, dividing into four groups: undecalcified group, 30% formic acid group, 10% hydrochloric acid group and 10% nitric acid group. Immunohistochemical staining was performed after treatment for 2, 6, 18 and 24 h. There was no change in the proportion and intensity of TRPS1 cells in the formic acid decalcification group within 18 h, but decreased significantly after 24 h. The staining intensity of TRPS1 and the proportion of stained cells were significantly decreased in the hydrochloric acid decalcification group since 2 h treatment. The percentage and intensity of positive cells in the nitric acid decalcification group changed little or no change within 6 h, and then gradually decreased with the extension of time. Another three invasive breast cancer samples were used to compare the effects of different decalcification solutions on the same case. In brief, we conclude that the effect of 30% formic acid decalcification on TRPS1 staining is small when the time is less than 18 h. 10% nitric acid decalcification should be controlled within 6 h, which has little effect on TRPS1 staining, and 10% hydrochloric acid decalcification will lead to significantly less positive TRPS1 staining, so it is not recommended for breast bone metastasis tissue decalcification.
Simulating realistic patient profiles from pharmacokinetic models by a machine learning postprocessing correction of residual variability
Authors: Kaikousidis Christos , Bies Robert R. , Dokoumetzidis Aristides
Published: June 2024

We address the problem of model misspecification in population pharmacokinetics (PopPK), by modeling residual unexplained variability (RUV) by machine learning (ML) methods in a postprocessing step after conventional model building. The practical purpose of the method is the generation of realistic virtual patient profiles and the quantification of the extent of model misspecification, by introducing an appropriate metric, to be used as an additional diagnostic of model quality. The proposed methodology consists of the following steps: After developing a PopPK model, the individual residual errors IRES = DV–IPRED, are computed, where DV are the observations and IPRED the individual predictions and are modeled by ML to obtain IRESML. Correction of the IPREDs can then be carried out as DVML = IPRED + IRESML. The methodology was tested in a PK study of ropinirole, for which a PopPK model was developed while a second deliberately misspecified model was also considered. Various supervised ML algorithms were tested, among which Random Forest gave the best results. The ML model was able to correct individual predictions as inspected in diagnostic plots and most importantly it simulated realistic profiles that resembled the real data and canceled out the artifacts introduced by the elevated RUV, even in the case of the heavily misspecified model. Furthermore, a metric to quantify the extent of model misspecification was introduced based on the R2 between IRES and IRESML, following the rationale that the greater the extent of variability explained by the ML model, the higher the degree of model misspecification present in the original model.
TiO2‐Based Schottky Diodes as Bidirectional Switches for Bipolar Resistive Memories
Authors: Zhang Xijian , Jin Jidong , Kim Jaekyun , Balocco Claudio , Zhang Jiawei , Song Aimin
Published: June 2024

This study presents TiO2‐based Schottky diodes designed as bidirectional switches for bipolar resistive memories. The TiO2 films in these Schottky diodes are prepared through an anodization process. The reverse current of these diodes exhibits an exponential increase with rising reverse voltage, ultimately matching the forward current. When two diodes are connected back‐to‐back, they demonstrate superior current–voltage symmetry and provide a wider off‐state voltage range compared to a single diode, reaching up to 3.65 V. The adjustable off‐state voltage range (0.40–3.65 V) of the switch, whether utilizing two diodes or a single diode, correlates well with the TiO2 layer thickness and oxygen partial pressure during Pt electrode sputtering. These diodes possess bidirectional switching characteristics and can serve as effective switch elements to address the sneak‐path issue in bipolar resistive memories.
Efficacy and safety of adoptive T‐cell therapy in treating cytomegalovirus infections post‐haematopoietic stem cell transplantation: A systematic review and meta‐analysis
Authors: Taherian Mohammad Reza , Azarbar Pouya , Barkhordar Maryam , Toufani Shahin , Aliabadi Leyla Sharifi , Bahri Tanaz , Ahmadvand Mohammad , Yaghmaie Marjan , Daneshvar Alireza , Vaezi Mohammad
Published: June 2024

Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo‐HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta‐analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo‐HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta‐analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta‐analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman–Tukey transformation was applied for analysis. In the meta‐analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor‐derived T‐cell treatments exhibited a higher response rate (93.66%) compared to third‐party sources (88.94%). HLA‐matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft‐versus‐host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post‐HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one‐arm studies to provide robust evidence for clinical decision‐making.
Association between Epstein‐Barr virus LMP‐1 and Hodgkin lymphoma LMP‐1 mechanisms in Hodgkin lymphoma development
Authors: Oliveira Leonam Oliver Durval , Costa Igor Brasil , Quaresma Juarez Antônio Simões
Published: June 2024

Hodgkin lymphoma is histologically characterised by the presence of Hodgkin (H) and Reed‐Sternberg (RS) cells originating from germinal centre B‐cells rearranged in the IgV gene. The formation of multinucleated RS cells is a product of telomere organisation in a process initiated by telomere aggregate accumulation in mononuclear H cells and may be mediated by latent membrane protein 1 (LMP‐1) expression. LMP‐1 is the main oncoprotein of EBV and supports several tumourigenic processes. LMP‐1 may rescue proapoptotic B‐cells through downregulation of B‐cell receptor (BCR) components, mimicking and inducing multiple distinct B‐cell signalling pathways to promote proliferation and survival, such as Janus kinase‐signal transducer and activator of transcription (JAK‐STAT), nuclear factor‐kappa b (NF‐кB), and cellular MYC (c‐MYC), and inducing telomere instability mainly through Telomere repeat binding factor 2 (TRF2) downregulation to promote the formation of multinucleated RS cells. This review presents recent discoveries regarding the influence of LMP‐1 on the surviving cellular signalling, genomic instability and mecanical formation of HRS cells.
Long‐term treatments alter acidification, fertility and carbon in soils of the Fork Mountain long‐term soil productivity experiment
Authors: Adams Mary Beth , Rau Benjamin M. , Peterjohn William T. , Fowler Zach , Kelly Charlene
Published: June 2024

Historic atmospheric acidic deposition resulting from the combustion of fossil fuels may alter the pools of important nutrients and base cations in sensitive forest soils. This raises concern that chronic acidic deposition, particularly when coupled with intensive forest biomass harvesting, may diminish long‐term soil fertility, forest productivity, and carbon storage potential. To address these concerns, the Fork Mountain long‐term soil productivity experiment was initiated in 1996 at the Fernow Experimental Forest, West Virginia. The replicated experimental design consists of 16 plots (0.2 ha) that receive one of four treatments: (1) whole‐tree harvesting (removal of all aboveground biomass, WT plots); (2) whole‐tree harvesting + ammonium‐sulfate fertilization (WT + NS plots); (3) whole‐tree harvesting + ammonium‐sulfate fertilization + dolomitic lime (WT + NS + Lime plots); and (4) untreated reference plots. We present forest floor and soil chemistry responses after ∼25 years of treatment and evaluate the temporal changes to illuminate these results. Soil acidification has occurred, and base cation movement through the soil profile was observed, with effective cation exchange capacity increasing slightly in the deepest soil horizon by the end of the 25 years. However, some of our hypotheses were not supported. In particular, soil C did not increase over time with fertilization/soil acidification but was mainly altered by WT harvesting, as were other nutrients. Dolomitic lime provided some amelioration of acidification, but surprisingly, most of the changes in base cations appeared to be the results of Mg, not Ca, likely due to greater tree requirements and uptake of Ca.
Sufficiency as relations of enoughness
Authors: Hartmann Eric
Published: June 2024

An expanding body of literature discusses the importance of sufficiency for sustainable development. However, conceptual vagueness stands in the way of the practical application of sufficiency as a sustainability strategy. The main contribution of this paper is the introduction of the concept of relations of enoughness, building on the general notion of ‘enough’, which is prevalent in sufficiency literature. Relations of enoughness will be explained based on the widespread use of sufficiency advocating for changes and reductions of individual consumption with the goal to reduce environmental impacts such as carbon dioxide emissions. Diverse uses and understandings of sufficiency can be united in a shared structure of ‘enough/too much/too little of X regarding Y’. Relations of enoughness can be connected to sustainability by expanding them into chains of enoughness, which serve as a conceptual foundation for the sustainable consumption corridor approach. Finally, the premises of sufficiency and potential for further research are discussed.
Impact of the COVID-19 Pandemic on International Cutaneous Squamous Cell Carcinoma Incidence: A Systematic Review and Meta-Analysis
Authors: Wall James , Gadsby-Davis Kieran , Mistry Khaylen , Levell Nick J. , Venables Zoe C.
Published: June 2024

Background

Non-melanoma skin cancer (NMSC) is the most common cancer globally in white ethinicity populations, and cutaneous squamous cell carcinoma (cSCC) is the second most common subtype. The COVID-19 pandemic severely impacted public and private healthcare systems. Many studies have reported reduced cancer diagnoses during the pandemic. The impact of the COVID-19 pandemic on global cSCC and NMSC incidence is poorly reported.

Objectives

The aim was to conduct a systematic review and meta-analysis to assess the impact of the COVID-19 pandemic on global cSCC and NMSC incidence rates, compared with 2019 incidence rates. Two primary outcome measures were used: crude incidence rate ratios (CIRR) and age-standardised incidence rate ratios (ASIRR).

Methods

A structured search was undertaken on 23 March 2023 using grey literature and four electronic databases: MEDLINE, CINAHL, EMBASE and Web of Science. Studies published before January 2020 were excluded. A quality assessment was undertaken using A. Lomas quality assessment tool. CIRR outcomes were synthesised in a meta-analysis, while ASIRR outcomes were narratively synthesised.

Results

Fourteen cancer registries were included, capturing data from 13 countries across Europe. Variation was observed in NMSC and cSCC incidence across the cancer registries. Pooled cSCC crude incidence rates in 2020 were equal to crude incidence rates in 2019 (cSCC-CIRR 1.00 (95% confidence interval (CI) 0.94–1.06). In 2021, the pooled result indicated a non-significant 8% increase in cSCC crude incidence rates, compared with 2019 (cSCC-CIRR 1.08 (95% CI 0.98–1.19). Significant reductions were reported in NMSC incidence across all meta-analyses in 2020 and 2021 compared with 2019. Heterogeneity was observed across most pooled estimates (I2>75%).

Conclusion

There was a lack of high quality data on cSCC incidence rates recorded during the pandemic outside of Europe. The COVID-19 pandemic resulted in no significant changes in cSCC incidence across Europe. By contrast, NMSC incidence fell across Europe following the pandemic. Significant reductions in pooled NMSC incidence rates may reflect a delay in basal cell carcinoma presentation, diagnosis and treatment. Although annual incidence rates for cSCC were not affected by the pandemic, delays in treatment may still have occurred, which may result in poorer outcomes yet to be fully understood.
Compressive behavior of steel slag fine aggregate concrete under impact loading
Authors: Liu Qiuyu , Xue Gang , Dong Wei , Li Jingjun
Published: June 2024

To investigate the compressive behavior of steel slag fine aggregate concrete (SSC) under impact loading, the normal concrete and steel slag fine aggregate concrete with varying steel slag fine aggregate (SSA) contents were prepared and a Split Hopkinson Pressure Bar (SHPB) with a diameter of 100 mm was used for the dynamic compression testing under various strain rates. The microstructure characteristics of concrete specimens were observed by scanning electron microscopy to investigate the impact behavior changes mechanism of SSC under dynamic loading. The research results indicate that the compressive strength, DIF, and impact toughness of the specimens exhibit significant strain rate effects, all of which increase with the increase of strain rate. At similar strain rates, both impact toughness and dynamic compressive strength show an upward trend with the increase of steel slag content, while DIF decreases with the increase of steel slag content. The microstructure of SSC is denser, and the hydration product of SSA fills the internal defects of concrete and significantly enhances the interface transition zone (ITZ) between fine aggregates and cement matrix, which has an enhancement effect on impact toughness and the dynamic compressive strength of concrete. The empirical formulas were proposed based on the testing results to predict the DIF of SSC with various SSA contents. The compression constitutive models considering strain rate and steel slag content of SSC were established, and the fitting consequences with the test results accord rather well.
Digital threads for sustainable concrete: A prototype traceability system
Authors: White Callum , Forsdyke Jessica , Harrison Mark , Desnerck Pieter , Lees Janet M.
Published: June 2024

Achieving traceability of concrete materials is a crucial step toward promoting sustainable concrete use. This includes creating accurate Environmental Product Declarations, minimizing mistakes during concrete placement, and improving understanding of the relationship between concrete constituents and performance. Despite these benefits, effective traceability for concrete materials has not yet been achieved in the laboratory environment or within wider practice. This work sets out a digital thread for concrete use and the functional requirements for a traceability framework for adoption in a laboratory environment. Traceable resource units (TRUs) are identified, and the primary critical tracking events for each TRU are described. A prototype traceability system is developed to link the necessary properties, constituent material data, production information, and performance results for concrete materials. The prototype system incorporates a novel inkjet printer QR code fingerprinting solution that is demonstrated to be highly effective for concrete specimens and for various media, including paper and metal, used to transport and store raw concrete constituent materials. A laboratory test series demonstrated a 100% readability rate with the proposed QR fingerprinting solution according to standard measures. This work advances knowledge of the appropriate traceable resource units and critical tracking events within concrete practice, develops effective marking procedures and forms a prototype constituent‐to‐product traceability system.
Machine learning applications in vadose zone hydrology: A review
Authors: Li Xiang , Nieber John L. , Kumar Vipin
Published: June 2024

Machine learning (ML) has been broadly applied for vadose zone applications in recent years. This article provides a comprehensive review of such developments. ML applications for variables corresponding to different complex vadose zone processes are summarized mostly in a prediction context. By analyzing and assessing these applications, we discovered extensive usages of classic ML models with relatively limited applications of deep learning (DL) approaches in general. We also recognized a lack of benchmark datasets for soil property research as well as limited integration of physics‐based vadose zone principles into the ML approaches. To facilitate this interdisciplinary research of ML in vadose zone characterization and processes, a paradigm of knowledge‐guided machine learning is suggested along with other data‐driven and ML model‐based research suggestions to advance future research.
Energy Transition Subsidies
Authors: de Vries Annick , Werner Gijsbert , Wijlhuizen Elsenoor , Toom Victor , Bovens Mark , Hulscher Suzanne
Published: June 2024

This chapter takes a closer look at the distributive effects of three energy transition subsidies in the Netherlands. We chose these three schemes because they each target different groups: businesses, homeowners and minimum wage earners. We first discuss how the various subsidies work and how they are funded. We then consider which distributive principles we can identify in these three schemes. We explain how other distributive justice considerations and principles could also have been deployed.
Procedural Justice and Distributive Issues
Authors: de Vries Annick , Werner Gijsbert , Wijlhuizen Elsenoor , Toom Victor , Bovens Mark , Hulscher Suzanne
Published: June 2024

This chapter uses the example of the yellow vests in France. The example shows that a just climate policy is about more than the fair distribution of costs and benefits. The way policies are made is also a matter of justice. We therefore examine the theme of procedural justice, and in particular the justice of the policymaking process. We pay special attention to how citizens are involved.
Public Perspectives of Distribution Issues
Authors: de Vries Annick , Werner Gijsbert , Wijlhuizen Elsenoor , Toom Victor , Bovens Mark , Hulscher Suzanne
Published: June 2024

In this chapter, we examine what citizens themselves consider to be just distributions of climate costs. We do this in two ways. We first discuss the existing research on this topic, and then present the results of our own research into public perspectives of distributive justice. A key finding is that more than three-quarters of respondents consider fair burden sharing to be important; often more important than reducing carbon emissions. However, this is not yet adequately reflected in current climate policy.
Distributive Justice in Climate Policy
Authors: de Vries Annick , Werner Gijsbert , Wijlhuizen Elsenoor , Toom Victor , Bovens Mark , Hulscher Suzanne
Published: June 2024

The final chapter concludes that there is currently insufficient systematic attention to distributive justice in Dutch climate policy. Various distributive principles are often overlooked in policymaking. The key message therefore is that all climate policy should take the fair distribution of climate costs into account. In addition to effectiveness and legality, climate measures should also be assessed from the perspective of justice. Failure to do so could erode public support for climate policy, and so delay or even prevent the implementation of the policy measures.
On the absence of supergravity solutions for localized, intersecting sources
Authors: Bardzell Jacob , Federico Kevin , Smith Danielle , Wrase Timm
Published: June 2024

Abstract

For decades intersecting D-branes and O-planes have been playing a very important role in string phenomenology in the context of particle physics model building and in the context of flux compactifications. The corresponding supergravity equations are hard to solve so generically solutions only exist in a so-called smeared limit where the delta function sources are replaced by constants. We are showing here that supergravity solutions for two perpendicularly intersecting localized sources in flat space do not exist for a generic diagonal metric Ansatz. We show this for two intersecting sources with p = 1, 2, 3, 4, 5, 6 spatial dimensions that preserve 8 supercharges, and we allow for fully generic fluxes.
Casimir effect and holographic dual of wedges
Authors: Miao Rong-Xin
Published: June 2024

Abstract

This paper investigates the Casimir effect of a wedge and its holographic dual. We prove that the displacement operator universally determines the wedge Casimir effect in the smooth limit. Besides, we argue that the wedge Casimir energy increases with the opening angle and test it with several examples. Furthermore, we construct the holographic dual of wedges in AdS/BCFT in general dimensions. We verify that our proposal can produce the expected Casimir effect within smooth and singular limits. We observe that the Casimir energy density of a wedge increases with the brane tension. Next, we discuss the wedge contribution to holographic entanglement entropy and find it increases with the opening angle, similar to the wedge Casimir energy. Finally, we briefly discuss the holographic polygon in AdS3/BCFT2 and its generalization to higher dimensions.
Electroweak phase transition with a double well done doubly well
Authors: Agrawal Prateek , Blasi Simone , Mariotti Alberto , Nee Michael
Published: June 2024

Abstract

We revisit the electroweak phase transition in the scalar singlet extension of the standard model with a ℤ2 symmetry. In significant parts of the parameter space the phase transition occurs in two steps — including canonical benchmarks used in experimental projections for gravitational waves. Domain walls produced in the first step of the transition seed the final step to the electroweak vacuum, an effect which is typically neglected but leads to an exponentially enhanced tunnelling rate. We improve previous results obtained for the seeded transition, which made use of the thin-wall or high temperature approximations, by using the mountain pass algorithm that was recently proposed as a useful tool for seeded processes. We then determine the predictions of the seeded transition for the latent heat, bubble size and characteristic time scale of the transition. Differences compared to homogeneous transitions are most pronounced when there are relatively few domain walls per hubble patch, potentially leading to an enhanced gravitational wave signal. We also provide a derivation of the percolation criteria for a generic seeded transition, which applies to the domain wall seeds we consider as well as to strings and monopoles.
Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models
Authors: Baek Hye Suk , Hong Victor Sukbong , Kang Hyunsu , Lee Sang-Jin , Lee Jin-Young , Kang Hyunju , Jeong Seungik , Jung Hyunho , Park Jong Wook , Kwon Taeg Kyu , Son Chang-Nam , Kim Sang Hyon , Lee Jinho , Kim Ki-Suk , Kim Shin
Published: June 2024

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/β, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.
Otud6b induces pulmonary arterial hypertension by mediating the Calpain-1/HIF-1α signaling pathway
Authors: Liu Yu , Tang Bailin , Wang Hongxin , Lu Meili
Published: June 2024

Pulmonary hypertension (PAH) is a cardiopulmonary disease in which pulmonary artery pressure continues to rise, leading to right heart failure and death. Otud6b is a member of the ubiquitin family and is involved in cell proliferation, apoptosis and inflammation. The aim of this study was to understand the role and mechanism of Otud6b in PAH. C57BL/6 and Calpain-1 knockout (KO) mice were exposed to a PAH model induced by 10% oxygen. Human pulmonary artery endothelial cells (HPACEs) and human pulmonary artery smooth muscle cells (HPASMCs) were exposed to 3% oxygen to establish an in vitro model. Proteomics was used to determine the role of Otud6b and its relationship to Calpain-1/HIF-1α signaling. The increased expression of Otud6b is associated with the progression of PAH. ROtud6b activates Otud6b, induces HIF-1α activation, increases the production of ET-1 and VEGF, and further aggravates endothelial injury. Reducing Otud6b expression by tracheal infusion of siOtud6b has the opposite effect, improving hemodynamic and cardiac response to PAH, reducing the release of Calpain-1 and HIF-1α, and eliminating the pro-inflammatory and apoptotic effects of Otud6b. At the same time, we also found that blocking Calpain-1 reduced the effect of Otud6b on HIF-1α, and inhibiting HIF-1α reduced the expression of Calpain-1 and Otud6b. Our study shows that increased Otud6b expression during hypoxia promotes the development of PAH models through a positive feedback loop between HIF-1α and Calpain-1. Therefore, we use Otud6b as a biomarker of PAH severity, and regulating Otud6b expression may be an effective target for the treatment of PAH.

Graphical Abstract
Association between medial meniscal extrusion and knee structural progression in adults with symptomatic knee osteoarthritis — a prospective cohort study
Authors: Zeng Mengjie , Cicuttini Flavia M. , Wluka Anita E. , Jones Graeme , Hill Catherine L. , Ding Changhai , Wang Yuanyuan
Published: June 2024

Objective

To examine the association between medial meniscal extrusion and structural progression in adults with symptomatic knee osteoarthritis (OA).

Methods

This prospective cohort study examined 176 participants with symptomatic knee OA recruited into a randomised controlled trial. The participants underwent magnetic resonance imaging (MRI) of the study knee at baseline and approximately 2 years later. Meniscal extrusion, tibial cartilage volume, and tibiofemoral bone marrow lesions (BMLs) were measured from MRI using validated methods.

Results

Participants with medial meniscal extrusion ≥ 3 mm had a higher prevalence of lateral tibiofemoral BMLs at baseline (OR = 2.21, 95% CI 1.06–4.61, p = 0.035), and those with medial meniscal extrusion 2–3 mm had a higher likelihood of lateral BML worsening over 2 years (OR = 3.76, 95% CI 1.35–10.52, p = 0.011), compared with those with medial meniscal extrusion < 2 mm. Participants with stable medial meniscal extrusion had a lower likelihood of lateral BML worsening compared with those with regression of medial meniscal extrusion over 2 years (OR = 0.20, 95% CI 0.07–0.56, p = 0.002). There were no associations between medial meniscal extrusion and tibial cartilage volume or medial tibiofemoral BMLs.

Conclusions

Our study showed associations between medial meniscal extrusion and baseline prevalence and worsening over 2 years of lateral tibiofemoral BMLs in people with symptomatic knee OA. Although the reasons for the lack of associations in the medial compartment are not clear, our results suggest a role of medial meniscal extrusion in predicting structural progression in lateral knee OA and that meniscal extrusion might be a potential target in the management of knee OA.
Donor’s age influences outcome in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide - a single center experience
Authors: Zielińska Patrycja , Wieczorkiewicz-Kabut Agata , Białas Krzysztof , Koclęga Anna , Gruenpeter Karolina , Kopińska Anna , Woźniczka Krzysztof , Noster Izabela , Gromek Tomasz , Czyż Jarosław , Grosicki Sebastian , Wierzbowska Agnieszka , Krzanowski Jacek , Butrym Aleksandra , Helbig Grzegorz
Published: June 2024

Haploidentical stem cell transplantation (haplo-SCT) using post-transplantation cyclophosphamide (post-Cy) is considered a reasonable therapeutic option for patients who lack matched donor or who urgently need transplant procedure due to high risk disease. We analyzed the results of haplo-SCT performed in years 2018–2023. Eighty one patients (46 males) at median age of 52 years underwent haplo-SCT using peripheral blood as a stem cell source in most cases. Indications included hematological malignancies (acute leukemias in 88% of cases). In 25 cases (31%) transplantation was performed in relapsed/refractory disease. Majority of patients (61%) presented with very high and high disease risk index (DRI). Conditioning regimens were as follows: nonmyeloablative − 46 cases (57%), myeloablative – in 18 (22%) and reduced intensity – 17(20%). 90% of patients engrafted. All patients received unified immunosuppressive treatment (post-Cy/TAC/MMF). Median follow-up time was 12 months The cumulative incidence of acute and chronic GVHD was 37.5% and 37.6%, respectively. Estimated 2-year overall survival (OS) was 43.1% and donor’s age was the only factor influencing survival. The 2-year progression-free survival (PFS) was 42.5%, whereas relapse incidence (RI) − 35%. The cumulative incidence of non-relapse mortality (NRM) was 44% and was mostly due to infections. Haplo-SCT is a feasible treatment option for hematological patients. Younger donor improves post-transplant survival. Strategies to reduce infection-related mortality and relapse rate remain a challenge.
Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors
Authors: Piscitelli Joseph , Reddy Micaela B. , Wollenberg Lance , Del Frari Laurence , Gong Jason , Matschke Kyle , Williams Jason H.
Published: June 2024

Background

A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032.

Methods

This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects.

Results

Among 11 PK evaluable patients, encorafenib Cmax and AUClast were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil.

Conclusion

The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment.

Clinical trial registration

ClinicalTrials.gov NCT03864042, registered 6 March 2019.
Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial
Authors: Mc Laughlin Anna M. , Hess Dagmar , Michelet Robin , Colombo Ilaria , Haefliger Simon , Bastian Sara , Rabaglio Manuela , Schwitter Michael , Fischer Stefanie , Eckhardt Katrin , Hayoz Stefanie , Kopp Christoph , Klose Marian , Sessa Cristiana , Stathis Anastasios , Halbherr Stefan , Huisinga Wilhelm , Joerger Markus , Kloft Charlotte
Published: June 2024

Study objectives

TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1’s population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling.

Methods

The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored.

Results

Medians $$\pm$$
±
standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0−∞ were 0.342 $$\pm$$
±
0.134 mg/L and 40.1 $$\pm$$
±
18.9 mg·h/L, respectively. The median half-life (95 h) was 23.5 h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate.

Conclusion

The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies.

Clinical trial registration

ClinicalTrials.gov–NCT03387917–January 2, 2018
Well-Posedness and Regularity of Solutions to Neural Field Problems with Dendritic Processing
Authors: Avitabile Daniele , Chemetov Nikolai V. , Lima P. M.
Published: June 2024

We study solutions to a recently proposed neural field model in which dendrites are modelled as a continuum of vertical fibres stemming from a somatic layer. Since voltage propagates along the dendritic direction via a cable equation with nonlocal sources, the model features an anisotropic diffusion operator, as well as an integral term for synaptic coupling. The corresponding Cauchy problem is thus markedly different from classical neural field equations. We prove that the weak formulation of the problem admits a unique solution, with embedding estimates similar to the ones of nonlinear local reaction–diffusion equations. Our analysis relies on perturbing weak solutions to the diffusion-less problem, that is, a standard neural field, for which weak problems have not been studied to date. We find rigorous asymptotic estimates for the problem with and without diffusion, and prove that the solutions of the two models stay close, in a suitable norm, on finite time intervals. We provide numerical evidence of our perturbative results.