bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of Abutment Selection in the Tridimensional Implant Position: Considerations for Predictable Implant Restorative Long‐Term Outcomes
Authors: Lanis Alejandro , Akhondi Samuel , Pedrinaci Ignacio , Tavelli Lorenzo , Puisys Algirdas
Published: December 2024

Objective

To explore the influence of abutment selection on 3D implant positioning, emphasizing the synergy between surgical and prosthetic considerations for achieving predictable long‐term outcomes in implant‐supported restorations.

Main Considerations

Implant dentistry has transitioned from a purely surgical approach to a prosthetically driven methodology that prioritizes implant‐supported restoration (ISR). This shift has been bolstered by advancements in digital technologies and abutment designs, which allow for more precise implant positioning and better management of biological, mechanical, and esthetic outcomes. The selection of appropriate abutments plays a pivotal role in optimizing the 3D implant position, influencing peri‐implant tissue stability and the overall success of the restoration. This manuscript explores into the biorestorative concept, highlighting how virtual planning can preemptively assess abutment configurations and their interactions with surrounding tissues, guiding implant placement to achieve desired results.

Clinical Significance

The integration of digital planning and strategic abutment selection prior to implant placement ensures optimal 3D implant positioning respecting fundamental biological and prosthetic parameters. This approach minimizes complications, improves long‐term tissue stability, and enhances patient outcomes by aligning surgical procedures with the specific prosthetic needs.
Partial Substitution of Egg White Protein by Sodium Caseinate/Tannin Acid/Octenyl Succinate Starch Composite: A Study on the Physicochemical Properties in Cake and Ice Cream
Authors: Zhan Fuchao , Zhou Xiaorui , Jiang Ying , Youssef Mahmoud , Teng Yongxin , Li Jing , Li Bin
Published: December 2024

The development of egg substitutes to partially or completely replace eggs is a noteworthy food trend in academia and industry. Previous studies have systematically investigated the potential of sodium caseinate (Na‐Cas)/tannic acid (TA)/octenyl succinate starch (OSA‐Starch) composites as foaming agents. The objective of this study was to extend the previous study and explore the potential application of Na‐Cas/TA/OSA‐Starch composites as egg replacers. Cakes and ice creams were produced by replacing 25%, 50%, and 75% of egg white with Na‐Cas/TA/OSA‐Starch composites. Some physical, rheological, and textural properties of cake and ice cream were determined to evaluate the feasibility of replacing egg white with Na‐Cas/TA/OSA‐Starch. Compared to the control, 25% Na‐Cas/TA/OSA‐Starch composites replacement of egg whites resulted in an increase in specific volume of the prepared cakes, an increase in hardness, a decrease in elasticity, and an increase in chewiness. As the amount of Na‐Cas/TA/OSA‐Starch composites substituted for eggs increased, the melt resistance of the ice cream decreased, the hardness increased, and the viscosity decreased, while the hardness and chewiness of the cake tended to increase. In conclusion, Na‐Cas/TA/OSA‐Starch composites have great potential as a new food ingredient for functional dairy ingredients in ice cream and cakes.
Substrate Uptake by TonB‐Dependent Outer Membrane Transporters
Authors: Braun Volkmar
Published: December 2024

TonB is an essential component of an energy‐generating system that powers active transport across the outer membrane (OM) of compounds that are too large or too scarce to diffuse through porins. The TonB‐dependent OM transport proteins (TBDTs) consist of β barrels forming pores that are closed by plugs. The binding of TonB to TBDTs elicits plug movement, which opens the pores and enables nutrient translocation from the cell surface into the periplasm. TonB is also involved in the uptake of certain proteins, particularly toxins, through OM proteins that differ structurally from TBDTs. TonB binds to a sequence of five residues, designated as the TonB box, which is conserved in all TBDTs. Energy from the proton motive force (pmf) of the cytoplasmic membrane is transmitted to TonB by two proteins, ExbB and ExbD. These proteins form an energy‐transmitting protein complex consisting of five ExbB proteins, forming a pore that encloses the ExbD dimer. This review discusses the structural changes that occur in TBDTs upon interaction with TonB, as well as the interaction of ExbB‐ExbD with TonB, which is required to transmit the energy of the pmf and thereby open TBDT pores. TonB facilitates import of a wide range of substrates.
Umthetho Wethu Ngumthetho Sisekelo, Futhi Unamalungelo*
Authors: MnisiWeeks Sindiso
Published: December 2024

Abomdabu baseNingizimu Afrika bathi imithetho yabo igxile kakhulu esimisweni soBu‐Ntu kodwa imiphakathi yabo itholakala ivame ukubonisa okuphambene nalowo mthetho. Kungani lokhu? Uyini umthetho abathi banawo? Ziyini izimpande zawo? Futhi singazilandelela kanjani ngokuthembekile ukuze sizazi impela? Lesi sihloko sibuyela ekujuleni (okungukuthi, umlando ongarekhodiwe/ongabhaliwe, wangaphambi kwekoloniyali) wabaNtu, abayiningi labantu abakhuluma izilimi ezihlobene zase‐Sub‐Saharan Africa. Sifunisisa ngemvelaphi ejulile yobuNtu nobunjalo babo. Lokhu okubhalwe lapha kusekelwe ebufakazini obuvela kwezinye izimpande zobuhlakani bomdabu wabaNtu kanye nokutholwe, budonswa ngasikhathi sinye, ngokubuza emphakathini mayelana nokuchazwa komthetho wesiNtu ebantwini bomdabu abakhuluma isiNguni eNingizimu Afrika namuhla. Ngakho‐ke, lesi sihloko simele (ngamanye amagama, sisekela) ukuchithwa nokuqedwa kobukoloni ngokuthi sichaze ukuthi umthetho wesiNtu uthi unomthethosisekelo wawo (lapho inhlanganisela yenhlalo yabantu isekelwe khona), nombono wawo wamalungelo; lokho kufanele ngempela ukuqashelwa (ngokomthetho) kanye nokuhlonishwa esikhundleni semithetho ezalwa yingqondo yobukoloni.
Our law is constitutional law, and it has rights*
Authors: MnisiWeeks Sindiso
Published: December 2024

Indigenous Southern Africans say that their laws are fundamentally grounded in the principle of Ubu‐Ntu (humane‐ness), but their communities are found empirically to often show the opposite of that law. Why is this? What is the law to which they lay claim to having? What are its roots and how can we reliably trace and know them? Reverting to the deep (i.e., unrecorded/unwritten precolonial) history of the Ntu, who make up the largest language group of Indigenous inhabitants of Sub‐Saharan Africa, this article digs into the deep origins of Ntu identity and being. Based on evidence drawing simultaneously from the alter‐Native intellectual roots of the Ntu and ethnographic findings on articulations of vernacular law in Nguni‐speaking society in South Africa today, the article makes the decolonizing case that Indigenous law lays claim to having its own constitutional law (in which its peoples’ social compact is grounded), with its very own conception of rights, that is wholly due (legal) recognition and respect in place of laws born of colonial logics.
Contrasting strategies in morphological and physiological response to drought stress among temperate forest understory forbs and graminoids
Authors: Petek‐Petrik A. , Petrík P. , Halmová M. , Plichta R. , Matoušková M. , Houšková K. , Chudomelová M. , Urban J. , Hédl R.
Published: December 2024

Drought stress can profoundly affect plant growth and physiological vitality, yet there is a notable scarcity of controlled drought experiments focused on herbaceous species of the forest understorey.

In this study, we collected seeds from five forb and four graminoid species common in European temperate forests. Seeds were germinated under controlled glasshouse conditions and subjected to moderate drought stress for 5 weeks. We assessed biomass partitioning, stomatal and leaf morphology, leaf gas exchange, minimum leaf conductance (gmin), and chlorophyll fluorescence parameters.

Comparison of the two ecological guilds revealed that graminoids had a higher R/S, improved WUE, greater carboxylation efficiency, and enhanced non‐photochemical quenching under drought conditions compared to forbs. In contrast, forbs had significantly lower gmin, with higher total biomass and total leaf area. Despite these differences in morpho‐physiological functional traits, both groups experienced a similar relative reduction in biomass after drought stress. Key predictors of biomass accumulation under drought included photochemical quenching, stomatal traits, total leaf area and gmin. A negative correlation between biomass and gmin suggests that plants with lower residual water loss after stomatal closure can accumulate more biomass under drought stress. Additionally, gmin was positively correlated with guard cell length, suggesting that larger stomata contribute to higher residual water loss.

Contrasting strategies in morpho‐physiological responses to drought define the differences between the two groups. In graminoids, drought resistance suggests greater emphasis on stress tolerance as a survival strategy. In contrast, forbs were able to maintain higher biomass and total leaf area, indicating a competitive strategy for maximizing resource acquisition.
Conditions that increase the perceived likelihood of temporary restriction of firearm access: An investigation in male firearm owners
Authors: Gilroy Shawn P. , Tucker Raymond P. , Hill Ryan M. , Anestis Michael D. , Bryan Craig J. , Bauer Brian W.
Published: December 2024

Introduction

This study evaluated hypothetical participation in temporary voluntary removal of firearms from the home to reduce future suicide risk in 408 adult male firearm owners.

Methods

A delay discounting approach was applied to evaluate the degree to which these choices were influenced by two dimensions of reinforcer efficacy—delay and magnitude. The decision‐making task sampled choice behavior across various durations of temporary voluntary removal of firearms (Delay) and differences in stated potential risk of suicide (Magnitude) as a result of that choice.

Results

Results of mixed‐effects modeling indicated that the subjective value of immediate access to a firearm was differentially sensitive to both delay and magnitude. Additionally, the scaling of these effects was linked to various other indicators of firearm‐specific safety (e.g., use of trigger locks) and suicidality risk (e.g., intolerance of uncertainty).

Conclusions

These results provide additional support for behavioral models of decision‐making (i.e., delay discounting) when evaluating how specific environmental arrangements and framing may support (or potentially discourage) engagement in means safety activities, inclusive of temporary firearms access restriction. These findings suggest that further analysis of the ecological underpinnings of these choices may help to guide more targeted efforts to engage with firearm owners in safety planning when there are concerns about the potential for suicide.
Planning antepartum directed donations in preparation for neonatal cardiac surgery in the absence of compatible donors
Authors: Bienz Marc , Constanzo‐Yanez Jessica , Baillargeon Nadia , Leiva‐Torres Gabriel André , Boileau Mélissa , Cloutier Marc , Laforce‐Lavoie Audrey , Robitaille Nancy
Published: December 2024

Background

Homozygous inheritance of the RN haplotype, characterized by the absence of the high frequency antigen Sec, as well as partial C and e antigens, is rare and is associated with potential for alloimmunization. Anti‐Sec has been reported to be associated with a risk of delayed hemolytic transfusion reaction and hemolytic disease of the fetus and newborn (HDFN).

Results

We report the case of a 36‐year‐old pregnant woman with known sickle cell trait (SCT) and homozygous for the RN haplotype with anti‐Sec, anti‐c, and anti‐e. Morphological ultrasound identified dextro‐transposition of the great arteries in the fetus. Neonatal cardiac surgery was planned with cardiopulmonary bypass support. Due to the rarity of this genotype, there were no compatible donors in our registry. For this reason, in addition to two previously glycerolized maternal donations, the mother donated three units during pregnancy and one unit postpartum.

Discussion

This case highlights the many complexities for the blood supplier pertaining to organizing blood donations during pregnancy, the risk of leukoreduction failure and jellification during the deglycerolization process of units from donors with rare blood carrying the SCT, as well as planning the rare‐blood inventory and managing expiry dates to provide transfusion support during delivery, neonatal surgery, and the postoperative period. This case also exemplifies the importance of a strong partnership between blood suppliers and medical teams.
Patient-level analysis of the cost and variation in melatonin prescribing patterns in those under 18 in the North East of England
Authors: McLellan Elizabeth Miriam , Haq Iram J , Ebdon Anne-Marie , Vasey Nicola , Anderson Kirstie N
Published: December 2024

Background

Melatonin is widely used to promote sleep in both normally developing children and adolescents and those with neurodevelopmental disorders. It has an evidence base as both hypnotic and chronobiotic although the optimum dose and timing remain unclear. There are now a wide variety of different preparations of melatonin both immediate and prolonged release. We reviewed annual national and regional prescribing data and undertook a detailed review of one year of melatonin prescriptions issued to those under 18 within one of the UK’s dedicated paediatric hospitals, this included a cost analysis. This was to understand whether prescribing was appropriate, whether behavioural therapies had been recommended first and whether there had been consideration of other causes of poor sleep, such as sleep apnoea.

Methods

Between November 2020 and October 2021, 220 patients under 18 had one or more melatonin prescriptions issued to treat poor sleep. The audit assessed whether prescriptions were issued in accordance with local Melatonin Shared Care Guidance standards that emphasise: an initial behavioural approach, fixed timing, use of licensed preparations and review of benefit. This included a detailed review of electronic patient care records. A cost analysis of the different preparations was also made.

Results adherence to the audit were not met for any of the audit standards, only 9% had a prior behavioural intervention, and only 15% had another sleep disorder considered. Community prescribers were more likely to give advice on timing and review any subsequent benefit. The total costs of prescriptions were £13 299 of which £8736 was issued as off licence, liquid suspension.

Conclusion

The audit highlighted a lack of knowledge about appropriate melatonin prescribing and led to a trust-wide sleep education programme. It additionally highlighted the cost and potential risk of inappropriate prescribing and a clear need for better access to effective behavioural interventions.
Bicriteria Shapes: Hierarchical Grouping and Aggregation of Polygons with an Efficient Graph-Cut Approach
Authors: Rottmann Peter , Driemel Anne , Haverkort Herman , Röglin Heiko , Haunert Jan-Henrik
Published: December 2024

An important task of pattern recognition and map generalization is to partition a set of disjoint polygons into groups and to aggregate the polygons within each group to a representative output polygon. We introduce a new method for this task called bicriteria shapes. Following a classical approach, we define the output polygons by merging the input polygons with a set of triangles that we select from a conforming Delaunay triangulation of the input polygons’ exterior. The innovation is that we control the selection of triangles with a bicriteria optimization model that is efficiently solved via graph cuts. In particular, we minimize a weighted sum that combines the total area of the output polygons and their total perimeter. In a basic problem, we ask for a single solution that is optimal for a preset parameter value. In a second problem, we ask for a set containing an optimal solution for every possible value of the parameter. We discuss how this set can be approximated with few solutions and show that it is hierarchically nested. Hence, the output is a hierarchical clustering that corresponds to multiple levels of detail. An evaluation with building footprints as input and a comparison with α-shapes that are based on the same underlying triangulation conclude the article. An advantage of bicriteria shapes compared to α-shapes is that the sequence of solutions for decreasing values of the parameter is monotone with respect to the total perimeter of the output polygons, resulting in a monotonically decreasing visual complexity.
Compressing Neural Networks Using Learnable 1-D Non-Linear Functions
Authors: Singh Gaurav , Bazargan Kia
Published: December 2024

As deep learning models grow in size to achieve state-of-the-art accuracy, there is a pressing need for compact models. To address this challenge, we introduce a novel operation called Personal Self-Attention (PSA). It is specifically designed to learn non-linear 1-D functions, enhancing existing spline-based methods while remaining compatible with gradient backpropagation. By integrating these non-linear functions with linear transformations, we can achieve the accuracy of larger models but with significantly smaller hidden dimensions, which is crucial for FPGA implementations.

We evaluate PSA by implementing it in a Multi-Layer Perceptron (MLP)-based vision model, ResMLP, and testing it on the CIFAR-10 classification task. MLP is gaining increasing popularity due to its widespread use in large-language models. Our results confirm that PSA achieves equivalent accuracy with a 2x smaller hidden size compared to conventional MLPs. Furthermore, by quantizing our non-linear function into a simple lookup table, we reduce the number of operations required by 45%-28%, which offers significant benefits for hardware accelerators. To showcase this, we design an end-to-end unrolled streaming accelerator for ResMLP, demonstrating that our compressed model maintains an 88% accuracy while reducing LUT + DSP resource requirements by 25%, and doubling throughput to 32kFPS. Additionally, we implement a fixed-size SIMD accelerator for the same compressed model that achieves a 62.1% improvement in throughput while only consuming 3.5% extra LUTs.
AED-PADA: Improving Generalizability of Adversarial Example Detection via Principal Adversarial Domain Adaptation
Authors: Peng Heqi , Wang Yunhong , Yang Ruijie , Li Beichen , Wang Rui , Guo Yuanfang
Published: December 2024

Adversarial example detection, which can be conveniently applied in many scenarios, is important in the area of adversarial defense. Unfortunately, existing detection methods suffer from poor generalization performance because their training process usually relies on the examples generated from a single known adversarial attack and there exists a large discrepancy between the training and unseen testing adversarial examples. To address this issue, we propose a novel method, named Adversarial Example Detection via Principal Adversarial Domain Adaptation (AED-PADA). Specifically, our approach identifies the Principal Adversarial Domains (PADs), i.e., a combination of features of the adversarial examples generated by different attacks, which possesses a large portion of the entire adversarial feature space. Subsequently, we pioneer to exploit Multi-source Unsupervised Domain Adaptation in adversarial example detection, with PADs as the source domains. Experimental results demonstrate the superior generalization ability of our proposed AED-PADA. Note that this superiority is particularly achieved in challenging scenarios characterized by employing the minimal magnitude constraint for the perturbations.
Probing Quantum Materials with Uniaxial Stress
Authors: Hicks Clifford W. , Jerzembeck Fabian , Noad Hilary M.L. , Barber Mark E. , Mackenzie Andrew P.
Published: December 2024

Over the past approximately 10 years, it has become routine to use piezoelectric actuators to apply large anisotropic stresses to correlated electron materials. Elastic strains exceeding 1% can often be achieved, which is sufficient to qualitatively alter the magnetic and/or electronic structures of a wide range of correlated electron materials. Experiments fall into two broad groups. In one, explicit use is made of the capacity of anisotropic stress to reduce the point group symmetry of the lattice, for example, from tetragonal to orthorhombic. In the other, anisotropic stress is used as a more general, powerful tuning method that, within the elastic limit of the material under test, does not introduce disorder. In this review, we provide a brief recent history of strain tuning, describe current methodology, provide selected examples of the types of experiment that have been done, and discuss the thermodynamics of uniaxial stress.
Microstructure Characterization of Battery Materials Based on Voxelated Image Data: Computation of Active Surface Area and Tortuosity
Authors: Daubner S. , Nestler B.
Published: December 2024

The reliable computation of microstructure metrics such as specific surface area and tortuosity factors is key to bridge the gap between the battery microscale and fast, homogenized cell models. In this work, we present an approach to compute the surface area of phases based on pixelated image data which is both easy-to-implement and computationally efficient. The concept is inspired from the diffuse surface representation in phase-field methods. Subsequently, the approach is validated and compared with common python libraries on two benchmark cases and actual battery microstructure data. The results underline the reliability and fast computational performance of the approach. Furthermore, the concept of through-feature connectivity in pixelated image data is introduced and explored to quantify the reliability of tortuosity factor computations. Overall, this work enhances the computational tools to bridge the scale from battery microstructures to cell models and gives an overview of state-of-the-art methodology. The developed code is published to further accelerate the scientific progress in this field.
Passive Filler Ionic Conductivity Enhancement of Poly(Ethylene Glycol) Diacrylate Solid-State Electrolytes
Authors: Hoffmann Alexander J. , Fawaz Wissam , Ng K. Y. Simon
Published: December 2024

Solid polymer electrolytes are promising alternatives to traditional liquid electrolytes for use in lithium batteries. Poly(ethylene glycol) diacrylate (PEGDA) is a versatile cross-linkable monomer that promotes easy incorporation of a variety of filler materials for solid electrolyte synthesis without the use of solvents. This study examines the effects that varying concentrations of SiO2, CeZrO4, V2O5, and succinonitrile have on the electrochemical performance of UV-cured PEGDA electrolytes. A composite polymer electrolyte containing 8% V2O5 and 30% succinonitrile in PEGDA was synthesized and exhibited a room-temperature ionic conductivity of 1.43 × 10–4 S cm−1. The improvement in ionic conductivity of this electrolyte may be attributed to the synergistic effect of the two incorporated fillers resulting in decreased crystallinity of the polymer matrix. This study demonstrates that polymer electrolyte characteristics can be optimized by combining the benefits of multiple fillers.
Guidelines for assessing ventricular pressure-volume relationships in rodents
Authors: Wearing Oliver H. , Chesler Naomi C. , Colebank Mitchel J. , Hacker Timothy A. , Lorenz John N. , Simpson Jeremy A. , West Christopher R.
Published: December 2024

Ventricular catheterization with a pressure-volume (PV) catheter is the gold-standard method for assessing in vivo cardiac function in animal studies, providing valuable “load-independent” indices of systolic and diastolic heart performance. PV studies are commonly performed to elucidate mechanistic insights into cardiovascular disease using surgical and genetically engineered rat and mouse models, but there is considerable heterogeneity in how these studies are performed. Wide variation in protocol design, volume calibration, anesthesia, manipulation of cardiac loading conditions, how load-independent indices of cardiac function are derived, as well as in data analysis and reporting is constraining reliability and reproducibility in the field. The purpose of this manuscript is to combine our collective expertise in performing open- and closed-chest left and right ventricle PV studies in rodents to provide consensus guidelines on how to perform, analyze, and interpret these studies using either conductance or admittance PV catheters. We first review recent methodological reporting in rodent PV studies in this journal and discuss important details required to improve reproducibility within and across PV studies. We then recommend steps to obtain high-quality PV data, from volume calibration to choice of anesthetic agent and acquiring load-independent indices of both systolic and diastolic function. We also consider between- and within-animal variation and recommend how to perform data analysis and visualization. We hope that this consensus paper guides those performing PV studies in rodents and helps align the field with best practices in surgical/analytical methodologies and reporting, facilitating better reliability and reproducibility in the PV field.
Aesthetic Clinical Case for Immediate Implant Therapy for Maxillary Central Incisor
Authors: Guzman Gerardo , Rojas-Rueda Silvia , Floriani Franciele , Jurado Carlos A. , Apiazu-Flores Francisco X. , Fischer Nicholas G.
Published: December 2024

This case report features a female patient with the chief complaint of needing to replace an anterior crown. After a comprehensive oral assessment and cone beam computed tomography (CBCT) radiographic examination, it was determined that the crown on Tooth #9 was subgingivally fractured. The procedure involved atraumatic extraction of Tooth #9, followed by immediate implant placement. Xenograft bone graft material was placed to complete the space between the buccal bone and the implant. A connective tissue graft (CTG), 1 mm thick and 5 mm wide, was harvested from the palate and placed. The final implant crown was restored using a prefabricated abutment with a titanium base and zirconia ceramic dental material. A well‐planned combined treatment, including atraumatic tooth extractions for immediate implants and ideal contouring of soft tissues, can significantly impact the outcome of aesthetic restorations. A single immediate implant‐supported crown in the aesthetic zone was able to fulfill the patient’s aesthetic expectations at the 2‐year follow‐up.
Iranian Medicinal Plants in Diabetes Management: A Narrative Review of Traditional Herbal Remedies and Their Hypoglycemic Effects
Authors: Afsharmanesh Mohammad Reza , Mohammadi Zeinab , Jafari Seyyed Mehdi
Published: December 2024

Diabetes mellitus is a significant global health concern, especially in Iran. Currently, numerous oral antihyperglycemic agents and insulin are prescribed to manage diabetes. Historically, in Middle Eastern countries, medicinal herbals were used to manage diabetes in patients. Furthermore, the adverse effects of some diabetes management drugs provide an eager potential for researchers to find novel alternative treatments that reduce the side effects and also increase their efficacy. In addition, the rich history of Iranian traditional medicine reveals the vital role of traditional herbals and their compounds in treating and mitigating diabetes mellitus and its associated complications. Several studies conducted to investigate the hypoglycemic properties related to these plant species. In this narrative review, we aimed at a comprehensive study of Iranian plant species with antidiabetic properties through experimental evidence. Our review illustrated that the traditional herbal active ingredients are not well‐defined, limiting their standardization. Current efforts focus on identifying these components to improve their therapeutic efficacy.
Clinical Characteristics and Outcomes of Central Nervous System Tumors Harboring NTRK Gene Fusions
Authors: Lamoureux Audrey-Anne , Fisher Michael J. , Lemelle Lauriane , Pfaff Elke , Amir-Yazdani Pouneh , Kramm Christof , De Wilde Bram , Kazanowska Bernarda , Hutter Caroline , Pfister Stefan M. , Sturm Dominik , Jones David T.W. , Orbach Daniel , Pierron Gaëlle , Raskin Scott , Drilon Alexander , Diamond Eli L. , Harada Guilherme , Zapotocky Michal , Zamecnik Josef , Krskova Lenka , Ellezam Benjamin , Weil Alexander G. , Venne Dominic , Barritault Marc , Leblond Pierre , Coltin Hallie , Hammad Rawan , Tabori Uri , Hawkins Cynthia , Hansford Jordan R. , Meyran Deborah , Erker Craig , McFadden Kathryn , Sato Mariko , Gottardo Nicholas G. , Dholaria Hetal , Nørøxe Dorte Schou , Goto Hiroaki , Ziegler David S. , Lin Frank Y. , Parsons Donald Williams , Lindsay Holly , Wong Tai-Tong , Liu Yen-Lin , Wu Kuo-Sheng , Franson Andrea T. , Hwang Eugene , Aguilar-Bonilla Ana , Cheng Sylvia , Cacciotti Chantel , Massimino Maura , Schiavello Elisabetta , Wood Paul , Hoffman Lindsey M. , Cappellano Andréa , Lassaletta Alvaro , Van Damme An , Llort Anna , Gerber Nicolas U. , Spalato Ceruso Mariella , Bendel Anne E. , Skrypek Maggie , Hamideh Dima , Mushtaq Naureen , Walter Andrew , Jabado Nada , Alsahlawi Aysha , Farmer Jean-Pierre , Coleman Christina , Mueller Sabine , Mazewski Claire , Aguilera Dolly , Robison Nathan J. , O’Halloran Katrina , Abbou Samuel , Berlanga Pablo , Geoerger Birgit , Øra Ingrid , Moertel Christopher L. , Razis Evangelia D. , Vernadou Anastasia , Ducray François , Bronnimann Charlotte , Seizeur Romuald , Clarke Matthew , Resnick Adam C. , Alves Mélanie , Jones Chris , Doz François , Laetsch Theodore W. , Perreault Sébastien
Published: December 2024

Purpose:

Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients.

Experimental Design:

We conducted an international retrospective cohort study of patients with TRK fusion–driven central nervous system tumors.

Results:

A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment.

Conclusions:

Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.
Inhibition of PSF Activity Overcomes Resistance to Treatment in Cancers Harboring Mutant p53
Authors: Takayama Ken-ichi , Sato Tomohiro , Honma Teruki , Yoshida Minoru , Inoue Satoshi
Published: December 2024

Mutations in the TP53 tumor suppressor genes are prevalent in aggressive cancers. Pharmacologic reactivation of dysfunctional p53 due to mutations is a promising strategy for treating such cancers. Recently, a multifunctional proline- and glutamine-rich protein, polypyrimidine tract–binding protein–associated splicing factor (PSF), was identified as a key driver of aggressive cancers. PSF promotes the expression of numerous oncogenes by modulating epigenetic and splicing mechanisms. We previously screened a small-molecule library and discovered compound No. 10-3 as a potent PSF inhibitor. Here, we report the discovery of a No. 10-3 analog, 7,8-dimethoxy-4-(4-methoxy-phenyl)-chromen-2-one (C-30), as a potent PSF inhibitor. Compared with No. 10-3, C-30 treatment specifically suppressed the growth and induced apoptosis of mutant p53-bearing and therapy-resistant cancer cells. Interestingly, C-30 activated a set of p53-regulated genes in therapy-resistant cancer cells. A comprehensive analysis of PSF and p53-binding regions demonstrated a higher level of PSF-binding potential in mutant p53-expressing cancer cells around genomic regions identified as p53-binding peaks in p53 wild-type cancer cells. Treatment of mutant p53-expressing cancer cells with C-30 decreases PSF binding around these sites, leading to activated histone acetylation. We further demonstrated that C-30 impaired tumor growth and increased the expression of p53 target genes in vivo. These results suggested that C-30 produces tumor-suppressive effects similar to the functional reactivation of p53, providing a rationale for the inhibition of PSF activity as a promising therapy against treatment-resistant cancer.
Efficacy of CBP/p300 Dual Inhibitors against Derepression of KREMEN2 in cBAF-Deficient Cancers
Authors: Sasaki Mariko , Kato Daiki , Yoshida Hiroshi , Shimizu Takafumi , Ogiwara Hideaki
Published: December 2024

The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex is divided into three subcomplexes: cBAF, PBAF, and ncBAF. Constituent genes (e.g., SMARCB1, SMARCA4, SMARCA2, and SS18) of the SWI/SNF complex often harbor genetic abnormalities in various cancers. Previously, we found that histone acetyltransferases CBP/p300 dual inhibitors could be promising treatments for SMARCB1-deficient cancers. We show that treatment with CBP/p300 dual inhibitors causes synthetic lethality in cBAF-deficient cancers such as SMARCA4/SMARCA2-deficient and SS18–SSX fusion cancers. Given the sensitivity to CBP/p300 dual inhibitors and their commonality with SWI/SNF subcomplexes containing each subunit, CBP/p300 dual inhibitors could be promising treatments for cancers harboring abnormalities in constituent genes included in the entire cBAF subcomplex. Because SMARCA4/SMARCA2-deficient and SS18–SSX fusion cancer cells depend on transcriptional upregulation of KREMEN2 due to SMARCA4/SMARCA2 deficiency and SS18–SSX fusion, we clarified that synthetic lethality is induced by repressing expression of KREMEN2 by simultaneous inhibition of CBP/p300. In addition, simultaneous inhibition of CBP/p300 led to transcriptional downregulation of KREMEN2, followed by apoptosis induction via KREMEN1. Furthermore, treatment with CBP/p300 dual inhibitor suppressed the growth of xenografts derived from SMARCA4/SMARCA2-deficient and SS18–SSX fusion cancer cells, resulting from repression of KREMEN2 and induction of apoptosis. Thus, CBP/p300 dual inhibitors could be promising for SMARCA4/SMARCA2-deficient lung cancer and SS18–SSX fusion synovial sarcoma, which are entirely deficient in the cBAF complex.

Significance:

In this study, we clarified that the cBAF subcomplex is deficient in the SWI/SNF complex, resulting in dependency on the CBP/p300 paralog pair. Simultaneous inhibitors of the CBP/p300 paralog pair show promise for cBAF-deficient lung cancer, as well as rare cancers such as malignant rhabdoid tumors, epithelioid sarcomas, and synovial sarcomas.
A Novel Variant in the Cyto-Tail of SMO Gene Underlying Isolated Postaxial Polydactyly
Authors: Javed Khan Muhammad , Abdullah A. , Khan Hammal , Zaman Atteaya , Ahmed Sohail , Iqbal Palwasha , Bilal Muhammad , Ullah Kifayat , Hasni Muhammad Sharif , Ullah Imran , Mis Emily Kathryn , Lakhani Saquib Ali , Ahmad Wasim
Published: December 2024

Background: Polydactyly is one of the most common hereditary limb malformations, characterized by presence of additional digits in hands and/or feet. It is present either in isolated form or in combination with other features. Preaxial polydactyly with extra digit on the outside of the thumb or big toe, and postaxial polydactyly with extra digit on the outside of the little finger or little toe are the two main forms of polydactyly. Methods and Results: In the present study, two unrelated consanguineous families segregating PAP in an autosomal recessive manner were investigated. Whole exome sequencing, followed by segregation analysis using Sanger sequencing, revealed a homozygous missense variant [c.1792 G>A; p.(Gly598Arg); NM_005631.5] in the SMO in both families. Proteins SMO, PTCH, and GLI act as major components of the Sonic hedgehog pathway, which transmits signals to embryonic cells for cellular differentiation. Homology modeling revealed that the variant in SMO may disrupt proper protein folding and interaction with other molecules. Conclusion: Our study has revealed the second direct involvement of a sequence variant in the SMO causing isolated polydactyly. This study will highlight the importance of the inclusion of the SMO gene in screening individuals presenting polydactyly in hands and feet.
Atypical Presentation of an Ovarian Yolk Sac Tumor in an 80-Year-Old Woman: A Case Report and Review of the Literature
Authors: Maldonado Vanessa , Masvidal María , Morente Laguna Vanessa , Cimerman Jacqueline , Martinez Soriano Salvador
Published: December 2024

Introduction: Ovarian yolk sac tumors after the menopause are very rare. Case Presentation: We report an atypical case of yolk sac tumor in an octogenarian woman, who presented to the hospital with anasarca, ascites, toxic syndrome, and an abdominal mass. Serum alpha-fetoprotein (AFP) levels were highly increased (246,720 ng/mL), and malignant cells with positive AFP immunohistochemical expression were detected in a diagnostic paracentesis. The definitive diagnosis was established by histopathological examination of the surgical specimen and immunohistochemical detection of positivity for AFP, glypican 3, cytokeratin AE1/AE3, and focal positivity for SALL4 and CK7. Adjuvant chemotherapy was refused by the patient. Postoperative AFP values decreased to normal limits. One year after surgery, she remains in good clinical condition without evidence of tumor recurrence. In a review of the literature, 11 cases of yolk sac tumors in postmenopausal women were collected. The mean age of the patients was 63.4 years (range 58–82 years). Frequent findings were FIGO stage II, cytoreductive surgery, immunohistochemical analyses of a large panel of markers, postoperative chemotherapy, and no tumor recurrence (except in 1 patient who died), although the length of follow-up was relatively short or unclearly stated. Conclusion: The present case report illustrates that yolk sac tumors in very old women may have a favorable clinical course without signs of recurrence even in the absence of radical surgical resection with curative intent and associated adjuvant chemotherapy.
Fetal-to-Neonatal Transition of an Infant with Transposition of the Great Arteries and Intact Ventricular Septum: A Case Report
Authors: Weeda Jesse A. , te Pas Arjan B. , Haak Monique C. , Blom Nico A. , van der Palen Roel L.F.
Published: December 2024

Introduction: Transposition of the great arteries (TGA), especially with intact ventricular septum (TGA-IVS), presents unique challenges during fetal-to-neonatal transition, which can contribute to developing persistent pulmonary hypertension of the newborn (PPHN). Case Presentation: A male newborn with TGA-IVS, delivered via caesarean section, presented with hypoxemia and tachycardia immediately after birth (preductal SpO2: 50–60%, post-ductal SpO2: 70–75%). Echocardiography revealed a floppy interatrial septum and two interatrial connections with bidirectional shunting. Ductal flow showed systolic right-to-left shunting, suggesting high pulmonary vascular resistance. Immediate post-birth management included non-invasive respiratory support with continuous positive airway pressure at 100% oxygen and administration of prostaglandin E2 to maintain ductal patency. Despite initial low oxygen saturation levels, escalation of intensive treatments was deferred based on continuous trend monitoring of vital signs and echocardiographic indicators. Oxygenation and circulation gradually improved within the first 2 h after birth to normal values, obviating escalation of intensive interventions like intubation, nitric oxide and/or balloon atrial septostomy. Arterial switch operation at day 3 post-birth was successful. Conclusion: This case highlights the possible contribution of fetal-to-neonatal transition in TGA-IVS to developing PPHN, which may subside after transition. Moreover, this case highlights the potential for providing a gentle hemodynamic transition without invariably needing early invasive interventions after birth.
Obesogens and Energy Homeostasis: Definition, Mechanisms of Action, Exposure, and Adverse Effects on Human Health
Authors: Yilmaz Bayram , Erdogan Cihan Suleyman , Sandal Suleyman , Kelestimur Fahrettin , Carpenter David O.
Published: December 2024

Background: Obesity is a major risk factor for noncommunicable diseases and is associated with a reduced life expectancy of up to 20 years, as well as with other consequences such as unemployment and increased economic burden for society. It is a multifactorial disease, and physiopathology of obesity involves dysregulated calorie utilization and energy balance, disrupted homeostasis of appetite and satiety, lifestyle factors including sedentary lifestyle, lower socioeconomic status, genetic predisposition, epigenetics, and environmental factors. Some endocrine-disrupting chemicals (EDCs) have been proposed as “obesogens” that stimulate adipogenesis leading to obesity. In this review, definition of obesogens, their adverse effects, underlying mechanisms, and metabolic implications will be updated and discussed. Summary: Disruption of lipid homeostasis by EDCs involves multiple mechanisms including increase in the number and size of adipocytes, disruption of endocrine-regulated adiposity and metabolism, alteration of hypothalamic regulation of appetite, satiety, food preference and energy balance, and modification of insulin sensitivity in the liver, skeletal muscle, pancreas, gastrointestinal system, and the brain. At a cellular level, obesogens can exert their endocrine disruptive effects by interfering with peroxisome proliferator-activated receptors and steroid receptors. Human exposure to chemical obesogens mainly occurs by ingestion and, to some extent, by inhalation and dermal uptake, usually in an unconscious manner. Persistent pollutants are lipophilic features; thus, they bioaccumulate in adipose tissue. Key Messages: Although there are an increasing number of reports studying the effects of obesogens, their mechanisms of action remain to be elucidated. In addition, epidemiological studies are needed in order to evaluate human exposure to obesogens.
Gray Matter Reserve Modulates the Association between Glymphatic System Function and Cognition in Patients with Type 2 Diabetes Mellitus
Authors: Xia Wenqing , Yin Xiao , Zhang Yujie , Ge Shenghui , Chen Yuchen , Ma Jianhua
Published: December 2024

Introduction: The glymphatic system is regarded as a key factor in the pathogenesis of neurodegenerative diseases. Given the heightened risk of cognitive impairment in patients with type 2 diabetes mellitus (T2DM), the possible alterations in the glymphatic system in T2DM patients remain to be explored. Diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) index can be utilized to model the glymphatic system in humans. Our aim was to explore the relationship between the ALPS index and cognitive function in patients with T2DM and whether this relationship is modulated by gray matter (GM) integrity anchored by the ALPS index. Methods: All participants underwent evaluation using a comprehensive cognitive assessment scale to determine their neurocognitive status. The ALPS index was calculated based on DTI data, and the disparity in ALPS index values between patients with T2DM and healthy controls (HCs) was examined. Furthermore, multiple linear regression analysis was conducted in the T2DM group to identify the GM regions associated with the ALPS index, and the volumes of the GM partitions were extracted. The volume of GM partitions was used as the regulating variable, the ALPS index was used as the independent variable, and cognitive test scores were used as the dependent variable in our analysis. Results: The ALPS index differed significantly between the two groups, and the ALPS index in patients with T2DM was significantly lower than that in HCs. In addition, our analysis revealed a correlation between the ALPS index and GM volume in the insular region, consistent with the observed GM atrophy in the patient cohort. Moreover, a significant negative correlation was observed between the ALPS index in patients and performance on the Trail-Making Test-A (TMT-A), and this relationship was moderated by GM integrity. In patients with more severe GM atrophy, the ALPS index was more strongly correlated with cognitive function. Conclusions: In this study, a decreased ALPS index was found in T2DM patients, indicating impaired glymphatic function in this population. Furthermore, a significant association was detected between the ALPS index and cognitive performance in T2DM patients, and this correlation was influenced by GM integrity. Therefore, the ALPS index has the potential to be used as a biomarker of cognitive impairment in diabetic patients. Further studies are needed to investigate the diagnostic and therapeutic implications of glymphatic dysfunction in T2DM patients with cognitive impairment.
Global longitudinal strain correlates poorly with mortality in people with diabetes mellitus and receiving haemodialysis
Authors: Al-Chalabi Saif , Alezergawi Sally , Green Darren , Sinha Smeeta , Kalra Philip A.
Published: December 2024

Introduction:
Haemodialysis (HD) is a life-sustaining treatment for individuals with end-stage kidney disease (ESKD). However, the risk of mortality remains significantly higher compared to the general population, even when matched for age and sex. Global longitudinal strain (GLS), derived from speckle tracking echocardiography, has shown promise as a predictor of mortality in HD patients. However, its prognostic utility in patients with multiple cardiovascular risk factors such as diabetes mellitus (DM) and receiving HD, remains unclear. This study aimed to evaluate the prognostic value of GLS in HD patients, with and without DM.

Methods:
This prospective study was a long term follow up extension study of an earlier published study that investigated a cohort of haemodialysis patients from a single centre with a comprehensive cardiovascular imaging protocol. All patients had an echocardiography with the use of speckle-tracking software to determine GLS. Patients were divided into Group A (with DM) and Group B (without DM). Patients were followed up until death, major adverse cardiovascular events (MACE), transplantation or the censoring date (29 February 2024). Statistical analyses were performed using univariate Cox proportional hazards models.

Results:
A total of 184 patients receiving HD were included in the analysis. Patients with DM (Group A) had significantly higher all-cause mortality (ACM) (47.1% vs. 20.7%, P<0.001) and a lower chance of receiving a kidney transplant (13.2% vs. 43.1%, P<0.001). In Group A, GLS did not predict ACM, whereas in Group B, a GLS cutoff of −15.76% correlated with higher 5-year ACM (P=0.036). Left ventricular ejection fraction (LVEF) was a significant predictor of ACM in Group A (HR 0.98; P=0.036).

Conclusion:
GLS is a poor predictor of adverse outcomes in HD patients with DM, likely due to their high cardiovascular risk. In contrast, GLS was a significant predictor of mortality in non-diabetic HD patients. LVEF may be a more reliable prognostic indicator in high-risk diabetic patients.