bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs
Authors: Bradley Sophie , Young Scott , Bakke Anne Marie , Holcombe Lucy , Waller Daniel , Hunt Alysia , Pinfold Kathleen , Watson Phillip , Logan Darren W.
Published: September 2022

Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong (r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.
Nation-Wide Routinely Collected Health Datasets in China: A Scoping Review
Authors: Liu Yishu , Xiao Shaoming , Yin Xuejun , Gao Pei , Wu Jing , Xiong Shangzhi , Hockham Carinna , Hone Thomas , Wu Jason H. Y. , Pearson Sallie Anne , Neal Bruce , Tian Maoyi
Published: September 2022

Objectives: The potential for using routinely collected data for medical research in China remains unclear. We sought to conduct a scoping review to systematically characterise nation-wide routinely collected datasets in China that may be of value for clinical research.

Methods: We searched public databases and the websites of government agencies, and non-government organizations. We included nation-wide routinely collected databases related to communicable diseases, non-communicable diseases, injuries, and maternal and child health. Database characteristics, including disease area, data custodianship, data volume, frequency of update and accessibility were extracted and summarised.

Results: There were 70 databases identified, of which 46 related to communicable diseases, 20 to non-communicable diseases, 1 to injury and 3 to maternal and child health. The data volume varied from below 1000 to over 100,000 records. Over half (64%) of the databases were accessible for medical research mostly comprising communicable diseases.

Conclusion: There are large quantities of routinely collected data in China. Challenges to using such data in medical research remain with various accessibility. The potential of routinely collected data may also be applicable to other low- and middle-income countries.
Angular Trajectory Design for MR-SPS Using Bezier Shaping Approach
Authors: Xu Song , Huo Mingying , Qi Naiming , Feng Wenyu , Lin Tong , Li Zheng
Published: September 2022

Solar power satellite (SPS) is a kind of large-scale on-orbit servicing spacecraft collecting solar energy in space and transmitting energy to the earth. The solar arrays of the SPS must point to the sun to collect enough solar energy and the antenna must point to the rectenna on the ground to transmit energy. But due to the limitation of the control effort, accurate solar and earth orientation may not be achieved. This paper focuses on the MR-SPS, and establishes the attitude kinematics and dynamics model of a MW-level MR-SPS. Angular trajectory based on Bezier shaping approach is generated at different time of a year to satisfy the control constraints. The simulation results demonstrate the effectiveness of the proposed method. Even if the control torque is limited to a small amount, the optimal angular trajectory can still ensure high average energy receiving efficiency.
Characterisation and Design of Direct Numerical Simulations of Turbulent Statistically Planar Flames
Authors: Sternin Andrej , Martinez Daniel , Sternin Daniel , Haidn Oskar , Tajmar Martin
Published: September 2022

This work aims to provide support for the design of reliable DNSs for statistically planar flames. Improved simulation design strategies are developed. Therefore, design criteria for the simulative domain are discussed. The gained mathematical relations for all of the relevant physical quantities were channelled into a deterministic calculation strategy for mesh features. To choose design parameter values within the mathematical formulations, guidelines were formulated. For less controllable variables, namely the viscosity and Prandtl number, a measurement technique was developed. A new determination strategy to determine characteristic points within the flame front was conducted. In order to present and compare cases with different Prandtl numbers, normalisation of the x-axis of the regime diagram was suggested.
Morpho-Histological Studies of the Gastrointestinal Tract of the Orange-Rumped Agouti (Dasyprocta leporina Linnaeus, 1758), with Special Reference to Morphometry and Histometry
Authors: Jones Kegan Romelle , John Roger Edmund , Sundaram Venkatesan
Published: September 2022

The morphology of the gastrointestinal tract (GI) is a strong indicator of a species’ dietary habits. The objective of this study was to describe and quantitatively analyze the gross and microanatomy of the digestive tract of the orange/red-rumped agouti (Dasyprocta leporina) and relate it to the feeding habits of this animal. The digestive tracts of six adult males were used for this study. The results showed that the esophagus was thick (mean thickness of 1023.78 ± 28.97 μm) and lined by keratinized epithelium with scant esophageal glands. Mucosa-associated lymphocytic infiltration was robust throughout the GI tract. These findings suggest that the esophagus was well adapted to a coarse diet. The simple stomach with well-developed gastric glands in the fundus region (mean thickness of 605.39 ± 28.68 μm) was indicative of an adaptation to a carnivorous diet. The small intestine constituted approximately 80% of the length of the GI tract. The remarkable development of the jejunum with a greater villus length (mean thickness of 182.50 ± 27.38 μm) indicated a greater absorptive capacity in frugivorous and carnivorous diets. The long cecum and well-developed colon clearly indicated that the GI tract was well adapted to frugivorous and herbivorous diets. Overall, D. leporina showed that it is well adapted to an omnivorous diet. These results suggest that D. leporina can be fed a balanced omnivorous dry diet with a high protein content of plant or animal origin that is well suited to the architecture of the GI tract in captivity.
Temporal Changes in the Faecal Microbiota of Beef Cattle on Feedlot Placement
Authors: Maslen Brianna N. , Gray Lesley A. , Ghorashi Seyed A. , White Jason D. , Campbell Michael A. , Pant Sameer D.
Published: September 2022

The microbial communities that inhabit the intestinal tract play an important role in modulating health and productivity. Environmental stressors can impact microbial communities, which can significantly influence host physiology. Cattle are subjected to several environmental stressors when placed on feedlots, such as transportation stress, exposure to feedlot environments and change in diet and management. Exposure to these stressors could influence host gut microbiota, which in turn, could potentially influence host health and performance. The aim of the current study was to characterise the temporal changes that occur in intestinal microbiota as a consequence of feedlot placement by profiling 16s rRNA sequences in rectal faecal samples. When faecal microbiome profiles were compared in terms of relative abundances and alpha diversity metrics, the results showed significant, observable changes in profiles 2 days post-feedlot induction. Furthermore, beta-diversity analysis indicated that the phylogenetic similarity between samples significantly decreased on day 2 (PERMANOVA, p < 0.001). These trends were suggestive of a short-term reduction in microbial diversity coupled with decreased similarity between animals. These changes warrant further investigation and could provide opportunities for improved performance, health and even welfare of feedlot cattle in future.
Effect of Sheep Grazing, Stocking Rates and Dolomitic Limestone Application on the Floristic Composition of a Permanent Dryland Pasture, in the Montado Agroforestry System of Southern Portugal
Authors: Carreira Emanuel , Serrano João , Gomes Carlos J. Pinto , Shahidian Shakib , Paniagua Luís L. , Pilirito Alexandre , Lopes Castro José , Carvalho Mário , Pereira Alfredo F.
Published: September 2022

The Montado is a complex agroforestry–pastoral ecosystem due to the interactions between soil–pasture–trees–animals and climate. The typical Montado soil has an acidic pH and manganese toxicity, which affect the pasture’s productivity and pasture floristic composition (PFC). The PFC, on the other hand, can also be influenced by the type and intensity of grazing, which can lead to significant decreases in the amount of biomass produced and the biodiversity of species in the pasture. The objective of this study was to evaluate the effect of grazing type, by sheep, and different stocking rates on the PFC throughout the vegetative pasture cycle in areas with and without dolomitic limestone application. Thus, four treatments (P1UC to P4TC) were constituted: P1UC—without limestone application (U) and continuous grazing (CG); P2UD—U and deferred grazing (DG); P3TD—with the application of limestone (T) and DG; P4TC—T and CG. In DG plots, the placement and removal of the animals were carried out as a function of the average height of the pasture (placement—10 cm; removal—3 to 5 cm). The PFC was characterized in winter, at the peak of spring and in late spring. The PFC data were subjected to a multilevel pattern analysis (ISA). The combination of rainfall and temperature influenced the pasture growth rates and consequently the height of the pasture at different times of the year. Therefore, with the different growth rates of the pasture throughout the year, the sheep remain for different periods of time in the deferred grazing treatments. In the four treatments, 103 plant species were identified. The most representative botanical families in the four treatments were Asteraceae, Fabaceae and Poaceae. ISA identified 14 bioindicator species: eight for the winter period, three for the late spring vegetative period and three for the TC treatment.
Microsporidia as a Potential Threat to the Iberian Lynx (Lynx pardinus)
Authors: Izquierdo Fernando , Ollero Dolores , Magnet Angela , Galván-Díaz Ana L. , Llorens Sergio , Vaccaro Lucianna , Hurtado-Marcos Carolina , Valdivieso Elizabeth , Miró Guadalupe , Hernández Leticia , Montoya Ana , Bornay-Llinares Fernando J. , Acosta Lucrecia , Fenoy Soledad , del Águila Carmen
Published: September 2022

Lynx pardinus is one of the world’s most endangered felines inhabiting the Iberian Peninsula. The present study was performed to identify the presence of microsporidia due to the mortality increase in lynxes. Samples of urine (n = 124), feces (n = 52), and tissues [spleen (n = 13), brain (n = 9), liver (n = 11), and kidney (n = 10)] from 140 lynxes were studied. The determination of microsporidia was evaluated using Weber’s chromotrope stain and Real Time-PCR. Of the lynxes analyzed, stains showed 10.48% and 50% positivity in urine and feces samples, respectively. PCR confirmed that 7.69% and 65.38% belonged to microsporidia species. The imprints of the tissues showed positive results in the spleen (38.46%), brain (22.22%), and liver (27.27%), but negative results in the kidneys. PCR confirmed positive microsporidia results in 61.53%, 55.55%, 45.45%, and 50%, respectively. Seroprevalence against Encephalitozoon cuniculi was also studied in 138 serum samples with a positivity of 55.8%. For the first time, the results presented different species of microsporidia in the urine, feces, and tissue samples of Lynx pardinus. The high titers of anti-E. cuniculi antibodies in lynx sera confirmed the presence of microsporidia in the lynx environment. New studies are needed to establish the impact of microsporidia infection on the survival of the Iberian lynx.
Analytical Methods to Assess Polyphenols, Tannin Concentration, and Astringency in Hard Apple Cider
Authors: Sommer Stephan , Anderson Andrea Faeth , Cohen Seth D.
Published: September 2022

The production of hard apple cider frequently involves considerations based on the balance between fermentable sugars and titratable acidity and/or pH. However, these are not the only attributes that influence the sensory properties of cider. Various groups of polyphenols and tannins influence bitterness, astringency, and mouthfeel, as well as color of the product. In this study, 19 single variety hard apple ciders were evaluated using analytical methods originally developed for wines. The aim was to determine how the cider matrix affects the functionality of each method. The results indicate that most assays work with sufficient accuracy with the exception of protein precipitation methods. Due to interferences of polysaccharides with the protein reaction, those assays are poorly reproducible and do not reflect the actual polyphenol or tannin concentration. The analytical determination of astringency is also influenced by this interference, since it traditionally uses the concept of protein precipitation as well. Liquid chromatography as a selective method can be readily applied to cider. Other colorimetric methods or non-protein precipitation methods, such as the Folin-Ciocalteu assay, the Methylcellulose Precipitation assay, and the Iron-Reactive Phenolics assay, can be used to classify apple ciders and make decisions based on the desired bitterness and astringency profile.
A System Architecture of a Fusion System for Multiple LiDARs Image Processing
Authors: Jung Minwoo , Kim Dae-Young , Kim Seokhoon
Published: September 2022

LiDAR sensors are extensively used in autonomous vehicles and their optimal use is a critical concern. In this paper, we propose an embedded software architecture for multiple LiDAR sensors, i.e., a fusion system that acts as an embedded system for processing data from multiple LiDAR sensors. The fusion system software comprises multiple clients and a single server. The client and server are connected through inter-process communication. Multiple clients create processes to process the data from each LiDAR sensor via a multiprocessing method. Our approach involves a scheduling method for efficient multiprocessing. The server uses multithreading to optimize the internal functions. For internal communication within the fusion system, multiple clients and a single server are connected using the socket method. In sequential processing, the response time increases in proportion to the number of connected LiDAR sensors. By contrast, in the proposed software architecture, the response time decreases in inverse proportion to the number of LiDAR sensors. As LiDAR sensors become increasingly popular in the field of autonomous driving, the results of this study can be expected to make a substantial contribution to technology development in this domain.
Three Strategies of Urban Renewal for One National Outline Plan TAMA38: The Impact of Multiparametric Decision-Making on Neighborhood Regeneration
Authors: Shach-Pinsly Dalit
Published: September 2022

The urban renewal of deteriorated areas is a challenge for many city decision-makers. In this study, we aimed to understand the role and impact of the Israeli national outline plan, TAMA38, on urban renewal areas by examining three urban renewal strategies. This plan was developed to strengthen individual buildings against earthquakes, but it also serves as a catalyst for the renewal of deteriorated individual residential buildings in old neighborhoods, particularly in high-demand districts. TAMA38 focuses on the renovation of individual buildings, primarily residential, but neglects the comprehensive vision of the public and private needs of the neighborhood/site complex, of which the individual building is only one component. To understand which planning strategy will achieve better spatial results under TAMA38, a broader examination is required. The objective of this study was to assess the performance of three urban sites developed under the TAMA38 program in the city of Haifa using three main strategies: (1) one comprehensive plan led by one developer with a change in building locations (2) one comprehensive plan but led by diverse developers, while building locations remain unchanged and (3) individual building renewals with no comprehensive plan. The methodology for this analysis was based on the evaluation of various quantitative and quality parameters that influence the performance of the built environment. The results of the research emphasize the need to choose an urban renewal strategy tailored to a specific location, as well as the need for the authority to take responsibility for planning open public spaces throughout the process.
How Photochemically Consumed Volatile Organic Compounds Affect Ozone Formation: A Case Study in Chengdu, China
Authors: Liu Hefan , Wang Ning , Chen Dongyang , Tan Qinwen , Song Danlin , Huang Fengxia
Published: September 2022

Surface ozone (O3) pollution has not improved significantly in recent years. It is still the primary air pollution problem in many megacities in China during summertime. In high temperature and intense radiation weather, volatile organic compounds (VOCs) are easily oxidized and degraded to induce O3 pollution. In order to understand the impact of difference between photochemical initial concentration (PIC) of VOCs and the actual measured concentration on O3 formation, a campaign was carried out during O3 pollution in Chengdu (25 July–5 August 2021). During this O3 pollution episode, the maximum value of O3 concentration reached 335.0 μg/m3, and the precursor concentrations increased significantly. The mean values of VOCmeasured and VOCPICs were 19.7 ppbv and 30.7 ppbv, corresponding to O3 formation potential (OFP) of 175.3 μg/m3 and 478.8 μg/m3, respectively, indicating that the consumption of VOCs content could not be ignored. Alkenes accounted for 77.2% of VOCs consumption. Alkenes and aromatics contributed 63.0% and 29.2% to OFP values which derived from PIC of each VOC species. The relative incremental reactivity analysis based on PICs showed that the O3 formation was controlled by the cooperation of nitrogen oxides (NOx) and VOCs, and the effect of NOx emission reduction was better.
Cost–Benefit Analysis of Synergistic CO2 and NOx Energy-Efficient Technologies for the Road Transport Sector in China
Authors: Ping Liying , Wang Yuan , Lee Lien-Chieh , Peng Binbin , Ahmed Bushra Y. , Zhang Hongyu , Ma Wenchao
Published: September 2022

The transportation sector is a major source of greenhouse gases and air pollutants, and it has a crucial effect on the synergistic reduction of NOx and carbon. In order to find the energy-efficient vehicle technologies with the highest net reduction potential and lowest net reduction cost over the life cycle, this study traced the CO2 and NOx emission streams of 33 energy-efficient technologies, hidden in the supply chain during the production phase, through structural path analysis, and measured the emission reductions during the use phase using the emission factor method. Moreover, we applied structural decomposition analysis to quantify the three main drivers, including emission intensity, industrial structure, and final demand, of changes in CO2 and NOx emissions from 11 transport subsectors during 2012–2018. Results indicate that CO2 emissions of the transport sector more than doubled from 2012 to 2018; however, the influence of NOx was less significant. The final demand of the road subsector was the most significant driver contributing to CO2 emission changes, with an increase of 109.27 Mt. The emission intensity of road transportation caused the greatest mitigation effect on NOx emission changes, with a decrease of 1902 Kt. The findings of the scenario analysis demonstrate that the most efficient action of the pure electric technology for passenger cars reduces 20.92 Mt NOx emissions, and the parallel hybrid technology for heavy trucks offers the greatest cost effectiveness with a net abatement of 2577 Mt CO2 over its life cycle. Consequently, the aggressive development of new energy technology has become a prerequisite strategy to synergistically reduce CO2 and NOx emissions.
Finite Element Analysis of a New Non-Engaging Abutment System for Three-Unit Implant-Supported Fixed Dental Prostheses
Authors: Byun Soo-Hwan , Seo Joung-Hwa , Cho Ran-Yeong , Yi Sang-Min , Kim Lee-Kyong , Han Hyun-Sook , On Sung-Woon , Kim Won-Hyeon , An Hyun-Wook , Yang Byoung-Eun
Published: September 2022

(1) Background: The stability of implants plays a significant role in the success of osseointegration. The stability of the connection between the fixture and the abutment is one of the critical factors affecting osseointegration. When restoring multiple, non-parallel, and splinted implants, achieving a passive fit can be complicated and challenging. A new EZ post non-engaging abutment system of the BlueDiamond® (BD) implant allows a wide connection angle while achieving a passive prosthesis fit. This study aimed to confirm the new abutment system’s clinical applicability by evaluating its biomechanical characteristics using finite element analysis (FEA). (2) Methods: The implant-supported fixed three-unit dental prostheses model was reproduced for two groups of AnyOne® (AO) and BD implants using FEA. The loading conditions were a preload of 200 N in the first step and loads of 100 N (axial), 100 N (15°), or 30 N (45°) in the second step. (3) Results: The peak Von Mises stress (PVMS) value of the fixture in the BD group was more than twice that in the AO group. In contrast, the PVMS values of the abutment and abutment screws were lower in the BD group than in the AO group. The AO group revealed higher maximal principal stress (MPS) values than that of the BD group in the cortical bone, cancellous bone, and crown. The average stress of the outer surface of the abutment was lower in the AO group than in the BD group. The stress distribution for the inner surface of the fixture confirmed that the BD group displayed a lower stress distribution than the AO group under axial and 15° loads; however, the average stress was 1.5 times higher at the 45° load. The stress values of the entire surface where the cortical and cancellous bone were in contact with the fixture were measured. The AO group showed a higher stress value than the BD group in both cortical and cancellous bone. (4) Conclusions: In the AO group, the PVMS value of the fixture and the stress distribution at the contact surface between the fixture and the abutment were lower than those of the BD group, suggesting that the stability of the fixture would be high. However, due to the high stress in the fastening area of the abutment and abutment screw, the risk of abutment fracture in the AO group is higher than that of the BD group. Therefore, the new EZ post non-engaging abutment of the BD implant can be used without any problems in clinics, similar to the non-engaging abutment of the AO implant, which has been widely used in clinical practice.
Coumarin-Encapsulated Solid Lipid Nanoparticles as an Effective Therapy against Methicillin-Resistant Staphylococcus aureus
Authors: Alqarni Mohammed H. , Foudah Ahmed I. , Alam Aftab , Salkini Mohammad A. , Muharram Magdy M. , Labrou Nikolaos E. , Rawat Pinki
Published: September 2022

Bacterial infections caused by antibiotic-resistant pathogens are a significant public health problem. This is because the transmission of infectious diseases is shifting, and new antibiotic-resistant strains of bacteria are emerging. The development of biofilms that are resistant to antibiotics poses another hurdle to drugs and treatment alternatives. Therefore, there is an urgent need to develop innovative strategies to effectively eliminate antibiotic-resistant microorganisms effectively. Natural coumarins have broad spectrum bioactivity and the potential for lower resistance. Coumarin is a secondary metabolite found in certain plants, fungi, and bacteria. It is highly effective against methicillin-resistant Staphylococcus aureus (MRSA). Therefore, coumarin can be used as an alternative to combat MRSA. However, most antibacterial agents lack selective targeting of pathological sites, limiting the efficacy of their antibacterial activity. Efficient MRSA treatments can be achieved through nanoparticle (NPs)-based targeted therapies. To address this challenge, a novel coumarin-loaded solid lipid nanocarrier for MRSA was developed to overcome this challenge. The developed systems exhibited a particle size of 138.5 ± 76.06 nm and a polydispersity index (PDI) of 0.245 ± 0.00. The zeta potential of coumarin-loaded SLNs was reported to be −22.2 ± 8.15 mV with a spherical shape. The encapsulation efficiency of coumarin was reported to be 63.09 ± 3.46% in the final formulation. The developed formulation was biocompatible with a minimum inhibitory concentration (MIC) of 1.08 µg/mL. This study suggests that coumarin-loaded SLNs can effectively treat MRSA infections.
Sensors Based on the Carbon Nanotube Field-Effect Transistors for Chemical and Biological Analyses
Authors: Deng Yixi , Liu Lei , Li Jingyan , Gao Li
Published: September 2022

Nano biochemical sensors play an important role in detecting the biomarkers related to human diseases, and carbon nanotubes (CNTs) have become an important factor in promoting the vigorous development of this field due to their special structure and excellent electronic properties. This paper focuses on applying carbon nanotube field-effect transistor (CNT-FET) biochemical sensors to detect biomarkers. Firstly, the preparation method, physical and electronic properties and functional modification of CNTs are introduced. Then, the configuration and sensing mechanism of CNT-FETs are introduced. Finally, the latest progress in detecting nucleic acids, proteins, cells, gases and ions based on CNT-FET sensors is summarized.
Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants
Authors: Bottino Cristina , Della Chiesa Mariella , Sorrentino Stefania , Morini Martina , Vitale Chiara , Dondero Alessandra , Tondo Annalisa , Conte Massimo , Garaventa Alberto , Castriconi Roberta
Published: September 2022

High-risk neuroblastomas (HR-NB) still have an unacceptable 5-year overall survival despite the aggressive therapy. This includes standardized immunotherapy combining autologous hemopoietic stem cell transplantation (HSCT) and the anti-GD2 mAb. The treatment did not significantly change for more than one decade, apart from the abandonment of IL-2, which demonstrated unacceptable toxicity. Of note, immunotherapy is a promising therapeutic option in cancer and could be optimized by several strategies. These include the HLA-haploidentical αβT/B-depleted HSCT, and the antibody targeting of novel NB-associated antigens such as B7-H3, and PD1. Other approaches could limit the immunoregulatory role of tumor-derived exosomes and potentiate the low antibody-dependent cell cytotoxicity of CD16 dim/neg NK cells, abundant in the early phase post-transplant. The latter effect could be obtained using multi-specific tools engaging activating NK receptors and tumor antigens, and possibly holding immunostimulatory cytokines in their construct. Finally, treatments also consider the infusion of novel engineered cytokines with scarce side effects, and cell effectors engineered with chimeric antigen receptors (CARs). Our review aims to discuss several promising strategies that could be successfully exploited to potentiate the NK-mediated surveillance of neuroblastoma, particularly in the HSCT setting. Many of these approaches are safe, feasible, and effective at pre-clinical and clinical levels.
Regulating the p53 Tumor Suppressor Network at PML Biomolecular Condensates
Authors: Liebl Magdalena C. , Hofmann Thomas G.
Published: September 2022

By forming specific functional entities, nuclear biomolecular condensates play an important function in guiding biological processes. PML biomolecular condensates, also known as PML nuclear bodies (NBs), are macro-molecular sub-nuclear organelles involved in central biological processes, including anti-viral response and cell fate control upon genotoxic stress. PML condensate formation is stimulated upon cellular stress, and relies on protein–protein interactions establishing a PML protein meshwork capable of recruiting the tumor suppressor p53, along with numerous modifiers of p53, thus balancing p53 posttranslational modifications and activity. This stress-regulated process appears to be controlled by liquid–liquid phase separation (LLPS), which may facilitate regulated protein-unmixing of p53 and its regulators into PML nuclear condensates. In this review, we summarize and discuss the molecular mechanisms underlying PML nuclear condensate formation, and how these impact the biological function of p53 in driving the cell death and senescence responses. In addition, by using an in silico approach, we identify 299 proteins which share PML and p53 as binding partners, thus representing novel candidate proteins controlling p53 function and cell fate decision-making at the level of PML nuclear biocondensates.
Clinical Testing for Mismatch Repair in Neoplasms Using Multiple Laboratory Methods
Authors: Yang Richard K. , Chen Hui , Roy-Chowdhuri Sinchita , Rashid Asif , Alvarez Hector , Routbort Mark , Patel Keyur P. , Luthra Raja , Medeiros L. Jeffrey , Toruner Gokce A.
Published: September 2022

Background: A deficiency in DNA mismatch repair function in neoplasms can be assessed by an immunohistochemical (IHC) analysis of the deficiency/loss of the mismatch repair proteins (dMMR) or by PCR-based methods to assess high microsatellite instability (MSI-H). In some cases, however, there is a discrepancy between the IHC and MSI analyses. Several studies have addressed the issue of discrepancy between IHC and MSI deficiency assessment, but there are limited studies that also incorporate genetic/epigenetic alterations. Methods: In this single-institution retrospective chart-review study, we reviewed 706 neoplasms assessed between 2015 and 2021. All eligible neoplasms were assessed by IHC testing, MSI analysis by PCR-based assay, and tumor-normal paired next-generation sequencing (NGS) analysis. Eighty percent of neoplasms with MLH1 protein loss had a concurrent MLH1 promoter methylation analysis. Mutation data for MMR genes, IHC, MSI analysis, and tumor histology were correlated with each other. Results: Fifty-eight (8.2%) of 706 neoplasms had MSI-H by PCR and/or dMMR by IHC. Of the 706 analyzed neoplasms, 688 neoplasms (98%) had concordant results: MSI-H/dMMR (n = 44), microsatellite-stable (MSS)/proficient MMR (pMMR) (n = 625), and MSI-Low (L)/pMMR (n = 19). Of the remaining 18 neoplasms, 9 had a major discordance: MSS/loss of MSH2 and MSH6 (n = 3), MSS/loss of MSH6 (n = 2), MSS/Loss of MLH1 and PMS2 (n = 1), and MSI-High/pMMR (n = 3). In total, 57% of cases with dMMR and 61% of cases with MSI-H had a null mutation of an MMR gene mutation (or methylation of the MLH1 promoter), whereas this figure was 1% for neoplasms with a normal IHC or MSI pattern (p < 0.001). Among 9 cases with major discordance between MSI and IHC, only 3 cases (33%) had an underlying genetic/epigenetic etiology, whereas 37 (76%) of 49 cases with MSI-H and/or dMMR and without major discordance had an underlying genetic abnormality (p = 0.02). Discussion: For most neoplasms, IHC and PCR-based MSI testing results are concordant. In addition, an underlying genetic abnormality (a null mutation of an MMR gene or MLH1 promoter methylation) was attributable to dMMR and/or MSI-H findings. For neoplasms with major discordance in IHC and MSI testing, the addition and integration of NGS results and MLH1 promoter methylation analyses can be beneficial for resolving borderline cases, thereby facilitating patient management.
Prognostic Value of the Serum HER2 Extracellular Domain Level in Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Wu Yun , Li Lixi , Zhang Di , Ma Fei
Published: September 2022

An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different modalities remains controversial. Herein, we aimed to evaluate the prognostic value of serum HER2 extracellular domain (sHER2 ECD) in breast cancer and to identify its correlation with the efficacy of different treatment regimens. A systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases was conducted to identify studies exploring the association between HER2 ECD level and clinical outcomes among patients with breast cancer. Using the random effects models, pooled hazard ratios (HRs), and odds ratios (ORs) with 95% confidence intervals (CI), were calculated for progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), and the objective response rate (ORR). Heterogeneity was further evaluated by subgroup and sensitivity analysis. Overall, 40 studies comprising 12,229 patients were included in this systematic review and meta-analysis. Elevated HER2 ECD levels were associated with worse PFS (HR 1.74, 95% CI 1.40–2.17; p < 0.001), and this effect was observed in patients treated with chemotherapy (HR 1.81, 95% CI 1.37–2.39; p < 0.001), endocrine therapy (HR 1.91, 95% CI 1.57–2.32; p < 0.001), and trastuzumab (HR 1.74, 95% CI 1.31–2.30; p < 0.001). However, this association was not present in patients treated with tyrosine kinase inhibitors (TKIs) (HR 1.44, 95% CI 0.85–2.43, p = 0.17). The HRs/ORs for an elevated HER2 ECD level for DFS, OS, and ORR were 2.73 (95% CI 2.17–3.42; p < 0.001), 2.13 (95% CI 1.77–2.57; p < 0.001), and 0.80 (95% CI 0.49–1.31; p = 0.381), respectively. An elevated sHER2 ECD was an unfavorable prognostic factor in breast cancer but did not affect the efficacy of tyrosine kinase inhibitors such as lapatinib. Detection of sHER2 ECD may be helpful for clinicians selecting the appropriate anti-HER2 therapy for patients with HER2-positive breast cancer.
Modern Management Options for Ph+ ALL
Authors: Ribera Josep-Maria , Chiaretti Sabina
Published: September 2022

Impressive advances have been achieved in the management of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) since the initial concurrent use of imatinib and standard chemotherapy. The attenuation of chemotherapy has proven to be equally effective and less toxic, the use of third generation TKI upfront has improved the frequency of complete molecular response and the survival rate, and the combination of tyrosine kinase inhibitors with immunotherapy has further increased the rate of molecular response to 70–80% after consolidation, which has been translated into a survival rate of 75–90% in recent trials. As a result of these improvements, the role of allogeneic hematopoietic stem cell transplantation is being redefined. The methodology of measurable residual disease assessment and the detection of ABL1 mutations are also improving and will contribute to a more precise selection of the treatment for newly diagnosed and relapsed or refractory (R/R) patients. Finally, new compounds combined with immunotherapeutic approaches, including cellular therapy, are being used as rescue therapy and will hopefully be included in first line therapy in the near future. This article will review and update the modern management of patients with Ph+ ALL.
Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma
Authors: Isberner Nora , Gesierich Anja , Balakirouchenane David , Schilling Bastian , Aghai-Trommeschlaeger Fatemeh , Zimmermann Sebastian , Kurlbaum Max , Puszkiel Alicja , Blanchet Benoit , Klinker Hartwig , Scherf-Clavel Oliver
Published: September 2022

Patients treated with dabrafenib and trametinib for BRAFV600-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.
Association between Energy Balance-Related Factors and Clinical Outcomes in Patients with Ovarian Cancer: A Systematic Review and Meta-Analysis
Authors: Stelten Stephanie , Schofield Christelle , Hartman Yvonne A. W. , Lopez Pedro , Kenter Gemma G. , Newton Robert U. , Galvão Daniel A. , Hoedjes Meeke , Taaffe Dennis R. , van Lonkhuijzen Luc R. C. W. , McIntyre Carolyn , Buffart Laurien M.
Published: September 2022

Background: This systematic review and meta-analysis synthesized evidence in patients with ovarian cancer at diagnosis and/or during first-line treatment on; (i) the association of body weight, body composition, diet, exercise, sedentary behavior, or physical fitness with clinical outcomes; and (ii) the effect of exercise and/or dietary interventions. Methods: Risk of bias assessments and best-evidence syntheses were completed. Meta-analyses were performed when ≥3 papers presented point estimates and variability measures of associations or effects. Results: Body mass index (BMI) at diagnosis was not significantly associated with survival. Although the following trends were not supported by the best-evidence syntheses, the meta-analyses revealed that a higher BMI was associated with a higher risk of post-surgical complications (n = 5, HR: 1.63, 95% CI: 1.06–2.51, p = 0.030), a higher muscle mass was associated with a better progression-free survival (n = 3, HR: 1.41, 95% CI: 1.04–1.91, p = 0.030) and a higher muscle density was associated with a better overall survival (n = 3, HR: 2.12, 95% CI: 1.62–2.79, p < 0.001). Muscle measures were not significantly associated with surgical or chemotherapy-related outcomes. Conclusions: The prognostic value of baseline BMI for clinical outcomes is limited, but muscle mass and density may have more prognostic potential. High-quality studies with comprehensive reporting of results are required to improve our understanding of the prognostic value of body composition measures for clinical outcomes. Systematic review registration number: PROSPERO identifier CRD42020163058.
Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season
Authors: Sydykov Akylbek , Petrovic Aleksandar , Maripov Abdirashit M. , Gredic Marija , Bermes Daniel Gerd , Kushubakova Nadira , Muratali Uulu Kubatbek , Pilz Christina , Cholponbaeva Meerim , Duishobaev Melis , Satybaldyev Samatbek , Satieva Nurgul , Mamazhakypov Argen , Sartmyrzaeva Meerim , Omurzakova Nazgul , Kerimbekova Zhainagul , Baktybek Nursultan , Kulchoroeva Cholpon , Pak Oleg , Zhao Lan , Weissmann Norbert , Avdeev Sergey , Maslov Leonid N. , Ghofrani Hossein Ardeschir , Schermuly Ralph Theo , Sarybaev Akpay S. , Kosanovic Djuro
Published: September 2022

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.
The RNA-Binding Landscape of HAX1 Protein Indicates Its Involvement in Translation and Ribosome Assembly
Authors: Balcerak Anna , Macech-Klicka Ewelina , Wakula Maciej , Tomecki Rafal , Goryca Krzysztof , Rydzanicz Malgorzata , Chmielarczyk Mateusz , Szostakowska-Rodzos Malgorzata , Wisniewska Marta , Lyczek Filip , Helwak Aleksandra , Tollervey David , Kudla Grzegorz , Grzybowska Ewa A.
Published: September 2022

HAX1 is a human protein with no known homologues or structural domains. Mutations in the HAX1 gene cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported the RNA-binding capacity of HAX1, but the role of this binding in physiology and pathology remains unexplained. Here, we report the transcriptome-wide characterization of HAX1 RNA targets using RIP-seq and CRAC, indicating that HAX1 binds transcripts involved in translation, ribosome biogenesis, and rRNA processing. Using CRISPR knockouts, we find that HAX1 RNA targets partially overlap with transcripts downregulated in HAX1 KO, implying a role in mRNA stabilization. Gene ontology analysis demonstrated that genes differentially expressed in HAX1 KO (including genes involved in ribosome biogenesis and translation) are also enriched in a subset of genes whose expression correlates with HAX1 expression in four analyzed neoplasms. The functional connection to ribosome biogenesis was also demonstrated by gradient sedimentation ribosome profiles, which revealed differences in the small subunit:monosome ratio in HAX1 WT/KO. We speculate that changes in HAX1 expression may be important for the etiology of HAX1-linked diseases through dysregulation of translation.
Gingival Margins’ Modifications during Orthodontic Treatment with Invisalign First®: A Preliminary Study
Authors: Lione Roberta , Gazzani Francesca , Moretti Sofia , Danesi Carlotta , Cretella Lombardo Elisabetta , Pavoni Chiara
Published: September 2022

The aim of the study was to assess modifications of gingival morphology at the end of Phase I treatment with Invisalign First. Eighteen subjects (ten females, eight males, mean age nine years) treated with Invisalign First were selected. The following parameters were measured on intraoral photographs before treatment (T0) and after the first set of aligners (T1) at level of permanent incisors, deciduous canines and molars: gingival margin height (GMH) and deciduous canine inclination (DCI). A paired t-test was used to evaluate T1-T0 changes. The level of significance was established at 5%. Deciduous canines’ GMH showed a major reduction between T1 and T0 accounting for 0.87 mm and 0.86 mm, respectively on the right and left sides. DCI increased for all patients in the interval T0–T1 on both sides, +7.11° on the right and +7.5° on the left. Tooth movement during Invisalign First induced significant modifications of gingival contour resulting in a more harmonious smile.
Developmental Milestones of Infancy and Associations with Later Childhood Neurodevelopmental Outcomes in the Adolescent Brain Cognitive Development (ABCD) Study
Authors: Zhuo Haoran , Xiao Jingyuan , Tseng Wan-Ling , Liew Zeyan
Published: September 2022

The age at attaining infancy developmental milestones has been associated with later neurodevelopmental outcomes, but evidence from large and diverse samples is lacking. We investigated this by analyzing data of 5360 singleton children aged 9–10 from 17 states in the US enrolled in the Adolescent Brain Cognitive Development (ABCD) study during 2016–2020. Delays in four milestones (first roll over, unaided sitting, unaided walking, and speaking first words) were defined using the 90th percentile of age at attainment reported by children’s biological mothers. Childhood neurocognitive function was measured by research assistants using the NIH toolbox, and children reported their behavioral problems using the Brief Problem Monitor. Linear mixed-effects models were employed to investigate the association between delays in single or multiple milestones and childhood neurobehavioral outcomes. Delays in first roll over, unaided sitting, or walking were associated with poorer childhood neurocognitive function, while delay in speaking first words was associated with both poorer neurocognitive function and behavioral problems. Children who had delays in both motor and language milestones had the worst neurocognitive function and behavioral outcomes. Our results suggest that delays in motor and language milestone attainment during infancy are predictive of childhood neurobehavioral outcomes.