bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographic, sex and socioeconomic disparities in esophageal cancer incidence in China: A population‐based study
Authors: Ran Xianhui , Zeng Hongmei , Zheng Rongshou , Sun Kexin , Han Bingfeng , Wang Shaoming , Chen Ru , Li Li , Wei Wenqiang , He Jie
Published: September 2023

Geographic and sex differences in esophageal cancer have been reported in China, but data are lacking at the local level. We aimed to investigate geographic and sex disparities in esophageal cancer incidence among Chinese counties and whether county‐level socioeconomic status was associated with these variations. We obtained esophageal cancer data from 2015 to 2017 for 782 counties from population‐based cancer registries in China. We calculated age‐standardized incidence rates and male‐to‐female incidence rate ratios (IRRs) by county. We performed hotspot analysis to identify geographical clusters. We used negative binomial regression models to analyze the association between incidence rates and county‐level socioeconomic factors. There were significant geographic disparities in esophageal cancer incidence, with 8.1 times higher rate in the 90th‐percentile county than in the 10th‐percentile county (23.7 vs 2.9 per 100 000 person‐years). Clusters of elevated rates were prominent across north‐central China. Nationally, men had 2.9 times higher incidence of esophageal cancer than women. By county, the male‐to‐female IRRs ranged from 1.1 to 21.1. Clusters of high male‐to‐female IRRs were observed in northeast China. Rurality (IRR 1.16, 95% CI 1.10‐1.22), per capita gross domestic product (IRR 0.95, 0.92‐0.98) and percentage of people with a high school diploma (IRR 0.86, 0.84‐0.87) in a county were significantly associated with esophageal cancer incidence. The male‐to‐female IRRs were higher in counties with higher socioeconomic status. Substantial differences in incidence rates and sex ratios of esophageal cancer exist between Chinese counties, and county‐level socioeconomic status was associated with these variations. These findings may inform interventions to reduce these disparities.
Spinster homolog 2 reduces malignancies of glioblastoma via PTEN/PI3K/AKT pathway
Authors: Liang Weiye , Liu Mingkai , Su Yuling , Wen Yulin , Wang Lili , Shan Jiajie , Zhao Jie , Xie Keping , Wang Jian
Published: September 2023

The molecular mechanisms of glioblastoma (GBM) are unclear, and the prognosis is poor. Spinster homolog 2 (SPNS2) is reportedly involved in pathological processes such as immune response, vascular development, and cancer. However, the biological function and molecular role of SPNS2 in GBM are unclear. SPNS2 is aberrantly low expressed in glioma. Survival curves, risk scores, prognostic nomograms, and univariate and multifactorial Cox regression analyses showed that SPNS2 is an independent prognostic indicator significantly associated with glioma progression and prognosis. Cell function assays and in vivo xenograft transplantation were performed that downregulation of SPNS2 promoted GBM cell growth, migration, invasion, epithelial–mesenchymal transition (EMT), anti‐apoptosis, drug resistance, and stemness, while overexpression of SPNS2 had the opposite effect. Meanwhile, the functional enrichment and signaling pathways of SPNS2 in the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and RNA sequencing were analyzed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA). The above results were related to the inhibition of the PTEN/PI3K/AKT pathway by SPNS2. In addition, we predicted that SPNS2 is closely associated with immune infiltration in the tumor microenvironment by four immune algorithms, ESTIMATE, TIMER, CIBERSORT, and QUANTISEQ. In particular, SPNS2 was negatively correlated with the infiltration of most immune cells, immunomodulators, and chemokines. Finally, single‐cell sequencing analysis also revealed that SPNS2 was remarkably correlated with macrophages, and downregulation of SPNS2 promotes the expression of M2‐like macrophages. This study provides new evidence that SPNS2 inhibits malignant progression, stemness, and immune infiltration of GBM cells through PTEN/PI3K/AKT pathway. SPNS2 may become a new diagnostic indicator and potential immunotherapeutic target for glioma.
Coadministration of Acetaminophen and Troglitazone: Pharmacokinetics and Safety
Authors: Young Malcolm A. , Lettis Sally , Eastmond Richard
Published: September 2023

Troglitazone, a PPAR‐g agonist, enhances the actions of insulin on muscle and liver. It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite. Acetaminophen also undergoes metabolism by conjugation. This three‐way crossover study in 12 healthy male volunteers was conducted to investigate the effects of acetaminophen on the metabolism of troglitazone and vice versa. No statistically or clinically relevant differences in area under the concentrationtime curve extrapolated to infinity (AUC0‐∞ were observed for troglitazone, its quinone metabolite, or acetaminophen. A statistically significant decrease in troglitazone sulfate conjugate during administration with acetaminophen was not clinically relevant. No statistically or clinically relevant differences were observed in maximum concentration (Cmax), time to Cmax (tmax), or elimination half‐life of troglitazone, its two main metabolites, and acetaminophen or in acetaminophen urinary sulfate excretion, although there was a slight decrease in acetaminophen glucuronide excretion during administration with troglitazone. Adverse events were minor and similar between treatments. These findings suggest that troglitazone and acetaminophen can be coadministered without adverse clinical consequences.
Modelling three‐dimensional cancer‐associated cachexia and therapy: The molecular basis and therapeutic potential of interleukin‐6 transignalling blockade
Authors: Cosentino Marianna , Forcina Laura , Zouhair Mariam , Apa Ludovica , Genovese Desirèe , Boccia Caterina , Rizzuto Emanuele , Musarò Antonio
Published: September 2023

Background

Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin‐6 (IL‐6) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways.

Methods

We employed a three‐dimensional ex vivo muscle engineered tissue (X‐MET) to model cancer‐associated cachexia and to study the effectiveness of selective inhibition of IL‐6 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X‐MET model. A dose of 1.2 ng/mL of glycoprotein‐130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL‐6 transignalling.

Results

C26‐conditioned medium induced a cachectic‐like phenotype in the X‐MET, leading to a decline of muscle mass (−60%; P < 0.001), a reduction in myosin expression (−92.4%; P < 0.005) and a reduction of the contraction frequency spectrum (−94%). C26‐conditioned medium contains elevated amounts of IL‐6 (8.61 ± 4.09 pg/mL) and IL6R (56.85 ± 10.96 pg/mL). These released factors activated the signal transducer and activator of transcription 3 (STAT3) signalling in the C26_CM X‐MET system (phosphorylated STAT3/TOTAL +54.6%; P < 0.005), which in turn promote an enhancement of Il‐6 (+69.2%; P < 0.05) and Il6r (+43%; P < 0.05) gene expression, suggesting the induction of a feed‐forward loop. The selective neutralization of IL‐6 transignalling, by gp130Fc, in C26_CM X‐MET prevented the hyperactivation of STAT3 (−55.8%; P < 0.005), countered the reduction of cross‐sectional area (+28.2%; P < 0.05) and reduced the expression of proteolytic factors including muscle ring finger‐1 (−88%; P < 0.005) and ATROGIN1 (−92%; P < 0.05), thus preserving the robustness and increasing the contractile force (+20%) of the three‐dimensional muscle system. Interestingly, the selective inhibition of IL‐6 transignalling modulated gene regulatory networks involved in myogenesis and apoptosis, normalizing the expression of pro‐apoptotic miRNAs, including miR‐31 (−53.2%; P < 0.05) and miR‐34c (−65%; P < 0.005), and resulting in the reduction of apoptotic pathways highlighted by the sensible reduction of cleaved caspase 3 (−92.5%; P < 0.005) in gp130Fc‐treated C26_CM X‐MET.

Conclusions

IL‐6 transignalling appeared as a promising target to counter cancer cachexia‐related alterations. The X‐MET model has proven to be a reliable drug‐screening tool to identify novel therapeutic approaches and to test them in preclinical studies, significantly reducing the use of animal models.
Skeletal muscle adaptations in patients with lung cancer: Longitudinal observations from the whole body to cellular level
Authors: Snoke Deena B. , Bellefleur Emma , Rehman Hibba Tul , Carson James A. , Poynter Matthew E. , Dittus Kim L. , Toth Michael J.
Published: September 2023

Background

Cancer and its treatment can adversely affect skeletal muscle, impacting physical function, treatment response and survival. No studies, however, have comprehensively characterized these muscle adaptations longitudinally in human patients at the cellular level.

Methods

We examined skeletal muscle size and function from the whole body to the sub‐cellular level in 11 patients with non‐small cell lung cancer (NSCLC; 6 male/5 female, mean age 58 ± 3 years) studied over a 2‐month observation period starting during their first cycle of standard of care cancer treatment and in 11 age‐ and sex‐matched healthy controls (HC) without a current or past history of cancer. Biopsies of the vastus lateralis were performed to assess muscle fibre size, contractility and mitochondrial content, along with assessments of physical function, whole muscle size and function, and circulating cytokines.

Results

Body weight, composition and thigh muscle area and density were unaltered over time in patients with NSCLC, while muscle density was lower in patients with NSCLC versus HC (P = 0.03). Skeletal muscle fibre size decreased by 18% over time in patients (all P = 0.02) and was lower than HC (P = 0.02). Mitochondrial fractional area and density did not change over time in patients, but fractional area was lower in patients with NSCLC compared with HC (subsarcolemmal, P = 0.04; intermyofibrillar, P = 0.03). Patients with NSCLC had higher plasma concentrations of IL‐6 (HC 1.40 ± 0.50; NSCLC 4.71 ± 4.22; P < 0.01), GDF‐15 (HC 569 ± 166; NSCLC 2071 ± 1168; P < 0.01) and IL‐8/CXCL8 (HC 4.9 ± 1.8; NSCLC 10.1 ± 6.0; P = 0.02) compared with HC, but there were no changes in inflammatory markers in patients with NSCLC over time. No changes were observed in markers of satellite cell activation or DNA damage in patients and no group differences were noted with HC. Whole‐muscle strength was preserved over time in patients with NSCLC coincident with improved single fibre contractility.

Conclusions

This study is the first to comprehensively examine longitudinal alterations in skeletal muscle fibre size and function in patients with NSCLC and suggests that muscle fibre atrophy occurs during cancer treatment despite weight stability and no changes in conventional clinical measurements of whole body or thigh muscle size over this period.
Mesenchymal stem cell‐derived exosomes in myocardial infarction: Therapeutic potential and application
Authors: Li Jing , Tang Yuting , Yin Leijing , Lin Xiaofang , Luo Zhengyang , Wang Shuxin , Yuan Ludong , Liang Pengfei , Jiang Bimei
Published: September 2023

Myocardial infarction refers to the irreversible impairment of cardiac function resulting from the permanent loss of numerous cardiomyocytes and the formation of scar tissue. This condition is caused by acute and persistent inadequate blood supply to the heart's arteries. In the treatment of myocardial infarction, Mesenchymal stem cells (MSCs) play a crucial role because of their powerful therapeutic effects.

These effects primarily stem from the paracrine secretion of multiple factors by MSCs, with exosome‐carried microRNAs being the most effective component in promoting cardiac function recovery after infarction. Exosome therapy has emerged as a promising cell‐free treatment for myocardial infarction as a result of its relatively simple composition, low immunogenicity and controlled transplantation dose. Despite these advantages, maintaining the stability of exosomes after transplantation and enhancing their targeting effect remain significant challenges in clinical applications. In recent developments, several approaches have been designed to optimize exosome therapy. These include enhancing exosome retention, improving their ability to target specific effects, pretreating MSC‐derived exosomes and employing transgenic MSC‐derived exosomes. This review primarily focuses on describing the biological characteristics of exosomes, their therapeutic potential and their application in treating myocardial infarction.
Synthesis, characterization, antibacterial activity and cytotoxicity of (1′R,2′S,7a′S)‐2′‐(2,5‐dichlorothiophene‐3‐carbonyl)‐1′‐(aryl)‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizin]‐2‐one derivatives
Authors: Al‐Refai Mahmoud , Ali Basem F. , Al‐Masri Eman K. , Mansi Iman A. , Aljaar Nayyef , Abu‐Irmaileh Bashaer , Geyer Armin , Ivlev Sergei I.
Published: September 2023

The synthesis and bioactivity studies of a series of (1′R,2′S,7a′S)‐2′‐(2,5‐dichlorothiophene‐3‐carbonyl)‐1′‐(aryl)‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizin]‐2‐one derivatives are described here. The spirooxindole title compounds were obtained from the regio‐ and diastereoselective 1,3‐dipolar cycloaddition reaction between an intermediate azomethine ylide and different chalcones. The structures of all compounds were proposed based on elemental analysis, ATR‐FTIR, 1H NMR, 13C NMR, ESIMS, and HRESIMS. Single crystal x‐ray structure determinations for some derivatives confirm the proposed structures. All synthesized compounds showed high cytotoxicity toward A549, HCT116, MCF7, DU145, and K562 but eight of them were also toxic toward normal skin fibroblast cell lines. Compound 4b showed moderate cytotoxicity toward A549 and MCF7 while 4c was highly cytotoxic toward DU145 and K562 and moderately toxic toward other cell lines. Both compounds were nontoxic toward normal skin fibroblast which makes them good drug candidates.
Correlates of postnatal human cytomegalovirus transmission in term babies in the first year
Authors: d'Angelo Piera , Zelini Paola , Zavaglio Federica , Piccini Stefania , Cirasola Daniela , Arossa Alessia , Spinillo Arsenio , Lilleri Daniele , Baldanti Fausto
Published: September 2023

Postnatal human cytomegalovirus (HCMV) infection in newborns is well characterized for preterm infants but less so for term infants. We sought to analyze the rates and routes of HCMV transmission in full‐term infants during the first year of life. A cohort of 120 HCMV seropositive mothers and their 122 newborns were tested after delivery for HCMV‐DNA shedding in different bodily fluids. Postnatal HCMV infection was defined as the detection of >2.5 × 102 HCMV‐DNA copies/mL in infants' saliva swabs. Maternal neutralizing antibody serum titer, HCMV‐specific T‐cell response, and HCMV glycoprotein B immunoglobulin G on breastmilk were analyzed. HCMV shedding was detected in 67 of 120 mothers (55.8%), and 20 of 122 infants (16.4%) developed HCMV infection within the first 3 months of life. Six additional infants were infected during the first year, for a postnatal infection rate of 21.3%. Viral shedding was more frequent in breastmilk than saliva, urine, and vaginal secretions, and the mothers of infected infants showed higher levels of HCMV‐DNA in milk. No association was found between the antibody levels in serum or milk and maternal viral shedding, whereas a slightly lower frequency of HCMV‐specific CD4+ T‐cells with long‐term memory phenotype was observed in women with HCM‐DNA‐positive milk. About one out of five infants develop HCMV infection within the first year of life. Breastmilk appears the major route of transmission of the infection, maternal saliva has a minor role whereas the role of vaginal secretions is negligible.
Influence of pre‐treatment methods on quality indicators and mineral composition of plant milk from different sources of raw materials
Authors: Lavrentev Filipp V. , Baranovskaia Darina A. , Shiriaev Valerii A. , Fomicheva Daria A. , Iatsenko Viktotiia A. , Ivanov Maksim S. , Ashikhmina Mariia S. , Morozova Olga V. , Iakovchenko Natalia V.
Published: September 2023

BACKGROUND

Pre‐treatment of plant materials is essential in producing plant‐based products and can affect their various organoleptic and physicochemical characteristics. This work aimed to study the effect of pre‐treatment of vegetable raw materials, namely ultrasonic processing and freezing of raw materials under various low‐temperature conditions, to obtain multiple types of vegetable milk and determine their characteristics.

RESULTS

It is shown that by applying a certain kind of pre‐treatment of vegetable raw materials it is possible to adjust organoleptic parameters and the content of solids, protein, fat, carbohydrates, fiber and mineral composition of various types of vegetable milk from soy, rice, oats, wheat, peas, buckwheat, pumpkin seeds and lentils. Ultrasound pre‐treatment allows increasing of polyphenol content by an average of 15–20% for all types of plant milk, except for lentil milk. The results showed that ultrasound treatment for 3 min had the most significant effect on the overall acceptability for lentils, pumpkin, rice and pea milk. Pre‐freezing at a temperature regime of −17 and –85 °C contributed to an increase in Fe, K, Zn, Ca, Mg, Si and P by an average of 30–100%, depending on the plant material.

CONCLUSION

Pre‐treatment of vegetable raw materials, including freezing and ultrasonic treatment, can positively affect the macro‐ and micronutrient composition of plant milk. However, the effect may vary depending on the type of raw material and processing conditions. © 2023 Society of Chemical Industry.
Soy protein isolate–guar gum–goose liver oil O/W Pickering emulsions that remain stable under accelerated oxidation at high temperatures
Authors: Fan Xiankang , Li Chunwei , Shi Zihang , Xia Qiang , Du Lihui , Zhou Changyu , Pan Daodong
Published: September 2023

Background

Goose liver oil (GLO) is a solid–liquid mixture, rich in polyunsaturated fatty acids and high in nutritional value, but poor in fluidity and easily oxidized. Therefore, oil‐in‐water (O/W) Pickering emulsions of three polysaccharides and soy protein isolate (SPI) with GLO were prepared to improve the stability of it.

Results

Sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), Fourier‐transform infrared spectroscopy, and zeta potential revealed that the SPI and complexes with konjac glucomannan, pectin, and guar gum (GG) ranged from 17 to 75 kDa, with the site of action being the –OH stretch and the amide group, and bound by hydrogen bonding. Adding konjac glucomannan and GG significantly increased the water contact angle of the SPI to 74.1° and 59.0°, respectively. Therefore, the protein–polysaccharide complexes could enhance the emulsion stability. In addition, the O/W Pickering emulsions with GLO had near‐Newtonian fluid rheological properties with a significant increase in apparent viscosity and viscoelasticity, forming a dual network structure consisting of a ductile and flexible protein network and a rigid and brittle polysaccharide network. The microstructure observation indicated that the O/W emulsions were spherical and homogeneous. The highest emulsification activity was observed for the SPI–GG–GLO emulsions, without significant delamination or flocculation and high oxidative stability after 7 days in storage.

Conclusion

These results demonstrate that the construction of SPI–GG–GLO O/W Pickering emulsions can stabilize GLO even at high temperatures that promote oxidation. © 2023 Society of Chemical Industry.
Assessing the effects of drought on rainfed maize water footprints based on remote sensing approaches
Authors: Li Bo , Qin Lijie , Qi Hang , Wang Jianqin , Dang Yongcai , Lv Mingzhu , He Hongshi
Published: September 2023

BACKGROUND

Drought affects the characteristics of water use during crop production and so quantitatively evaluating the impacts is important. However, it remains unclear how crop water use responds to drought. To address this gap, water footprint (WF) and standardized precipitation evapotranspiration index (SPEI) were calculated by remote sensing approaches to assess the effects of drought on crop water use. Rainfed maize is the most important crop in Jilin Province, and its growth and water use are more susceptible to drought. The present study explored not only the impact of growing season drought on the maize WF values in Jilin Province, but also the response of WF values to drought at different time scales.

RESULTS

Spatially, 72.94% of the WFblue pixels showed a non‐significant increase, and the WFgreen in 68% pixels decreased significantly, being mainly concentrated in the middle region. Furthermore, the pixels affected by monthly time scale drought were mainly in the middle region, whereas the pixels affected by annual time scale drought were mainly in the western region.

CONCLUSION

Drought not only affected on the source and structure of agricultural water consumption, but also had different effects on WF values at different time scale. These effects had obvious spatial differences. The present study systematically explored the effects of drought on the WF values for rainfed maize in different climate regions and a consideration of these effects could provide valuable information on rainfed maize growth and the agricultural water use response to a changing climate. © 2023 Society of Chemical Industry.
Characterization of vestibular schwannoma tissues using liquid chromatography‐tandem mass spectrometry analysis of specific peptide fragments separated by in‐sample tryptic protein digestion followed by mathematical analysis
Authors: Tesařová Michaela , Boušková Tereza , Cejnar Pavel , Šantrůček Jiří , Peterková Lenka , Fík Zdeněk , Sázelová Petra , Kašička Václav , Hynek Radovan
Published: September 2023

Vestibular schwannoma is the most common benign neoplasm of the cerebellopontine angle. Its first symptoms include hearing loss, tinnitus, and vestibular symptoms, followed by cerebellar and brainstem symptoms, along with palsy of the adjacent cranial nerves. However, the clinical picture has unpredictable dynamics and currently, there are no reliable predictors of tumor behavior. Hence, it is desirable to have a fast routine method for analysis of vestibular schwannoma tissues at the molecular level. The major objective of this study was to verify whether a technique using in‐sample specific protein digestion with trypsin would have the potential to provide a proteomic characterization of these pathological tissues. The achieved results showed that the use of this approach with subsequent liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) analysis of released peptides allowed a fast identification of a considerable number of proteins in two differential parts of vestibular schwannoma tissue as well as in tissues of control healthy samples. Furthermore, mathematical analysis of MS data was able to discriminate between pathological vestibular schwannoma tissues and healthy tissues. Thus, in‐sample protein digestion combined with LC‐MS/MS separation and identification of released specific peptides followed by mathematical analysis appears to have the potential for routine characterization of vestibular schwannomas at the molecular level. Data are available via ProteomeXchange with identifier PXD045261.
Novel Linear Piezo‐resistive Auxetic Meta‐Sensors with Low Young's Modulus by a Core–Shell Conceptual Design and Electromechanical Modelling
Authors: Taherkhani Bahman , Bodaghi Mahdi , Mousavi Nejad Souq Seyyed Sajad , Malmir Chegini Motaleb , Nemati Mohammad
Published: September 2023

Production of piezo‐resistive auxetic sensors is usually carried out through mixing and coating methods. Although these methods are beneficial, Young's modulus of mixed sensors becomes high because of using a high percentage of sensing elements while the durability of coated sensors gets low due to the separation of sensing elements from the sensor surface. This article presents a new core–shell metamaterial model to address the mentioned problems. The shell and the core are produced of polydimethylsiloxane (PDMS) rubber and a mixture of PDMS/graphite powders (73.45 wt% graphite powders), respectively. A finite element model is developed via COMSOL software to predict the electromechanical behaviors of the created sensor and verified by an experimental study. Scanning electron microscope imaging is conducted to detect the separations of the graphite particles. The main important feature of this meta‐sensor is to possess a linear sensitivity due to having zero Poisson's ratio. The advantage of this method is that Young's modulus of the sensor does not decrease (unlike the mixing method), and the sensor‐coated particles do not separate from the sensor after a while (unlike the coating method). The introduced model has advantages that promote potential applications such as using sensory gloves to detect, for instance, human hand movements.
DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors
Authors: Liu Anbu , Zhang Shaoting , Wang Ming , Zhang Liangying , Xu Shidong , Nasimian Ahmad , Li Shujing , Zhao Sien , Cao Xu , Tian Jinhai , Yu Yuanyuan , Fan Zhaoyang , Xiao Kun , Zhao Hui , Kazi Julhash U. , Ma Lijun , Sun Jianmin
Published: September 2023

Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild‐type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first‐line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild‐type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT‐targeted therapy. The development of drug‐resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
Investigations of effective dispersion models for electroosmotic flow with rigid and free boundaries in a thin strip
Authors: Schulz Raphael , Gärttner Stephan , Ray Nadja
Published: September 2023

Reactive flow and transport in porous media is topic of intense research since decades. Since dispersion is one of the key parameters in solute transport, its accurate modeling is essential to avoid wrong predictions of flow and transport behavior. In this research, we investigate novel effective dispersion models for reactive transport of electrically charged chemical species in a thin, potentially evolving strip taking into account Taylor–Aris and electroosmotic‐induced dispersion as well as their cross‐coupling effects. We prove positivity of the dispersion coefficient and the existence and uniqueness of strong solutions in the fixed geometry setting. Moreover, we numerically investigate scenarios for both the fixed and evolving geometry situation. The simulation results illustrate the possibility of separating charged species, such that the findings of this study can lead to a better understanding of mixing and separation processes of charged solutes and an improved prediction of breakthrough curves. Finally, we study the limits of vanishing channel width, precipitation layer thickness, and molecular diffusion. We show convergence of the solutions to the corresponding limit cases such as a hyperbolic model or the fixed geometry case. From these results, we can rate the impact of distinct dispersion mechanisms and evaluate the necessity of a detailed modeling for different parameter regimes.
Asymmetrically Substituted s‐Triazine Phosphonates by One‐Step Synthesis
Authors: Vogt Claudia , Höhne Carl‐Christoph , Limburger Jennifer , König Alexander , Wagener Tobias , Kroke Edwin
Published: September 2023

Asymmetrically substituted s‐triazine phosphonates with up to three different phosphonate groups C3N3RR'R” with R, R’, R”=PO(OR”’) and R”’=for example, methyl, ethyl, isopropyl or n‐butyl are interesting as polymer additives like flame retardants. Typically, these compounds are obtained by multiple synthesis steps. However, this leads to high production costs, which are a disadvantage for commercial use. Here we report the one‐step synthesis of mixtures of asymmetrical s‐triazine phosphonates which is an easy way to adjust the thermal behaviour and other properties such as viscosities of the compounds. The synthesis is based on a Michaelis–Arbuzov reaction. A complete conversion of the reactants to the target compounds is observed which was proofed by detailed 1H, 13C and 31P NMR investigations and elemental analysis. The thermal behaviour was compared with thermogravimetric analysis (TGA).
Targeting a faster time‐to‐solution of mortar‐based contact problems
Authors: Steimer Christopher , Mayr Matthias , Popp Alexander
Published: September 2023

While mortar methods are undoubtedly among the most prominent and accurate approaches in computational contact mechanics, they come with considerable cost. The required numerical effort originates not only from the evaluation of the mortar integrals but also from the solution of the system of linear equations within Newton‐type solvers. While each of these cost factors has been analyzed and addressed individually in the past, this contribution outlines approaches and first results to comprehensively reduce the time to solution by combining dynamic load balancing techniques with algebraic multigrid preconditioners. We present a proof of concept for a three‐dimensional unilateral contact simulation with an evolving contact zone.
Multifield computational model for human brain development: Explicit numerical stabilization
Authors: Zarzor Mohammad Saeed , Steinmann Paul , Budday Silvia
Published: September 2023

The morphological surface of the human brain is still puzzling to scientists. During the last few decades, studies have addressed different aspects of this phenomenon. The underlying cellular processes occurring at the microscopic scale are certainly important for the folding process. However, there is also an essential contribution from mechanical forces generated at the macroscopic scale during these processes. Many previous studies confirmed this fact, but still, most of them have not considered the link between cellular processes and mechanical forces. Recently, we have explained how the proliferation in different zones of the brain, cell migration, and neuronal connectivity affect the folding through a multifield computational model coupling an advection‐diffusion model with the theory of finite growth. We mathematically describe the cellular behavior of cells to control mechanical growth in both radial and circumferential directions. To deal with issues regarding numerical stability of the advection‐diffusion equation, which lead to temporal and spatial numerical oscillations, reduced efficiency of the numerical solver, and inaccurate results, we introduce an artificial diffusivity, which we apply only when the actual cell density does not satisfy the balance equation. The proposed method stabilizes the numerical solution and significantly improves the simulation results without additional numerical cost. It allows us to study brain development in 2D and 3D.
The synergistic impacts of hybrid nanofillers of graphene nanoplatelets/carbon nanotubes on curing behavior of an epoxy‐vinyl ester interpenetrating polymer network nanocomposite coating
Authors: Molaei Afrooz , Jannesari Ali
Published: September 2023

This study investigated the synergistic effects of hybrid graphene nanoplatelet (GnP)/multi walled carbon nanotube (MWCNT) nanofillers at various loadings on the kinetics of curing of the epoxy (EP)/vinyl ester (VE) interpenetrating polymer network (IPN) system, with a mass ratio of 1:1. Fourier transform infrared spectroscopy (FTIR), dynamic mechanical thermal analyzer (DMTA) and differential scanning calorimetry (DSC) were used to monitor the interpenetration process of EP and VE and likely interactions between the components of the different resin systems in IPN. The curing behavior of all prepared samples under non‐isothermal conditions was studied using DSC at four heating rates. Two different isoconversional approaches were applied to evaluate the reaction kinetics, that is, the Friedman and the advanced Vyazovkin methods. The obtained activation energy curves for all samples revealed a complex curing behavior involving three stages; early IPN stage, IPN growth stage, and late IPN stage. Then, the activation energy values for each reaction step were determined based on the Friedman method. The presence of GnP/MWCNT nanoparticles showed no catalytic effect on the reaction of VE with methyl ethyl ketone peroxide (MEKP). In contrast, incorporating GnP/MWCNT nanoparticles significantly decreases the activation energy values of the reaction of ring opening of epoxides with methyl tetrahydrophthalic anhydride (MTHPA) 1‐methyl imidazole (‐Mi) and the reaction of esterification of the hydroxyl groups of VE with MTHPA.

Highlights

Model‐free methods used to curing study of epoxy‐vinyl ester IPN nanocomposites

FTIR, DSC and DMTA used for evaluation IPN formation of EP/VE

It showed that the improvement of dispersion and compatibility by using of GnP/MWCNT hybrid

Frideman and Vyazovkin methods used to calculate Ea of nanocomposites

DSC thermograms were deconvoluted into three individual peaks.
Understanding significantly reinforced polymethyl methacrylate composites induced by two‐dimensional Tin+1Cn from an atomistic perspective
Authors: He Liangze , Li Chenliang , Lv Kezhen , Ding Xiaomin , Feng Liyang , Lv Xiaolong
Published: September 2023

MXenes, which have good reinforcing and toughening effects, can serve as excellent polymer additives. However, the mechanism whereby MXenes act has not been revealed. In this study, to understand the reinforcement effect of Tin+1Cn on polymethyl methacrylate (PMMA) from an atomistic perspective, we used molecular dynamics to conduct unidirectional tensile simulations of PMMA composites reinforced with monolayer Ti2C and Ti3C2 sheets. The results showed that Ti3C2 can more significantly improve the mechanical properties of the PMMA polymer than Ti2C, and the yield stress and Young's modulus of the Ti3C2/PMMA complexes were respectively 54.39% and 73.46% higher than the Ti2C/PMMA complexes. To further reveal the interaction mechanism between Tin+1Cn and PMMA, different separation speeds were used to simulate the pull‐out of Tin+1Cn from the PMMA matrix. The results showed that, in addition to the enhancement of interfacial strength by non‐bonding van der Waals forces, there were TiO and CTi bonds between Tin+1Cn and PMMA, which further increased the interfacial strength. Ti3C2 formed a denser interfacial region with PMMA, it could more effectively resist the formation and expansion of cracks. These findings may provide an important theoretical basis to design new type of MXene/polymer composites with excellent mechanical properties.

Highlights

MXene greatly improved the mechanical properties of the PMMA matrix.

Formation of chemical bonds improved connection between the MXene and PMMA.

The addition of MXene slows down the rate of crack propagation in PMMA.
Nanoscale hydroxyapatite/chitosan polymer coatings: Synthesis and characterization
Authors: Saeedi Fateme , Montazeri Arash
Published: September 2023

The present work involves the coating synthesis of nano‐hydroxyapatite/chitosan (nHA/CS) on a Mg‐2 wt% Zn scaffold with the pulse electrodeposition (PED) technique. In practice, to render coatings more corrosion‐resistant and biocompatibility in simulated body fluids, the impact of PED factors, such as mean current density (j), a duty cycle, and coating duration (t), was investigated. Further, Fourier transform infrared spectroscopy, scanning electron microscope, x‐ray diffraction, energy‐dispersion spectrometer, and water contact angle (WCA) were studied to characterize coatings. The corrosion resistance of coatings was investigated by impedance evaluations and potentiodynamic polarization. The results obtained from analyses revealed that the optimum conditions for synthesizing the nHA/CS coating were achieved when applying j = 20 mA/cm2, a duty cycle = 0.4, and a duration of 60 minutes. The coatings' microstructure and Ca/P ratio were influenced by PED factors, which included nano spherical‐shaped and 1.65. Furthermore, the corrosion rate was decreased from 19.603 to 1.492 mm yr−1 after being modified by optimum coating. Moreover, the high hydrophilic properties are assigned to this coating with a WCA of 29.9 compared to other coatings and the Mg scaffold. The biological properties of the optimum coating were assessed through in‐vitro experiments involving MG63 cells, which included the evaluations of cell adhesion and cytotoxicity. The results obtained from the corrosion and in‐vitro experiments indicate that the nanocomposite coating, upon optimization, holds potential as a scaffold for bone tissue engineering.

Highlights

Using Mg‐2 wt% Zn scaffold as a substrate for nanocomposite coatings.

Pulse electrodeposition method for the synthesis of nano‐hydroxyapatite/chitosan (nHA/CS) coatings.

Pulse electrodeposition (PED) method to modify morphology, corrosion resistance, and biocompatibility.

Optimum PED parameters: j = 20 mA/cm2, duty cycle = 0.4, and t = 60 min.
Monocyte and neutrophil to lymphocyte ratios in hospitalized children with RSV bronchiolitis
Authors: Burrack Nitzan , Adar Assaf , Goldbart Aviv , Weissmann Sarah , Cohen Bracha , Hazan Itai , Horev Amir , Golan‐Tripto Inbal
Published: September 2023

Objective

Acute bronchiolitis is the most common cause of hospitalization in young children. Data on monocyte‐to‐lymphocyte‐ratio (MLR) and neutrophil‐to‐lymphocyte‐ratio (NLR) as biomarkers are limited. We aim to evaluate these ratios in children hospitalized with respiratory syncytial virus (RSV) bronchiolitis and their value as biomarkers for severe clinical outcomes.

Study Design

A single‐center retrospective cohort study of children aged <2 years hospitalized due to RSV bronchiolitis, between January 2018 and March 2022, with a complete blood count upon admission. We divided the cohort into quartiles based on MLR and NLR values. We examined associations between quartiles and four clinical severity outcomes.

Results

A total of 2038 children (median age: 4.4 months, IQR: 1.9−9.8) were included in the study. The median MLR and NLR values for quartiles 1−4 were 0.14, 0.22, 0.30, 0.47, and 0.37, 0.70, 1.16, 2.29, respectively. Children with higher MLR had higher hospitalization rates to the pediatric intensive care unit (PICU) (Q1 2.4%, Q4 9.4%, p < .001), extended hospital stays (Q1 19.4%, Q4 32%, p < .001), and lower minimal oxygen saturation (Q1 90%, Q4 87%, p < .001). Cut‐off values of 0.34 for MLR and 0.67 for NLR optimally identified PICU admissions. In a model accounting for age and sex, the fourth MLR quartile had an RR of 3.4 (95% CI: 1.76−7.22) and successfully predicted PICU admissions (area under the curve = 0.73; 95% CI: 0.681−0.789).

Conclusions

MLR and NLR are potential biomarkers for identifying children with RSV bronchiolitis at a higher risk for severe outcomes, specifically PICU admission.
Insights into the solution structure and transcriptional regulation of the MazE9 antitoxin in Mycobacterium tuberculosis
Authors: Roy Tanaya Basu , Sarma Siddhartha P.
Published: September 2023

The present study endeavors to decode the details of the transcriptional autoregulation effected by the MazE9 antitoxin of the Mycobacterium tuberculosis MazEF9 toxin–antitoxin system. Regulation of this bicistronic operon at the level of transcription is a critical biochemical process that is key for the organism's stress adaptation and virulence. Here, we have reported the solution structure of the DNA binding domain of MazE9 and scrutinized the thermodynamic and kinetic parameters operational in its interaction with the promoter/operator region, specific to the mazEF9 operon. A HADDOCK model of MazE9 bound to its operator DNA has been calculated based on the information on interacting residues obtained from these studies. The thermodynamics and kinetics of the interaction of MazE9 with the functionally related mazEF6 operon indicate that the potential for intracellular cross‐regulation is unlikely. An interesting feature of MazE9 is the cis ⇌ trans conformational isomerization of proline residues in the intrinsically disordered C‐terminal domain of this antitoxin.
Understanding liver function tests: part 2
Authors: Parsons Graham
Published: September 2023

Liver function tests (LFTs) are useful blood tests to help identify liver disease, but their interpretation can be challenging. Part 2 in this two‐part series on understanding LFTs focuses on a case study of drug‐induced liver injury (DILI) to illustrate how to respond to abnormal LFT results.
Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact
Authors: Huang Yu‐Ting , Huang Yen‐Ming , Kung Fan‐Lu , Lin Chun‐Jung , Jao Tun , Ho Yunn‐Fang
Published: September 2023

The anticonvulsant valproic acid (VPA) despite complex pharmacokinetics has been in clinical use for nearly 6 decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those less than 10 years of age are lacking. To decipher clinical puzzles, physiologically‐based pharmacokinetic (PBPK) models of VPA and its hepatotoxic metabolite 4‐ene‐VPA were constructed and simulated with particularly integrated information of drug‐metabolizing enzyme ontogeny. Adult and pediatric PK data of VPA (n = 143 subjects) and 4‐ene‐VPA (n = 8 subjects) collected from previous reports were used for model development and validation. Sensitivity analyses were performed to characterize ontogeny impacts of CYP2C9 and UGT2B7 on dispositions of VPA and 4‐ene‐VPA across age groups. Optimal VPA dosing for each pediatric age group was also predicted and objectively judged by ensuring VPA efficacy and avoiding 4‐ene‐VPA hepatotoxicity. The study revealed UGT2B7 ontogeny was quite influential on VPA clearance even in neonates and small children. Intrinsic clearance of CYP2C9 was the most prominent determinant for areas under the concentration‐time curve of VPA and 4‐ene‐VPA in infants, and toddlers/preschoolers, reflecting higher hepatotoxicity risk due to noxious 4‐ene‐VPA accumulation in these groups. The ontogeny‐based PBPK approach complements conventional allometric methods in dosing estimation for the young by providing more mechanistic insight of the processes changing with age. The established ontogeny‐based PBPK approach for VPA therapy deserves further corroboration by real‐world therapeutic data to affirm its clinical applicability.
Cinnamaldehyde inhibits cytokine storms induced by the ORF3a protein of SARS‐CoV‐2 via ROS‐elimination in activated T cells
Authors: Ma Jing , Chen Xu , Xue Rui , Wang Fei , Dong Jun , Tao Ning , Qin Zhihai
Published: September 2023

Cytokine storms are the cause of complications in patients with severe COVID‐19, and it becomes the target of therapy. Several natural compounds were selected to screen the inhibitory effect on T‐cell proliferation by Fluorescence‐Activated Cell Sorting (FACS) and cytokine production by enzyme‐linked immunosorbent assay (ELISA). Open reading frame 3a (ORF3a) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) stimulates the specific T‐cell activation model in vivo and in vitro. The coculture system included the macrophage cell line RAW264.7 and splenocytes. Reactive oxygen species (ROS) levels and glycolysis in T cells were evaluated. Cinnamaldehyde effectively inhibits cytokine storms both in vitro and in vivo. It decreased inflammatory cytokine (such as IFN‐γ, TNF‐α, IL‐6, and IL‐2) production by murine peripheral blood cells upon direct stimulation with ConA, after immunization with the MHV‐A59 virus or ORF3a peptide from SARS‐CoV‐2. Cinnamaldehyde restored the percentage of T cells, which was originally decreased in the peripheral blood and splenocytes of ORF3a‐immunized mice. In a coculture system, cinnamaldehyde reduced the secretion of inflammatory cytokines from macrophages in a T‐cell dependent manner. Furthermore, cinnamaldehyde decreased the ROS level in activated T cells, which in turn reduced glycolysis and the activation of T cells. Cinnamaldehyde can be used as a candidate molecule for COVID‐19.
Prescribed performance event‐triggered control for MIMO switched nonlinear systems with unstable subsystems
Authors: Fan Zhida , Wang Fenglan , Long Lijun
Published: September 2023

This article investigates the problem of prescribed performance event‐triggered tracking control for a class of multi‐input‐multi‐output (MIMO) switched uncertain nonlinear systems, in which the solvability of the prescribed performance event‐triggered control problem for each subsystem is unnecessary. By developing a proper switching law, a prescribed performance event‐triggered low‐complexity state‐feedback control method is set up to solve the problem. Furthermore, the result above is extended to MIMO switched uncertain nonlinear systems with unavailable states by developing a prescribed performance event‐triggered low‐complexity output‐feedback control and a high‐gain observer. Also, Zeno phenomenon for the event‐triggered mechanism and the switching law is excluded. Finally, two examples verify the results obtained.