Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps.

Background: Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death. The epidermal growth factor family member neuregulin-1 (NRG1) reduces cell death by activating the protein kinase B (AKT) signalling pathway. Moreover, AKT signalling negatively regulates STING activity. We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis. Additionally, we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression. Methods: A random-pattern skin flap model was generated on the backs of C57BL/6 mice. The skin flap survival area was determined. The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis. Cluster of differentiation 34 immunohistochemistry (IHC) and haematoxylin and eosin (H&E) staining of the flap sections revealed microvessels. Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps. The levels of angiogenesis, oxidative stress, necroptosis, pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC, immunofluorescence and Western blotting. Packaging adeno-associated virus (AAV) was used to activate STING in flaps. Results: NRG1 promoted the survival of ischaemic flaps. An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1. Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis, pyroptosis and STING activity were reduced in the NRG1 group. The phosphorylation of AKT and forkhead box O3a (FOXO3a) were increased after NRG1 treatment. The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1. The ability of NRG1 to phosphorylate AKT-FOXO3a, inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206. Conclusions: NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.

Machine learning-driven prognostic analysis of cuproptosis and disulfidptosis-related lncRNAs in clear cell renal cell carcinoma: a step towards precision oncology.

Cuproptosis and disulfidptosis, recently discovered mechanisms of cell death, have demonstrated that differential expression of key genes and long non-coding RNAs (lncRNAs) profoundly influences tumor development and affects their drug sensitivity. Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, presently lacks research utilizing cuproptosis and disulfidptosis-related lncRNAs (CDRLRs) as prognostic markers. In this study, we analyzed RNA-seq data, clinical information, and mutation data from The Cancer Genome Atlas (TCGA) on ccRCC and cross-referenced it with known cuproptosis and disulfidptosis-related genes (CDRGs). Using the LASSO machine learning algorithm, we identified four CDRLRs-ACVR2B-AS1, AC095055.1, AL161782.1, and MANEA-DT-that are strongly associated with prognosis and used them to construct a prognostic risk model. To verify the model's reliability and validate these four CDRLRs as significant prognostic factors, we performed dataset grouping validation, followed by RT-qPCR and external database validation for differential expression and prognosis of CDRLRs in ccRCC. Gene function and pathway analysis were conducted using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) for high- and low-risk groups. Additionally, we have analyzed the tumor mutation burden (TMB) and the immune microenvironment (TME), employing the oncoPredict and Immunophenoscore (IPS) algorithms to assess the sensitivity of diverse risk categories to targeted therapeutics and immunosuppressants. Our predominant objective is to refine prognostic predictions for patients with ccRCC and inform treatment decisions by conducting an exhaustive study on cuproptosis and disulfidptosis.

A mucosal recovery software tool for endoscopic submucosal dissection in early gastric cancer.

Background: Due to the limited diagnostic ability, the low detection rate of early gastric cancer (EGC) is a serious health threat. The establishment of the mapping between endoscopic images and pathological images can rapidly improve the diagnostic ability to detect EGC. To expedite the learning process of EGC diagnosis, a mucosal recovery map for the mapping between ESD mucosa specimen and pathological images should be performed in collaboration with endoscopists and pathologists, which is a time-consuming and laborious work. Methods: 20 patients at the Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College from March 2020 to July 2020 were enrolled in this study. We proposed the improved U-Net to obtain WSI-level segmentation results, and the WSI-level results can be mapped to the macroscopic image of the specimen. For the convenient use, a software pipeline named as "Pathology Helper" for integration the workflow of the construction of mucosal recovery maps was developed. Results: The MIoU and Dice of our model can achieve 0.955 ± 0.0936 and 0.961 ± 0.0874 for WSI-level segmentation, respectively. With the help of "Pathology Helper", we can construct the high-quality mucosal recovery maps to reduce the workload of endoscopists and pathologists. Conclusion: "Pathology Helper" will accelerate the learning of endoscopists and pathologists, and rapidly improve their abilities to detect EGC. Our work can also improve the detection rate of early gastric cancer, so that more patients with gastric cancer will be treated in a timely manner.

Thoracic aortic reactivity in obese patients submitted to aerobic exercise / Reatividade da aorta torácica em pacientes obesos submetidos ao exercício aeróbico / Reactividad de la aorta torácica en pacientes obesos sometidos a ejercicio aeróbico

ABSTRACT Introduction: Aerobic exercise can improve the function of the cardiovascular circulatory system, reducing morbidity and mortality from cardiovascular disease by stimulating the production of endogenous self-protection. Activating potassium channels in vascular smooth muscle cells can cause vasodilation and increase blood flow, lowering blood pressure. There is a sensitivity to intracellular ATP and ADP concentration among the variety of potassium channels distributed in vascular smooth muscle cells, which vary mainly during aerobic physical activity. Objective: Explore the effect of aerobic exercise on the vascular reactivity of the thoracic aorta in patients with obesity and hyperlipidemia. Methods: Randomized controlled trial in twenty male Wistar rats weighing 250g and two months old. The control group remained at rest while the experimental group performed aerobic exercise on a treadmill at increasing speed for eight weeks. The rats were dissected, and dilatators and vasoconstrictors drugs stimulated their blood vessels in a tamponade solution. Observation of vascular changes was measured under controlled tensioning. Results: The blockade of KATP channels in vascular smooth muscle caused tonic contraction of vascular smooth muscle cells and increased blood pressure. Conclusion: Long-term regular aerobic exercise may induce changes in rats' thoracic aortic vascular function and vascular smooth muscle reactivity. Aerobic exercise can also significantly improve the activity of KATP channels. Evidence Level II; Therapeutic Studies - Investigating the results.

RESUMO Introdução: O exercício aeróbico pode melhorar a função do sistema circulatório cardiovascular, reduzindo a morbidade e mortalidade de doenças cardiovasculares estimulando a produção de autoproteções endógenas. A ativação de canais de potássio nas células musculares lisas vasculares pode causar vasodilatação e aumentar o fluxo sanguíneo, diminuindo a pressão sanguínea. Há uma sensível a concentração de ATP intracelular e ADP dentre a variedade de canais de potássio distribuídos em células musculares lisas vasculares, que variam principalmente durante a atividade física aeróbica. Objetivo: Explorar o efeito do exercício aeróbico na reatividade vascular da aorta torácica em pacientes com obesidade e hiperlipidemia. Métodos: Estudo randomizado controlado em vinte ratos Wistar machos de 250g e 2 meses de idade. O grupo controle permaneceu sob repouso enquanto o experimental realizava exercícios aeróbicos em esteira com velocidade crescente durante 8 semanas. Os ratos foram dissecados e seus vasos sanguíneos estimulados com drogas vasoconstritoras e dilatadoras em solução tampão. A observação das alterações vasculares foi mensurada sob tensionamento controlado. Resultados: O bloqueio dos canais KATP no músculo liso vascular causou contração tônica das células musculares lisas vasculares e aumento da pressão arterial. Conclusão: Exercícios aeróbicos regulares de longo prazo podem induzir alterações na função vascular da aorta torácica e reatividade do músculo liso vascular em ratos. O exercício aeróbico também pode melhorar significativamente a atividade dos canais KATP. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El ejercicio aeróbico puede mejorar la función del sistema circulatorio cardiovascular, reduciendo la morbilidad y la mortalidad de las enfermedades cardiovasculares al estimular la producción de autoprotección endógena. La activación de los canales de potasio en las células del músculo liso vascular puede causar vasodilatación y aumentar el flujo sanguíneo, reduciendo la presión arterial. Existe una sensibilidad a la concentración intracelular de ATP y ADP entre la variedad de canales de potasio distribuidos en las células del músculo liso vascular, que varían principalmente durante la actividad física aeróbica. Objetivo: Explorar el efecto del ejercicio aeróbico sobre la reactividad vascular de la aorta torácica en pacientes con obesidad e hiperlipidemia. Métodos: Ensayo controlado aleatorio en veinte ratas Wistar macho de 250 g y 2 meses de edad. El grupo de control permaneció en reposo mientras que el grupo experimental realizó ejercicios aeróbicos en una cinta de correr a velocidad creciente durante 8 semanas. Las ratas fueron disecadas y sus vasos sanguíneos fueron estimulados con fármacos vasoconstrictores y dilatadores en solución amortiguada. La observación de los cambios vasculares se midió bajo tensión controlada. Resultados: El bloqueo de los canales KATP en el músculo liso vascular provocó una contracción tónica de las células del músculo liso vascular y un aumento de la presión arterial. Conclusión: El ejercicio aeróbico regular a largo plazo puede inducir cambios en la función vascular de la aorta torácica y en la reactividad del músculo liso vascular en ratas. El ejercicio aeróbico también puede mejorar significativamente la actividad del canal KATP. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

Breakthrough pressure of oil displacement by water through the ultra-narrow kerogen pore throat from the Young-Laplace equation and molecular dynamic simulations.

As one common unconventional reservoir, shale plays a pivotal role to compensate the depletion of conventional oil resources. There are numerous nanoscale pores and ultra-narrow pore throats (sub 2 nm) in shale media. To displace oil through ultra-narrow pore throats by water, one needs to overcome excessively-high capillary pressure. Understanding the water-oil two-phase displacement process through pore throats is critical to numerical simulation on tight/shale oil exploitation and ultimate oil recovery estimation. In this work, we use molecular dynamics simulations to investigate oil (represented by n-octane) displacement by water through a ~2 nm kerogen (represented by Type II-C kerogen) pore throat. Besides, the applicability of the Young-Laplace equation to the ultra-narrow kerogen pore throat has been assessed. We find that although the Type II-C kerogen is generally oil-wet, water has an excellent displacement efficiency without the oil film on the substrate, thanks to the hydrogen bonding formed between water and heteroatoms (such as O, N, and S) on the kerogen surface. Unlike previous studies, the capillary pressure obtained from the widely used Young-Laplace equation shows a good agreement with the breakthrough pressure obtained from MD simulations for the ∼2 nm kerogen pore throat. Our work indicates that explicitly considering intermolecular interactions as well as atomistic and molecular level characteristics is imperative to study the two-phase displacement process through ultra-narrow pore throats.

Natural gas vaporization in a nanoscale throat connected model of shale: multi-scale, multi-component and multi-phase.

Production of hydrocarbons from shale is a complex process that necessitates the extraction of multi-component hydrocarbons trapped in multi-scale nanopores. While advances in nanofluidics have allowed researchers to probe thermodynamics and transport in single, discrete nanochannels, these studies present a highly simplified version of shale reservoirs with homogeneous pore structures and/or single-component fluid compositions. In this study, we develop and apply a 30 000-pore nanomodel that captures the inherent heterogeneity in reservoir pore sizes (100 nm pores gated by 5 nm-pores) to study vaporization of a representative natural gas hydrocarbon mixture. The nanomodel matches major North American formations in the volumetric and number contributions of the pore sizes, porosity (10.5%), and ultra-low permeability (44 nD). Combined experimental and analytical results show 3000× slower vaporization owing to the nanoscale throat bottlenecks. At low temperatures, mixture effects reduce rates further with stochastic vaporization of light components in large pores dominating. Collectively this approach captures the coupled complexity of multicomponent, multiphase fluids in multiscale geometries that is inherent to this resource.

Hyalinizing clear cell carcinoma of salivary glands: A retrospective study focused on uncommon morphology, immunohistochemistry, and detection of gene fusion using fluorescence in situ hybridization.

AIMS: To investigate histological, immunohistochemical, and molecular features, especially uncommon morphology of hyalinizing clear cell carcinoma (HCCC) to expand the morphological spectrum of HCCC. METHODS AND RESULTS: We examined 5 cases of HCCC by histological, immunohistochemical, and molecular analysis. Generally, 5 HCCC cases shared similar characteristics, exhibiting clear to slightly eosinophilic cells arranged in cords, nests, islands, or trabeculae with a hyalinized stroma, while myxoid stroma, perineural invasion, and polygonal cells with high-grade nuclei were observed in 3 cases. Immunohistochemically, 5 cases were entirely immunoreactive for CKpan, whereas 80% HCCC cases were positive for P63, and CK14. None expressed immunoreactivity for S-100, Calponin, or GFAP. The positive rate of Ki-67 staining was about 5% in the classic area of case 3, but 40% in the high-grade area. As for the result of FISH findings, EWSR1 gene break was detected in all 5 HCCC cases. CONCLUSIONS: Our study has expanded the morphological spectrum of HCCC, and proposed the diagnosis of HCCC should be confirmed by fully analyzing histological, immunohistochemical, and molecular features practically.