Roles of leukemia inhibitory factor receptor in cancer.

Leukemia inhibitory factor receptor (LIFR), in complex with glycoprotein 130 (gp130) as the receptor for leukemia inhibitory factor (LIF), can bind to a variety of cytokines and subsequently activate a variety of signaling pathways, including Janus kinase/signal transducer and activator of transcription 3. LIF, the most multifunctional cytokines of the interleukin-6 family acts as both a growth factor and a growth inhibitor in different types of tumors. LIF/LIFR signaling regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, invasion. However, due to the activation of different signaling pathways, opposite regulatory effects are observed in certain tumor cells. Therefore, the role of LIFR in human cancers varies across different tumor and tissue, despite their recognized value in tumor treatment and prognosis observation is affirmed. Given its aberrant expression in numerous tumor cells and crucial regulatory function in tumorigenesis and progression, LIFR is considered as a promising targeted therapeutic agent. This review provides an overview of LIFR's initiating signaling pathway function as a cytokine receptor and summarize the current literature on the role of LIFR in cancer and its possible use in therapy.

Fluoride impairs vascular smooth muscle A7R5 cell lines via disrupting amino acids metabolism.

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.

PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation.

BACKGROUND: Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing. METHODS: The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1's role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation. RESULTS: Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling. CONCLUSIONS: Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.

Acute Effects of Local High-Frequency Percussive Massage on Deep Fascial and Muscular Stiffness and Joint Range of Motion in Young Adult Men.

BACKGROUND: Local high-frequency percussive (HFP) massage has recently found widespread application in physical therapy. Although HFP massage reportedly improves range of motion (ROM), the mechanism underlying its action has not yet been proven. This study aimed to clarify whether a 5-minute percussive massage regimen affects muscular or connective tissues, such as the deep fascia and deep intermuscular fascia and the change in joint ROM. METHOD: The study sample was calculated using G*Power analysis program, and this study enrolled 15 healthy men who underwent 5-minute HFP massage to the medial gastrocnemius muscle. Shear-wave elastography was used to measure tissue stiffness in the deep fascia, muscle, and deep intermuscular fascia through shear-wave velocity as well as the ROM of the volunteers' ankle joint dorsiflexion before and after the HFP massage. A value of P < .05 was used to declare statistical significance, and post hoc was used to calculate the effect size using G*Power. RESULTS: Shear-wave velocity revealed a significant change in the deep fascia (P = .003; shear-wave velocity: -0.7 m/s) and significant increase in ROM of ankle dorsiflexion (P = .002; increase in ROM: 3.0°) after 5 minutes of HFP massage. However, the muscle and deep intermuscular fascia did not exhibit any significant changes. CONCLUSIONS: HFP massage for 5 minutes modified the stiffness of the deep fascia and concurrently improved the ankle joint-dorsiflexion ROM. This method can be used as an intervention to decrease stiffness of the deep fascia and increase the ROM efficiently.

Change in the sub-sesamoid soft tissue thickness under different loading conditions.

[Purpose] To measure the sub-sesamoid soft tissue thickness change from non-loading to self-weight loading conditions. [Participants and Methods] The study included 17 female participants for the study. A questionnaire was used to collect the demographic data and participant anamnesis, such as the presence of foot injuries and diabetes. The measured height and weight were used to calculate the body mass index. Participants were required to stand on an evaluation device from non-loading to 100% loading conditions to measure the sub-sesamoid soft tissue thickness. [Results] Significant differences were observed between the tibial and fibular sub-sesamoid soft tissue thicknesses under non-loading and all loading conditions. Significant soft tissue thinning was observed with a change from non-loading to 25% loading condition. However, no significant differences in the rate of change were observed between the tibial and fibular sub-sesamoid soft tissue thicknesses at 100% loading. [Conclusion] The sub-fibular sesamoid soft tissue was thicker than the sub-tibial sesamoid soft tissue in all loading conditions. The sub-sesamoid soft tissue thickness change was larger during initial loading stage than during the late loading stage, which may be normal in healthy females in their 20s.

Pi-inducedin-situaggregation of sevelamer nanoparticles for vascular embolization.

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.

Thermal Error Prediction and Compensation of Digital Twin Laser Cutting Based on T-XGBoost.

Laser cutting belongs to non-contact processing, which is different from traditional turning and milling. In order to improve the machining accuracy of laser cutting, a thermal error prediction and dynamic compensation strategy for laser cutting is proposed. Based on the time-varying characteristics of the digital twin technology, a hybrid model combining the thermal elastic-plastic finite element (TEP-FEM) and T-XGBoost algorithms is established. The temperature field and thermal deformation under 12 common working conditions are simulated and analyzed with TEP-FEM. Real-time machining data obtained from TEP-FEM simulation is used in intelligent algorithms. Based on the XGBoost algorithm and the simulation data set as the training data set, a time-series-based segmentation algorithm (T-XGBoost) is proposed. This algorithm can reduce the maximum deformation at the slit by more than 45%. At the same time, by reducing the average volume strain under most working conditions, the lifting rate can reach 63% at the highest, and the machining result is obviously better than XGBoost. The strategy resolves the uncontrollable thermal deformation during cutting and provides theoretical solutions to the implementation of the intelligent operation strategies such as predictive machining and quality monitoring.

A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis.

Although clinically associated with the progression of multiple cancers, the biological function of p21-activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5-aspartyl aminopeptidase (DNPEP)-ubiquitin-specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5-elicited signaling in breast cancer progression.

A novel PAK4-CEBPB-CLDN4 axis involving in breast cancer cell migration and invasion.

Claudin-4 (CLDN4), a crucial member of tight junction proteins, is aberrantly expressed in breast cancer cells and contributes to cell migration and invasion. However, the mechanisms controlling CLDN4 expression in breast cancer are poorly understood. Here, we reported that CLDN4 expression correlated positively with p21-activated kinase 4 (PAK4) expression in human breast cancer tissues. Knockdown of PAK4 in MDA-MB-231 and ZR-75-30 cells suppressed CLDN4 expression and significantly inhibited cell migration and invasion. Conversely, restoration of CLDN4 expression in PAK4-knockdown cells reversed the inhibition of migration and invasion. We identified CCAAT/enhancer-binding protein ß (CEBPB) as a novel transcriptional regulator of CLDN4 and confirmed that CEBPB bound to the -1093 to -991 bp region of the CLDN4 promoter. Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr-235. In summary, we showed that PAK4-mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion. Our results might contribute to understanding the mechanisms of CLDN4 regulation and suggest PAK4-CEBPB-CLDN4 axis as a potential therapeutic target for breast cancer.

Analysis of disease organ as a novel phenotype towards disease genetics understanding.

Discerning the modular nature of human diseases through computational approaches calls for diverse data. The finding sites of diseases, like other disease phenotypes, possess rich information in understanding disease genetics. Yet, analysis of the rich knowledge of disease finding sites has not been comprehensively investigated. In this study, we built a large-scale disease organ network (DON) based on 76,561 disease-organ associations (for 37,615 diseases and 3492 organs) extracted from the United Medical Language System (UMLS) Metathesaurus. We investigated how phenotypic organ similarity among diseases in DON reflects disease gene sharing. We constructed a disease genetic network (DGN) using curated disease-gene associations and demonstrated that disease pairs with higher organ similarities not only are more likely to share genes, but also tend to share more genes. Based on community detection algorithm, we showed that phenotypic disease clusters on DON significantly correlated with genetic disease clusters on DGN. We compared DON with a state-of-art disease phenotype network, disease manifestation network (DMN), that we have recently constructed, and demonstrated that DON contains complementary knowledge for disease genetics understanding.