Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer.

The deficiency in available targeted agents and frequency of chemoresistance are primary challenges in clinical management of triple-negative breast cancer (TNBC). The aberrant expression of USP21 and JAK2 represents a characterized mechanism of TNBC progression and resistance to paclitaxel (PTX). Despite its clear that high expression of USP21-mediated de-ubiquitination leads to increased levels of JAK2 protein, we lack regulator molecules to dissect the mechanisms that the interaction between USP21 and JAK2 contributes to the phenotype and resistance of TNBC. Here, we report a USP21/JAK2/STAT3 axis-targeting regulator 13c featuring a N-anthraniloyl tryptamine scaffold that showed excellent anti-TNBC potency and promising safety profile. Importantly, the therapeutic potential of using 13c in combination with PTX in PTX-resistant TNBC was demonstrated. This study showcases N-anthraniloyl tryptamine derivatives as a novel anti-TNBC chemotype with a pharmacological mode of action targeting the USP21/JAK2/STAT3 axis and provides a potential therapeutic target for the treatment of TNBC.

Durable anti-fog micro-nano structures fabricated by laser ablation of aluminum film on resin/glass.

This study presents a technique for processing transparent glass and resin substrates using a low-cost laser marker to create a micro-nano-structured surface with exceptional anti-fog properties. The approach involved depositing an aluminum (Al) film on the transparent substrates as an absorbing layer, followed by rapid laser marker ablation. This ablation process effectively removed the majority of the Al film, resulting in the formation of hierarchical hillock-hollow micro-structures and the dispersion of Al-based nano-particles throughout the surface. The resulting structure on resin glasses demonstrated anti-fog performance even after 629 days storage in the laboratory, which marked the longest antifog record. It exhibited impressive antifog property without visible degradation for the first 9 months, which though degraded substantially afterwards. Furthermore, the micro-nano structure played a key role in reducing the contact angle of the surface. The contact angle experienced a significant reduction from a value of 64° for the control resin to 6.9° for the treated resin, while it was reduced from 44° for the control glass to 0° for the treated glass, indicating superhydrophilicity. This 0° superhydrophilic state persisted for a period of 25 days.

Adipocyte-derived exosomes promote the progression of triple-negative breast cancer through circCRIM1-dependent OGA activation.

Triple-negative breast cancer (TNBC) has an escalating morbidity and a dismal prognosis. Obesity has been reported to be strongly linked to adverse TNBC outcomes. Exosomes (Exos) transport RNA and proteins between cells and serve as intermediaries for cell-to-cell communication. Accumulated evidence suggests that adipose-secreted circular RNAs (circRNAs) can modulate protein glycosylation in TNBC to facilitate tumor cell outgrowth. Herein, exo-circCRIM1 expression was found to be elevated in TNBC patients with a high body fat percentage. Functional experiments demonstrated that by inhibiting miR-503-5p, exo-circCRIM1 enhanced TNBC evolution and metastasis while activating glycosylation hydrolase OGA. Furthermore, OGA negatively regulates FBP1 by decreasing its protein stability. Moreover, the levels of OGA and FBP1 were positively related to the infiltration level of some immune cells in TNBC. These findings indicate that exo-cirCRIM1 secreted by adipocytes contributes to TNBC progression by inhibiting miR-503-5p and activating the OGA/FBP1 signaling pathway. The findings reveal a novel intercellular signaling pathway mediated by adipose-derived exosomes and suggest that treatment targeting the secreted exosome-circCRIM1 may reverse TNBC progression.

Effect of Sonication and Ceria Doping on Nanoparticles Fabricated by Laser Marker Ablation of Ti in Water.

By employing the laser marker fast ablation technique in water, combined with the innovative inclusion of sonication, we successfully developed Ti-based nanoparticles with improved characteristics. sonication increased the nanoparticle concentration in the colloid, reduced nanoparticle size, and also narrowed size distribution. Our findings also provide valuable insights into the influence of laser parameters, such as wavelength and fluence, on nanoparticle properties. UV laser led to small nanoparticles compared with 1064 nm laser. Additionally, high laser fluence appeared to increase the ablated particle size until a plateau fluence at 28.5 J/cm2; at 38 J/cm2, the particle size decreased. Notably, all synthesized particles exhibited a regular spherical shape, as confirmed by energy dispersive X-ray spectroscopy (EDS) mapping, which also indicated that the majority of Ti-based particles were in an oxidized state. Additionally, the presence of rutile TiO2 in the particles was further confirmed by X-ray diffraction (XRD) analysis. Ceria doping Titania nanoparticles was also attempted.

Inducing ferroptosis has the potential to overcome therapy resistance in breast cancer.

Breast cancer is the most common type of malignancy among women. Due to the iron-dependent character of breast cancer cells, they are more sensitive to ferroptosis compared to normal cells. It is possible to reverse tumor resistance by inducing ferroptosis in breast cancer cells, thereby improving tumor treatment outcomes. Ferroptosis is highly dependent on the balance of oxidative and antioxidant status. When ferroptosis occurs, intracellular iron levels are significantly increased, leading to increased membrane lipid peroxidation and ultimately triggering ferroptosis. Ferroptotic death is a form of autophagy-associated cell death. Synergistic use of nanoparticle-loaded ferroptosis-inducer with radiotherapy and chemotherapy achieves more significant tumor suppression and inhibits the growth of breast cancer by targeting cancer tissues, enhancing the sensitivity of cells to drugs, reducing the drug resistance of cancer cells and the toxicity of drugs. In this review, we present the current status of breast cancer and the mechanisms of ferroptosis. It is hopeful for us to realize effective treatment of breast cancer through targeted ferroptosis.

Database Mining Detected a Cuproptosis-Related Prognostic Signature and a Related Regulatory Axis in Breast Cancer.

Background: Breast cancer is the frequent cause of disease burden related to cancer among women. It affects one in 20 women globally and up to one in eight women in high-income countries. Cuproptosis is a copper-induced modality of mitochondrial cell death that is involved in tumor proliferation and metastasis. Methods: To construct a prognostic cuproptosis-related signature, LASSO Cox regression analysis was employed. Additionally, ceRNA was developed with an aim of exploring the possible lncRNA-miRNA-mRNA regulatory axis in breast cancer. Results: The expression of FDX1, DLD, DLAT, LIAS, LIPT1, GLS MTF1, and PDHA1 was downregulated, while CDKN2A expression level was elevated in breast cancer in contrast with normal tissue. We furthermore reviewed the genetic mutation landscape of genes linked to cuproptosis in breast cancer. Prognosis analysis revealed poor OS and RFS rates in breast cancer patients with elevated levels of CDKN2A and PDHA1 and low levels of MTF1, DLD, LIPT1, and FDX1. We then constructed a cuproptosis-related signature with six genes (DKN2A, MTF1, PDHA1, DLD, LIPT1, and FDX1) for breast cancer, which predicted the OS rate with an accuracy that ranged from medium to high. Further analysis demonstrated a significant correlation between the cuproptosis-related prognostic signature and pTNM stage, MSI score, drug sensitivity, TMB score, and immune cell infiltration. Moreover, we identified the lncRNA XIST/miR-92b-3p/MTF1 regulatory axis for breast cancer. Conclusion: Multiomics approaches were used to create a cuproptosis-related signature with six genes (DKN2A, MTF1, PDHA1, DLD, LIPT1, and FDX1) for breast cancer. We discovered the lncRNA XIST/miR-92b-3p/MTF1 regulatory axis for breast cancer, which has not yet been investigated previously.

Numerical and experimental studies on needle impact characteristics in ultrasonic shot peening.

Ultrasonic shot peening(USP) is an advanced surface treatment technology for obtaining excellent surface properties or manufacturing a three-dimensional curved surface of the metal sheets. The impact of the medium driven by ultrasonic vibration is significant to parameter optimization and excellent performance of the USP technology. However, the impact characteristics of the medium lack careful study, which is a complex dynamic analysis involving many factors, such as collision, plastic deformation, air pressure, etc. In this paper, a detection system is successfully developed to investigate the needle impact force and frequency against the material surface, consisting of a piezoelectric load sensor, oscilloscope, and a single needle USP device. Moreover, the FE model of the needle impact is developed simultaneously to study the characteristics of residual stress implantation induced by needle impact. Based on the experiment and FE simulation results, it is discovered that the impacts with high speed primarily determine the thickness of the modified layer implanted with residual stress during multiple impacts at different rates. According to residual stress implantation characteristics, the low-speed impact whose speed does not reach 50% of the maximum impact speed was defined as the ineffective impact. Besides, increasing the amplitude of ultrasonic vibration results in a significant increase in the maximum impact force and the effective impact frequency. The travel distance of needle impact has a considerable effect on the effective impact frequency, but it has little effect on the maximum impact force. Finally, it was concluded that the low air pressure plays a positive role in the needle impact. Furthermore, excessive air pressure hinders the needle impact and results in a decline in the effective impact frequency and the maximum impact force.

Experimental and Analytical Investigations on Tribological Properties of PTFE/AP Composites.

The tribological properties of polytetrafluoroethylene (PTFE)/AP (poly(para-phenyleneterephthalamide) (PPTA) pulp) composites under different test conditions (load: 2N, 10N; frequency: 1 Hz, 4 Hz; amplitude: 2 mm, 8 mm) were holistically evaluated. PTFE/AP composites with different AP mass ratios of 3%, 6%, and 12% as a skeleton support material were prepared. The coefficient of friction (COF) and wear rate were determined on a ball-on-disk tribometer. Furthermore, the morphology, element composition, and chemical structure of the transfer membrane were analyzed accordingly. The relationships between load, frequency, amplitude, and tribological properties were further investigated. According to the wear mechanism, AP enables effective improvement in the stiffness and wear resistance, which is also conducive to the formation of transfer films.

The effect of a comprehensive care and rehabilitation program on enhancing pelvic floor muscle functions and preventing postpartum stress urinary incontinence.

This study was to investigate the incidence and the risk factors of postpartum stress urinary incontinence (SUI), and the effect of comprehensive care and rehabilitation program (CCRP) on preventing postpartum SUI.In stage I, 479 puerperae were recruited within 1 week postpartum, then the postpartum SUI incidence at 8th week and its risk factors were investigated. In stage II, 240 vaginal delivery puerperae were enrolled within 1 week postpartum and randomly assigned to CCRP group or control group as 1:1 ratio. The postpartum SUI incidence and pelvic floor muscle function indexes were evaluated at 8th week.In stage I, the postpartum SUI incidence was 25.7%, and SUI puerperae presented with higher body mass index (BMI), vaginal delivery rate, newborn weight, and larger newborn head diameter compared with non-SUI puerperae. Besides, the vaginal delivery, the elevated age and BMI were independent risk factors for postpartum SUI. In stage II, the postpartum SUI incidence in CCRP group was decreased compared with control group, and the vaginal resting pressure, vaginal squeezing pressure, and vaginal contraction duration were increased in CCRP group compared to control group at 8th week postpartum.The incidence of postpartum SUI is 25.7%, and the vaginal delivery, increased age, and BMI are independent risk factors for postpartum SUI. More importantly, CCRP strengthens pelvic floor muscle functions and decreases postpartum SUI incidence in puerperae.

Phosphorylated Heat Shock Protein 27 Inhibits Lipopolysaccharide-Induced Inflammation in Thp1 Cells by Promoting TLR4 Endocytosis, Ubiquitination, and Degradation.

The aims of this study were to investigate the effect of Hsp27 on LPS-induced inflammation and identify the precise mechanisms about how Hsp27 regulates LPS-induced TLR4 signaling in Thp1 cells. Thp1 cells were transfected with Flag-Hsp27 or pcDNA3.1, and then treated with LPS for indicated time. TNF-α, IL-1ß, and IL-6 were determined by ELISA. The protein levels of Hsp27, p-Hsp27 (Ser15, Ser78, and Ser82), and TLR4 were measured by Western blotting. In vitro study showed that over-expression of Hsp27 downregulated the release of TNF-α, IL-1ß, and IL-6 and suppressed the activation of TLR4 signals after stimulated by LPS. The location of TLR4 and RAB5 was detected by confocal microscopy. Immunoprecipitation was used to determine the ubiquitination and degradation of TLR4 and interaction between Hsp27 and TLR4. Results showed that Hsp27 could promote TLR4 endocytosis and ubiquitination and degradation. Further research revealed that Hsp27 was phosphorylated after LPS, only phosphorylated Hsp27 can interact with TLR4 and inhibit the activation of TLR4 signaling, which was demonstrated by inhibition of Hsp27 phosphorylation with inhibitors or transfection of Hsp27 mutants into Thp1 cells. Phosphorylated Hsp27 reduced the release of TNF-α, IL-1ß, and IL-6, and suppressed the activation of TLR4 signaling by promoting TLR4 endocytosis, ubiquitination, and degradation.

Tackling Complex Emergency Response Solutions Evaluation Problems in Sustainable Development by Fuzzy Group Decision Making Approaches with Considering Decision Hesitancy and Prioritization among Assessing Criteria.

In order to be prepared against potential balance-breaking risks affecting economic development, more and more countries have recognized emergency response solutions evaluation (ERSE) as an indispensable activity in their governance of sustainable development. Traditional multiple criteria group decision making (MCGDM) approaches to ERSE have been facing simultaneous challenging characteristics of decision hesitancy and prioritization relations among assessing criteria, due to the complexity in practical ERSE problems. Therefore, aiming at the special type of ERSE problems that hold the two characteristics, we investigate effective MCGDM approaches by hiring interval-valued dual hesitant fuzzy set (IVDHFS) to comprehensively depict decision hesitancy. To exploit decision information embedded in prioritization relations among criteria, we firstly define an fuzzy entropy measure for IVDHFS so that its derivative decision models can avoid potential information distortion in models based on classic IVDHFS distance measures with subjective supplementing mechanism; further, based on defined entropy measure, we develop two fundamental prioritized operators for IVDHFS by extending Yager's prioritized operators. Furthermore, on the strength of above methods, we construct two hesitant fuzzy MCGDM approaches to tackle complex scenarios with or without known weights for decision makers, respectively. Finally, case studies have been conducted to show effectiveness and practicality of our proposed approaches.

Bergapten prevents lipopolysaccharide-induced inflammation in RAW264.7 cells through suppressing JAK/STAT activation and ROS production and increases the survival rate of mice after LPS challenge.

Bergapten (BG) is a cumarine-derivate compound in many medicinal plants. Here, in vitro and in vivo experimental results indicated that BG possesses anti-inflammatory properties, Based on this, we further investigated the precise molecular mechanisms of BG in LPS-stimulated inflammation response. Studies revealed that BG inhibited LPS-stimulated productions of TNF-α, IL-1ß, IL-6, PGE2 and NO as well as the expression of iNOS and COX-2, and at the same time, it increased LPS-induced release of IL-10 in a dose-dependent manner in RAW264.7 cells. Mechanistically, BG suppressed the activations of JAK/STAT, but not that of MAPKs and NF-κB. In addition, BG, as an antioxidant, prevented the accumulation of ROS, which further exerted its anti-inflammatory function. In vivo researches revealed that BG decreased LPS-induced mortality in mice. In conclusions, BG may be a potential candidate for inflammation therapy via inhibiting JAK/STAT activation and ROS production in RAW264.7 cells.

Long-lasting balanced immunity and protective efficacy against respiratory syncytial virus in mice induced by a recombinant protein G1F/M2.

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract illness in young children. We have engineered a recombinant candidate vaccine G1F/M2, consisting of a cytotoxic T lymphocyte (CTL) epitope of RSV-M2 protein and a domain of RSV-G protein. In this study, the long-term immunogenicity and protective effect were evaluated. In G1F/M2-immunized mice, special antibodies lasted for more than 19 weeks, and the IgG1/IgG2a ratio remained a balanced level till the end of the study, suggesting mixed Th1/Th2 type of responses. Concomitantly, G1F/M2 elicited long-lived RSV-specific CTL activity that was detectable at 12 weeks after the final immunization. Stronger CTL responses were induced with immunization once more at 13 weeks after the last immunization in G1F/M2-primed mice than those in F/M2-primed mice. These results suggest that G1F/M2-induced long-lasting balanced humoral and cellular immunity responses, and immunological memory in mice. Furthermore, following RSV challenge, long-term protective efficacy was observed. RSV replication in lungs of G1F/M2-primed mice elicited also mixed Th1/Th2 responses, a property that is considered advantageous for the safety of an RSV vaccine. Therefore, G1F/M2 is a promising RSV subunit vaccine.