Advanced machine learning unveils CD8 + T cell genetic markers enhancing prognosis and immunotherapy efficacy in breast cancer.

BACKGROUND: Breast cancer (BC) is the most common cancer in women and poses a significant health burden, especially in China. Despite advances in diagnosis and treatment, patient variability and limited early detection contribute to poor outcomes. This study examines the role of CD8 + T cells in the tumor microenvironment to identify new biomarkers that improve prognosis and guide treatment strategies. METHODS: CD8 + T-cell marker genes were identified using single-cell RNA sequencing (scRNA-seq), and a CD8 + T cell-related gene prognostic signature (CTRGPS) was developed using 10 machine-learning algorithms. The model was validated across seven independent public datasets from the GEO database. Clinical features and previously published signatures were also analyzed for comparison. The clinical applications of CTRGPS in biological function, immune microenvironment, and drug selection were explored, and the role of hub genes in BC progression was further investigated. RESULTS: We identified 71 CD8 + T cell-related genes and developed the CTRGPS, which demonstrated significant prognostic value, with higher risk scores linked to poorer overall survival (OS). The model's accuracy and robustness were confirmed through Kaplan-Meier and ROC curve analyses across multiple datasets. CTRGPS outperformed existing prognostic signatures and served as an independent prognostic factor. The role of the hub gene TTK in promoting malignant proliferation and migration of BC cells was validated. CONCLUSION: The CTRGPS enhances early diagnosis and treatment precision in BC, improving clinical outcomes. TTK, a key gene in the signature, shows promise as a therapeutic target, supporting the CTRGPS's potential clinical utility.

O2-evolving and ROS-activable nanoparticles for treatment of multi-drug resistant Cancer by combination of photodynamic therapy and chemotherapy.

Herein, a novel nano-system IF7-ROSPCNP, which is O2-evolving and reactive oxygen species (ROS)-activable, was developed for enhancing the combination chemotherapy and photodynamic therapy (PDT). The nanoparticles composed of photosensitizers (disulfonated meso-tetraphenylporphine, TPPS2a) and catalase in the inner core, doxorubicin (DOX) in the polymeric shell and functionalized on its surface with IF7 peptide, which specially bind to annexin 1. As confirmed that the structure of IF7-ROSPCNP was able to remain intact under normal physiological conditions. After IF7-ROSPCNP was selectively entrapped by the annexin 1-positive and ROS-abundant MCF-7/ADR cells, the shell of nanoparticles was ruptured and the entrapped photosensitizers were completely released out. Under irradiation, ROS was continuously produced and the DOX, which was conjugated to the terminal of polylactic copolymer (mPEG-PLA) by a ROS-cleavable linkage, was subsequently released. With such strategy, cellular uptake of drugs was dramatically improved resulted in an enhanced cytotoxicity and anti-tumor effect on drug resistant cancer.

Nanoemulsion-based transdermal delivery of third-generation steroidal and non-steroidal aromatase inhibitors in preclinical models.

Aromatase inhibitors are effective in treating hormone receptor-positive breast cancer, particularly in postmenopausal women. However, the challenges of inconsistent dissolution, variable absorption and side effects with oral administration persist. To address these issues, transdermal delivery has emerged as a viable alternative. In our study, we have developed nanoemulsion-based transdermal creams containing third-generation aromatase inhibitors Exemestane (EXE) or Letrozole (LE) and evaluated their toxicity, anti-tumour effects and androgenic potency using preclinical models including Bama minipigs, DMBA-induced breast cancer rats and orchidectomized male rats. The results of our study are significant, suggesting that both creams effectively penetrated the skin, demonstrating an impressive anti-breast cancer effect. Importantly, EXE cream had no organ toxicity at the tested dose, providing a reassuring safety profile for its use. In contrast, LE cream displayed reversible toxicity from drug molecule itself in animals at the given dose, dissipating after 3 weeks of withdrawal and recovery. This study establishes a solid foundation for the safe clinical use of third-generation aromatase inhibitors. It highlights transdermal creams as a promising drug delivery carrier for administering them.

Influencing factors of care dependence in patients with coronary heart disease after percutaneous coronary intervention-A cross-sectional study.

AIM: Care dependence has been scarcely investigated in coronary heart disease patients after percutaneous coronary intervention. This study aimed to investigate the association between frailty, self-efficacy, combined effects of frailty and self-efficacy, mental health, and care dependence in coronary heart disease patients after percutaneous coronary intervention. DESIGN: Cross-sectional study. METHODS: Data from 400 patients after percutaneous coronary intervention were collected from 2017-2020. Logistic regression model and mediating analysis were used to identify the association between frailty, self-efficacy, combined effects of frailty and self-efficacy, and care dependence. RESULTS: Patients with frailty and self-efficacy tended to have severe care dependence symptoms. There was no correlation between frailty symptoms, self-efficacy, and care dependence in patients without symptoms of anxiety or depression. But in patients with anxiety or depression symptoms, there is a strong correlation between frailty symptoms, lower self-efficacy, and care dependence. Mental health played an inhibitory effect on frailty and care dependence.

Rational Design of Conductive Pathways in Flexible Tactile Sensors via Indirect 3D-Printing of Liquid Metal for High-Precision Monitoring and Recognition.

Highly sensitive and conformal sensors are essential for the implementation of human-machine interfaces, health monitoring, and rehabilitation prostheses. The proper adjustment of conductive pathways in the sensing materials is essential for their sensitive transduction of mechanical stimuli into electrical signals. However, the rational, precise, and wide-range control of electrical networks within traditional conductive composites is difficult due to the randomly distributed fillers. Herein, we adopt an indirect 3D-printing method to fabricate pressure sensors with various microchannels for liquid metal (LM) to form consistent and tunable conductive pathways. LM is highly conductive, fluidic, and incompressible at ambient conditions, which guarantees the reliable regulation and function of our pressure sensor. Additive manufacturing provides a facile way to construct complicated microchannels with different lengths, different orientations, cross-sectional sizes, depth-width ratios, and shapes, which can effectively modulate the sensitivity and the sensing range. Under the optimized structural configurations, our sensor achieves a high sensitivity of 1.139 kPa-1, a detection range of 0-68 kPa (loading process), and stability of over 5000 cycles, whose sensing performance is better than most microchannel-filled LM sensors. It can achieve high-accuracy monitoring of pulse, speaking and gestures, and exhibit a full recognition of objects under the assistance of machine learning. This work can provide new ideas on the design of conductive pathways in flexible electronics and expand the application of recyclable LM in human-machine interfaces.

Ultra-robust, high-adhesive, self-healing, and photothermal zwitterionic hydrogels for multi-sensory applications and solar-driven evaporation.

Zwitterionic hydrogels have received considerable attention owing to their characteristic structures and integrating multifunctionality. However, the superhydrophilicity-induced poor mechanical properties severely hinder their potential applications. Besides, from the perspective of wide applications, zwitterionic hydrogels with integrated high mechanical properties, conductivity and multifunctionalities including self-adhesive, self-healing, and photothermal properties are highly desirable yet challenging. Herein, a new class of high-performance and multifunctional zwitterionic hydrogels are designed based on the incorporation of polydopamine-coated liquid metal nanoparticles (LM@PDA). Due to the efficient energy dissipation endowed by the isotropically extensible deformation of LM@PDA and the multiple interactions within the hydrogel matrix, the resultant hydrogels exhibited ultrahigh robustness with tensile strength of up to 1.3 MPa, strain of up to 1555% and toughness of up to 7.3 MJ m-3, superior or comparable to those of most zwitterionic hydrogels. The introduced LM@PDA also endows the hydrogels with high conductivity, versatile adhesion, autonomous self-healing, excellent injectability, three-dimensional printability, degradability, and photothermal conversion performance. These preferable properties enable the hydrogels promising as wearable sensors with multiple sensory capabilities for a wide range of strain values (1-500%), pressures (0.5-200 kPa) and temperatures (20-80 °C) with an impressive temperature coefficient of resistance (up to 0.15 °C-1). Moreover, these hydrogels can be also applied as solar evaporators with a high water evaporation rate (up to 2.42 kg m-2 h-1) and solar-thermal conversion efficiency (up to 90.3%) for solar desalination and wastewater purification. The present work can pave the way for the future development of zwitterionic hydrogels and beyond.

The transdermal cream of Formestane anti-breast cancer by controlling PI3K-Akt pathway and the tumor immune microenvironment.

Background: Treatment of ER+ breast cancer with intramuscular formulation of Formestane (4-OHA) shrinks the tumor within weeks. Since the tedious way of intramuscular administration and side effects are not suited for adjuvant treatment, Formestane was withdrawn from the market. A new transdermal formulation of 4-OHA cream may overcome the defects and retain the effect of shrinking the breast cancer tumor. However, the effects of 4-OHA cream on breast cancer need further confirmatory studies. Methods: In this work, in vivo, the influence of 4-OHA cream on breast cancer was evaluated using the mode of 7,12-dimethylbenz(a)anthracene (DMBA) induced rat mammary cancer. We explored the common molecule mechanisms of action of 4-OHA cream and its injection formulation on breast cancer through RNA- sequencing-based transcriptome analysis and several biochemical experiments. Results: The results showed that the cream substantially reduced the entire quantity, size, and volum of tumors in DMBA-treated rats consistent with 4-OHA injection, and indicated that there were comprehensive signals involved in 4-OHA antitumor activity, such as ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and proteoglycans in cancer. In addition, we observed that both 4-OHA formulations could enhance immune infiltration, especially CD8+ T cells, B cells, natural killer cells, and macrophages infiltration, in the DMBA-induced mammary tumor tissues. The antitumor effects of 4-OHA partly depended on these immune cells. Conclusion: 4-OHA cream could inhibit breast cancer growth as its injection formulation and may provide a new way for neoadjuvant treatment of ER+ breast cancer.

Dermal repeated dose toxicity study of the anti-breast cancer drug Formestane cream in Bama minipig.

Formestane (4-OHA) has been proven to be highly effective with high systemic tolerability in treating ER+ breast cancer. However, its intramuscular administration and associated side effects make it unsuitable for adjuvant treatment, leading to its withdrawal from the market. In contrast, Formestane cream may offer a solution by providing a more convenient route of administration and retaining its tumor-shrinking effects. This suggests that 4-OHA cream could have promising clinical applications. However, before clinical application, it is necessary to evaluate the potential toxicity of the cream in animals. This study evaluated the toxicity of 4-OHA cream on female Bama minipigs in vivo by analyzing hematology, biochemistry, and histopathology. The results showed that there was no significant difference between the cream-treated group and the control normal group for each parameter analyzed, indicating that 4-OHA cream was non-dermal toxic to minipigs. This finding provides a basis for the safe clinical use of the cream.

Self-Powered Multifunctional Electronic Skin Based on Carbon Nanotubes/Poly(dimethylsiloxane) for Health Monitoring.

Flexible and multifunctional electronic skin (e-skin) has received remarkable attention for its potential applications in health monitoring, human-machine interface, and artificial sensory nerves. However, conventional multifunctional e-skins require complex material systems, sophisticated fabrication, and external power supplies, leading to increased preparation cost and duration, thus hindering their large-scale utilization. Herein, a self-powered multifunctional e-skin system with properties of pressure, temperature, underwater sensing, and photothermal heating is designed based on carbon nanotubes/poly(dimethylsiloxane) (CNT/PDMS) acting as both the multifunctional sensing layer and the cathode of the power supply. Our micropyramidal structured e-skin exhibits outstanding pressure sensitivity (1.51 × 103 kPa-1) over a wide sensing range (2.5-255.7 kPa) and maintains ultralong-term durability (>20 000 cycles). It can also provide personalized photothermal therapy at an adjustable temperature (40-110 °C) and heating area under near-infrared irradiation due to the photothermal effect of CNTs, with the temperature being detected synchronously by current signals. Additionally, the hydrophobicity of the CNT/PDMS film endows our device with underwater sensing capability. Furthermore, practical healthcare applications have been demonstrated with reliable signal quality and stability, such as daily activities and underwater movements/temperature monitoring, SOS Morse code communication, and human-machine interface. This work could provide insight on developing simple, stable, and wearable healthcare devices with self-power supply and multifunction.

Role of human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C3) in the extrahepatic metabolism of the steroidal aromatase inactivator Formestane.

The clinical use of the steroidal aromatase inhibitor Formestane (4-hydroxandrostenedione, 4-OHA) in the treatment of advanced ER+ breast cancer has been discontinued, and therefore, interest in this remarkable drug has vanished. As a C-19 sterol, 4-OHA can undergo extensive intracellular metabolism depending on the expression of specific enzymes in the corresponding cells. We used the metabolites 4ß-hydroxyandrosterone, 4ß-hydroxyepiandrosterone and its 17ß-reduced derivative as standards for the proof of catalytic activity present in the cell culture medium and expressed by the isolated enzymes. All of the aldo-keto reductases AKR1C1, AKR1C2, AKR1C3 and AKR1C4 catalysed the reduction of the 3-keto-group and the Δ4,5 double bond of 4-OHA at the same time. Molecular docking experiments using microscale thermophoresis and the examination of the kinetic behaviour of the isolated enzymes with the substrate 4-OHA proved that AKR1C3 had the highest affinity for the substrate, whereas AKR1C1 was the most efficient enzyme. Both enzymes (AKR1C1and AKR1C3) are highly expressed in adipose tissue and lungs, exhibiting 3ß-HSD activity. The possibility that 4-OHA generates biologically active derivatives such as the androgen 4-hydroxytestosterone or some 17ß-hydroxy derivatives of the 5α-reduced metabolites may reawaken interest in Formestane, provided that a suitable method of administration can be developed, avoiding oral or intramuscular depot-injection administration.