Systematic simulation of tumor cell invasion and migration in response to time-varying rotating magnetic field.

Cancer invasion and migration play a pivotal role in tumor malignancy, which is a major cause of most cancer deaths. Rotating magnetic field (RMF), one of the typical dynamic magnetic fields, can exert substantial mechanical influence on cells. However, studying the effects of RMF on cell is challenging due to its complex parameters, such as variation of magnetic field intensity and direction. Here, we developed a systematic simulation method to explore the influence of RMF on tumor invasion and migration, including a finite element method (FEM) model and a cell-based hybrid numerical model. Coupling with the data of magnetic field from FEM, the cell-based hybrid numerical model was established to simulate the tumor cell invasion and migration. This model employed partial differential equations (PDEs) and finite difference method to depict cellular activities and solve these equations in a discrete system. PDEs were used to depict cell activities, and finite difference method was used to solve the equations in discrete system. As a result, this study provides valuable insights into the potential applications of RMF in tumor treatment, and a series of in vitro experiments were performed to verify the simulation results, demonstrating the model's reliability and its capacity to predict experimental outcomes and identify pertinent factors. Furthermore, these findings shed new light on the mechanical and chemical interplay between cells and the ECM, offering new insights and providing a novel foundation for both experimental and theoretical advancements in tumor treatment by using RMF.

Gradient Rotating Magnetic Fields Impairing F-Actin-Related Gene CCDC150 to Inhibit Triple-Negative Breast Cancer Metastasis by Inactivating TGF-ß1/SMAD3 Signaling Pathway.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal malignancy in women, with a lack of effective targeted drugs and treatment techniques. Gradient rotating magnetic field (RMF) is a new technology used in oncology physiotherapy, showing promising clinical applications due to its satisfactory biosafety and the abundant mechanical force stimuli it provides. However, its antitumor effects and underlying molecular mechanisms are not yet clear. We designed two sets of gradient RMF devices for cell culture and animal handling. Gradient RMF exposure had a notable impact on the F-actin arrangement of MDA-MB-231, BT-549, and MDA-MB-468 cells, inhibiting cell migration and invasion. A potential cytoskeleton F-actin-associated gene, CCDC150, was found to be enriched in clinical TNBC tumors and cells. CCDC150 negatively correlated with the overall survival rate of TNBC patients. CCDC150 promoted TNBC migration and invasion via activation of the transforming growth factor ß1 (TGF-ß1)/SMAD3 signaling pathway in vitro and in vivo. CCDC150 was also identified as a magnetic field response gene, and it was marked down-regulated after gradient RMF exposure. CCDC150 silencing and gradient RMF exposure both suppressed TNBC tumor growth and liver metastasis. Therefore, gradient RMF exposure may be an effective TNBC treatment, and CCDC150 may emerge as a potential target for TNBC therapy.

Correction: MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer.

Correction for 'MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer' by Jie Liu et al., Biomater. Sci., 2022, 10, 4596-4611, https://doi.org/10.1039/D2BM00543C.

Recent progress of mechanosensitive mechanism on breast cancer.

The mechanical environment is important for tumorigenesis and progression. Tumor cells can sense mechanical signals by mechanosensitive receptors, and these mechanical signals can be converted to biochemical signals to regulate cell behaviors, such as cell differentiation, proliferation, migration, apoptosis, and drug resistance. Here, we summarized the effects of the mechanical microenvironment on breast cancer cell activity, and mechanotransduction mechanism from cellular microenvironment to cell membrane, and finally to the nucleus, and also relative mechanosensitive proteins, ion channels, and signaling pathways were elaborated, therefore the mechanical signal could be transduced to biochemical or molecular signal. Meanwhile, the mechanical models commonly used for biomechanics study in vitro and some quantitative descriptions were listed. It provided an essential theoretical basis for the occurrence and development of mechanosensitive breast cancer, and also some potential drug targets were proposed to treat such disease.

Recent progress on the effect of extracellular matrix on occurrence and progression of breast cancer.

Breast cancer (BC) metastasis is an enormous challenge targeting BC therapy. The extracellular matrix (ECM), the principal component of the BC metastasis niche, is the pivotal driver of breast tumor development, whose biochemical and biophysical characteristics have attracted widespread attention. Here, we review the biological effects of ECM constituents and the influence of ECM stiffness on BC metastasis and drug resistance. We provide an overview of the relative signal transduction mechanisms, existing metastasis models, and targeted drug strategies centered around ECM stiffness. It will shed light on exploring more underlying targets and developing specific drugs aimed at ECM utilizing biomimetic platforms, which are promising for breast cancer treatment.

CL4-modified exosomes deliver lncRNA DARS-AS1 siRNA to suppress triple-negative breast cancer progression and attenuate doxorubicin resistance by inhibiting autophagy.

Triple-negative breast cancer (TNBC) is a fatal disease. Drug resistance and the lack of effective drugs are the leading causes of death in patients with TNBC. Recently, long non-coding RNAs have been proven to be effective drug design targets owing to their high tissue specificity; however, an effective drug delivery system is necessary for their clinical application. In this study, we constructed a novel nanodrug delivery system based on the epidermal growth factor receptor (EGFR)-targeted aptamer CL4-modified exosomes (EXOs-CL4) for the targeted delivery of aspartyl-tRNA synthetase-antisense RNA 1 (DARS-AS1) small interfering RNA (siRNA) and doxorubicin (DOX) to TNBC cells in vitro and in vivo. This delivery system exerted potent anti-proliferation, anti-migration, and pro-apoptotic effects on TNBC cells. Silencing DARS-AS1 increased the sensitivity of TNBC cells to DOX by suppressing the transforming growth factor-ß (TGF-ß)/Smad3 signaling pathway-induced autophagy, thereby enhancing the synergetic antitumor effects. Collectively, our findings revealed that EXOs-CL4-mediated delivery of DARS-AS1 siRNA can be used as a new treatment strategy for DOX-resistant TNBC. Moreover, EXOs-CL4 can be used as effective drug delivery systems for targeted TNBC therapy.

The effect of magnetic fields on tumor occurrence and progression: Recent advances.

Malignancies are the leading human health threat worldwide. Despite rapidly developing treatments, poor prognosis and outcome are still common. Magnetic fields have shown good anti-tumoral effects both in vitro and in vivo, and represent a potential non-invasive treatment; however, the specific underlying molecular mechanisms remain unclear. We here review recent studies on magnetic fields and their effect on tumors at three different levels: organismal, cellular, and molecular. At the organismal level, magnetic fields suppress tumor angiogenesis, microcirculation, and enhance the immune response. At the cellular level, magnetic fields affect tumor cell growth and biological functions by affecting cell morphology, cell membrane structure, cell cycle, and mitochondrial function. At the molecular level, magnetic fields suppress tumors by interfering with DNA synthesis, reactive oxygen species level, second messenger molecule delivery, and orientation of epidermal growth factor receptors. At present, scientific experimental evidence is still lacking; therefore, systematic studies on the biological mechanisms involved are urgently needed for the future application of magnetic fields to tumor treatment.

MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer.

RNA interference is a promising way to treat cancer and the construction of a stable drug delivery system is critically important for its application. Gelatin nanospheres (GNs) comprise a biodegradable drug vehicle with excellent biocompatibility, but there are limited studies on its delivery and role in the stabilization of miRNA and siRNA. Breast cancer is the most diagnosed type of female cancer worldwide. Abnormal miRNA expression is closely related to the occurrence and progression of estrogen receptor-positive (ER+) breast cancer. In this study, miR-4458 was upregulated in ER+ breast cancer and could inhibit MCF-7 cell viability, colony formation, migration, and invasion. Collagen type XI alpha 1 (COL11A1) was identified as a directly interacting protein of miR-4458 and an important component of the extracellular matrix. High COL11A1 expression was positively correlated with poor prognosis, lower overall survival, disease-free survival, and a late tumor-node-metastasis stage. COL11A1 knockdown could inhibit MCF-7 cell migration and invasion. GNs were used to load a miR-4458 mimic or COL11A1 siRNA (si-COL11A1) to achieve sustained and controlled release in xenograft nude mice. Their tumor volume was decreased, tumor cell apoptosis was promoted, and hepatic metastasis was significantly inhibited. Moreover, the DDR2/SRC signaling pathway was inactivated after transfection with the miR-4458 mimic and si-COL11A1. In conclusion, GNs can be potentially used to deliver siRNA or miRNA, and miR-4458 and COL11A1 can be possible targets for ER+ breast cancer treatment.

Exosomes deliver lncRNA DARS-AS1 siRNA to inhibit chronic unpredictable mild stress-induced TNBC metastasis.

Triple-negative breast cancer (TNBC) is a rapidly recurring and highly metastatic malignancy with high heterogeneity and chemoradiotherapy resistance. Chronic unpredictable mild stress (CUMS) can induce the occurrence of tumors and enhance lymphatic infiltration and distant metastasis through direct interaction with the sympathetic nervous system; however, its relevance in TNBC is yet to be clarified. In this study, DARS-AS1, a newly reported CUMS-responsive lncRNA, was found to be enriched in TNBC clinical tumors and cells and positively correlated with late clinical stage in patients with TNBC. DARS-AS1 overexpression significantly enhanced the migration and invasion of TNBC tumors by inhibiting miR-129-2-3p and upregulated CDK1 to activate the NF-κB/STAT3 signaling pathway both in vitro and in vivo. Treatment with DARS-AS1 siRNA-loaded exosomes (EXOs) substantially slowed CUMS-induced TNBC cell growth and liver metastasis. Therefore, DARS-AS1 represents a potential therapeutic target for metastatic TNBC, and EXOs may serve as siRNA delivery carriers in clinical therapy.

Dual-wavelength surface plasmon resonance holographic microscopy for simultaneous measurements of cell-substrate distance and cytoplasm refractive index.

Studying the basic characteristics of living cells is of great significance in biological research. Bio-physical parameters, including cell-substrate distance and cytoplasm refractive index (RI), can be used to reveal cellular properties. In this Letter, we propose a dual-wavelength surface plasmon resonance holographic microscopy (SPRHM) to simultaneously measure the cell-substrate distance and cytoplasm RI of live cells in a wide-field and non-intrusive manner. Phase-contrast surface plasmon resonance (SPR) images of individual cells at wavelengths of 632.8 nm and 690 nm are obtained using an optical system. The two-dimensional distributions of cell-substrate distance and cytoplasm RI are then demodulated from the phase-contrast SPR images of the cells. MDA-MB-231 cells and IDG-SW3 cells are experimentally measured to verify the feasibility of this approach. Our method provides a useful tool in biological fields for dual-parameter detection and characterization of live cells.

Effect of Comprehensive Rehabilitation Training Program in Orthopedic Nursing of Patients with Residual Limb Injury Caused by Crush.

This study was developed to explore the role and application value of a comprehensive rehabilitation training (CRT) program based on the remote monitoring system of limb rehabilitation training (LRT-RM system) in the rehabilitation nursing of patients with residual limb injuries caused by crush. The LRT-RM system was constructed based on the characteristics of limb movement and using the time-domain analysis method and support vector machine (SVM). The 84 crush injury patients were selected as the research objects and divided into a control group (Con group, received conventional rehabilitation therapy) and a CRT group (received conventional rehabilitation therapy + functional training) according to different therapies, with 42 people in each group. The incidence of compound injuries and the incidence of residual limb injuries were counted and compared for patients in two groups. The differences in renal function, blood electrolytes, and biochemical indicators before and after treatment were analyzed. The MOS 36-item short-form health survey (SF-36) scale was selected to evaluate the improvement of physical and mental health of the patients before treatment and 1 month (time point (TP1)), 3 months (TP2), 6 months (TP3), and 12 months (TP4) after the treatment. It was found that, after the intervention, the values of serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), K+, P3+, and white blood cells (WBC) of patients in CRT group were obviously lower than those of Con group (P < 0.05), and the values of carbon dioxide combining power (CO2CP), Ca2+, hemoglobin (Hb), red blood cell (RBC), total protein (TP), and albumin (ALB) were obviously higher than the values in Con group (P < 0.05). In the CRT group, the residual limb injury rate was lower in elbow, wrist, shoulder joint, ankle joint, and toe (P < 0.05) and extremely lower in knee joint in contrast to that in the Con group (P < 0.001). The score of SF-36 was dramatically higher than that in the Con group (P < 0.05). It suggested that the CRT program based on the LRT-RM system was helpful for the rehabilitation of patients with crush injuries, and it can reduce the incidence of residual limb injuries in patients. Results of this study could provide a reference basis for the treatment of residual limb injuries caused by crush.

Unsupervised Data Mining and Effect of Fast Rehabilitation Nursing Intervention in Fracture Surgery.

At present, the most commonly used surgical treatment for fractures caused by external force injury is clinical, and unsupervised data mining is more advantageous in the face of the unknown format of perioperative network data. Therefore, this research aims to explore the application effect of unsupervised data mining in the concept of rapid rehabilitation nursing intervention after fracture surgery. 80 patients who underwent fracture surgery in the Department of Orthopedics of XXX Hospital were determined as the subjects, who were rolled into a research group (group R, 40 cases) and a control group (group C, 40 cases) by drawing lots. An unsupervised data mining algorithm based on unsupervised data mining for support vector machines (VDMSVMs) was proposed and applied to two groups of patients undergoing perioperative fracture surgery with the rapid rehabilitation nursing intervention and basic routine nursing. The results showed that the number of important features selected by the VDMSVM algorithm (5) was obviously more than that of the compressed edge fragment sampling (CEFS) algorithm (1) and the multicorrelation forward searching (MCFS) algorithm (2) (P < 0.05). The number of noise features screened by the VDMSVM algorithm (3) was much less in contrast to that of the CEFS algorithm and the MCFS algorithm, which was 8 and 10, respectively (P < 0.05). The Visual Analogue Scale (VAS) scores of the fracture site at the 4th, 8th, 12th, and 16th hour after surgery in group R were all lower than the scores in group C (P < 0.05). The length of hospital stay (LoHS) in group R was greatly shorter than that in group C (P < 0.05). After different nursing methods, the World Health Organization Quality of Life (WHOQOL-BREF) score of patients in group R (89.64 points) was greatly higher than the score in group C (61.45 points) (P < 0.05). The nursing satisfaction score of group R was 92.35 ± 3.65 points, and that in group C was 2.14 ± 1.25 points, respectively (P < 0.05). The test results verified the effectiveness of the feature selection of the VDMSVM algorithm. The rapid rehabilitation nursing intervention was conductive to reducing the postoperative pain of fracture patients, shortening the LoHS of patients, improving the quality of life (QOL) of fracture surgery patients, and increasing the patient's satisfaction with nursing.

Static Magnetic Field (0.2-0.4 T) Stimulates the Self-Renewal Ability of Osteosarcoma Stem Cells Through Autophagic Degradation of Ferritin.

Static magnetic field (SMF) can alter cell fate decisions in many ways. However, the effects of SMF on cancer stem cells (CSCs) are little-known. In this particular study, we evaluate the biological effect of moderate-intensity SMF on osteosarcoma stem cells (OSCs) and try to clarify the underlying mechanisms of action. First, we demonstrated that prolonged exposure to SMF induced the proliferation and tumorsphere formation in K7M2 and MG63 OSCs. Moreover, SMF promoted the release of ferrous iron (Fe2+ ) and provoked reactive oxygen species (ROS) in OSCs. Interestingly, SMF evidently triggered the autophagic degradation of ferritin, which is characterized by the activation of microtubule-associated protein 1 light chain 3 (LC3) and nuclear receptor co-activator 4 (NCOA4), and downregulation of ferritin heavy chain 1 (FTH1) in OSCs. Particularly, the colony-forming ability of K7M2 OSCs promoted by SMF was obviously abolished by using a small interfering RNA (siRNA) against NCOA4. Finally, treatment of the tumor-bearing mice with SMF did not affect the tumor volume or tumor mass, nor pulmonary metastasis of K7M2 OSCs, but the SMF-treated K7M2 OSCs caused a preference of pulmonary metastasis in a mouse model, which suggested that SMF might induce the metastatic characteristic of OSCs. Consequently, this paper demonstrates for the first time that the cumulative SMF exposure promoted the self-renewal ability of OSCs via autophagic degradation of ferritin, implying that ferritinophagy may be a potential molecular target for cancer. © 2021 Bioelectromagnetics Society.

Iron overload induces apoptosis of osteoblast cells via eliciting ER stress-mediated mitochondrial dysfunction and p-eIF2α/ATF4/CHOP pathway in vitro.

Iron is an essential element for crucial biological function; whereas excess iron sedimentation impairs the main functions of tissues or organs. Cumulative researches have shown that the disturbances in iron metabolism, especially iron overload is closely concatenating with bone loss. Nevertheless, the specific process of iron overload-induced apoptosis in osteoblasts has not been thoroughly studied. In this study, our purpose is to elucidate the mechanism of osteoblast apoptosis induced by iron overload via the MC3T3-E1 cell line. Ferric ammonium citrate (FAC) was utilized to simulate iron overload conditions in vitro. These results showed that treatment with FAC dose-dependently induced the apoptosis of MC3T3-E1 cells at 48 h, dysfunction of iron metabolism, and increased intracellular reactive oxygen species (ROS) levels. Following, FAC does-dependently caused the calcium dyshomeostasis, decreased the calcium concentration in endoplasmic reticulum (ER), but increased the crosstalk between ER and mitochondria, and calcium concentration in the mitochondria. Moreover, FAC dose-dependently decreased mitochondrial membrane potential (MMP) and enhanced the expression of apoptosis related proteins (Bax, Cyto-C and C-caspase3). We furthermore revealed that FAC treatment activated the ER-mediated cell apoptosis via p-eIF2α/ATF4/CHOP pathway in MC3T3-E1 osteoblasts cells. In addition, pretreatment with the N-acetylcysteine (NAC) or Tauroursodeoxycholate Sodium (TUDC) attenuated cell apoptosis, ROS levels, mitochondria fragmentation and ER stress-related protein expression, and recovered the protein expression related to iron metabolism. In conclusion, our finding suggested that iron overload induced apoptosis via eliciting ER stress, which resulted in mitochondrial dysfunction and activated p-eIF2α/ATF4/CHOP pathway.

Real-time and wide-field mapping of cell-substrate adhesion gap and its evolution via surface plasmon resonance holographic microscopy.

As one of the most common biological phenomena, cell adhesion plays a vital role in the cellular activities such as the growth and apoptosis, attracting tremendous research interests over the past decades. Taking the cell evolution under drug injection as an example, the dynamics of cell-substrate adhesion gap can provide valuable information in the fundamental research of cell contacts. A robust technique of monitoring the cell adhesion gap and its evolution in real time is highly desired. Herein, we develop a surface plasmon resonance holographic microscopy to achieve the novel functionality of real-time and wide-field mapping of the cell-substrate adhesion gap and its evolution in situ. The cell adhesion gap images of mouse osteoblast cells and human breast cancer cells have been effectively extracted in a dynamic and label-free manner. The proposed technique opens up a new avenue of revealing the cell-substrate interaction mechanism and renders the wide applications in the biosensing area.

Anticancer mechanisms of metformin: A review of the current evidence.

Metformin, a US Food and Drug Administration-approved "star" drug used for diabetes mellitus type 2, has become a topic of increasing interest to researchers due to its anti-neoplastic effects. Growing evidence has demonstrated that metformin may be a promising chemotherapeutic agent, and several clinical trials of metformin use in cancer treatment are ongoing. However, the anti-neoplastic effects of metformin and its underlying mechanisms have not been fully elucidated. In this review, we present the newest findings on the anticancer activities of metformin, and highlight its diverse anticancer mechanisms. Several clinical trials, as well as the limitations of the current evidence are also demonstrated. This review explores the crucial roles of metformin and provides supporting evidence for the repurposing of metformin as a treatment of cancer.