Serplulimab combined with gemcitabine, nab-paclitaxel and stereotactic body radiotherapy as the first-line treatment for patients with metastatic pancreatic adenocarcinoma in China: a multicentre, single-arm, phase II trial (ICSBR) protocol.

INTRODUCTION: Patients with pancreatic ductal adenocarcinoma (PDAC) remain a poor prognosis despite the development of chemotherapy. Although programmed cell death 1 (PD-1) blockade has shown great efficacy in various solid tumours, its application in treating PDAC is limited. Recent studies have indicated that chemotherapy or stereotactic body radiotherapy (SBRT) may improve the antitumour effect of PD-1 blockade in patients with PDAC. The objective of this study is to evaluate the efficacy and safety of combined therapy comprising PD-1 blockade, gemcitabine plus nab-paclitaxel chemotherapy and SBRT for patients with metastatic PDAC. METHODS AND ANALYSIS: This is a multicentre, single-arm, prospective phase II clinical trial. Forty-three patients diagnosed with metastatic PDAC will be enrolled. The eligible patients will be intravenously administered 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel on days 1 and 8 of the 21-day cycle. Serplulimab (200 mg) will be administered intravenously on day 1 of the 21-day cycle. Furthermore, during the second cycle, the patients will undergo SBRT with doses of 33 Gy in five fractions for primary lesions or doses of 24 Gy in three fractions for metastases. The primary endpoint is the 6-month progression-free survival (PFS) rate. The secondary endpoints overall survival, PFS, overall response rate, disease control rate, time to progression, duration of response, duration of disease control and safety. Moreover, this trial seeks to investigate biomarkers such as circulating tumour DNA and circulating hybrid cells in patients diagnosed with metastatic PDAC. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University. The study results will be presented at international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300073237.

Is decreasing problematic mobile phone use a pathway for alleviating adolescent depression and sleep disorders? A randomized controlled trial testing the effectiveness of an eight-session mindfulness-based intervention.

Objective: The present study aimed to evaluate the efficacy of a mindfulness-based cognitive therapy (MBCT) intervention in reducing problematic mobile phone use, depression, and sleep disorders among adolescents. Additionally, it sought to investigate whether the decrease in problematic mobile phone use acted as a mediator in the relationship between the MBCT intervention and adolescent depression and sleep disorders. Methods: In a randomized controlled trial, a total of 104 adolescents were randomly assigned to the mindfulness group (n = 52) or the wait-list control group (n = 52). The mindfulness group students completed eight 45-min sessions of mindfulness training in four weeks. The outcomes were measured at baseline, postintervention, and at the 2-month follow-up. Results: Compared with the control group, the mindfulness group had significantly greater levels of mindfulness and lower levels of problematic mobile phone use, depression, and sleep disorders postintervention. The intervention effects were maintained at the 2-month follow-up. In addition, decreased problematic mobile phone use significantly mediated the association between the MBCT intervention and decreased depression and decreased sleep disorders. Conclusion: The findings suggest that MBCT could improve adolescent depression and sleep disorders and that decreasing problematic mobile phone use is an effective pathway accounting for the MBCT intervention effect on adolescent depression and sleep disorders.

Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity.

BACKGROUND: Liguzinediol (Lig) has emerged as a promising candidate for mitigating Doxorubicin (DOX)-induced cardiotoxicity, a significant limitation in the clinical application of this widely used antineoplastic drug known for its efficacy. This study aimed to explore the effects and potential mechanisms underlying Lig's protective role against DOX-induced cardiotoxicity. METHODS: C57BL/6 mice were treated with DOX. Cardiac function changes were observed by echocardiography. Cardiac structure changes were observed by HE and Masson staining. Immunofluorescence was applied to visualize the cardiomyocyte apoptosis. Western blotting was used to detect the expression levels of AMP-activated protein kinase (AMPK), sirtuin 3 (SIRT3), Caspase-3 and gasdermin E N-terminal fragment (GSDME-N). These experiments confirmed that Lig had an ameliorative effect on DOX-induced cardiotoxicity in mice. RESULTS: The results demonstrated that Lig effectively countered myocardial oxidative stress by modulating intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Lig reduced levels of creatine kinase (CK) and lactate dehydrogenase (LDH), while ameliorating histopathological changes and improving electrocardiogram profiles in vivo. Furthermore, the study revealed that Lig activated the AMPK/SIRT3 pathway, thereby enhancing mitochondrial function and attenuating myocardial cell apoptosis. In experiments with H9C2 cells treated with DOX, co-administration of the AMPK inhibitor compound C (CC) led to a significant increase in intracellular ROS levels. Lig intervention reversed these effects, along with the downregulation of GSDME-N, interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), suggesting a potential role of Lig in mitigating Caspase-3/GSDME-mediated pyroptosis. CONCLUSION: The findings of this study suggest that Lig effectively alleviates DOX-induced cardiotoxicity through the activation of the AMPK/SIRT3 pathway, thereby presenting itself as a natural product with therapeutic potential for preventing DOX-associated cardiotoxicity. This novel approach may pave the way for the development of alternative strategies in the clinical management of DOX-induced cardiac complications.

Type X collagen knockdown inactivate ITGB1/PI3K/AKT to suppress chronic unpredictable mild stress-stimulated triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, has a poor prognosis and limited access to efficient targeted treatments. Chronic unpredictable mild stress (CUMS) is highly risk factor for TNBC occurrence and development. Type X collagen (COL10A1), a crucial protein component of the extracellular matrix, ranks second among all aberrantly expressed genes in TNBC, and it is significantly up-regulated under CUMS. Nevertheless, the impact of CUMS and COL10A1 on TNBC, along with the underlying mechanisms are still unclear. In this research, we studied the effect of CUMS-induced norepinephrine (NE) elevation on TNBC, and uncovered that it notably enhanced TNBC cell proliferation, migration, and invasion in vitro, and also fostering tumor growth and lung metastasis in vivo. Additionally, our investigation found that COL10A1 directly interacted with integrin subunit beta 1 (ITGB1), then activates the downstream PI3K/AKT signaling pathway, thereby promoting TNBC growth and metastasis, while it was reversed by knocking down of COL10A1 or ITGB1. Our study demonstrated that the TNBC could respond to CUMS, and advocate for COL10A1 as a pivotal therapeutic target in TNBC treatment.

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.

Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM.

After myocardial infarction (MI), there is a notable disruption in cellular calcium ion homeostasis and mitochondrial function, which is believed to be intricately linked to endoplasmic reticulum (ER) stress. This research endeavors to elucidate the involvement of glucose regulated protein 75 (GRP75) in post-MI calcium ion homeostasis and mitochondrial function. In MI rats, symptoms of myocardial injury were accompanied by an increase in the activation of ER stress. Moreover, in oxygen-glucose deprivation (OGD)-induced cardiomyocytes, it was confirmed that inhibiting ER stress exacerbated intracellular Ca2+ disruption and cell apoptosis. Concurrently, the co-localization of GRP75 with IP3R and VDAC1 increased under ER stress in cardiomyocytes. In OGD-induced cardiomyocytes, knockdown of GRP75 not only reduced the Ca2+ levels in both the ER and mitochondria and improved the ultrastructure of cardiomyocytes, but it also increased the number of contact points between the ER and mitochondria, reducing mitochondria associated endoplasmic reticulum membrane (MAM) formation, and decreased cell apoptosis. Significantly, knockdown of GRP75 did not affect the protein expression of PERK and hypoxia-inducible factor 1α (HIF-1α). Transcriptome analysis of cardiomyocytes revealed that knockdown of GRP75 mainly influenced the molecular functions of sialyltransferase and IP3R, as well as the biosynthesis of glycosphingolipids and lactate metabolism. The complex interaction between the ER and mitochondria, driven by the GRP75 and its associated IP3R1-GRP75-VDAC1 complex, is crucial for calcium homeostasis and cardiomyocyte's adaptive response to ER stress. Modulating GRP75 could offer a strategy to regulate calcium dynamics, diminish glycolysis, and thereby mitigate cardiomyocyte apoptosis.

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.

Accurate leukocyte detection based on deformable-DETR and multi-level feature fusion for aiding diagnosis of blood diseases.

In standard hospital blood tests, the traditional process requires doctors to manually isolate leukocytes from microscopic images of patients' blood using microscopes. These isolated leukocytes are then categorized via automatic leukocyte classifiers to determine the proportion and volume of different types of leukocytes present in the blood samples, aiding disease diagnosis. This methodology is not only time-consuming and labor-intensive, but it also has a high propensity for errors due to factors such as image quality and environmental conditions, which could potentially lead to incorrect subsequent classifications and misdiagnosis. Contemporary leukocyte detection methods exhibit limitations in dealing with images with fewer leukocyte features and the disparity in scale among different leukocytes, leading to unsatisfactory results in most instances. To address these issues, this paper proposes an innovative method of leukocyte detection: the Multi-level Feature Fusion and Deformable Self-attention DETR (MFDS-DETR). To tackle the issue of leukocyte scale disparity, we designed the High-level Screening-feature Fusion Pyramid (HS-FPN), enabling multi-level fusion. This model uses high-level features as weights to filter low-level feature information via a channel attention module and then merges the screened information with the high-level features, thus enhancing the model's feature expression capability. Further, we address the issue of leukocyte feature scarcity by incorporating a multi-scale deformable self-attention module in the encoder and using the self-attention and cross-deformable attention mechanisms in the decoder, which aids in the extraction of the global features of the leukocyte feature maps. The effectiveness, superiority, and generalizability of the proposed MFDS-DETR method are confirmed through comparisons with other cutting-edge leukocyte detection models using the private WBCDD, public LISC and BCCD datasets. Our source code and private WBCCD dataset are available at https://github.com/JustlfC03/MFDS-DETR.

A chitosan-based conductive double network hydrogel doped by tannic acid-reduced graphene oxide with excellent stretchability and high sensitivity for wearable strain sensors.

Conductive hydrogels usually suffer from weak mechanical properties and are easily destroyed, resulting in limited applications in flexible electronics. Concurrently, adding conductive additives to the hydrogel solution increases the probability of agglomeration and uneven dispersion issues. In this study, the biocompatible natural polymer chitosan was used as the network substrate. The rigid network employed was the Cit3-ion crosslinked chitosan (CS) network, and the MBA chemically crosslinked polyacrylamide (PAM) network was used as the flexible network. Tannic acid-reduced graphene oxide (TA-rGO), which has excellent conductivity and dispersibility, is used as a conductive filler. Thus, a CS/TA-rGO/PAM double network conductive hydrogel with excellent performance, high toughness, high conductivity, and superior sensing sensitivity was prepared. The prepared CS/TA-rGO/PAM double network conductive hydrogels have strong tensile properties (strain and toughness as high as 2009 % and 1045 kJ/cm3), excellent sensing sensitivity (GF value was 4.01), a wider strain detection range, high cycling stability and durability, good biocompatibility, and antimicrobial properties. The hydrogel can be assembled into flexible wearable devices that can not only dynamically detect human movements, such as joint bending, facial expression changes, swallowing, and saying, but also recognize handwriting and enable human-computer interaction.