The phosphorylation-deubiquitination positive feedback loop of the CHK2-USP7 axis stabilizes p53 under oxidative stress.

p53 regulates multiple signaling pathways and maintains cell homeostasis under conditions of DNA damage and oxidative stress. Although USP7 has been shown to promote p53 stability via deubiquitination, the USP7-p53 activation mechanism has remained unclear. Here, we propose that DNA damage induces reactive oxygen species (ROS) production and activates ATM-CHK2, and CHK2 then phosphorylates USP7 at S168 and T231. USP7 phosphorylation is essential for its deubiquitination activity toward p53. USP7 also deubiquitinates CHK2 at K119 and K131, increasing CHK2 stability and creating a positive feedback loop between CHK2 and USP7. Compared to peri-tumor tissues, thyroid cancer and colon cancer tissues show higher CHK2 and phosphorylated USP7 (S168, T231) levels, and these levels are positively correlated. Collectively, our results uncover a phosphorylation-deubiquitination positive feedback loop involving the CHK2-USP7 axis that supports the stabilization of p53 and the maintenance of cell homeostasis.

Mechanism and clinical progression of solid tumors bone marrow metastasis.

The rich blood supply of the bone marrow provides favorable conditions for tumor cell proliferation and growth. In the disease's early stages, circulating tumor cells can escape to the bone marrow and form imperceptible micro metastases. These tumor cells may be reactivated to regain the ability to grow aggressively and eventually develop into visible metastases. Symptomatic bone marrow metastases with abnormal hematopoiesis solid tumor metastases are rare and have poor prognoses. Treatment options are carefully chosen because of the suppression of bone marrow function. In this review, we summarized the mechanisms involved in developing bone marrow metastases from tumor cells and the clinical features, treatment options, and prognosis of patients with symptomatic bone marrow metastases from different solid tumors reported in the literature.

Insights on E1-like enzyme ATG7: functional regulation and relationships with aging-related diseases.

Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases.

Covalent organic framework with donor-acceptor structure for rapid and sensitive photothermal sensing detection.

Given the serious harm caused by dietary intake of diethylstilbestrol (DES), it is urgent to explore rapid and sensitive DES sensing methods. In this work, a photothermal DES immunochromatography sensor based on covalent organic framework (COF) was constructed. The performance of COF in the field of photothermal sensing was systematically investigated for the first time. A donor-acceptor type of COF with a photothermal conversion rate of 51.17 % was synthesized. The logarithm of the DES concentrations-temperature change value standard curve was plotted. The intensity of the photothermal sensing signal was inversely proportional to the sample concentration. The detection limit of the proposed photothermal method (0.24 µg·L-1) was 10 times higher than that of visual detection (3 µg·L-1). This work not only constructed a novel detection method for DES sensing, but also provided a feasible demonstration for the application of COF in photothermal sensing and expanded the application of their photothermal properties.

ATM-CHK2-TRIM32 axis regulates ATG7 ubiquitination to initiate autophagy under oxidative stress.

Oxidative stress-induced autophagy helps to prevent cellular damage and to maintain homeostasis. However, the regulatory pathway that initiates autophagy remains unclear. We previously showed that reactive oxygen species (ROS) function as signaling molecules to activate the ATM-CHK2 pathway and promote autophagy. Here, we find that the E3 ubiquitin ligase TRIM32 functions downstream of ATM-CHK2 to regulate ATG7 ubiquitination. Under metabolic stress, ROS induce ATM phosphorylation at S1981, which in turn phosphorylates CHK2 at T68. We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy. In addition, Chk2-/- mice show an aggravated infarction phenotype and reduced phosphorylation of TRIM32 and ubiquitination of ATG7 in a stroke model. We propose a molecular mechanism for autophagy initiation by ROS via the ATM-CHK2-TRIM32-ATG7 axis to maintain intracellular homeostasis and to protect cells exposed to pathological conditions from stress-induced tissue damage.

DCNNLFS: A Dilated Convolutional Neural Network with Late Fusion Strategy for Intelligent Classification of Gastric Histopathology Images.

Gastric cancer has a high incidence rate, significantly threatening patients' health. Gastric histopathology images can reliably diagnose related diseases. Still, the data volume of histopathology images is too large, making misdiagnosis or missed diagnosis easy. The classification model based on deep learning has made some progress on gastric histopathology images. However, traditional convolutional neural networks (CNN) generally use pooling operations, which will reduce the spatial resolution of the image, resulting in poor prediction results. The image feature in previous CNN has a poor perception of details. Therefore, we design a dilated CNN with a late fusion strategy (DCNNLFS) for gastric histopathology image classification. The DCNNLFS model utilizes dilated convolutions, enabling it to expand the receptive field. The dilated convolutions can learn the different contextual information by adjusting the dilation rate. The DCNNLFS model uses a late fusion strategy to enhance the classification ability of DCNNLFS. We run related experiments on a gastric histopathology image dataset to verify the excellence of the DCNNLFS model, where the three metrics Precision, Accuracy, and F1-Score are 0.938, 0.935, and 0.959.

Mesenchymal stem cells in the treatment of spinal cord injury: Mechanisms, current advances and future challenges.

Spinal cord injury (SCI) has considerable impact on patient physical, mental, and financial health. Secondary SCI is associated with inflammation, vascular destruction, and subsequent permanent damage to the nervous system. Mesenchymal stem cells (MSCs) have anti-inflammatory properties, promoting vascular regeneration and the release neuro-nutrients, and are a promising strategy for the treatment of SCI. Preclinical studies have shown that MSCs promote sensory and motor function recovery in rats. In clinical trials, MSCs have been reported to improve the American Spinal Injury Association (ASIA) sensory and motor scores. However, the effectiveness of MSCs in treating patients with SCI remains controversial. MSCs promote tumorigenesis and ensuring the survival of MSCs in the hostile environment of SCI is challenging. In this article we examine the evidence on the pathophysiological changes occurring after SCI. We then review the underlying mechanisms of MSCs in the treatment of SCI and summarize the potential application of MSCs in clinical practice. Finally, we highlight the challenges surrounding the use of MSCs in the treatment of SCI and discuss future applications.

Pyrolysis Kinetics of Lignin-Based Flame Retardants Containing MOFs Structure for Epoxy Resins.

This study describes the preparation of a lignin-based expandable flame retardant (Lignin-N-DOPO) using grafting melamine and covering 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) using the Mannich reaction. Then, through in situ growth, a metal-organic framework (MOF) HKUST-1 (e.g., Cu3(BTC)2, BTC = benzene-1,3,5-tricarboxylate)/lignin-based expandable flame retardant (F-lignin@HKUST-1) was created. Before that, lignin epoxy resin containing phosphorus (P) and nitrogen (N) components had been created by combining epoxy resin (EP) with F-lignin@HKUST-1. Thermogravimetric analysis was used to examine the thermal characteristics of epoxy resin (EP) composite. The findings indicate that the thermal stability of EP is significantly affected by the presence of F-lignin@HKUST-1. Last but not least, the activation energy (E) of EP/15% F-lignin@HKUST-1 was examined using four different techniques, including the Kissinger-SY iteration method, the Ozawa-SY iteration method, the Lee-Beck approximation-iteration method, and the Gorbatchev approximation-iteration method. It was discovered that the activation energy was significantly higher than that of lignin. Higher activation energy suggests that F-lignin@HKUST-1 pyrolysis requires more energy from the environment, which will be significant about the application of lignin-based flame retardants.

Case report: Hilar metastasis of breast cancer: A single-center retrospective case-control study.

Purpose: The lungs are a common metastatic organ in breast cancer, mainly due to blood metastasis. On imaging, most metastatic lesions show a peripheral round mass in the lung, occasionally with a hilar mass as the primary manifestation, showing burr and lobulation signs. This study aimed to investigate breast cancer patient's clinical characteristics and prognosis with two different metastatic sites in the lung. Methods: We retrospectively analyzed patients admitted to the First Hospital of Jilin University between 2016 and 2021 diagnosed with breast cancer lung metastases. Forty breast cancer patients with hilar metastases (HM) and 40 patients with peripheral lung metastases (PLM) were matched 1:1 using a pairing method. To analyze the patient's prognosis, the clinical characteristics of patients with two different metastatic sites were compared using the chi-square test, Kaplan-Meier curve, and Cox proportional hazards model. Results: The median follow-up time was 38 months (2-91 months). The median age of patients with HM was 56 years (25-75 years), and that of patients with PLM was 59 years (44-82 years). The median overall survival (mOS) was 27 months in the HM group and 42 months in the PLM group (p = 0.001). The results of the Cox proportional hazards model showed that the histological grade (hazard ratio = 2.741, 95% confidence interval 1.442-5.208, p = 0.002) was a prognostic factor in the HM group. Conclusion: The number of young patients in the HM group was higher than that in the PLM group, with higher Ki-67 indexes and histological grades. Most patients had mediastinal lymph node metastasis, with shorter DFI and OS and poor prognosis.

Dual Proton/Silver-Catalyzed Serial (5 + 2)-Cycloaddition and Nazarov Cyclization of (E)-2-Arylidene-3-hydroxyindanones with Conjugated Eneynes: Synthesis of Indanone-Fused Benzo[cd]azulenes.

A one-pot step-economic tandem process involving (5 + 2)-cycloaddition and Nazarov cyclization reactions has been reported for the facile synthesis of indanone-fused benzo[cd]azulenes from (E)-2-arylidene-3-hydroxyindanones and conjugated eneynes. This highly regio- and stereoselective bisannulation reaction is enabled by dual silver and Brønsted acid catalysis and opens up a new avenue for the construction of important bicyclo[5.3.0]decane skeletons.

Biomaterials delivery strategies to repair degenerated intervertebral discs by regulating the inflammatory microenvironment.

Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain. Although IVDD cannot directly cause death, it can cause pain, psychological burdens, and economic burdens to patients. Current conservative treatments for IVDD can relieve pain but cannot reverse the disease. Patients who cannot tolerate pain usually resort to a strategy of surgical resection of the degenerated disc. However, the surgical removal of IVDD can affect the stability of adjacent discs. Furthermore, the probability of the reherniation of the intervertebral disc (IVD) after surgery is as high as 21.2%. Strategies based on tissue engineering to deliver stem cells for the regeneration of nucleus purposes (NP) and annulus fibrosus (AF) have been extensively studied. The developed biomaterials not only locally withstand the pressure of the IVD but also lay the foundation for the survival of stem cells. However, the structure of IVDs does not provide sufficient nutrients for delivered stem cells. The role of immune mechanisms in IVDD has recently become clear. In IVDD, the IVD that was originally in immune privilege prevents the attack of immune cells (mainly effector T cells and macrophages) and aggravates the disease. Immune regulatory and inflammatory factors released by effector T cells, macrophages, and the IVD further aggravate IVDD. Reversing IVDD by regulating the inflammatory microenvironment is a potential approach for the treatment of the disease. However, the biological factors modulating the inflammatory microenvironment easily degrade in vivo. It makes it possible for different biomaterials to modulate the inflammatory microenvironment to repair IVDD. In this review, we have discussed the structures of IVDs and the immune mechanisms underlying IVDD. We have described the immune mechanisms elicited by different biological factors, including tumor necrosis factors, interleukins, transforming growth factors, hypoxia-inducible factors, and reactive oxygen species in IVDs. Finally, we have discussed the biomaterials used to modulate the inflammatory microenvironment to repair IVDD and their development.

Acquired hyperfibrinolysis as the presenting sign of metastatic breast cancer: A case report.

Fibrinolysis is a bleeding disorder characterized by hypofibrinogenemia caused by abnormal activation of fibrinolytic system function. Patients with cancer are prone to hypercoagulable and should be vigilant for the risk of venous thrombosis. However, patients with tumors in which bleeding is the first manifestation are relatively rare. The present study reports the case of a 52-year-old woman with metastatic breast cancer with acquired hyperfibrinolysis as the first manifestation. Hyperfibrinolysis is an important sign and manifestation of disease progression. In this case, fibrinogen was used as a sensitive biomarker of tumor burden to specifically predict the efficacy of the antitumor therapy. Effective antitumor therapy can improve the hyperfibrinolysis of patients, and so the fibrinogen levels gradually increased. In conclusion, the present case showed acquired hyperfibrinolysis with bleeding symptoms, which is an uncommon paraneoplastic phenomenon in breast cancer, especially when combined with bone marrow metastasis, as in the present case. Timely diagnosis and treatment of the primary disease is the fundamental way to improve hyperfibrinolysis. As an effective biomarker, fibrinogen level predicts the changes in a patient's illness and guides the clinical diagnosis and treatment process.

Cooperative Tracking Control of Unknown Discrete-Time Linear Multiagent Systems Subject to Unknown External Disturbances.

This article studies the tracking problem of a class of heterogeneous linear minimum-phase discrete-time multiagent systems (MASs) with unknown agent parameters in the presence of bounded disturbances. By introducing a distributed adaptive observer and a reference model, a novel framework is proposed to convert the complicated cooperative tracking problem of unknown heterogeneous MASs into a cooperative tracking problem of the reference models to the leader and a local robust model reference adaptive control problem. It is shown that under the adaptive controller designed based on the proposed framework, the tracking errors between the outputs of all the agents and the output of the leader converge to a residual set. It is also shown that the tracking errors will converge to zero asymptotically when the disturbances are absent. Compared with the existing related works, our main contribution is that the proposed framework could deal with the unknown MASs with arbitrary individual relative degrees and do not rely on any global graph information. Finally, the effectiveness of the proposed controller is illustrated by an example.

Dickkopf-1 drives tumor immune evasion by inducing PD-L1 expression in hepatocellular carcinoma.

Understanding the mechanisms regulating PD-L1 expression in hepatocellular carcinoma (HCC) is important to improve the response rate to PD-1/PD-L1 blockade therapy. Here, we show that DKK1 expression is positively associated with PD-L1 expression and inversely correlated with CD8+ T cell infiltration in human HCC tumor specimens. In a subcutaneous xenograft tumor model, overexpression of DKK1 significantly promotes tumor growth, tumoral PD-L1 expression, but reduces tumoral CD8+ T cell infiltration; whereas knockdown of DKK1 has opposite effects. Moreover, enforced expression of DKK1 dramatically promotes PD-L1 expression, Akt activation, ß-catenin phosphorylation and total protein expression in HCC cells. By contrast, knockdown of DKK1 inhibits all, relative to controls. In addition, CKAP4 depletion, Akt inhibition, or ß-catenin depletion remarkably abrogates DKK1 overexpression-induced transcriptional expression of PD-L1 in HCC cells. Reconstituted expression of the active Akt1 largely increased PD-L1 transcriptional expression in HCC cells. Similarly, expression of WT ß-catenin, but not the phosphorylation-defective ß-catenin S552A mutant, significantly promotes PD-L1 expression. Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-ß-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/ß-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.

Primary site surgery of de novo stage IV HER2-positive breast cancer in the era of new drug treatments.

Objective: The surgical treatment of the primary site has been a subject of controversy in patients with de novo metastatic breast cancer. In recent years, studies using large databases and retrospective analyses have provided evidence of the survival benefits of localized surgery for these patients. However, due to the improved prognosis associated with novel antitumor agents and the widespread use of anti-HER2 therapy, it is important to investigate the role of primary site surgery in the context of new drug treatments for stage IV HER2-positive breast cancer. Methods: This retrospective analysis included patients with metastatic breast cancer at diagnosis who were consulted at the First Hospital of Jilin University between 2016 and 2022. We compared the patients' clinical and pathological characteristics, treatment regimens, and prognosis between the surgery and non-surgery groups. Results: A total of 96 patients with stage IV HER2-positive breast cancer were included in the study, with 24 patients (25%) undergoing surgery for the primary lesion. Patients with lower Eastern Cooperative Oncology Group (ECOG) scores, earlier T-stage, metastases confined to one organ/site, and fewer metastases were more likely to undergo surgery. Patients in the surgical group had longer progression-free survival (median 25.7 vs. 15.9 months, p=0.073) and overall survival (median 79.1 vs. 48 months, p=0.073) compared to patients in the non-surgical group, however, there was no statistical difference. Univariate and multivariate Cox regression analysis suggested that the choice of first-line targeted therapy regimens rather than surgical treatment influenced the patients' prognoses. In the subgroup of patients receiving first-line targeted therapy with trastuzumab plus pertuzumab, the decision to undergo surgery on the primary site did not have a statistically significant effect on prognosis. Conclusion: Primary site surgery does not improve the prognosis of de novo stage IV HER2-positive breast cancer. In the era of anti-HER2 therapy, primary surgery is not recommended, except in exceptional circumstances.

Engineered nanomaterials trigger abscopal effect in immunotherapy of metastatic cancers.

Despite advances in cancer treatment, metastatic cancer is still the main cause of death in cancer patients. At present, the treatment of metastatic cancer is limited to palliative care. The abscopal effect is a rare phenomenon in which shrinkage of metastatic tumors occurs simultaneously with the shrinkage of a tumor receiving localized treatment, such as local radiotherapy or immunotherapy. Immunotherapy shows promise for cancer treatment, but it also leads to consequences such as low responsiveness and immune-related adverse events. As a promising target-based approach, intravenous or intratumoral injection of nanomaterials provides new opportunities for improving cancer immunotherapy. Chemically modified nanomaterials may be able to trigger the abscopal effect by regulating immune cells. This review discusses the use of nanomaterials in killing metastatic tumor cells through the regulation of immune cells and the prospects of such nanomaterials for clinical use.

Different treatment regimens in breast cancer visceral crisis: A retrospective cohort study.

Objective: Breast cancer visceral crisis (VC) is caused by excessive tumor burden leading to severe organ dysfunction with poor prognosis. Traditional chemotherapy reduces the quality of life of patients without significantly improving survival. The aim of this study was to investigate the clinical characteristics of patients with VC and the prognosis by using different treatment options. Methods: According to the 5th European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) international consensus guidelines for advanced breast cancer guidelines (ABC 5), patients who were treated in the First Hospital of Jilin University from 2018 to 2022 and diagnosed with breast cancer VC were retrospectively analyzed. The analysis focused on the characteristics of the patients, the treatment regimens, and prognosis. Results: A total of 133 patients were included in this study. As for metastasis breast cancer subtype, 92 (69.18%) were hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER-2) negative, 20 (15.04%) had HER-2 overexpression, and 21 (15.78%) were triple negative. All patients had an mOS of 11.2 months (range, 1.1-107.8 months). In different types of VC, the median overall survival (mOS) of bone marrow metastasis (BMM) was 18.0 months (range, 2.0-107.8 months), that of diffuse liver metastasis (DLM) was 8.1 months (range, 1.3-30.2 months), and that of meningeal metastasis (MM) was 9.0 months (range, 1.2-53.8 months). In 92 HR+, Her-2- patients using different treatment regimens, mOS was 6.2 months (range, 1.2-29.8 months) in the chemotherapy group while it was 24.3 months (range, 3.1-107.8 months) in the endocrine therapy (ET) group. Multivariate Cox regression analysis suggested that Eastern Cooperative Oncology Group (ECOG) scores and type of VC were associated with survival. Conclusion: Prognosis varied in different types of VC. Patients with BMM had the best prognosis, and DLM had the worst. As treatment options continue to progress, our retrospective study showed a significant prolongation of overall survival (OS) in patients with VC compared to previous studies.

A New Topology-Switching Strategy for Fault Diagnosis of Multi-Agent Systems Based on Belief Rule Base.

Effective fault-diagnosis strategies have been the focus of research on multi-agent systems (MASs). In this paper, the belief rule base (BRB)-based distributed fault-diagnosis problem for MASs is investigated, and a topology-switching strategy is developed to increase the reliability of fault-diagnosis model. Firstly, a BRB-based distributed fault-diagnosis model is constructed for the MAS with multiple faults, then expert knowledge is used to judge whether the agent is faulty. Then, considering that the system may be influenced by the fault or some other factors and thus leading to a decrease in the accuracy of the fault-diagnosis results, a topology-switching strategy based on the average distance of the output diagnosis accuracy is proposed to update the topology of the agent so that the fault-diagnosis results can be more reliable. Note that the topology-switching threshold is designed based on the average distance between the accuracy of the fault diagnosis of each agent. The method proposed in this paper can solve the problem when the fault-diagnosis accuracy of the model is affected by some common factors and thus decreases, and can improve the reliability of the fault-diagnosis model very well. Finally, the effectiveness of the BRB-based distributed fault-diagnosis model and the proposed topology-switching strategy to improve the fault-diagnosis accuracy is verified by simulation examples.

Application of mesenchymal stem cell-derived exosomes from different sources in intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a main cause of lower back pain, leading to psychological and economic burdens to patients. Physical therapy only delays pain in patients but cannot eliminate the cause of IVDD. Surgery is required when the patient cannot tolerate pain or has severe neurological symptoms. Although surgical resection of IVD or decompression of the laminae eliminates the diseased segment, it damages adjacent normal IVD. There is also a risk of re-protrusion after IVD removal. Cell therapy has played a crucial role in the development of regenerative medicine. Cell transplantation promotes regeneration of degenerative tissue. However, owing to the lack of vascular structure in IVD, sufficient nutrients cannot be provided for transplanted mesenchymal stem cells (MSCs). In addition, dead cells release harmful substances that aggravate IVDD. Extracellular vesicles (EVs) have been extensively studied as an emerging therapeutic approach. EVs generated by paracrine MSCs retain the potential of MSCs and serve as carriers to deliver their contents to target cells to regulate target cell activity. Owing to their double-layered membrane structure, EVs have a low immunogenicity and no immune rejection. Therefore, EVs are considered an emerging therapeutic modality in IVDD. However, they are limited by mass production and low loading rates. In this review, the structure of IVD and advantages of EVs are introduced, and the application of MSC-EVs in IVDD is discussed. The current limitations of EVs and future applications are described.

A new unmanned aerial vehicle intrusion detection method based on belief rule base with evidential reasoning.

With the growing security demands in the public, civil and military fields, unmanned aerial vehicle (UAV) intrusion detection has attracted increasing attention. In view of the shortcomings of the current UAV intrusion detection model using Wi-Fi data traffic in terms of detection accuracy, sample size reduction, and model interpretability, this paper proposes a new detection algorithm for UAV intrusion. This paper presents an interpretable intrusion detection model for UAVs based on the belief rule base (BRB). BRB can effectively use various types of information to establish any nonlinear relationship between the model input and output. It can model and simulate any nonlinear model and optimize the model parameters. However, the rule combination explosion problem is encountered in BRB if there are too many attributes. Therefore, an evidential reasoning (ER) algorithm is proposed for solving this problem. By combining the capabilities of the ER and the BRB methodologies, a new evaluation model, named the EBRB-based model, is proposed here for predicting UAV intrusion detection, even in the case of a massive number of attributes. The global optimization of the model is ensured. A new interpretable and globally optimized UAV intrusion detection model is proposed, which is the main contribution of this paper. An experimental case is used to demonstrate the implementation and application of the proposed UAV intrusion detection method.