Search

Testis Expressed 19 (TEX19) is one of cancer/testis antigens identified in recent years and is related to the oncogenesis and progress of several cancers. This study aimed to reveal the role of TEX19 in ovarian cancer (OC) and searched for potential candidate epitope peptides of TEX19 to facilitate clinical application. TEX19 levels were evaluated by immunohistochemistry (IHC) in 98 human ovarian tissue samples. The correlation of TEX19 levels with patients' clinicopathological features was assessed. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis were utilized to detect TEX19 levels in ovarian cell lines and TEX19-deficient cells. The level of TEX19 in OVCAR-3 and A2780 was knocked down by small interfering RNA (siRNA), and loss-of-function assays were used to determine the biological effects of TEX19 on the proliferation, migration, and invasion of OC cells. Subsequently, candidate epitope peptides from TEX19 were predicted and verified by the IEDB database, pepsite2 website, MOE software, and T2 cell binding assay. TEX19 was significantly upregulated in OC which correlated to higher TNM stage, lymph node involvement, and invasiveness. Knockdown of TEX19 inhibited proliferation, migration, and invasion of OC cells. Additionally, we screened four peptides derived from TEX19 and found TL to be the dominant peptide with the greatest affinity with HLA-A*0201. Our data indicated a cancer-promoting effect of TEX19 in OC and demonstrated that TL could be a potential candidate for an anti-tumor epitope vaccine of OC, suggesting that TEX19 is a promising biomarker and immunotherapeutic target for OC. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is extensively utilized in the clinical management of both solid and hematological malignancies. Nevertheless, the clinical application of this treatment is significantly limited by adverse reactions and toxicity that may arise during or after administration. Its cytotoxic effects are multifaceted, with cardiotoxicity being the most prevalent side effect. Furthermore, it has the potential to adversely affect other organs, including the brain, kidneys, liver, and so on. Notably, it has been reported that DOX may cause renal failure in patients and there is currently no effective treatment for DOX-induced kidney damage, which has raised a high concern about DOX-induced nephrotoxicity (DIN). Although the precise molecular mechanisms underlying DIN remain incompletely elucidated, prior research has indicated that reactive oxygen species (ROS) are pivotal in this process, triggering a cascade of detrimental pathways including apoptosis, inflammation, dysregulated autophagic flux, and fibrosis. In light of these mechanisms, decades of research have uncovered several DIN-associated signaling pathways and found multiple potential therapeutic agents targeting them. Thus, this review intends to delineate the DIN associated signaling pathways, including AMPK, JAKs/STATs, TRPC6/RhoA/ROCK1, YAP/TEAD, SIRTs, Wnt/β-catenin, TGF-β/Smad, MAPK, Nrf2/ARE, NF-κB, and PI3K/AKT, and to summarize their potential regulatory agents, which provide a reference for the development of novel medicines against DIN., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H 2 S)-mediated protein S-sulfhydration has been shown to play critical roles in several diseases. Tumor-associated macrophages (TAMs) are the predominant population of immune cells present within solid tumor tissues, and they function to restrict antitumor immunity. However, no previous study has investigated the role of protein S-sulfhydration in TAM reprogramming in breast cancer (BC). Therefore, the aim is to investigate whether protein S-sulfhydration can regulate TAM reprogramming and its underlying mechanism in BC. The results showed that in BC, the CTH-H 2 S axis is positively correlated with the presence of an anti-tumor phenotype in TAMs. NaHS, as an H 2 S donor, repolarized TAMs into M1 macrophages to block the tumor-promoting activities of TAMs both in vitro and in vivo. Mechanistically, H 2 S-mediated S-sulfhydration of the protein chaperone glucose-regulated-protein 78 (GRP78) induced endoplasmic reticulum transmembrane protein kinase-1α (IRE-1α) dissociation from GRP78, which enhanced the phosphatase activity of IRE-1α itself in BC-TAMs, while the Cys420 site mutation of GRP78 interfered with these effects. Collectively, GRP78 S-sulfhydrylation mediated by H 2 S at the Cys420 residue decreased the tumor burden and inhibited lung metastasis of BC through reprograming TAMs via activating the IRE-1α pathway, indicating that targeting GRP78 S-sulfhydration represents a promising intervention for TAM-M1 repolarization in BC., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cardiomyopathy constitutes a global health burden. It refers to myocardial injury that causes alterations in cardiac structure and function, ultimately leading to heart failure. Currently, there is no definitive treatment for cardiomyopathy. This is because existing treatments primarily focus on drug interventions to attenuate symptoms rather than addressing the underlying causes of the disease. Notably, the cardiomyocyte loss is one of the key risk factors for cardiomyopathy. This loss can occur through various mechanisms such as metabolic disturbances, cardiac stress (e.g., oxidative stress), apoptosis as well as cell death resulting from disorders in autophagic flux, etc. Sirtuins (SIRTs) are categorized as class III histone deacetylases, with their enzyme activity primarily reliant on the substrate nicotinamide adenine dinucleotide (NAD (+)). Among them, Sirtuin 1 (SIRT1) is the most intensively studied in the cardiovascular system. Forkhead O transcription factors (FOXOs) are the downstream effectors of SIRT1. Several reports have shown that SIRT1 can form a signaling pathway with FOXOs in myocardial tissue, and this pathway plays a key regulatory role in cell loss. Thus, this review describes the basic mechanism of SIRT1-FOXOs in inhibiting cardiomyocyte loss and its favorable role in cardiomyopathy. Additionally, we summarized the SIRT1-FOXOs related regulation factor and prospects the SIRT1-FOXOs potential clinical application, which provide reference for the development of cardiomyopathy treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Photoacoustic computed tomography (PACT) has evoked extensive interest for applications in preclinical and clinical research. However, the current systems suffer from the limited view provided by detection setups, thus impeding the sufficient acquisition of intricate tissue structures. Here, we propose an approach to enable fast 3D full-view imaging. A hemispherical ultrasonic transducer array combined with a planar acoustic reflector serves as the ultrasonic detection device in the PACT system. The planar acoustic reflector can create a mirrored virtual transducer array, and the detection view range can be enlarged to cover approximately 3.7 π steradians in our detection setup. To verify the effectiveness of our proposed configuration, we present the imaging results of a hair phantom, an in vivo zebrafish larva, and a leaf skeleton phantom. Furthermore, the real-time dynamic imaging capacity of this system is demonstrated by observing the movement of zebrafish within 2 s. This strategy holds great potential for both preclinical and clinical research by providing more detailed and comprehensive images of biological tissues., Competing Interests: The authors declare no conflicts of interest., (© 2024 Optica Publishing Group.)

Myocardial ischemia causes extensive damage, further exacerbated by reperfusion, a phenomenon called myocardial ischemia/reperfusion injury (MIRI). Nowadays, the pathological mechanisms of MIRI have received extensive attention. Oxidative stress, multiple programmed cell deaths, inflammation and others are all essential pathological mechanisms contributing to MIRI. Mitochondria are the energy supply centers of cells. Numerous studies have found that abnormal mitochondrial function is an essential "culprit" of MIRI, and mitophagy mediated by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin signaling pathway is an integral part of maintaining mitochondrial function. Therefore, exploring the association between the PINK1/Parkin signaling pathway-mediated mitophagy and MIRI is crucial. This review will mainly summarize the crucial role of the PINK1/Parkin signaling pathway-mediated mitophagy in MIR-induced several pathological mechanisms and various potential interventions that affect the PINK1/Parkin signaling pathway-mediated mitophagy, thus ameliorating MIRI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of this study is to construct models for predicting platinum resistance in high-grade serous ovarian cancer (HGSOC) derived from quantitative spatial heterogeneity indicators obtained from 18 F-FDG PET/CT images., Methods: A retrospective study was conducted on patients diagnosed with HGSOC. Quantitative indicators of spatial heterogeneity were generated using conventional features and Haralick texture features from both CT and PET images. Three groups of predictive models (conventional, heterogeneity, and integrated) were built. Each group's optimal model was the one with the highest area under curve (AUC). Postoperative immunohistochemical staining for Ki-67 and p53 was conducted. The correlation between the heterogeneity indicators and scores for Ki-67 and p53 was assessed by Spearman's correlation coefficient (ρ)., Results: A total of 286 patients (54.6 ± 9.3 years) were enrolled. And 107 spatial heterogeneity indicators were extracted. The optimal models for each group were obtained using the Gradient Boosting Machine (GBM) algorithm. There was an AUC of 0.790 (95% CI: 0.696, 0.885) in the conventional model for the validation set, and an AUC of 0.904 (95% CI: 0.842, 0.966) in the heterogeneity model for the validation set. The integrated model achieved the highest predictive performance, with an AUC value of 0.928 (95% CI: 0.872, 0.984) for the validation set. Spearman's correlation showed that HU_Kurtosis had the strongest correlation with p53 scores with ρ = 0.718, while cluster site entropy had the strongest correlation with Ki-67 scores with ρ = 0.753., Conclusions: Adding quantitative spatial heterogeneity indicators derived from PET/CT images can improve the prediction of platinum resistance in patients with HGSOC. Spatial heterogeneity indicators were related to Ki-67 and p53 scores., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

As a chemotherapy agent, doxorubicin is used to combat cancer. However, cardiotoxicity has limited its use. The existing strategies fail to eliminate doxorubicin-induced cardiotoxicity, and an in-depth exploration of its pathogenesis is in urgent need to address the issue. Endoplasmic reticulum stress (ERS) occurs when Endoplasmic Reticulum (ER) dysfunction results in the accumulation of unfolded or misfolded proteins. Adaptive ERS helps regulate protein synthesis to maintain cellular homeostasis, while prolonged ERS stimulation may induce cell apoptosis, leading to dysfunction and damage to tissue and organs. Numerous studies on doxorubicin-induced cardiotoxicity strongly link excessive activation of the ERS to mechanisms including oxidative stress, calcium imbalance, autophagy, ubiquitination, and apoptosis. The researchers also found several clinical drugs, chemical compounds, phytochemicals, and miRNAs inhibited doxorubicin-induced cardiotoxicity by targeting ERS. The present review aims to outline the interactions between ERS and other mechanisms in doxorubicin-induced cardiotoxicity and summarize ERS's role in this type of cardiotoxicity. Additionally, the review enumerates several clinical drugs, phytochemicals, chemical compounds, and miRNAs targeting ERS for considering therapeutic regimens that address doxorubicin-induced cardiotoxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Zhang, Tan, Zhang, Zhao and Dong.)

Cardiomyopathies are a group of heterogeneous diseases, characterized by abnormal structure and function of the myocardium. For many years, it has been a hot topic because of its high morbidity and mortality as well as its complicated pathogenesis. The E2Fs, a group of transcription factors found extensively in eukaryotes, play a crucial role in governing cell proliferation, differentiation, and apoptosis, meanwhile their deregulated activity can also cause a variety of diseases. Based on accumulating evidence, E2Fs play important roles in cardiomyopathies. In this review, we describe the structural and functional characteristics of the E2F family and its role in cardiomyocyte processes, with a focus on how E2Fs are associated with the onset and development of cardiomyopathies. Moreover, we discuss the great potential of E2Fs as biomarkers and therapeutic targets, aiming to provide a reference for future research., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Social support can be divided into emotional support, tool support, and information support in function or mode. Emotional support is an encouragement, expressed as love and care, respect and value, encouragement and compassion, and psychological resilience due to adaptation to adversity and stressors, which is conducive to personal positive psychological adjustment and good functional status. This study aims to explore the status of resilience and social support in elderly stroke patients and examine the correlation between the 2 factors., Methods: Convenience sampling was used to survey 280 elderly stroke ischemic patients admitted to the Department of Neurology in our hospital from January to December 2020. General information, resilience, and social support were assessed through questionnaires., Results: The participants had a moderate level of resilience, with an average score of 63.77 ± 9.99. The total social support score ranged with an average score of 33.72 ± 5.77, indicating a relatively low level of social support. After the Pearson correlation analysis, there was a positive correlation between resilience and social support, namely, r = 0.277, P < 0.05., Conclusions: Enhancing social support among elderly stroke patients is an effective way to improve their psychological resilience., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiomyopathies (CMs) are highly heterogeneous progressive heart diseases characterised by structural and functional abnormalities of the heart, whose intricate pathogenesis has resulted in a lack of effective treatment options. Mitsugumin 53 (MG53), also known as Tripartite motif protein 72 (TRIM72), is a tripartite motif family protein from the immuno-proteomic library expressed primarily in the heart and skeletal muscle. Recent studies have identified MG53 as a potential cardioprotective protein that may play a crucial role in CMs. Therefore, the objective of this review is to comprehensively examine the underlying mechanisms mediated by MG53 responsible for myocardial protection, elucidate the potential role of MG53 in various CMs as well as its dominant status in the diagnosis and prognosis of human myocardial injury, and evaluate the potential therapeutic value of recombinant human MG53 (rhMG53) in CMs. It is expected to yield novel perspectives regarding the clinical diagnosis and therapeutic treatment of CMs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardio-metabolic diseases, including a cluster of metabolic disorders and their secondary affections on cardiovascular physiology, are gradually brought to the forefront by researchers due to their high prevalence and mortality, as well as an unidentified pathogenesis. tRNA-derived small RNAs (tsRNAs), cleaved by several specific enzymes and once considered as some "metabolic junks" in the past, have been proved to possess numerous functions in human bodies. More interestingly, such a potential also seems to influence the progression of cardio-metabolic diseases to some extent. In this review, the biogenesis, classification and mechanisms of tsRNAs will be discussed based on some latest studies, and their relations with several cardio-metabolic diseases will be highlighted in sequence. Lastly, some future prospects, such as their clinical applications as biomarkers and therapeutic targets will also be mentioned, in order to provide researchers with a comprehensive understanding of the research status of tsRNAs as well as its association with cardio-metabolic diseases, thus presenting as a beacon to indicate directions for the next stage of study., Competing Interests: Declaration of competing interest All the authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Orbit-induced localized spin angular momentum (OILS) has recently garnered significant attention. This paper introduces periodic edge dislocation (PED) into the tight focusing system. The study delves into the tight focusing characteristics of the radially polarized vortex plane beam with PED, demonstrating that PED serves as a straightforward and effective means of manipulating OILS, especially when both the orbital angular momentum and the polarization of the incident beam are fixed. Our findings indicate that the longitudinal OILS reaches its maximum when the difference between the period of PED and the vortex topological charge is equal to 1. Conversely, when the difference is 0, the transverse OILS reaches its maximum, while the longitudinal OILS reaches its minimum. Similar patterns are also observed in linearly polarized vortex beams. This research proposes a simple and practical way to control OILS, contributing to our understanding of optical orbit-spin coupling.

Ferroptosis is a recently identified form of programmed cell death that plays an important role in the pathophysiological process of osteoarthritis (OA). Herein, we investigated the protective effect of moderate mechanical stress on chondrocyte ferroptosis and further revealed the internal molecular mechanism. Intra-articular injection of sodium iodoacetate (MIA) was conducted to induce the rat model of OA in vivo, meanwhile, interleukin-1 beta (IL-1β) was treated to chondrocytes to induce the OA cell model in vitro. The OA phenotype was analyzed by histology and microcomputed tomography, the ferroptosis was analyzed by transmission electron microscope and immunofluorescence. The expression of ferroptosis and cartilage metabolism-related factors was analyzed by immunohistochemical and Western blot. Animal experiments revealed that moderate-intensity treadmill exercise could effectively reduce chondrocyte ferroptosis and cartilage matrix degradation in MIA-induced OA rats. Cell experiments showed that 4-h cyclic tensile strain intervention could activate Nrf2 and inhibit the NF-κB signaling pathway, increase the expression of Col2a1, GPX4, and SLC7A11, decrease the expression of MMP13 and P53, thereby restraining IL-1β-induced chondrocyte ferroptosis and degeneration. Inhibition of NF-κB signaling pathway relieved the chondrocyte ferroptosis and degeneration. Meanwhile, overexpression of NF-κB by recombinant lentivirus reversed the positive effect of CTS on chondrocytes. Moderate mechanical stress could activate the Nrf2 antioxidant system, inhibit the NF-κB p65 signaling pathway, and inhibit chondrocyte ferroptosis and cartilage matrix degradation by regulating P53, SLC7A11, and GPX4., (© 2024. The Author(s).)

In this paper, one kind of multi-focusing electric and magnetic field which is sourced from an azimuthally polarized vortex circular hyperbolic umbilic beam (APVCHUB) is presented. After passing through a high NA objective, both the electric and magnetic fields of the APVCHUBs will focus multiple times, and a high-purity longitudinal magnetic field ( p q =80 % ) will be generated. Besides, the mutual induction of the vortex phase and azimuthal polarization changes the electric and magnetic fields' vibration state and intensity distribution, making the longitudinal magnetic field carry an m-order concentric vortex. Our findings suggest that the APVCHUB could have potential applications in magnetic particle manipulation, extremely weak magnetic detection, data storage, semiconductor quantum dot excitation, etc.

Being a broad-spectrum anticancer drug, doxorubicin is indispensable for clinical treatment. Unexpectedly, its cardiotoxic side effects have proven to be a formidable obstacle. Numerous studies are currently devoted to elucidating the pathological mechanisms underlying doxorubicin-induced cardiotoxicity. Nrf2 has always played a crucial role in oxidative stress, but numerous studies have demonstrated that it also plays a vital part in pathological mechanisms like cell death and inflammation. Numerous studies on the pathological mechanisms associated with doxorubicin-induced cardiotoxicity demonstrate this. Several clinical drugs, natural and synthetic compounds, as well as small molecule RNAs have been demonstrated to prevent doxorubicin-induced cardiotoxicity by activating Nrf2. Consequently, this study emphasizes the introduction of Nrf2, discusses the role of Nrf2 in doxorubicin-induced cardiotoxicity, and concludes with a summary of the therapeutic modalities targeting Nrf2 to ameliorate doxorubicin-induced cardiotoxicity, highlighting the potential value of Nrf2 in doxorubicin-induced cardiotoxicity., (© 2023. The Author(s).)

Recently, long noncoding RNAs (lncRNAs) have been highlighted for extensive functionality in sepsis. In this study, we aimed to explore the role of RNF7 in the progression of sepsis. We initially established a rat model of sepsis through cecal ligation and puncture induction, whereupon RNF7 expression was determined by RT-qPCR. Following adenovirus infection, the role of RNF7 in muscle injury, skeletal muscle protein metabolism, oxidative stress, and inflammation in sepsis rats was analyzed. Then, downstream mechanisms of RNF7 were identified and validated. Further, lipopolysaccharide was applied to treat myoblast to further demonstrate the in vitro role of RNF7. Our results showed that RNF7 expression was upregulated during sepsis. Overexpression of RNF7 worsened the sepsis-induced skeletal muscle injury, induced skeletal muscle protein metabolism, oxidative stress, and inflammation in sepsis rats. Meanwhile, overexpression of RNF7 elevated thrombospondin-1 (THBS1) expression. Silencing of RNF7 inhibited THBS1 and activated the PI3K/Akt signaling pathway, arresting the release of inflammatory factors and oxidative stress levels in skeletal muscle cells. Altogether, RNF7 may promote skeletal muscle cell apoptosis while simultaneously inhibiting cell autophagy through the promotion of THBS1 and inactivation of the PI3K/Akt signaling pathway.

The Grüneisen parameter is a primary parameter of the initial sound pressure signal in the photoacoustic effect, which can provide unique biological information and is related to the temperature change information of an object. The accurate measurement of this parameter is of great significance in biomedical research. Combining X-ray-induced acoustic tomography and conventional X-ray computed tomography, we proposed a method to obtain the absolute Grüneisen parameter. The theory development, numerical simulation, and biomedical application scenarios are discussed. The results reveal that our method not only can determine the Grüneisen parameter but can also obtain the body internal temperature distribution, presenting its potential in the diagnosis of a broad range of diseases., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

N 6 -Methyladenosine (m 6 A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m 6 A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m 6 A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m 6 A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML., Competing Interests: Declaration of interests A US patent (no. 17/794,922) has been filed, with J.C., H. Weng, H.H., D.H., Y.M., H.L., and X.D. as inventors. J.C. is a Scientific Advisor for Race Oncology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Abstract: A new interdisciplinary approach based on medical imaging phenotypes, gene expression patterns, and clinical parameters, referred to as radiogenomics, has recently been developed for biomarker identification and clinical risk stratification in oncology, including for the assessment of ovarian cancer. Some radiological phenotypes (implant distribution, lymphadenopathy, and texture-derived features) are related to specific genetic landscapes (BRCA, BRAF, SULF1, the Classification of Ovarian Cancer), and integrated models can improve the efficiency for predicting clinical outcomes. The establishment of databases in medical images and gene expression profile with large sample size and the improvement of artificial intelligence algorithm will further promote the application of radiogenomics in ovarian cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

With the gradual increase of the aging population in Chinese society, the incidence of knee osteoarthritis showed an increasing trend. However, there are very few practical solutions for it. As a novel neuromuscular training technique, whole-body vibration training has become a candidate for treating knee osteoarthritis. In this review, we firstly elaborated on the mode of action and influence factors of the whole-body vibration training. Next, we summarized its effects in knee osteoarthritis, including improving knee function and some uncertain muscle function and proprioception effects. Next, we also summarized its possible mechanisms, including improving bone microstructure, delaying articular cartilage degeneration, modulating inflammatory cells and inflammatory factors. Then, we summarized the clinical effectiveness of whole-body vibration training by analyzing some clinical randomized controlled trials. Finally, based on the above summary, we analyzed and listed the limitations of whole-body vibration training in treating knee osteoarthritis and found the shortcomings in the existing studies. This review provides ideas for the future application of whole-body vibration training in the treatment of knee osteoarthritis., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aberrant expression of microRNAs (miRNAs) has been linked with ischemic brain injury (IBI), but the mechanistic actions behind the associated miRNAs remain to be determined. Of note, miR-129-5p was revealed to be downregulated in the serum of patients with IBI. In silico prediction identified a putative target gene, siah E3 ubiquitin protein ligase 1 (SIAH1), of miR-129-5p. Accordingly, this study plans to clarify the functional relevance of the interplay of miR-129-5p and SIAH1 in IBI. IBI was modeled by exposing human hippocampal neuronal cells to oxygen-glucose deprivation (OGD) in vitro and by occluding the middle cerebral artery (MCAO) in a mouse model in vivo. Apoptosis of hippocampal neuronal cells was assessed by annexin V-FITC/PI staining and TUNEL staining. The area of cerebral infarction was measured using TTC staining, along with neurological scoring on modeled mice. Loss of hippocampal neuronal cells in the peri-infarct area was monitored using Nissl staining. Downregulated miR-129-5p expression was found in OGD-induced hippocampal neuronal cells and MCAO-treated mice. Mechanistically, miR-129-5p was validated to target and inhibit SIAH1 through the application of dual-luciferase reporter assay. Additionally, enforced miR-129-5p inhibited the apoptosis of OGD-induced cells and decreased the cerebral infarct area, neurological scores and apoptosis of hippocampal neuronal cells by downregulating SIAH1 and activating the mTOR signaling pathway. Taken together, the results of this study reveal the important role and underlying mechanism of miR-129-5p in IBI, providing a promising biomarker for preventive and therapeutic strategies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: CD8 + T cell-mediated adaptive cellular immunity and natural killer (NK) cell-mediated innate immunity both play important roles in tumour immunity. This study aimed to develop therapeutic tumour vaccines based on double-activation of CD8 + T and NK cells., Methods: The immune Epitope database, Molecular Operating Environment software, and enzyme-linked immunosorbent assay were used for epitope identification. Flow cytometry, confocal microscopy, UPLC-QTOF-MS, and RNA-seq were utilized for evaluating immunity of PBMC-derived DCs, CD8 + T or NK cells and related pathways. HLA-A2.1 transgenic mice combined with immunologically reconstituted tumour-bearing mice were used to examine the antitumour effect and safety of epitope vaccines., Results: We identified novel HLA-A2.1-restricted extracellular matrix protein 1(ECM1)-derived immunodominant epitopes in which LA induced a potent immune response. We also found that LA-loaded DCs upregulated the frequency of CD3 + /CD8 + T cells, CD45RO + /CD69 + activated memory T cells, and CD3 - /CD16 + /CD56 + NK cells. We demonstrated cytotoxic granule release of LA/DC-CTLs or LA/DC-NK cells and cytotoxicity against tumour cells and microtissue blocks via the predominant IFN-γ/perforin/granzyme B cell death pathway. Further investigating the mechanism of LA-mediated CD8 + T activation, we found that LA could be internalized into DCs through phagocytosis and then formed a LA-MHC-I complex presented onto the DC surface for recognition of the T cell receptor to upregulate Zap70 phosphorylation levels to further activate CD8 + T cells by DC-CTL interactions. In addition, LA-mediated DC-NK crosstalk through stimulation of the TLR4-p38 MAPK pathway increased MICA/B expression on DCs to interact with NKG2D for NK activation. Promisingly, LA could activate CD8 + T cells and NK cells simultaneously via interacting with DCs to suppress tumours in vivo. Moreover, the safety of LA was confirmed., Conclusions: LA-induced immune antitumour activity through DC cross-activation with CD8 + T and NK cells, which demonstrated proof-of-concept evidence for the capability and safety of a novel therapeutic tumour vaccine.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma with high metastatic rate and high mortality rate, needing to find potential therapeutic targets and develop new therapy methods. The bioinformatics analysis was used in this study to find the targets. Firstly, the expression profile of ccRCC obtained from The Cancer Genome Atlas (TCGA) database and GSE53757 dataset were used to identify the significant up-regulated genes. IL20RB, AURKB and KIF18B with the top efficiency of capable of diagnosis ccRCC from para cancer tissue, were over-expressed in ccRCC samples, and expressed increasedly with the development of ccRCC. There was the closest correlation between AURKB and KIF18B in these three over-expressed genes. AURKB (high) or KIF18B (high) were all significantly correlated with higher T, N, M stage, G grade and shorter overall survival (OS) of ccRCC patients. Furthermore, the ccRCC patients with AURKB (high) + KIF18B (high) showed worse clinical characteristics and prognosis. Multivariate COX regression analysis indicated AURKB (high) and KIF18B (high) were all the independent prognostic risk factor without considering the interaction of AURKB and KIF18B. Moreover, considering the combination of each other, only AURKB (high) + KIF18B (high) expression was an independent prognostic risk factor for ccRCC patients, but not other situations. Collectively, AURKB was closely associated with KIF18B, and the combined expression of AURKB and KIF18B may be of great significance in ccRCC.

Objective: To explore the effect of treatment opportunity and course of hyperbaric oxygen (HBO) on the curative effect of cerebral resuscitation patients after successful cardiopulmonary resuscitation (CPR)., Methods: Eighty-nine patients who underwent cerebral resuscitation after CPR admitted to the second department of the First Hospital of Jilin University from June 2015 to June 2019 were enrolled. All patients underwent conventional drug therapy after admission, and HBO therapy was added on the basis of conventional drug therapy at different intervention times, and all patients received at least 3 courses of HBO treatment. Glasgow coma scale (GCS) score and amplitude-integrated electroencephalography (aEEG) score on different treatment opportunity (i.e. intervention of HBO within 12 hours, 12-72 hours, 4-7 days, 8-21 days after successful CPR) and different course of HBO (i.e. 1, 2 and 3 courses of treatment) were recorded. Repeated measurement analysis of variance was used to assess whether the treatment opportunity or course of treatment affects the GCS score and aEEG score. Then, paired sample t test was used to further analyze the results of repeated measurement analysis of variance and evaluate the specific effect of treatment course or intervention time on the efficacy., Results: A total of 89 patients were enrolled. 8, 20, 33 and 28 patients started HBO treatment at < 12 hours, 12-72 hours, 4-7 days and 8-21 days after successful CPR. (1) GCS score: repeated measurement analysis of variance (the Greenhouse-Geisser correction method was used) showed that the effect of course of HBO treatment on GCS score was statistically significant (F = 71.735, P = 0.000). The interaction between the duration of HBO treatment and the timing of intervention was not statistically significant (F = 0.455, P = 0.817). Paired sample t test showed that the means of GCS scores before HBO treatment and treatment 1, 2, 3 courses were 3.56, 4.80, 5.55 and 6.49 respectively, and the difference of pairwise pairing between different groups were statistically significant (all P < 0.01). (2) aEEG score: repeated measurement analysis of variance (the Greenhouse-Geisser correction method was used) showed that the effect of course of HBO treatment on aEEG score was statistically significant (F = 96.965, P = 0.000).The interaction between the duration of HBO treatment and the timing of intervention was not statistically significant (F = 1.735, P = 0.112). Paired sample t test showed that the means of aEEG scores before HBO treatment and treatment 1, 2, 3 courses were 1.71, 2.21, 2.52 and 3.03 respectively (all P < 0.01)., Conclusions: The effect of HBO on cerebral resuscitation after CPR is obvious. The longer the course of HBO is, the more significant the effect of cerebral resuscitation is. Within 21 days after successful CPR, the treatment opportunity of HBO had no significant effect on the effect of cerebral resuscitation.

Adriamycin(ADR) is still considered to be one of the most effective agents in the treatment of breast cancer (BrCa), its efficacy is compromised by intrinsic resistance or acquire characteristics of multidrug resistance. At present, there are few genetic alterations that can be exploited as biomarkers to guide targeted use of ADR in clinical. Therefore, exploring the determinants of ADR sensitivity is pertinent for their optimal clinical application. TP53 is the most frequently mutated gene in human BrCa, p53 mutation has been reported to be closely related to ADR resistance, whereas the underlying mechanisms that cause endogenous ADR resistance in p53-mutant BrCa cells are not completely understood. The aim of the present study was to investigate the potential roles of miRNA in the response to ADR in p53-mutated breast cancer. Here, we report that BrCa cells expressing mutp53 are more resistant to ADR than cells with wild-type p53 (wtp53). The DNA repair protein- Fanconi anemia complementation group F protein (FANCF) and the translesion synthesis DNA polymerase REV1 protein is frequently abundant in the context of mutant p53 of BrCa. By targeting two key factors, miR-30c increases the sensitivity of BrCa cells to ADR. Furthermore, p53 directly activates the transcription of miR-30c by binding to its promoter. Subsequent analyses revealed that p53 regulates REV1 and FANCF by modulating miR-30c expression. Mutation of the p53 abolished this response. Consistently, reduced miR-30c expression is highly correlated with human BrCa with p53 mutational status and is associated with poor survival. We propose that one of the pathways affected by mutant p53 to increase intrinsic resistance to ADR involves miR-30c downregulation and the consequent upregulation of FANCF and REV1. The novel miRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.

Background: LncRNA ZFAS1 (ZNFX1 antisense RNA1) plays key roles in the occurrence and progression of various cancers, including colorectal cancer, glioma, lung cancer, gastric cancer, and so on. To date, relatively little is known about its potential role in development and/or progression of clear cell renal cell carcinoma (ccRCC)., Methods: Expression level of ZFAS1 and miR-10a in 60 ccRCC and 20 adjacent non-tumor tissues were determined by using qRT-PCR. The effect of knockdown of ZFAS1 on cell proliferation, migration and invasion were measured by CCK-8 assay, transwell migration and invasion assay, respectively. The correlation of ZFAS1 and miR-10a was analyzed by bioinformatics DIANA TOOLS. Protein and mRNA expression of spindle and kinetochore-associated protein 1(SKA1) were determined by western blot and qRT-PCR analysis, respectively. Interactions between ZFAS1 and miR-10a were verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay, and interactions between miR-10a and SKA1 was verified by a luciferase reporter assay., Results: We observed that high-level expression of ZFAS1 is positively correlated with poor prognosis and shorter overall survival (OS) in patients with ccRCC. Knockdown of ZFAS1 significantly suppressed proliferation, migration and invasion of ccRCC cells. Furthermore, miR-10a was identified as a target of ZFAS1. Silencing miR-10a could attenuate the ability of ZFAS1 in promoting proliferation and metastasis of ccRCC. Subsequently, our studies validated that SKA1, as a key downstream target protein for miR-10a, is responsible for the biological role of ZFAS1. ZFAS1 positively regulated SKA1 expression via sponging miR-10a., Conclusions: Taken together, our findings suggest that ZFAS1 promotes growth and metastasis of ccRCC via targeting miR-10a/SKA1 pathway, which may represent a novel therapeutic target or biomarker for ccRCC., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

DNA and histone modifications have notable effects on gene expression 1 . Being the most prevalent internal modification in mRNA, the N 6 -methyladenosine (m 6 A) mRNA modification is as an important post-transcriptional mechanism of gene regulation 2-4 and has crucial roles in various normal and pathological processes 5-12 . However, it is unclear how m 6 A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m 6 A deposition globally. We show that m 6 A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m 6 A methyltransferase complex (MTC), which in turn facilitates the binding of the m 6 A MTC to adjacent RNA polymerase II, thereby delivering the m 6 A MTC to actively transcribed nascent RNAs to deposit m 6 A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m 6 A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m 6 A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.

Oxidative stress and inflammation are involved in paraquat-induced cytotoxicity. Silymarin can exert a potent antioxidative and anti-inflammatory effect in various pathophysiological processes. The aim of this current study is to explore the protective effect and potential mechanism of silymarin in paraquat-induced macrophage injury. Cells were pretreated with different doses of silymarin for 3h before exposure to paraquat. At 24h after exposure to paraquat, the paraquat-induced cytotoxicity to macrophage was measured via the MTT assay and LDH release. The levels of intracellular reactive oxygen species, GSH-Px, SOD, and lipid peroxidation product malondialdehyde were measured to evaluate the oxidative effect of paraquat. NLRP3 inflammasome and cytokines secretion in macrophage exposed to paraquat at 24h were measured via immunofluorescence microscopy, western blot or Elisa. Our results revealed that paraquat could dramatically cause cytotoxicity and reactive oxygen species generation, enhance TXNIP expression, and induce NLRP3 inflammasome activation and cytokines secretion. The pretreatment with silymarin could remarkably reduce the cytotoxicity, promote the expression of Trx and antioxidant enzymes, and suppress the TXNIP and NLRP3 inflammasome activation. In conclusion, silymarin attenuated paraquat-induced cytotoxicity in macrophage by inhibiting oxidative stress, NLRP3 inflammasome activation, cytokines secretion and apoptosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To investigate the effect of selective phosphatase inhibitors Salubrinal on autophagy and apoptosis in the lung tissue of rats with acute paraquat (PQ) poisoning, and to explore its mechanism., Methods: 200 Wistar rats were randomly divided into four groups by randomized arrangement table formed by computer, with 50 rats in each group. PQ poisoning model was reproduced by one time gastric lavage with 1 mL of 40 mg/kg PQ solution followed by intraperitoneal injection of 1 mL normal saline (NS) once a day. The rats in control group were lavaged once with 1 mL of NS followed by intraperitoneal injection of 1 mL NS twice a day. The rats in Sal 0.5 and Sal 1.0 groups were intraperitoneal injected with 1 mL Salubrinal 0.5 mg/kg or 1.0 mg/kg on the 1st, 3rd, and 5th day after PQ poisoning once a day. The lung tissue was harvested on the 7th day after poisoning, and the changes in histomorphology were observed using hematoxylin and eosin (HE) staining. The positive expression of autophagy-related protein LC3-II in lung tissue was observed after immunohistochemistry staining, and LC3-II and caspase-3 protein expressions were determined by Western Blot., Results: HE staining results showed partial abnormal pulmonary structure in the PQ poisoning group: collapse of pulmonary alveoli, enlargement of the cavity, local infiltration of inflammatory cells, increasing thickness in the alveoli wall and obvious bleeding in the local lung tissue. Compared with the PQ poisoning group, the above changes in Sal 0.5 and Sal 1.0 groups were obviously relieved. It was shown by immunohistochemistry staining that compared with control group, the positive expression of LC3-II was obviously decreased in the PQ poisoning group, Sal 0.5, and Sal 1.0 groups (A value: 78.34 ± 10.71, 76.52 ± 8.21, 77.48 ± 9.11 vs. 117.58 ± 15.26, all P<0.05). There was no significant difference in positive expression of LC3-II between each of the later three groups (all P>0.05). Western Blot results showed: compared with the control group, the protein expressions of LC3-II and caspase-3 were significantly increased in PQ poisoning group [LC3-II (A value): 0.22 ± 0.05 vs. 0.14 ± 0.03, caspase-3 (A value): 0.115 ± 0.013 vs. 0.023 ± 0.006, both P<0.05]. Compared with PQ poisoning group, the protein expressions of LC3-II and caspase-3 were obviously decreased in the Sal 0.5 and Sal 1.0 groups [LC3-II (A value): 0.19 ± 0.05, 0.18 ± 0.04 vs. 0.22 ± 0.05; caspase-3(A value): 0.078 ± 0.012, 0.076 ± 0.010 vs. 0.115 ± 0.013, all P<0.05]., Conclusions: The endoplasmic reticulum stress-autophagy is activated in the pulmonary cell of acute PQ poisoning rats. Salubrinal can decrease the autophagy and apoptosis in the lung of rats with acute PQ poisoning, which play a role in the treatment.

Introduction: It remains unclear whether the clinical outcomes of patients with acute myocardial infarction (AMI) receiving second- and first-generation drug-eluting stents (DES) are identical. The study aimed to investigate the differences in clinical utility between the two generations of DES in these specific subjects by a meta-analysis., Material and Methods: We systemically searched PubMed and EMBASE databases and the Cochrane Library up until January 2013. Randomized trials, which compared clinical outcomes of second-generation DES (everolimus- (EES) or zotarolimus-eluting stents (ZES)) with first-generation DES (sirolimus- or paclitaxel-eluting stents) in patients with AMI were included., Results: Five trials with 1720 AMI subjects were included in the meta-analysis. Pooled analysis demonstrated a trend toward lower incidence of stent thrombosis with the second-generation DES relative to the first-generation one (risk ratio (RR), 0.53; 95% confidence intervals (CI): 0.25-1.13; p = 0.10). However, the second-generation DES did not offer a significant advantage over the first-generation DES in reducing the incidence of target lesion revascularization (TLR) (RR = 1.73; 95% CI: 0.83-3.64; p = 0.15), major adverse cardiac events (MACEs) (RR = 0.97; p = 0.90), or all-cause death (RR = 1.00; p = 1.0). In addition, in elderly patients the second-generation DES seemed to reduce the occurrence of MACEs (RR = 0.65; p = 0.10) and stent thrombosis (RR = 0.40; p = 0.08), and the second-generation EES showed a potential benefit in lowering the MACE rate (RR = 0.55; p = 0.06)., Conclusions: The second-generation DES appeared to lower the risk of stent thrombosis in AMI patients. There might be a lower incidence of MACEs associated with the second-generation EES.

Objective: To compare the clinical characteristics and survival on Chinese patients with idiopathic pulmonary arterial hypertension (IPAH) and familiar pulmonary arterial hypertension (FPAH) during conventional therapy era and targeted therapy era., Methods: IPAH and FPAH patients who were referred between Jan 1999 and Oct 2004 in Fuwai Hospital were defined as conventional therapy era group (before 2005 no PAH-specific drug was available in China). All patients in this group were followed up till Jun 2005. IPAH and FPAH patients who were referred between Sep 2006 and Aug 2011 were defined as targeted therapy era group (new PAH-specific drugs were available in China since 2006) were analyzed. All patients in this group were followed up till Dec 2013. The primary endpoints were death and therapy medicine., Results: Seventy-two patients were enrolled in conventional therapy era group, 375 were enrolled in targeted therapy era group. The mean age was (35.9 ± 12.2) years and (34.5 ± 17.4) years respectively (P = 0.67), and women was predominant in both groups. There was no difference in WHO functional class and hemodynamic data between the two groups. About 90.3% patients were treated by calcium-channel blockers (CCB) in conventional therapy era group. In targeted therapy era group, almost all patients were treated by at least one PAH-specific drug, only 3.2% patients who had a positive response to acute pulmonary vasodilator testing were treated by CCB. The median survival time was 30.4 months in conventional therapy era group and 66.2 months in targeted therapy era group. The 1-, 2-, 3- and 5- year survival rates of IPAH and FPAH patients were 68.0%, 56.9%, 38.9% and 20.8% in conventional therapy era group, and 89.3%, 78.1%, 68.2% and 53.7% in targeted therapy era group respectively (P < 0.000 1)., Conclusion: Compared with conventional therapy era, the survival rate of Chinese IPAH and FPAH patients is significantly improved in targeted therapy era.

Objective: To explore the baseline clinical characteristics of patients with pulmonary arterial hypertension after operation for congenital heart disease (AO-CHD-PAH) in China., Methods: A total of 122 consecutive patients diagnosed as AO-CHD-PAH in Shanghai Pulmonary Hospital from September 1, 2006 to August 31, 2011 were retrospective analyzed., Results: Sixty-seven percent patients were female. The median age at procedure and diagnosis were 14.8 and 24.8 years old, respectively. The median duration from procedure of CHD to diagnosis of PAH was 7.3 years. The most frequent initial symptom (109/122, 89.3%) attributed to PAH was dyspnea on exertion. The frequent sign was accentuation of second heart sound on pulmonary valve area (113/122, 92.6%).Incidence of WHO functional PAH classes I/II was 53.3% (65/122) and mean 6 minutes walk distance was limited to (408.4 ± 103.3) m. Borg dyspnea score was 2.0 (1.0, 3.0).Right heart catheterization demonstrated severe elevated mean pulmonary arterial pressure [(71.6 ± 24.2) mmHg, 1 mmHg = 0.133 kPa] and pulmonary vascular resistance index [(29.1 ± 16.0) Wood U·m(2)] in this patient cohort. Cardiac index was (2.7 ± 0.9) L·min(-1)·m(-2), 90.2% (110/122) patients received PAH-specific therapy. The majority of PAH-specific therapy was phosphodiesterase type 5 inhibitor, which is somehow different from PAH-specific therapy regimen of American-European developed countries., Conclusions: PAH-specific therapy rate is satisfactory for pulmonary arterial hypertension after operation for congenital heart disease in China and phosphodiesterase type 5 inhibitors are predominant PAH-specific medication in China.

Bacillus Calmette-Guerin extract (BCGE) has been proven to be clinically effective for anaphylactic disease, infectious diseases and cancer. In this study, we investigated the effect of the intramuscular application of BCGE on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD). We established an AD model in BALB/c mice by repeated local exposure of DNCB to the ear and dorsal skin. Following intramuscular application of BCGE, the ear thickness, mast cell infiltration, serum total immunoglobulin E (IgE) and histamine level were measured. In addition, levels of interleukin (IL)-4, IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the ears were assayed. BCGE reduced AD symptoms based on ear thickness, dermatitis score, histopathological analysis and serum IgE levels. In addition, BCGE inhibited mast cell infiltration into the ear and elevation of serum histamine, increased IFN-γ level and suppressed IL-4, IL-13 and TNF-α levels in the ears. Furthermore, BCGE attenuated the NF-κBp65 expression in the nuclear extract of the ear tissue. Taken together, our results demonstrated that intramuscular application of BCGE exerts beneficial effects on the symptoms of AD suggesting that BCGE may be a candidate for the treatment of AD.