Extracellular matrix remodeling in the tumor immunity

The extracellular matrix (ECM) is a significant constituent of tumors, fulfilling various essential functions such as providing mechanical support, influencing the microenvironment, and serving as a reservoir for signaling molecules. The abundance and degree of cross-linking of ECM components are critical determinants of tissue stiffness. In the process of tumorigenesis, the interaction between ECM and immune cells within the tumor microenvironment (TME) frequently leads to ECM stiffness, thereby disrupting normal mechanotransduction and promoting malignant progression. Therefore, acquiring a thorough comprehension of the dysregulation of ECM within the TME would significantly aid in the identification of potential therapeutic targets for cancer treatment. In this regard, we have compiled a comprehensive summary encompassing the following aspects: (1) the principal components of ECM and their roles in malignant conditions; (2) the intricate interaction between ECM and immune cells within the TME; and (3) the pivotal regulators governing the onco-immune response in ECM

Effects of epigallocatechin-3-gallate on bovine oocytes matured

Objective Epigallocatechin-3-gallate (EGCG) is a major ingredient of catechin polyphenols and is considered one of the most promising bioactive compounds in green tea because of its strong antioxidant properties. However, the protective role of EGCG in bovine oocyte in vitro maturation (IVM) has not been investigated. Therefore, we aimed to study the effects of EGCG on IVM of bovine oocytes. Methods Bovine oocytes were treated with different concentrations of EGCG (0, 25, 50, 100, and 200 μM), and the nuclear and cytoplasmic maturation, cumulus cell expansion, intracellular reactive oxygen species (ROS) levels, total antioxidant capacity, the early apoptosis and the developmental competence of in vitro fertilized embryos were measured. The mRNA abundances of antioxidant genes (nuclear factor erythriod-2 related factor 2 [NRF2], superoxide dismutase 1 [SOD1], catalase [CAT], and glutathione peroxidase 4 [GPX4]) in matured bovine oocytes were also quantified. Results Nuclear maturation which is characterized by first polar body extrusion, and cytoplasmic maturation characterized by peripheral and cortical distribution of cortical granules and homogeneous mitochondrial distribution were significantly improved in the 50 μM EGCG-treated group compared with the control group. Adding 50 μM EGCG to the maturation medium significantly increased the cumulus cell expansion index and upregulated the mRNA levels of cumulus cell expansion-related genes (hyaluronan synthase 2, tumor necrosis factor alpha induced protein 6, pentraxin 3, and prostaglandin 2). Both the intracellular ROS level and the early apoptotic rate of matured oocytes were significantly decreased in the 50 μM EGCG group, and the total antioxidant ability was markedly enhanced. Additionally, both the cleavage and blastocyst rates were significantly higher in the 50 μM EGCG-treated oocytes after in vitro fertilization than in the control oocytes. The mRNA abundance of NRF2, SOD1, CAT, and GPX4 were significantly increased in the 50 μM EGCG-treated oocytes. Conclusion In conclusion, 50 μM EGCG can improve the bovine oocyte maturation, and the protective role of EGCG may be correlated with its antioxidative property

Complete sequences of KPC-2-encoding plasmid p628-KPC and CTX-M-55-encoding p628-CTXM coexisted in Klebsiella pneumoniae

A carbapenem-resistant Klebsiella pneumoniae strain 628 was isolated from a human case of intracranial infection in a Chinese teaching hospital. Strain 628 produces KPC-2 and CTX-M-55 encoded by two different conjugative plasmids, i.e., the IncFIIK plasmid p628-KPC and the IncI1 plasmid p628-CTXM, respectively. blaKPC-2 is captured by a Tn1721-based unit transposon with a linear structure ΔTn3-ISKpn27-blaKPC-2-ΔISKpn6-ΔTn1721, and this transposon together with a mercury resistance (mer) gene locus constitutes a 34 kb acquired drug-resistance region. blaKPC-2 has two transcription starts (nucleotides G and C located at 39 and 250 bp upstream of its coding region, respectively), which correspond to two promoters, i.e., the intrinsic P1 and the upstream ISKpn27/Tn3-provided P2 with the core -35/-10 elements TAATCC/TTACAT and TTGACA/AATAAT, respectively. blaCTX-M-55 is mobilized in an ISEcp1-blaCTX-M-55-Δorf477 transposition unit and appears to be the sole drug-resistant determinant in p628-CTXM. blaCTX-M-55 possesses a single transcription start (nucleotides G located at 116 bp upstream of its coding region), corresponding to the ISEcp1-provided P1 promoter with the core -35/-10 element TTGAAA/TACAAT. All the above detected promoters display a characteristic of constitutive expression. Coexistence of blaKPC and blaCTX-M in K. pneumoniae has been reported many times, but this is the first report to gain deep insights into genetic platforms, promoters, and expression of the two coexisted bla genes with determination of entire nucleotide sequences of the two corresponding plasmids

A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain

Association of tumor mutation burden and epidermal growth factor receptor inhibitor history with survival in patients with metastatic stage III/IV nonsmall-cell lung cancer: A retrospective study

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan–Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors

A Scaled Boundary Finite-Element Method with B-Differentiable Equations for 3D Frictional Contact Problems

Contact problems are among the most difficult issues in mathematics and are of crucial practical importance in engineering applications. This paper presents a scaled boundary finite-element method with B-differentiable equations for 3D frictional contact problems with small deformation in elastostatics. Only the boundaries of the contact system are discretized into surface elements by the scaled boundary finite-element method. The dimension of the contact system is reduced by one. The frictional contact conditions are formulated as B-differentiable equations. The B-differentiable Newton method is used to solve the governing equation of 3D frictional contact problems. The convergence of the B-differentiable Newton method is proven by the theory of mathematical programming. The two-block contact problem and the multiblock contact problem verify the effectiveness of the proposed method for 3D frictional contact problems. The arch-dam transverse joint contact problem shows that the proposed method can solve practical engineering problems. Numerical examples show that the proposed method is a feasible and effective solution for frictional contact problems

Identification of pyroptosis‐related clusters for prediction of overall survival and characterization of tumor microenvironment infiltration in laryngeal squamous cell carcinoma

Abstract Laryngeal squamous cell carcinoma (LSCC) accounts for one‐third of head and neck squamous carcinoma (HNSCC). Although improvements have been made in treatments, the prognosis of patients with LSCC is unsatisfactory. Pyroptosis creates an environment that inhibits tumor growth in various cancers, but pyroptosis regulation in the tumor immune microenvironment in LSCC remains little known. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to collect clinical traits and gene expression data of LSCC patients. We present a systematic overview of the immune microenvironment of LSCC based on genetics and transcriptional profiles of pyroptosis‐related genes (PRGs) and divide 220 LSCC into three distinct PRGclusters. Based on the three survival‐related PRGs identified in Lasso‐penalized Cox regression, samples from the training and validation cohorts were divided into two discrete geneClusters. We construct a prognostic model based on Risk score, quantify pyroptosis level and link it with patient outcome. Furthermore, we verified the expression level of one prognostic gene Basic Leucine Zipper ATF‐Like Transcription Factor at the tissue level in the validation experiment. These findings reveal the crucial role of pyroptosis and can assist in predicting patient prognosis, guiding optimal treatment choices, and developing new immunotherapies for LSCC

Reliability Analysis of High Concrete-Face Rockfill Dams and Study of Seismic Performance of Earthquake-Resistant Measures Based on Stochastic Dynamic Analysis

The randomness of earthquake excitation has a significant impact on the seismic performance of high earth-rock dams. In this paper, the seismic performance of geosynthetic-reinforced soil structures (GRSS) of high concrete face rockfill dams (CFRDs) is evaluated from the stochastic perspective. Multiple groups of seismic ground motions are generated based on spectral expression-random function non-stationary model. Taking Gushui CFRD as an example, this study calculates the failure probability of each damage level of non-reinforce slopes and reinforce slopes based on generalized probability density evolution method (GPDEM) and reliability analysis is presented though multiple evaluation indicators. The result shows that GRSS can reduce the mild damage of CFRDs during earthquake and restrain the moderate and severe damage. The influence of vertical spacing and length of GRSS on the seismic performance is obtained, which provides a reference for the seismic design and risk analysis of CFRDs

Reliability Analysis of High Concrete-Face Rockfill Dams and Study of Seismic Performance of Earthquake-Resistant Measures Based on Stochastic Dynamic Analysis

The randomness of earthquake excitation has a significant impact on the seismic performance of high earth-rock dams. In this paper, the seismic performance of geosynthetic-reinforced soil structures (GRSS) of high concrete face rockfill dams (CFRDs) is evaluated from the stochastic perspective. Multiple groups of seismic ground motions are generated based on spectral expression-random function non-stationary model. Taking Gushui CFRD as an example, this study calculates the failure probability of each damage level of non-reinforce slopes and reinforce slopes based on generalized probability density evolution method (GPDEM) and reliability analysis is presented though multiple evaluation indicators. The result shows that GRSS can reduce the mild damage of CFRDs during earthquake and restrain the moderate and severe damage. The influence of vertical spacing and length of GRSS on the seismic performance is obtained, which provides a reference for the seismic design and risk analysis of CFRDs