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After myocardial infarction (MI), ventricular dilation and the microscopic passive stretching of the infarcted border zone is the meaning contributor to the continuous expansion of myocardial fibrosis. Epicardial hydrogel patches have been demonstrated to alleviate this sequela of MI in small-animal models. However, these have not been successfully translated to humans or even large animals, in part because of challenges in attaining both the greater stiffness and slower viscoelastic relaxation that mathematical models predict to be optimal for application to larger, slower-beating hearts. Here, using borate-based dynamic covalent chemistry, we develop an injectable “heart rate matched” viscoelastic gelatin (VGtn) hydrogel with a gel point tunable across the stiffnesses and frequencies that are predicted to transspecies and cross-scale cardiac repair after MI. Small-animal experiments demonstrated that, compared to heart rate mismatched patches, the heart rate matched VGtn patches inhibited ventricular bulging and attenuated stress concentrations in the myocardium after MI. In particular, the viscoelastic patch can coordinate the microscopic strain at the infarction boundary. VGtn loaded with anti-fibrotic agents further reduced myocardial damage and promoted angiogenesis in the myocardium. The tuned heart rate matched patches demonstrated similar benefits in a larger-scale and lower heart rate porcine MI model. Results suggest that heart rate matched VGtn patches may hold potential for clinical translation.

Abstract Dynamically evolving adhesions between cells and extracellular matrix (ECM) transmit time‐varying signals that control cytoskeletal dynamics and cell fate. Dynamic cell adhesion and ECM stiffness regulate cellular mechanosensing cooperatively, but it has not previously been possible to characterize their individual effects because of challenges with controlling these factors independently. Therefore, a DNA‐driven molecular system is developed wherein the integrin‐binding ligand RGD can be reversibly presented and removed to achieve cyclic cell attachment/detachment on substrates of defined stiffness. Using this culture system, it is discovered that cyclic adhesion accelerates F‐actin kinetics and nuclear mechanosensing in human mesenchymal stem cells (hMSCs), with the result that hysteresis can completely change how hMSCs transduce ECM stiffness. Results are dramatically different from well‐known results for mechanotransduction on static substrates, but are consistent with a mathematical model of F‐actin fragments retaining structure following loss of integrin ligation and participating in subsequent repolymerization. These findings suggest that cyclic integrin‐mediated adhesion alters the mechanosensing of ECM stiffness by hMSCs through transient, hysteretic memory that is stored in F‐actin.

Abstract Background Intercostal nerve block (ICNB) is a very effective analgesic method. We aimed to explore the effect of preemptive analgesia with ultrasound-guided intercostal nerve block on postoperative analgesia in thoracoscopic surgery. Methods 126 patients, aged 18–70 years, with American Society of Anesthesiologists (ASA) physical status I-II and scheduled for thoracoscopic pulmonary resection were enrolled in this study. 119 patients were left for final analysis. Patients were randomly allocated to group ICNB and group CONTROL. Patients in CONTROL group were administered sufentanil with patient-controlled analgesia device after operation In group ICNB, patients received ropivacaine ICNB prior to surgery and patient-controlled analgesia device after operation. The primary outcome is visual analog scale pain score (VAS) at rest at 0,4, 8,16,24,48,72 and 168 h postoperatively and they were compared. Surgical outcomes and rescue analgesia requirement were also recorded. Results VAS scores were statistically significantly lower for ICNB group compared to control group at 0, 4, 8, 16, 24 and 48 h postoperatively. The duration of insertion of chest tube in ICBN group was shorter than that in control group, and the difference was statistically significant (4.69 ± 2.14 vs. 5.67 ± 2.86, P = 0.036). The postoperative hospital stay, incidence of nausea and vomiting and postoperative pulmonary infection rate in ICBN group were all lower than those in the control group, but there were no statistical differences. The frequency of rescue analgesia during 48 postoperative hours was different between the two groups (ICNB vs. Control; 9.83% vs. 31.03%, P = 0.004). Conclusions For patients undergoing thoracoscopic surgery, ultrasound-guided ICNB is simple, safe, and effective for providing acute postoperative pain management during the early postoperative stage. Trial registration Chinese clinical trials: chictr.org.cn, ChiCTR1900021017. Registred on 25/01/2019.

Abstract Background STIL centriolar assembly protein (STIL) is a cytoplasmic protein implicated in cellular growth and proliferation as well as chromosomal stability, which abnormal condition affected tumor immunity and tumor progression. However, the role of STIL in the biological mechanism of hepatocellular carcinoma (HCC) remains unclear. Methods Comprehensive bioinformatic approaches, in vitro functional assays, and validation were conducted to elucidate the oncogenic value of STIL in HCC. Results In the present study, we found that STIL may serve as an independent prognostic indicator and a potential oncogene in HCC. Gene set enrichment analysis (GSEA), and Gene set variation analysis (GSVA) showed that upregulated expression of STIL was positively associated with pathways enriched in the cell cycle and DNA damage response. Subsequently, we identified several non-coding RNAs (ncRNAs) accounting for the upregulation of STIL expression using a combination of in silico bioinformatics approaches (including expression analysis, correlation analysis, and survival analysis). Finally, CCNT2-AS1/SNHG1-has-miR-204-5p-STIL axis was screened out as the most potential upstream ncRNA-related pathway of STIL in HCC. Moreover, STIL expression is highly associated with the infiltration of immune cells, the expression of immune checkpoints, as well as the survival benefit of immunotherapy/chemotherapy. Conclusions Our study discloses that ncRNAs-mediated overexpression of STIL independently predicted poor prognosis and correlated with the efficacy of PD-1-targeted immunotherapy in HCC.

Human mesenchymal stem cells differentiate in response to mechanical adhesive interactions in their microenvironment. Here, the authors develop a culture platform that can dynamically mimic the cell-cell and cell-extracellular matrix interactions associated with development and mesenchymal differentiation in vivo.

Abstract Background Thoracoscopic segmentectomy is a common surgical procedure in thoracic surgery today. However, identifying the intersegmental plane is difficult in the surgical process. Therefore, we evaluated the feasibility of the arterial ligation method for determining the intersegmental plane and compared the demarcation status with the intravenous indocyanine green (ICG). Methods We retrospectively reviewed the records of 35 patients with peripheral small lung nodules who underwent thoracoscopic segmentectomy between May and December 2020. First, the preoperative three-dimensional reconstruction was performed to distinguish the location of lung nodules and the anatomical structures of targeted segmental arteries, veins, and bronchi. Second, the targeted segmental arteries were ligated, and the intersegmental plane was determined by the inflation-deflation technique. The waiting time for the appearance of the inflation-deflation line was recorded. Thirdly, the intersegmental plane was identified again using the ICG fluorescence method. Finally, the consistency of the two intersegmental planes was evaluated. Results The intersegmental planes were successfully observed in all patients using the arterial ligation method. Thirty-four patients underwent segmentectomy as planned, and one patient finally underwent lobectomy due to insufficient surgical margin. The waiting time for the appearance of the intersegmental plane by arterial ligation method was 13.7 ± 3.2 min (6–19 min). The intersegmental planes determined by the arterial ligation method and the ICG fluorescence method were comparable, with a maximum distance of no more than 5 mm between the two planes. The mean operative duration was 119.1 ± 34.9 min, and the mean blood loss was 76.9 ± 70.3 ml. No evident air leakage was found during the operation. Only one patient experienced a prolonged air leak (≥ 5 days) during the postoperative recovery. No atelectasis occurred in all cases. The chest tube duration was 3.1 ± 0.9 days. Conclusion The arterial ligation method can efficiently and accurately identify the intersegmental plane, comparable to the ICG fluorescence method.

T cell immune responses are critical for in both physiological and pathological processes. While biochemical cues are important, mechanical cues arising from the microenvironment have also been found to act a significant role in regulating various T cell immune responses, including activation, cytokine production, metabolism, proliferation, and migration. The immune synapse contains force-sensitive receptors that convert these mechanical cues into biochemical signals. This phenomenon is accepted in the emerging research field of immunomechanobiology. In this review, we provide insights into immunomechanobiology, with a specific focus on how mechanosensitive receptors are bound and triggered, and ultimately resulting T cell immune responses.

Abstract Background The lobar and segmental anatomy are the basis for anatomical pulmonary segmentectomy. Methods From October 2017 to June 2021, 136 patients with small pulmonary nodules scheduled for anatomical pulmonary segmentectomy at our institution underwent three‐dimensional (3D) lung reconstruction. The anatomy of the left upper lobe (LUL) was statistically analyzed and graphically mapped using the reconstructed models, and the role of this reconstruction method in performing pulmonary segmentectomy was explored. Results Through the analysis of the reconstructed models, the upper stem (S1 + 2 + 3) bronchus was classified as having two (94/136 cases) or three branches (42/136 cases). The upper stem artery had two branches in 24/136 patients, three in 60/136 cases, four in 44/136 cases, and five in 8/136 cases. A total of 103/136 upper stem veins had two branches, 26/136 had three branches, and 7/136 had four branches. The lingual stem (S4 + 5) bronchus was two‐branched in 116/136 cases and three‐branched in 20/136 cases, while the lingual artery was single‐branched in 61/136 cases, two‐branched in 70/136 cases, and three‐branched in rare cases (5/136 cases). The lingual stem vein was unbranched in 119/136 cases and two‐branched in 17/136 cases. Additionally, six unusual variants (

Patients with stage III lung adenocarcinoma (LUAD) have significant survival heterogeneity, meanwhile, CD8+ T cell has a remarkable function in immunotherapy. Therefore, developing novel biomarkers based on CD8+ T cell can help evaluate the prognosis and guide the strategy of immunotherapy for patients with stage III LUAD. Thus, we abstracted twelve datasets from multiple online databases and grouped the stage III LUAD patients into training and validation sets. We then used WGCNA and CIBERSORT, while univariate Cox analysis, LASSO analysis, and multivariate Cox analysis were performed. Subsequently, a novel CD8+ T cell-related classifier including HDFRP3, ARIH1, SMAD2, and UPB1 was developed, which could divide stage III LUAD patients into high- and low-risk groups with distinct survival probability in multiple cohorts (all P < 0.05). Moreover, a robust nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its powerful predictive capacity. Besides, we detected the difference in immune cell subpopulations and evaluated the potential benefits of immunotherapy between the two risk subsets. Finally, we verified the correlation between the gene expression and CD8+ T cells included in the model by immunohistochemistry and validated the validity of the model in a real-world cohort. Overall, we constructed a robust CD8+ T cell-related risk model originally which could predict the survival rates in stage III LUAD. What’s more, this model suggested that patients in the high-risk group could benefit from immunotherapy, which has significant implications for accurately predicting the effect of immunotherapy and evaluating the prognosis for patients with stage III LUAD.

BackgroundTriple negative breast cancer (TNBC) is characterized by poor prognosis and a lack of effective therapeutic agents owing to the absence of biomarkers. A high abundance of tumor-infiltrating regulatory T cells (Tregs) was associated with worse prognosis in malignant disease. Exploring the association between Treg cell infiltration and TNBC will provide new insights for understanding TNBC immunosuppression and may pave the way for developing novel immune-based treatments.Materials and MethodsPatients from TCGA were divided into Treg-high (Treg-H) and Treg-low (Treg-L) groups based on the abundance of Tregs according to CIBERSORT analysis. The association between expression level of Tregs and the clinical characteristics as well as prognosis of breast cancer were evaluated. Next, a Treg-related prognostic model was established after survival-dependent univariate Cox and LASSO regression analysis, companied with an external GEO cohort validation. Then, GO, KEGG and GSEA analyses were performed between the Treg-H and Treg-L groups. Masson and Sirius red/Fast Green staining were applied for ECM characterization. Accordingly, Jurkat T cells were encapsulated in 3D collagen to mimic the ECM microenvironment, and the expression levels of CD4, FOXP3 and CD25 were quantified according to immunofluorescence staining.ResultsThe expression level of Tregs is significantly associated with the clinical characteristics of breast cancer patients, and a high level of Treg cell expression indicates a poor prognosis in TNBC. To further evaluate this, a Treg-related prognostic model was established that accurately predicted outcomes in both TCGA training and GEO validation cohorts of TNBC patients. Subsequently, ECM-associated signaling pathways were identified between the Treg-H and Treg-L groups, indicating the role of ECM in Treg infiltration. Since we found increasing collagen concentrations in TNBC patients with distant migration, we encapsulated Jurkat T cells within a 3D matrix with different collagen concentrations and observed that increasing collagen concentrations promoted the expression of Treg biomarkers, supporting the regulatory role of ECM in Treg infiltration.ConclusionOur results support the association between Treg expression and breast cancer progression as well as prognosis in the TNBC subtype. Moreover, increasing collagen density may promote Treg infiltration, and thus induce an immunosuppressed TME.

Background: Anti-silencing function 1B (ASF1B), a histone H3-H4 chaperone, is crucial for S-phase progression and cell proliferation. Recent studies have shown that ASF1B may be used as a new proliferation marker for cancer prognosis. However, the prognostic value and effect of ASF1B on tumor cells and the immune microenvironment in hepatocellular carcinoma (HCC) remain unclear.Methods: We analyzed the expression of ASF1B and its prognostic value using The Cancer Genome Atlas (TCGA) database (as a training set) and other databases, and we validated the findings by immunohistochemistry in our clinical database, containing 141 HCC patients (as a validation set). Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to probe the tumor-associated biological processes of ASF1B in HCC. The interrelationships between ASF1B expression and tumor immunological characteristics were analyzed by multiple databases. The Imvigor210 cohort was retrieved to assess the ability of ASF1B to predict immunotherapy efficacy.Results: ASF1B was highly expressed in tumor tissue compared to paracancerous tissue. High ASF1B expression was associated with worse overall survival (OS) and progression-free survival (PFS) in the training set (p = 0.005, p < 0.001) and validation set (p < 0.001, p < 0.001). Multivariate analysis revealed that ASF1B was an independent prognostic factor associated with OS and PFS. GSEA and GSVA suggested that ASF1B was involved in tumor-associated biological processes, including the cell cycle, DNA replication, base excision repair, mismatch repair, RNA degradation, ubiquitin-mediated proteolysis, and nucleotide excision repair. Further analysis revealed that the levels of ASF1B were positively correlated with the immune cells infiltration of B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells. However, ASF1B was positively correlated with Treg cell infiltration and inhibitory immune checkpoints in exhausted T cells. Patients who received anti-PD-L1 immunotherapy with high ASF1B expression had a higher objective response.Conclusion: The ASF1B level is an independent prognostic factor and may serve as a potential immunotherapeutic target.

BackgroundBreast cancer progression has been gradually recognized as a bidirectional interaction between cancer cells and tumor microenvironment including stroma cells, immune cells, and the dynamically altered ECM. However, there still lacks direct experimental evidences about how ECM properties modulate the activities of stroma and immune cells.MethodThe transcriptomic data and corresponding clinical information of breast cancer pawere obtained from TCGA. Patients were divided into ECM-high, ECM-median and ECM-low groups based on ssGSEA scores of C-ECM genes. The prognostic value of ECM was confirmed by univariate/multivariate Cox regression and survival analyses. GO and KEGG analyses were performed between ECM-high and -low groups. Then associations between ECM characteristics and clinical stages were verified by Masson’s trichrome and Sirius red/Fast Green staining of clinical breast cancer tissues. To evaluate the effects of ECM on CAF induction and T cell activation, the MRC-5, NIH/3T-3, primary T cells and Jurkat T cells were encapsulated in 3D collagen with different densities and organizations, and the expression levels of CAF biomarkers and secretion levels of IL-2 were assessed.ResultsECM scores showed broad variation across paracancerous and cancer samples as well as breast cancer molecular subtypes, and patients with different ECM groups showed distinct prognosis. Immunological activity and ECM associated biology processes were identified by GO and KEGG analyses across ECM-high and -low groups. According to MCP-counter algorithm, the infiltration of T cells was significantly lower in the ECM-high group, while CAF abundance was significantly higher. It is furtherly confirmed by clinical samples that collagen density and organization were associate with breast cancer progression. Finally, in vitro 3D-cultured fibroblasts and T cells validated that the density and organization of collagen showed significant effects on CAF induction and T cell activation.ConclusionOur study revealed a new mechanism of T cell immunosuppression and CAF induction, which could be of central importance for the breast cancer invasion and may constitute novel therapeutic targets to improve breast cancer outcomes.

Abstract Electroacupuncture (EA) is a therapeutic modality in which the electrical stimulation is integrated with concepts of acupuncture to treat diseases. This study was designed to evaluate the connection between the electro-acupuncture induced increase in Na99mTcO4 uptake in the stomach wall, and the ionic molecule levels in the extracellular fluid in the acupoints. Wistar rats were treated by 2 or 100 Hz EA at Zusanli (ST 36) and Xiajuxu (ST 39) bilaterally for 60 minutes. The accumulation of Na99mTcO4 in the gastric wall and the free ions, including Ca2+, K+, Na+, and Cl−, in the acupoints were measured every 60 minutes. The radioactivity uptake in the stomach was significantly increased during EA, reaching peak at 180 minutes after the EA. The concentration of extracellular ions was also significantly increased during EA. The Ca2+ level continued to rise until 60 minutes after EA, then started to decrease at 120 minutes post-EA. The results suggest this up-regulatory effect of EA on gastric activity might be triggered by the increase of the extracellular ion levels, this effect lasts longer than stimulating the release of transmembrane Ca2+ flow alone. This might aid in providing a better understanding of the long-lasting effect claimed in acupuncture treatment.

Abstract Background As 3D printing technology emerge, there is increasing demand for a more customizable implant in the repair of chest-wall bony defects. This article aims to present a custom design and fabrication method for repairing bony defects of the chest wall following tumour resection, which utilizes three-dimensional (3D) printing and rapid-prototyping technology. Methods A 3D model of the bony defect was generated after acquiring helical CT data. A customized prosthesis was then designed using computer-aided design (CAD) and mirroring technology, and fabricated using titanium-alloy powder. The mechanical properties of the printed prosthesis were investigated using ANSYS software. Results The yield strength of the titanium-alloy prosthesis was 950 ± 14 MPa (mean ± SD), and its ultimate strength was 1005 ± 26 MPa. The 3D finite element analyses revealed that the equivalent stress distribution of each prosthesis was unifrom. The symmetry and reconstruction quality contour of the repaired chest wall was satisfactory. No rejection or infection occurred during the 6-month follow-up period. Conclusion Chest-wall reconstruction with a customized titanium-alloy prosthesis is a reliable technique for repairing bony defects.

Introduction: This study aims to identify the prognostic factors that influence therapeutic modalities for thyroid carcinoma showing thymus-like elements (CASTLE).Materials and Methods: Reported studies with CASTLE patients published between 2004 and 2018 were retrieved from a cross-database literature search. Three patients treated in our institute were also included as one case series. Standardized data collection was performed; data pertaining to clinical stages, treatment regimens, and survival time were collected and statistically analyzed.Results: Up to 26 case series of CASTLE were selected, including 51 males and 38 females with a median age of 48 years. Follow-up time ranged from 2 to 362 months and the median survival time was 158.03 months. Lymph node metastasis and tumor invasion of adjacent tissue both showed a significant negative effect on survival (p = 0.001 and 0.013, respectively). Radiotherapy significantly improved survival (p = 0.034), while neck dissection significantly prolonged survival only in patients with extrathyroidal extension (p = 0.043).Conclusions: Extrathyroidal infiltration and nodal metastasis are important factors in cancer outcomes. Radiation therapy appears to be important for better outcomes in CASTLE patients, and neck dissection is recommended for patients with extrathyroidal extension.

Patients with stage III lung adenocarcinoma (LUAD) have significant survival heterogeneity, meanwhile, CD8+ T cell has a remarkable function in immunotherapy. Therefore, developing novel biomarkers based on CD8+ T cell can help evaluate the prognosis and guide the strategy of immunotherapy for patients with stage III LUAD. Thus, we abstracted twelve datasets from multiple online databases and grouped the stage III LUAD patients into training and validation sets. We then used WGCNA and CIBERSORT, while univariate Cox analysis, LASSO analysis, and multivariate Cox analysis were performed. Subsequently, a novel CD8+ T cell-related classifier including HDFRP3, ARIH1, SMAD2, and UPB1 was developed, which could divide stage III LUAD patients into high- and low-risk groups with distinct survival probability in multiple cohorts (all P < 0.05). Moreover, a robust nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its powerful predictive capacity. Besides, we detected the difference in immune cell subpopulations and evaluated the potential benefits of immunotherapy between the two risk subsets. Finally, we verified the correlation between the gene expression and CD8+ T cells included in the model by immunohistochemistry and validated the validity of the model in a real-world cohort. Overall, we constructed a robust CD8+ T cell- related risk model originally which could predict the survival rates in stage III LUAD. What's more, this model suggested that patients in the high-risk group could benefit from immunotherapy, which has significant implications for accurately predicting the effect of immunotherapy and evaluating the prognosis for patients with stage III LUAD. [ABSTRACT FROM AUTHOR]