CTpathway: A Crosstalk-Based Pathway Enrichment Analysis Method for Cancer Research

Background: Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated. Methods: To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with \u3e440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in GPCM, we assign a risk score to genes in the GPCM and identify risk pathways enriched with the risk genes. Results: Analysis of \u3e8300 expression profiles covering ten cancer tissues and blood samples indicates that CTpathway outperforms the current state-of-the-art methods in identifying risk pathways with higher accuracy, reproducibility, and speed. CTpathway recapitulates known risk pathways and exclusively identifies several previously unreported critical pathways for individual cancer types. CTpathway also outperforms other methods in identifying risk pathways across all cancer stages, including early-stage cancer with a small number of differentially expressed genes. Moreover, the robust design of CTpathway enables researchers to analyze both bulk and single-cell RNA-seq profiles to predict both cancer tissue and cell type-specific risk pathways with higher accuracy. Conclusions: Collectively, CTpathway is a fast, accurate, and stable pathway enrichment analysis method for cancer research that can be used to identify cancer risk pathways. The CTpathway interactive web server can be accessed here http://www.jianglab.cn/CTpathway/ . The stand-alone program can be accessed here https://github.com/Bioccjw/CTpathway

Experimental Study on Fatigue Behaviour of Shot-Peened Open-Hole Steel Plates

This paper presents an experimental study on the fatigue behaviour of shot-peened open-hole plates with Q345 steel. The beneficial effects induced by shot peening on the fatigue life improvement are highlighted. The characteristic fatigue crack initiation and propagation modes of open-hole details under fatigue loading are revealed. The surface hardening effect brought by the shot peening is analyzed from the aspects of in-depth micro-hardness and compressive residual stress. The fatigue life results are evaluated and related design suggestions are made as a comparison with codified detail categories. In particular, a fracture mechanics theory-based method is proposed and demonstrated its validity in predicting the fatigue life of studied shot-peened open-hole details

Lateral wall osteotomy combined with embedded biodegradable implants for displaced intra-articular calcaneal fractures

Abstract Background The extensile lateral approach (ELA) has been widely used to treat displaced intra-articular calcaneal fractures (DIACFs) and remains the gold standard procedure. Orthopedic surgeons are extremely concerned of the high rate of wound complications. This study intended to report a new surgical technique of the lateral wall osteotomy combined with an embedded biodegradable implant for treating DIACFs and assess clinical and radiological results. Methods From May 2013 to December 2015, a total of 17 patients with 19 calcaneal fractures underwent surgical treatment using our new technique. Radiographic images, computed tomography (CT) scans, and magnetic resonance (MR) images of the operative limb were obtained to assess fracture healing and biodegradable implant degradation. American Orthopaedic Foot and Ankle Society (AOFAS) ankle/hindfoot score at the last follow-up was obtained to assess functional result for all cases. Böhler’s and Gissane’s angles, width, and height of the injured calcaneus were analyzed using preoperative and last follow-up radiographic images. Results All radiological parameters were significantly improved at the last follow-up, with an increase of 15.58°, 8.38°, and 7.65 mm in Böhler’s angle, Gissane’s angle, and calcaneal height, respectively, and a decrease of 2.51 mm in calcaneal width (p < 0.05). Mean AOFAS score at the last follow-up was 84.37 ± 9.98, with 9, 6, and 4 feet, having excellent, good, and fair rates, respectively. None had nonunion, delayed union, or malunion after a mean follow-up of 34.69 ± 5.22 months. One superficial infection occurred 6 days post-surgery. Conclusions Osteotomy of the lateral wall of the calcaneus allows tension-free suturing and avoids damage to penetrating branches of the lateral calcaneal artery (LCA). Biodegradable implants are easy to reshape and do not require surgical removal. However, they should be limited to Sander’s type II and III fractures only. Level of evidence Level IV, case series without control

Mesenchymal stromal cells: promising treatment for liver cirrhosis

Abstract Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future

Table2_Identification of effective diagnostic biomarker and immune cell infiltration characteristics in acute liver failure by integrating bioinformatics analysis and machine-learning strategies.xlsx

Background: To determine effective biomarkers for the diagnosis of acute liver failure (ALF) and explore the characteristics of the immune cell infiltration of ALF.Methods: We analyzed the differentially expressed genes (DEGs) between ALF and control samples in GSE38941, GSE62029, GSE96851, GSE120652, and merged datasets. Co-expressed DEGs (co-DEGs) identified from the five datasets were analyzed for enrichment analysis. We further constructed a PPI network of co-DEGs using the STRING database. Then, we integrated the two kinds of machine-learning strategies to identify diagnostic biomarkers of top hub genes screened based on MCC and Degree methods. And the potential diagnostic performance of the biomarkers for ALF was estimated using the AUC values. Data from GSE14668, GSE74000, and GSE96851 databases was performed as external verification sets to validate the expression level of potential diagnostic biomarkers. Furthermore, we analyzed the difference in the protein level of diagnostic biomarkers between normal and ALF mice models. Finally, we used CIBERSORT to estimate relative infiltration levels of 22 immune cell subsets in ALF samples and further analyzed the relationships between the diagnostic biomarkers and infiltrated immune cells.Results: A total of 200 co-DEGs were screened. Enrichment analyses depicted that they are highly enriched in metabolism and matrix collagen production-associated processes. The top 28 hub genes were obtained by integrating MCC and Degree methods. Then, the collagen type IV alpha 2 chain (COL4A2) was regarded as the diagnostic biomarker and showed excellent specificity and sensitivity. COL4A2 also showed a statistically significant difference and excellent diagnostic effectiveness in the verification set. In addition, there was a significant upregulation in the COL4A2 protein level in ALF mice models compared with the normal group. CIBERSORT analysis showed that activated CD4 T cells, plasma cells, macrophages, and monocytes may be implicated in the progress of ALF. In addition, COL4A2 showed different degrees of correlation with immune cells.Conclusion: In conclusion, COL4A2 may be a diagnostic biomarker for ALF, and immune cell infiltration may have important implications for the occurrence and progression of ALF.</p

Table1_Identification of effective diagnostic biomarker and immune cell infiltration characteristics in acute liver failure by integrating bioinformatics analysis and machine-learning strategies.xls

Background: To determine effective biomarkers for the diagnosis of acute liver failure (ALF) and explore the characteristics of the immune cell infiltration of ALF.Methods: We analyzed the differentially expressed genes (DEGs) between ALF and control samples in GSE38941, GSE62029, GSE96851, GSE120652, and merged datasets. Co-expressed DEGs (co-DEGs) identified from the five datasets were analyzed for enrichment analysis. We further constructed a PPI network of co-DEGs using the STRING database. Then, we integrated the two kinds of machine-learning strategies to identify diagnostic biomarkers of top hub genes screened based on MCC and Degree methods. And the potential diagnostic performance of the biomarkers for ALF was estimated using the AUC values. Data from GSE14668, GSE74000, and GSE96851 databases was performed as external verification sets to validate the expression level of potential diagnostic biomarkers. Furthermore, we analyzed the difference in the protein level of diagnostic biomarkers between normal and ALF mice models. Finally, we used CIBERSORT to estimate relative infiltration levels of 22 immune cell subsets in ALF samples and further analyzed the relationships between the diagnostic biomarkers and infiltrated immune cells.Results: A total of 200 co-DEGs were screened. Enrichment analyses depicted that they are highly enriched in metabolism and matrix collagen production-associated processes. The top 28 hub genes were obtained by integrating MCC and Degree methods. Then, the collagen type IV alpha 2 chain (COL4A2) was regarded as the diagnostic biomarker and showed excellent specificity and sensitivity. COL4A2 also showed a statistically significant difference and excellent diagnostic effectiveness in the verification set. In addition, there was a significant upregulation in the COL4A2 protein level in ALF mice models compared with the normal group. CIBERSORT analysis showed that activated CD4 T cells, plasma cells, macrophages, and monocytes may be implicated in the progress of ALF. In addition, COL4A2 showed different degrees of correlation with immune cells.Conclusion: In conclusion, COL4A2 may be a diagnostic biomarker for ALF, and immune cell infiltration may have important implications for the occurrence and progression of ALF.</p

Enhanced cellular compatibility of chitosan/collagen multilayers LBL modified nanofibrous mats

Developing novel, lightweight and biocompatible mesh for pelvic organ prolapse, a gynecological disease, has attracted the global interest of biomedical researchers. In our study, polycaprolactone and nylon 6 mats with excellent mechanical properties were fabricated via co-electrospinning. Positively charged chitosan with antimicrobial properties and negatively charged collagen with good biocompatibility were then assembled on the nanofiber mats via layer by layer (LBL) technology. SEM and mechanical property tests showed that LBL deposition increased the nanofibers’ diameter and elastic modulus. To evaluate the successful deposition process, the zeta potential, The Fourier-transform infrared, X-ray diffraction, and X-ray photoelectron spectroscopy analyses were conducted to systematically study the mats’ chemical characterization. The results indicated that the mats’ composition and structure significantly changed after LBL modification. Cell biology experiments demonstrated that the LBL-structured mats can facilitate cell growth, proliferation, and adhesion. Antibacterial tests confirmed their excellent antibacterial activity. Chitosan/Collagen-coated Polycaprolactone/Nylon 6 mats demonstrate considerable potential as implant materials for pelvic reestablishment in pelvic organ prolapse patients

Mitochondrial dysfunction: A promising therapeutic target for liver diseases

The liver is an important metabolic and detoxification organ and hence demands a large amount of energy, which is mainly produced by the mitochondria. Liver tissues of patients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mitochondrial lesions, mitochondrial DNA damage, disturbed mitochondrial dynamics, and compromised ATP production. Overproduction of mitochondrial reactive oxygen species induces oxidative damage to mitochondrial proteins and mitochondrial DNA, decreases mitochondrial membrane potential, triggers hepatocyte inflammation, and promotes programmed cell death, all of which impair liver function. Mitochondrial DNA may be a potential novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus. We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases, such as hepatocellular carcinoma, viral hepatitis, drug-induced liver injury, alcoholic liver disease, and non-alcoholic fatty liver disease. This review also discusses mitochondrion-centric therapies for treating liver diseases

scDR: Predicting Drug Response at Single-Cell Resolution

Heterogeneity exists inter- and intratumorally, which might lead to different drug responses. Therefore, it is extremely important to clarify the drug response at single-cell resolution. Here, we propose a precise single-cell drug response (scDR) prediction method for single-cell RNA sequencing (scRNA-seq) data. We calculated a drug-response score (DRS) for each cell by integrating drug-response genes (DRGs) and gene expression in scRNA-seq data. Then, scDR was validated through internal and external transcriptomics data from bulk RNA-seq and scRNA-seq of cell lines or patient tissues. In addition, scDR could be used to predict prognoses for BLCA, PAAD, and STAD tumor samples. Next, comparison with the existing method using 53,502 cells from 198 cancer cell lines showed the higher accuracy of scDR. Finally, we identified an intrinsic resistant cell subgroup in melanoma, and explored the possible mechanisms, such as cell cycle activation, by applying scDR to time series scRNA-seq data of dabrafenib treatment. Altogether, scDR was a credible method for drug response prediction at single-cell resolution, and helpful in drug resistant mechanism exploration