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Aims: Diffuse glioma is the most frequent intracranial tumor and remains universally lethal. Prognostic biomarkers have remained a focus in diffuse glioma during the last decades. More reliable predictors to adequately characterize the prognosis of diffuse glioma are essential. Cathepsin C (CTSC), a lysosomal cysteine protease, is an essential component of the lysosomal hydrolase family, with their potential roles in diffuse glioma remaining to be characterized Objective: We aimed to investigate the performance of CTSC in predicting prognosis and therapeutic targets in diffuse glioma. Method: The expression profile of CTSC in multiple tumors and more than 2000 glioma samples with corresponding clinical data were collected through authoritative public databases. The expression level of CTSC was evaluated by qPCR and IHC. The prognostic value of CTSC was assessed using the univariate and multivariate cox regression analysis. The ESTIMATE R package was used to evaluate the immune and stromal scores based on the gene expression profile. The CIBERSORT was applied to evaluate the relative levels of 22 immune cell subtypes by using the R package 'CIBERSORT' to define the cell composition of tumor tissues. In addition, the MCP counter was used to assess the absolute abundance of neutrophils. Result: CTSC was aberrantly expressed and significantly correlated with clinical outcomes in multiple tumors. CTSC was heterogeneously expressed across histologic types and tumor grades for diffuse glioma and highly enriched in IDH or IDH1-wildtype glioma. CTSC was positively associated with immune and stromal scores and infiltrating levels of M2 macrophages and neutrophils and negatively associated with infiltrating levels of NK cells. Additionally, CTSC was closely correlated with some immune checkpoint molecules, including CD276, CD80, CD86 and PD-L2. Conclusion: Conclusion: CTSC was involved in shaping the immunosuppressive microenvironment and acted as an independent indicator of a poor prognosis in diffuse glioma. Targeting CTSC for glioma therapies might provide promising prospects.

Tissue fibrosis is a key factor leading to disability and death worldwide; however, thus far, there are no approved treatments for fibrosis. Transforming growth factor (TGF)-β is a major pro-fibrotic cytokine, which is expected to become a target in the treatment of fibrosis; however, since TGF-β has a wide range of biological functions involving a variety of biological processes in the body, a slight change in TGF-β may have a systematic effect. Indiscriminate inhibition of TGF-β can lead to adverse reactions, which can affect the efficacy of treatment. Therefore, it has become very important to explore how both the TGF-β signaling pathway is inhibited and the safe and efficient TGF-β small molecule inhibitors or neutralizing antibodies are designed in the treatment of fibrotic diseases. In this review, we mainly discuss the key role of the TGF-β signaling pathway in fibrotic diseases, as well as the development of fibrotic drugs in recent years, and explore potential targets in the treatment of fibrotic diseases in order to guide subsequent drug development.

The self-renewal, pluripotency and differentiation of stem cells are regulated by various genetic and epigenetic factors. As a kind of RNA binding protein (RBP), the heterogeneous nuclear ribonucleoproteins (hnRNPs) can act as "RNA scaffold" and recruit mRNA, lncRNA, microRNA and circRNA to affect mRNA splicing and processing, regulate gene transcription and post-transcriptional translation, change genome structure, and ultimately play crucial roles in the biological processes of cells. Recent researches have demonstrated that hnRNPs are irreplaceable for self-renewal and differentiation of stem cells. hnRNPs function in stem cells by multiple mechanisms, which include regulating mRNA stability, inducing alternative splicing of mRNA, epigenetically regulate gene expression, and maintaining telomerase activity and telomere length. The functions and the underlying mechanisms of hnRNPs in stem cells deserve further investigation.

Rationale: Diffuse glioma patients have high mortality and recurrence despite multimodal therapies. This study aims to identify the potential tumor antigens for mRNA vaccines and subtypes suitable for the immunotherapy of patients with diffuse glioma. Methods: Gene expression profiles and corresponding clinical information were obtained from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) databases. Genetic alterations were extracted from cBioPortal. Differential gene analysis, survival analysis, correlation analysis, consensus clustering analysis, and immune cell infiltration analysis were conducted based on the various databases. Finally, the hub genes, the modules related to tumor antigens, and the immune subtypes were identified using WGCNA method. Results: Three over-expressed, amplified, and mutated tumor antigens, including KDR, COL1A2, and SAMD9, were associated with clinical outcomes. The expression of the three genes had a positive correlation with the abundance of antigen-presenting cells (APCs) and APC marker expression. Subsequently, three immune subtypes (Ims1, Ims2, and Ims3) were distinguished in the TCGA cohort, which exhibited distinct molecular, cellular, and clinical characteristics consistent with the CGGA cohort. Diffuse gliomas with subtype Ims1 were more malignant with immunosuppressive phenotypes and more associated with poor prognosis than the other two subtypes. The three antigens and the immune checkpoints were differentially expressed among the three immune subtypes. Finally, functional enrichment analysis of the genes related to tumor antigens and immune subtypes suggested that they are enriched in many immune-associated processes. Conclusions: KDR, COL1A2, and SAMD9 are potential antigens for developing mRNA vaccines against diffuse glioma. The results suggest that immunotherapy targeting these three antigens is more suitable for patients with subtype Ims1. This study provides insights into immunotherapy for diffuse glioma.

Stem cells are distinctive cells that have self-renewal potential and unique ability to differentiate into multiple functional cells. Stem cell is a frontier field of life science research and has always been a hot spot in biomedical research. Recent studies have shown that long non-coding RNAs (lncRNAs) have irreplaceable roles in stem cell self-renewal and differentiation. LncRNAs play crucial roles in stem cells through a variety of regulatory mechanisms, including the recruitment of RNA-binding proteins (RBPs) to affect the stability of their mRNAs or the expression of downstream genes. RBPs interact with different RNAs to regulate gene expression at transcriptional and post-transcriptional levels and play important roles in determining the fate of stem cells. In this review, the functions of lncRNAs and their RBPs in self-renewal and differentiation of stem cell are summarized. We focus on the four regulatory mechanisms by which lncRNAs and their RBPs are involved in epigenetic regulation, signaling pathway regulation, splicing, mRNA stability and subcellular localization and further discuss other noncoding RNAs (ncRNAs) and their RBPs in the fate of stem cells. This work provides a more comprehensive understanding of the roles of lncRNAs in determining the fate of stem cells, and a further understanding of their regulatory mechanisms will provide a theoretical basis for the development of clinical regenerative medicine.

3D collagen scaffold culture is a good tool to study glioma metastasis and recurrence in vitro.The effect of 3D collagen culture on the colony formation, the sphere formation, and drug sensitivity of glioma cells was observed by soft-agar colony formation assays, sphere formation assays, and CCK-8 assays, respectively. 3D-glioma-drug genes were identified by previous results and online databases. Gene enrichment and PPI analyses were performed by R software and Metacsape. Hub 3D-glioma-drug genes were screened by STRING and Cytoscape. TCGA and CGGA databases and R software were used to analyze the distribution of hub genes in glioma and their effects on the prognosis. Western Blot was used to verify the effect of 3D collagen culture on the expression of hub genes. miRNAs targeting hub genes were predicted by ENCORI.3D collagen scaffold culture promoted colony formation, sphere formation, and drug resistance of glioma cells. There were 77 3D-glioma-drug genes screened, and the pathways enriched in the protein interaction network mainly included responses to stressors, DNA damage and repair, and drug metabolism. Hub 3D-glioma-drug genes were AKT1, ATM, CASP3, CCND1, EGFR, PARP1, and TP53. These genes and predicted miRNAs were expressed differentially in glioma samples and partially affected the prognosis of patients with glioma. These findings suggested these hub genes and miRNAs may play a key role in the effects generated by the 3D culture model and become new markers for glioma diagnosis and treatment.

Metastasis is the main cause of death in patients with nasopharyngeal carcinoma (NPC). The molecular mechanisms underlying the metastasis of NPC remain to be elucidated. TBL1X has been shown abnormally expressed in diverse cancers. However, the role and mechanism of TBL1X in NPC remain unknown. Here, we showed TBL1X expression was significantly higher in metastatic NPC tissues compared to non-metastatic tissues and significantly correlated with TNM stage and metastasis of NPC patients. In addition, NPC patients with high TBL1X expression had a poor prognosis. TBL1X interacted with TCF4 to trans-activate Flot2 expression. TBL1X promoted NPC cell migration and invasion in vitro and

Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory coronavirus 2 is currently spreading throughout the world with a high rate of infection and mortality and poses a huge threat to global public health. COVID-19 primarily manifests as hypoxic respiratory failure and acute respiratory distress syndrome, which can lead to multiple organ failure. Despite advances in the supportive care approaches, there is still a lack of clinically effective therapies, and there is an urgent need to develop novel strategies to fight this disease. Currently, stem cell therapy and stem cell-derived organoid models have received extensive attention as a new treatment and research method for COVID-19. Here, we discuss how stem cells play a role in the battle against COVID-19 and present a systematic review and prospective of the study on stem cell treatment and organoid models of COVID-19, which provides a reference for the effective control of the COVID-19 pandemic worldwide.

Scar tissue removal combined with biomaterial implantation is considered an effective measure to repair chronic transected spinal cord injury (SCI). However, whether more scar tissue removal surgeries could affect the treatment effects of biomaterial implantation still needs to be explored. In this study, we performed the first scar tissue removal surgery in the 3rd month and the second in the 6th month after completely removing 1 cm of spinal tissue in canines. We found that Taxol-modified linear ordered collagen scaffold (LOCS + Taxol) implantation could promote axonal regeneration, neurogenesis, and electrophysiological and functional recovery only in canines at the first scar tissue removal surgery, but not in canines at the second scar tissue removal surgery. Interestingly, we found that more endogenous neural stem cells (NSCs) around the injured site could be activated in canines with the first rather than the second scar tissue removal. Furthermore, we demonstrated that Taxol could promote the neuronal differentiation of NSCs in the myelin inhibition microenvironment through the p38 MAPK signaling pathway in vitro. Therefore, we speculated that endogenous NSC activation by the first scar tissue removal surgery and its further differentiation into neurons induced by Taxol may contribute to functional recovery in canines. Together, LOCS + Taxol implantation in combination with the first scar tissue removal provides a promising therapy for chronic long-distance transected SCI repair with the help of scar tissue removal activated endogenous NSCs.

Background Gliomas account for the majority of fatal primary brain tumors, and there is much room for research in the underlying pathogenesis, the multistep progression of glioma, and how to improve survival. In our study, we aimed to identify potential biomarkers or therapeutic targets of glioma and study the mechanism underlying the tumor progression. Methods We downloaded the microarray datasets (GSE43378 and GSE7696) from the Gene Expression Omnibus (GEO) database. Then, we used weighted gene co-expression network analysis (WGCNA) to screen potential biomarkers or therapeutic targets related to the tumor progression. ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumors using Expression data) algorithm and TIMER (Tumor Immune Estimation Resource) database were used to analyze the correlation between the selected genes and the tumor microenvironment. Real-time reverse transcription polymerase chain reaction was used to measure the selected gene. Transwell and wound healing assays were used to measure the cell migration and invasion capacity. Western blotting was used to test the expression of epithelial-mesenchymal transition (EMT) related markers. Results We identified specific module genes that were positively correlated with the WHO grade but negatively correlated with OS of glioma. Importantly, we identified that 6 collagen genes (COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, and COL5A2) could regulate the immunosuppressive microenvironment of glioma. Moreover, we found that these collagen genes were significantly involved in the EMT process of glioma. Finally, taking COL3A1 as a further research object, the results showed that knockdown of COL3A1 significantly inhibited the migration, invasion, and EMT process of SHG44 and A172 cells. Conclusions In summary, our study demonstrated that collagen genes play an important role in regulating the immunosuppressive microenvironment and EMT process of glioma and could serve as potential therapeutic targets for glioma management.

Methyltransferase-like 7B (METTL7B) is a member of the methyltransferase-like protein family that plays an important role in the development and progression of tumors. However, its prognostic value and the correlation of METTL7B expression and tumor immunity in some cancers remain unclear. By analyzing online data, we found that METTL7B is abnormally overexpressed in multiple human tumors and plays an important role in the overall survival (OS) of patients with 8 cancer types and disease-free survival (DFS) of patients with 5 cancer types. Remarkably, METTL7B expression was positively correlated with the OS and DFS of patients with lower-grade glioma (LGG). In addition, a positive correlation between METTL7B expression and immune cell infiltration in LGG was observed. Moreover, we identified a strong correlation between METTL7B expression and immune checkpoint gene expression in kidney chromophobe (KICH), LGG and pheochromocytoma and paraganglioma (PCPG). Furthermore, METTL7B was involved in the extracellular matrix (ECM) and immune-related pathways in LGGs. Finally, in vitro experiments showed that knockdown of METTL7B inhibited the growth, migration, invasion and the epithelial–mesenchymal transition (EMT) of LGG cells. METTL7B expression potentially represents a novel prognostic biomarker due to its significant association with immune cell infiltration in LGG.

IntroductionGlioma is the most common primary cancer of the central nervous system with dismal prognosis. Long noncoding RNAs (lncRNAs) have been discovered to play key roles in tumorigenesis in various cancers, including glioma. Because of the relevance between immune infiltrating and clinical outcome of glioma, identifying immune-related lncRNAs is urgent for better personalized management.Materials and methodsSingle-sample gene set enrichment analysis (ssGSEA) was applied to estimate immune infiltration, and glioma samples were divided into high immune cell infiltration group and low immune cell infiltration group. After screening differentially expressed lncRNAs in two immune groups, least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct an immune-related prognostic signature. Additionally, we explored the correlation between immune infiltration and the prognostic signature.ResultsA total of 653 samples were appropriate for further analyses, and 10 lncRNAs were identified as immune-related lncRNAs in glioma. After univariate Cox regression and LASSO Cox regression analysis, six lncRNAs were identified to construct a prognostic signature for glioma, which could be taken as independent prognostic factors in both univariate and multivariate Cox regression analyses. Moreover, risk score was significantly correlated with all the 29 immune-related checkpoint expression (p < 0.05) in ssGSEA except neutrophils (p = 0.43).ConclusionThe study constructed an immune-related prognostic signature for glioma, which contributed to improve clinical outcome prediction and guide immunotherapy.

Additional file 8: Fig. S8.. The original data of the experimental validation.

ObjectiveTo describe and evaluate the impact of diseases control and prevention on epidemics dynamics and clinical features of SARS-CoV-2 outbreak in Shanghai.DesignA retrospective descriptive studySettingChinaParticipantsEpidemiology information was collected from publicly accessible database. 265 patients admitted to Shanghai Public Health Center with confirmed COVID-19 were enrolled for clinical features analysis.Main outcome measurePrevention and control measures taken by Shanghai government, epidemiological, demographic, clinical, laboratory and radiology data were collected. Weibull distribution, Chi-square test, Fisher’s exact test, t test or Mann-Whitney U test were used in statistical analysis.ResultsCOVID-19 transmission rate within Shanghai had reduced over 99% than previous speculated, and the exponential growth has been stopped so far. Epidemic was characterized by the first stage mainly composed of imported cases and the second stage where >50% of cases were local. The incubation period was 6.4 (95% CI 5.3 to 7.6) days and the mean onset-admission interval was 5.5 days (95% CI, 5.1 to 5.9). Median time for COVID-19 progressed to severe diseases were 8.5 days (IQR: 4.8-11.0 days). By February 11th, proportion of patients being mild, moderate, severe and critically ill were 1.9%(5/265), 89.8%(238/265), 3.8%(10/265), 4.5%(12/265), respectively; 47 people in our cohort were discharged, and 1 patient died.ConclusionStrict controlling of the transmission rate at the early stage of an epidemic in metropolis can quickly prohibit the spread of the diseases. Controlling local clusters is the key to prevent outbreaks from imported cases. Most COVID-19 severe cases progressed within 14 days of disease onset. Multiple systemic laboratory abnormalities had been observed before significant respiratory dysfunction.

Phospholipase C (PLC) is a pivotal enzyme in the phosphoinositide pathway that promotes the second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), to participate in eukaryotic signal transduction. Several PLC isozymes are associated with cancer, such as PLC-β1, PLC-δ1, PLC-e and PLC-γ1. However, the role of PLC-δ3 (PLCD3) in nasopharyngeal carcinoma (NPC) has not been investigated to date. In our previous study, we demonstrated that flotillin2 (Flot2) plays a pro-neoplastic role in NPC and is involved in tumour progression and metastasis. In the present study, we screened the interacting proteins of Flot2 using the yeast two-hybrid (Y2H) method and verified the interaction between PLCD3 and Flot2 by co-immunoprecipitation. We also investigated the biological functions of PLCD3 in NPC. Inhibition of PLCD3 expression impaired the malignant potential of 5-8F, a highly metastatic NPC cell line, by restraining its growth, proliferation, mobility and migration. The present study demonstrated that PLCD3 may be an oncogenic protein in NPC and that it plays an important role in the progression of NPC partially by interacting with Flot2.

Lung cancer, similar to other chronic diseases, occurs due to perturbations in multiple signaling pathways. Mono-targeted therapies are not ideal since they are not likely to be effective for the treatment and prevention of lung cancer, and are often associated with drug resistance. Therefore, the development of multi-targeted agents is required for novel lung cancer therapies. Thioredoxin reductase (TrxR or TXNRD1) is a pivotal component of the thioredoxin (Trx) system. Various types of tumor cells are able to overexpress TrxR/Trx proteins in order to maintain tumor survival, and this overexpression has been shown to be associated with clinical outcomes, including irradiation and drug resistance. Emerging evidence has indicated that oleanolic acid (OA) and its derivatives exhibit potent anticancer activity, and are able to overcome drug resistance in cancer cell lines. In the present study, it was demonstrated that a novel synthesized OA family compound, olean-28,13b-olide 2 (OLO-2), synergistically enhanced cisplatin (CDDP)-mediated apoptosis, led to the activation of caspase-3 and the generation of reactive oxygen species (ROS), induced DNA damage, and inhibited the activation of the extracellular-signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), AKT and nuclear factor-κB (NF-κB) pathways in human multidrug-resistant A549/CDDP lung adenocarcinoma cells. Subsequent analyses revealed that OLO-2 inhibited P-glycoprotein (P-gp or ABCB1) and TrxR by reducing their expression at the protein and mRNA levels, and by suppressing P-gp ATPase and TrxR activities. Further biological evaluation indicated that OLO-2 significantly reduced Trx and excision repair cross-complementary1 (ERCC1) protein expression and significantly inhibited the proliferation of drug-sensitive (A549) and multidrug-resistant (A549/CDDP) non-small cell lung cancer (NSCLC) cells, but had no effect on non-tumor lung epithelial-like cells. In addition, the present study demonstrated, for the first time, to the best of our knowledge, that overexpressing or knocking down TrxR in NSCLC cells enhanced or attenuated, respectively, the resistance of NSCLC cells against CDDP, which indicated that TrxR plays an important role in CDDP resistance and functions as a protector of NSCLC against chemotherapeutic drugs. OLO-2 treatment also exhibited up to 4.6-fold selectivity against human lung adenocarcinoma cells. Taken together, the results of the present study shed light on the drug resistance-reversing effects of OLO-2 in lung cancer cells.

Previously, we confirmed the anti-tumor effects of sodium butyrate (NaBu) in nasopharyngeal carcinoma (NPC). However, its molecular mechanisms have not be fully elucidated. In this study, we studied the effects of NaBu on autophagy and explored the relation between NaBu associated autophagy and apoptosis in NPC cells. EGFP-LC3 plasmids were introduced into NPC cells to observed the effects of NaBu on autophagy flux with or without chloroquine (CQ) addition. Autophagy markers were also detected by Western blot. Under NaBu treatment, autophagy and apoptosis markers were detected simultaneously at different time. Then, to explore the roles of autophagy in NaBu induced apoptosis, the effects of autophagy inhibition, via specific inhibitor treatment or key gene knockdown, were analyzed. At last, the upstream signaling and its roles in NaBu induced autophagy and apoptosis were also analyzed. Increased LC3 dots and LC3-II accumulation indicated that NaBu can promote autophagy flux in NPC cells. LC3-II accumulation was earlier than cleaved PARP increment suggesting autophagy activation is prior to apoptosis activation, which was validated by flow cytometry mediated apoptosis analysis. Moreover, autophagy inhibition, achieved by 3-MA treatment or BECN1 knockdown, can antagonize NaBu induced apoptosis reflecting by re-deregulated cPARP and apoptotic rates. Furthermore, NaBu treatment inhibited the AKT/mTOR axis indicated by deregulated p-AKT(S473) and p-mTOR(S2448) and ectopic AKT expression both suppressed NaBu induced autophagy and apoptosis. At last, Western blot showed that HDAC6 dependent EGFR deregulation may account for the NaBu associated AKT/mTOR inhibition. NaBu can induce autophagic apoptosis via suppressing AKT/mTOR axis in NPC cells. Our results suggest that combination of autophagy inhibitors and deacetylase inhibitors may not be recommended in NPC clinical treatment.

Three-dimensional (3D) culture has been increasingly used to investigate tumor cell biology for improved simulation of the natural developing environment. However, the way in which 3D culture affects the gene expression and biological functions of glioma cells remains to be fully elucidated. In the present study, 3D culture environments were established using collagen scaffolds with different pore sizes, followed by the comparison of gene expression profiles and associated biological functions of glioma cells, including the U87, U251 and HS683 cell lines, in 3D collagen scaffolds with conventional two-dimensional (2D) cultured cells. Finally, the possible signaling pathways regulating these differences were investigated. It was found that the 3D collagen scaffold culture upregulated the expression of genes associated with stemness, cell cycle, apoptosis, epithelia-mesenchymal transition, migration, invasion and glioma malignancy, and induced the corresponding functional changes. Apoptotic pathways, the Wnt pathway, Sonic Hedgehog pathway and Notch pathway, may be involved in the regulation of these changes. The aperture size of the collagen-scaffold did not appear to affect the gene expression or functions of the glioma cells. The results of the study suggested that the 3D collagen scaffold enhanced the malignancy of glioma cells and may be a promising in vitro platform for investigations of glioma.

Treatment of spinal cord injury (SCI) remains a clinical challenge worldwide because of the complicated inhibitory microenvironment formed post-injury, reduced axonal regenerative ability of spinal cord neurons, and scarcity of endogenous neurogenesis within the lesion center. Taxol, in addition to stabilizing microtubules, has shown potential for decreasing axonal degeneration and reducing scar formation after SCI in rodents. In this study, we further verified the therapeutic effects and clinical potential of Taxol on restriction of scar formation and promotion of neuronal regeneration and functional recovery after severe spinal cord transection in a large animal (canine) model. A linear-ordered collagen scaffold (LOCS) combined with Taxol was implanted into the injury site after the complete removal of 1 cm of spinal tissue. Afterwards, diligent nursing and multi-system rehabilitation were carried out during a half-year period of observation. The results showed that LOCS + Taxol implantation markedly promoted motor-evoked potentials and locomotion recovery. Moreover, histological analysis demonstrated that LOCS + Taxol implantation significantly increased neurogenesis and axon regeneration to reconnect the spinal cord stumps. Additionally, reduced glial scar formation was observed within the lesion site. Thus, LOCS + Taxol implantation treatment is a promising combinatorial therapy for the treatment of acute long-distance spinal cord defects.

To establish the cell line from specimens of resectable human gastrointestinal stromal tumors (GIST) and to verify the characteristics of cell biology in vitro.The tissues from biopsies of human GIST were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum. After growing to 90% confluence, the cells were detached for subculture and their characteristics, including morphology, growth kinetics, karyotype analysis, immunohistochemical analysis and tumorigenicity in nude mice were determined.GIST named GIST-H1 was successfully established. The cell line was passaged for more than 60 times 1 year. The characteristics demonstrated: The population doubling time calculated in the log phase of growth was 47.5 h. The cloning efficiency in the soft agar averaged 24.8%. Electronmicroscopically, there were rich ribosomes and mitochondrion in the cytoplasm. Immunohistochemical analysis showed CD117(+), SMA(+), dog-1(+), CD34(-), and S-100(-). Karyotype analysis illustrated aneuploidy with the modal chromosomal number 60-98. The GIST cells transplanted in nude mice had high tumorigenicity.The immortalized GIST cells are developed in vitro and have specific characteristics of GIST.