The role of transforming growth factor-ß (TGF-ß) in the formation of exhausted CD8 + T cells.

CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-ß (TGF-ß) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-ß is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-ß in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.

Chaperones Hsc70 and Hsp70 play distinct roles in the replication of bocaparvovirus minute virus of canines.

Minute virus of canines (MVC) belongs to the genus Bocaparvovirus (formerly Bocavirus) within the Parvoviridae family and causes serious respiratory and gastrointestinal symptoms in neonatal canines worldwide. A productive viral infection relies on the successful recruitment of host factors for various stages of the viral life cycle. However, little is known about the MVC-host cell interactions. In this study, we identified that two cellular proteins (Hsc70 and Hsp70) interacted with NS1 and VP2 proteins of MVC, and both two domains of Hsc70/Hsp70 were mediated for their interactions. Functional studies revealed that Hsp70 was induced by MVC infection, knockdown of Hsc70 considerably suppressed MVC replication, whereas the replication was dramatically promoted by Hsp70 knockdown. It is interesting that low amounts of overexpressed Hsp70 enhanced viral protein expression and virus production, but high amounts of Hsp70 overexpression weakened them. Upon Hsp70 overexpressing, we observed that the ubiquitination of viral proteins changed with Hsp70 overexpression, and proteasome inhibitor (MG132) restored an accumulation of viral proteins. In addition, we verified that Hsp70 family inhibitors remarkably decreased MVC replication. Overall, we identified Hsc70 and Hsp70 as interactors of MVC NS1 and VP2 proteins and were involved in MVC replication, which may provide novel targets for anti-MVC approach.

Disclosing Potential Therapeutic Targets Associated With Osimertinib Resistance in the Non-small Cell Lung Cancer Cell Line H1975.

BACKGROUND/AIM: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is a highly effective and valuable treatment option for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, such as T790M. However, acquired resistance ultimately limits its clinical application. In this study, we aimed to identify potential targets for overcoming osimertinib resistance. MATERIALS AND METHODS: The H1975/OSI cell line was induced in vitro through intermittent induction. Cell activity was measured using a cell counting kit-8 assay. Uni-omics and multi-omics analyses were conducted on the transcriptomic and proteomic (4D label-free) expression profiles, which involved differential expression analysis, GO functional annotation and KEGG pathway enrichment analysis, as well as correlation analysis of transcription factors and PPI network. RESULTS: H1975/OSI cells showed resistance towards osimertinib with IC50 values approximately 5.25-fold higher than H1975 cells. A total of 2519 genes were found to be differentially expressed genes (DEGs) and 1533 proteins were found to be differentially abundant proteins (DAPs). Furthermore, 147 genes that were differentially expressed at both the transcription and protein levels (TPGs) were identified as being differentially expressed in both the transcriptome and proteome. It was revealed that many pathways related to the structure and function of ribosomes, as well as metabolites, were altered. The highest connectivity genes of 147 TPGs included NOP56, DDX21, PDCD11, CCNB1, and TOP2A. The hub genes of the transcriptional regulatory network included DDX21, KPNA2, DDX5, BRCA1, LMNB1, and HIF1A. CONCLUSION: Collectively, our high-throughput analysis uncovered functional properties that interacted with gene signatures of H1975/OSI cells, and highlighted certain pathways and eleven hub genes that may be the potential targets for improving clinical osimertinib resistance.

High incidence of the virus among respiratory pathogens in children with lower respiratory tract infection in northwestern China.

Lower respiratory tract infection (LRTI) is one of the major reasons for childhood mortality that threaten the health of the public. We aimed to investigate the epidemiological pathogens and their infection analysis among children with LRTI. Sputum specimens were collected for polymerase chain reaction detection and microbiological tests to identify the viral infection and bacterial infection. The serological specimens were separated from venous blood using for Mycoplasma pneumoniae and Chlamydia pneumoniae detection. The virus was confirmed in 86.2% of the children. Human rhinovirus (38.3%), respiratory syncytial virus (32.1%), and parainfluenza virus type 3 (27.2%) were the most frequently identified pathogens. Patients with viral and bacterial coinfection showed younger age (p = 0.032), a higher proportion of wheezing rales (p = 0.032), three depressions sign (p = 0.028), and tachypnea (p = 0.038), and more likely associated with severe pneumonia (p = 0.035). Additionally, older children were more susceptible to viral-atypical bacterial coinfection (p = 0.032). Vomiting (p = 0.011) and fever (p = 0.003) were more likely to occur in children with viral-atypical bacterial coinfection. Attention should be paid to the virus infection of LRTI, as viral-bacterial coinfection and viral-atypical bacterial co-infection may have a detrimental impact on the gravity of LTRI.

Epidemiologic and clinical characteristics of human bocavirus infection in infants and young children suffering with community acquired pneumonia in Ningxia, China.

BACKGROUND: Pneumonia has a high incidence rate and is a major cause of mortality in children, mostly community-acquired pneumonia (CAP). Human bocavirus (HBoV), since it first identified in 2005, has been repeatedly associated with respiratory tract infections. Nevertheless, the role and related information of HBoV as a pathogen of CAP has not been fulfilled. Here our study is to assess the epidemiological and clinical features in HBoV-positive children with CAP. METHODS: A total of 878 secretions of lower respiratory samples were obtained, multiplex PCR was used to detect HBoV and other respiratory viruses. RESULTS: Of all cases, HBoV was detected in 10.0%, with a peak incidence of infection among children < 2 year old, and predominantly noted in autumn and winter. Only 8 patients were HBoV single infection. Co-infection with other respiratory viruses was observed in 86.4%. Moreover, co-infection with bacteria occurred in 27.3% and with Mycoplasma pneumoniae (MP) in 33.0% of HBoV-positive patients. Among all HBoV-positive samples co-infected with bacteria, 87.5% are gram negative bacteria. Compared with HBoV-negative group, age (P = 0.048), wheezing (P = 0.015), tachypnea (P = 0.016), lactate dehydrogenase (P = 0.026) and severe pneumonia (P = 0.023) were statistically significant in HBoV-positive patients. Furthermore, HBoV-positive patients less than 1 year old were more likely to have co-infection with bacteria (P = 0.007). CONCLUSIONS: HBoV can be detected alone in respiratory samples of children with CAP, maybe it is one of the causes of CAP in infants. The high incidence of severe pneumonia was found in HBoV-positive patients compared with HBoV-negative cases may indicate a relationship between severe pneumonia and HBoV.

Correction to: Oxymatrine Inhibits Bocavirus MVC Replication, Reduces Viral Gene Expression and Decreases Apoptosis Induced by Viral Infection.

In Fig. 2B, labels were misnamed in the original article. MVC label and MVC + OMT label were opposite. Now the correct Fig. 2 has been provided below.

Oxymatrine Inhibits Bocavirus MVC Replication, Reduces Viral Gene Expression and Decreases Apoptosis Induced by Viral Infection.

Oxymatrine (OMT), as the main active component of Sophoraflavescens, exhibits a variety of pharmacological properties, including anti-oxidative, anti-inflammatory, anti-tumor, and anti-viral activities, and currently is extensively employed to treat viral hepatitis; however, its effects on parvovirus infection have yet to be reported. In the present study, we investigated the effects of OMT on cell viability, virus DNA replication, viral gene expression, cell cycle, and apoptosis in Walter Reed canine cells/3873D infected with minute virus of canines (MVC). OMT, at concentrations below 4 mmol/L(no cellular toxicity), was found to inhibit MVC DNA replication and reduce viral gene expression at both mRNA and protein levels, which was associated with the inhibition of cell cycle S-phase arrest in early-stage of MVC infection. Furthermore, OMT significantly increased cell viability, decreased MVC-infected cell apoptosis, and reduced the expression of activated caspase 3. Our results suggest that OMT has potential application in combating parvovirus infection.