Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha ...(SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
Objectives
Ribonucleotide reductase M2 (RRM2) is a rate‐limiting enzyme involved in DNA repair and synthesis. This study aimed to investigate the expression level, clinicopathological significance, ...and prognostic value of RRM2 in oral squamous cell carcinoma (OSCC).
Materials and methods
Human OSCC tissue microarrays were used to detect the expression of RRM2, cancer stem cell (CSC) markers CD44 and aldehyde dehydrogenase 1 (ALDH1), and the epithelial–mesenchymal transition (EMT) marker Slug. The correlation of RRM2 expression with clinicopathological parameters was evaluated. The effects of RRM2 on cell proliferation, migration, and apoptosis were investigated.
Results
Compared with normal and dysplastic tissues, the expression of RRM2 in human primary OSCC was significantly increased, and its overexpression was correlated with advanced pathological grade. The overall survival rate of patients with high RRM2 expression was lower than that of patients with low RRM2 expression. The overexpression of RRM2 was significantly associated with OSCC recurrence, and its overexpression was correlated with the CSC markers CD44 and ALDH1 and the EMT marker Slug. The expression of RRM2 promotes the proliferation and migration of human OSCC cells and inhibits apoptosis.
Conclusion
Ribonucleotide reductase M2 may be a novel target in the diagnosis, prognosis, and therapy of OSCC.
Partial epithelial mesenchymal transition (p-EMT) was found to play a potential role in the initial stage of metastasis in human head and neck squamous cell carcinoma (HNSCC). Some long noncoding ...RNAs (lncRNAs) have been reported to function as promoters or inhibitors of cancer metastasis. This study aimed to identify p-EMT-related lncRNAs in HNSCC.
Differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DEGs) in HNSCC obtained from The Cancer Genome Atlas (TCGA) were screened out by using the "edgeR" package. DE-lncRNAs in the Oral squamous cell carcinoma (OSCC) lncRNA microarray dataset GSE84805 were screened out by using the "limma" package. Slug-related lncRNAs were determined by Pearson correlation analysis (|Pearson correlation coefficient| ≥ 0.4, p < 0.01) based on TCGA. Survival analysis were performed for the overlapping DE-lncRNAs by using the "Survival" package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to predict the potential functions of MYOSLID. RT-qPCR and In Site Hybridization (ISH) were used to explore the MYOSLID expression and its clinical significance in HNSCC specimens. Immunohistochemical staining, siRNA, wound healing assay, transwell assay, and western blot were used to explore the biological function and potential molecular mechanisms.
MYOSLID was identified as a Slug-related lncRNA and with prognostic value among the 9 overlapping DE-lncRNAs. GO and KEGG analyses revealed that MYOSLID was closely related to important biological processes and pathways that regulate cancer metastasis. The results of univariate and multivariate Cox regression analysis based on TCGA and HNSCC tissue microarray data suggested MYOSLID was an independent prognostic factor. MYOSLID expression in HNSCC was closely correlated with Slug, PDPN and LAMB3. The knockdown of MYOSLID in OSCC cell line significantly inhibited cell migration and invasion compared to those in the control cells. In addition, the knockdown of MYOSLID significantly reduced Slug, PDPN and LAMB3 expression levels. However, the knockdown of MYOSLID had no effect on the expression levels of the EMT biomarkers E-cadherin and Vimentin.
Our study revealed that MYOSLID expression was closely related to the p-EMT program in HNSCC, and it might be a new predictive biomarker for aggressive HNSCC.
The loss of major histocompatibility complex class I (MHC I) molecules is an important mechanism by which cancer cells escape immunosurveillance in head and neck squamous cell carcinoma (HNSCC). ...Several long non-coding RNAs (lncRNAs) have been implicated in immune response and regulation including antigen processing and presentation. However, few studies on lncRNAs regulating MHC I expression in HNSCC have been conducted. In this study, MHC I related lncRNAs were identified from the The Cancer Genome Atlas (TCGA) HNSCC database. One of the lncRNAs,
(
), was found to be associated with genes encoding MHC I molecules and patient prognosis in the TCGA database. KEGG and GO analyses suggested that
was closely related to antigen processing and presentation. qRT-PCR revealed high expression of
in human HNSCC tissues and HNSCC cell lines compared with normal mucosal tissues.
hybridization of the HNSCC tissue microarray revealed a correlation between high
expression and a favorable prognosis in our patient cohort. Silencing of
decreased MHC I protein expression, as evidenced by western blotting. Multiplex immunochemistry was performed to reveal the positive correlation between high
expression and an increased number of CD8
and CD4
T cells in the tumor microenvironment. Based on our study,
is a promising prognostic marker and a target for future therapeutic interventions.
Enhancing the response rate of immunotherapy will aid in the success of cancer treatment. Here, we aimed to explore the combined effect of immunogenic radiotherapy with anti-PD-L1 treatment in ...immunotherapy-resistant HNSCC mouse models.
The SCC7 and 4MOSC2 cell lines were irradiated in vitro. SCC7-bearing mice were treated with hypofractionated or single-dose radiotherapy followed by anti-PD-L1 therapy. The myeloid-derived suppressive cells (MDSCs) were depleted using an anti-Gr-1 antibody. Human samples were collected to evaluate the immune cell populations and ICD markers.
Irradiation increased the release of immunogenic cell death (ICD) markers (calreticulin, HMGB1 and ATP) in SCC7 and 4MOSC2 in a dose-dependent manner. The supernatant from irradiated cells upregulated the expression of PD-L1 in MDSCs. Mice treated with hypofractionated but not single-dose radiotherapy were resistant to tumour rechallenge by triggering ICD, when combined with anti-PD-L1 treatment. The therapeutic efficacy of combination treatment partially relies on MDSCs. The high expression of ICD markers was associated with activation of adaptive immune responses and a positive prognosis in HNSCC patients.
These results present a translatable method to substantially improve the antitumor immune response by combining PD-L1 blockade with immunogenic hypofractionated radiotherapy in HNSCC.
Compound Kushen injection (CKI) combined with intraperitoneal chemotherapy (IPC) is widely used in the treatment of malignant ascites (MA). However, evidence about its efficacy and safety remains ...limited. This review aimed to evaluate the efficacy and safety of CKI combined with IPC for the treatment of MA.
Protocol of this review was registered in PROSPERO (CRD42022304259). Randomized controlled trials (RCTs) on the efficacy and safety of IPC with CKI for the treatment of patients with MA were searched through 12 electronic databases and 2 clinical trials registration platforms from inception until 20 January 2023. The Cochrane risk-of-bias tool was used to assess the quality of the included trials through the risk of bias assessment. We included RCTs that compared IPC single used or CKI combined with IPC for patients with MA schedule to start IPC. The primary outcome was identified as an objective response rate (ORR), while the secondary outcomes were identified as the quality of life (QoL), survival time, immune functions, and adverse drug reactions (ADRs). The Revman5.4 and Stata17 software were used to calculate the risk ratio (RR) at 95% confidence intervals (CI) for binary outcomes and the mean difference (MD) at 95% CI for continuous outcomes. The certainty of the evidence was assessed according to the GRADE criteria.
A total of 17 RCTs were assessed, which included 1200 patients. The risk of bias assessment of the Cochrane risk-of-bias tool revealed that one study was rated high risk and the remaining as unclear or low risk. Meta-analysis revealed that CKI combined with IPC had an advantage in increasing ORR (RR = 1.31, 95% CI 1.20 to 1.43,
< 0.00001) and QoL (RR = 1.50, 95% CI 1.23 to 1.83,
< 0.0001) when compared with IPC alone. Moreover, the combined treatment group showed a lower incidence of myelosuppression (RR = 0.51, 95%CI 0.40-0.64,
< 0.00001), liver dysfunction (RR = 0.33, 95%CI 0.16 to 0.70,
= 0.004), renal dysfunction (RR = 0.39, 95%CI 0.17 to 0.89,
= 0.02), and fever (RR = 0.51, 95%CI 0.35 to 0.75,
= 0.0007) compared to those of the control group. The quality of evidence assessment through GRADE criteria showed that ORR, myelosuppression, and fever were rated moderate, renal dysfunction and liver dysfunction were rated low, and QoL and abdominal pain were rated very low.
The efficacy and safety of CKI combined with IPC were superior to that with IPC alone for the treatment of MA, which indicates the potentiality of the treatment. However, more high-quality RCTs are required to validate this conclusion.
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304259, identifier PROSPERO 2022 CRD42022304259.
Coronavirus disease 2019 (COVID-19) has infected over 124 million people worldwide. In addition to the development of therapeutics and vaccines, the evaluation of the sequelae in recovered patients ...is also important. Recent studies have indicated that COVID-19 has the ability to infect intestinal tissues and to trigger alterations of the gut microbiota. However, whether these changes in gut microbiota persist into the recovery stage remains largely unknown. Here, we recruited seven healthy Chinese men and seven recovered COVID-19 male patients with an average of 3-months after discharge and analyzed their fecal samples by 16S rRNA sequencing analysis to identify the differences in gut microbiota. Our results suggested that the gut microbiota differed in male recovered patients compared with healthy controls, in which a significant difference in Chao index, Simpson index, and β-diversity was observed. And the relative abundance of several bacterial species differed clearly between two groups, characterized by enrichment of opportunistic pathogens and insufficiency of some anti-inflammatory bacteria in producing short chain fatty acids. The above findings provide preliminary clues supporting that the imbalanced gut microbiota may not be fully restored in recovered patients, highlighting the importance of continuous monitoring of gut health in people who have recovered from COVID-19.
Azoospermia is one of the major reproductive disorders which cause male infertility in humans; however, the etiology of this disease is largely unknown. In the present study, six missense mutations ...of WT1 gene were detected in 529 human patients with non-obstructive azoospermia (NOA), indicating a strong association between WT1 mutation and NOA. The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. To examine the functions of this gene in spermatogenesis, Wt1 was deleted in adult testis using Wt1(flox) and Cre-ER(TM) mice strains. We found that inactivation of Wt1 resulted in massive germ cell death and only SCs were present in most of the seminiferous tubules which was very similar to NOA in humans. In investigating the potential mechanism for this, histological studies revealed that the blood-testis barrier (BTB) was disrupted in Wt1 deficient testes. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. Further studies found that the expression of cell polarity associated genes (Par6b and E-cadherin) and Wnt signaling genes (Wnt4, Wnt11) were downregulated in Wt1 deficient SCs, and that the expression of Par6b and E-cadherin was regulated by Wnt4. Our findings suggest that Wt1 is important in spermatogenesis by regulating the polarity of SCs via Wnt signaling pathway and that WT1 mutation is one of the genetic causes of NOA in humans.
Display omitted
Brevinin-1BYa is an amphibian skin-derived peptide that exhibits promising anti-microbial activity against gram-positive and -negative bacteria. However, the anti-tumor activity of ...Brevinin-1BYa remains unclear, and, more importantly, its therapeutic application is limited owing to its poor protease and reduction stability. In this study, a series of novel Brevinin-1BYa derivatives, including O-linked N-acetyl-glucosamine glyclopeptides and disulfide bond mimetics, were designed and synthesized. Additionally, their anti-tumor activity against human prostate cancer cell line C4-2B, human NSCLC cell line A549 (adenocarcinoma), and human hepatoma cells line HuH-7 was investigated. Among these, the thioether bridge substituted peptidomimetic Brevinin-1BYa-3 displayed improved reduction stability, more stable secondary structure, greater protease stability, and increased anti-tumor activity compared with the original peptide, rendering it a promising leading compound for drug development, particularly for applications against malignant tumors.
The effect of alcohol consumption on prostate health and reproductive hormone profiles has long been investigated and currently, no consensus has been reached. Additionally, large studies focusing on ...this topic are relatively rare in China. To investigate the association of alcohol consumption with prostate measurements and reproductive hormone profiles in Chinese population; and to examine the relationship between hormone levels and prostate measurements. This cross-sectional study included 4535 men from four representative provinces of China. Demographic details, family history of prostate disease, tobacco and alcohol consumption, as well as International Prostate Symptom Score (I-PSS) were collected through a questionnaire. Total prostate specific antingen (total PSA), free PSA, free PSA/total PSA ratio (f/tPSA), and reproductive hormones were measured in serum. Multi-variable regression models were used to test for association of alcohol consumption with markers of prostate health, used to test for association of alcohol consumption with reproductive hormones, and reproductive hormones with markers of prostate health. Alcohol consumption had no obvious impact on total PSA concentration and I-PSS. Current drinkers had lower level of free PSA (beta = -0.11, p = 0.02) and f/tPSA (beta = -0.03, p = 0.005), former drinkers also had lower level of free PSA (beta = -0.19, p = 0.02) when compared with never drinkers. Lower Luteinizing hormone (LH) (beta = -1.05, p = 0.01), sex hormone-binding globulin (SHBG) (beta = -4.71, p = 0.01) and higher estradiol (beta = 7.81, p = 0.01) was found in current drinkers than never drinkers, whereas higher LH (beta = 1.04, p = 0.04) and free testosterone (FT) (beta = 0.03, p = 0.02) was detected in former drinkers than never drinkers. Furthermore, LH was positively associated with f/tPSA (beta = 0.002, p = 0.006), SHBG was also positively related with free PSA (beta = 0.003, p = 0.003) and f/tPSA (beta = 0.0004, p = 0.01). Both total testosterone (TT) and FT were inversely related with I-PSS (OR = 0.97, 95% CI, 0.95-0.98; OR = 0.23, 95% CI, 0.11-0.45, respectively). Alcohol consumption could affect serum free PSA concentration and also f/tPSA ratio, and also acts as an endocrine disruptor on the male reproductive hormone profiles. LH and SHBG were positively related with fPSA and f/tPSA, and higher level of TT and FT may be helpful for improving participants' subjective symptoms.
PDF
