To evaluate the association between single nucleotide polymorphisms (SNPs) at the 194 and 399 codons of XRCC1, and the risk of severe acute skin and oral mucosa reactions in nasopharyngeal carcinoma ...patients in China.
114 patients with nasopharyngeal carcinoma were sequentially recruited in this study. Heparinized peripheral blood samples were taken for SNPs analysis before the start of radiation treatment. SNPs in XRCC1 (194Arg/Trp and 399Arg/Gln) gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Dermatitis at upper neck and oral mucositis were clinically recorded according to the Common Terminology Criteria for Adverse Events v.3.0.
The variant allele frequencies were 0.289 for XRCC1 194Trp and 0.263 for XRCC1 399Gln. Of the 114 patients, 24 experienced grade 3 acute dermatitis and 48 had grade 3 acute mucositis. The XRCC1 399Arg/Gln was significantly associated with the development of grade 3 dermatitis (Odds Ratio, 2.65; 95% CI, 1.04-6.73; p = 0.037, χ2 = 4.357). In addition, it was also associated with higher incidence of grade 3 mucositis with a borderline statistical significance (Odds Ratio, 2.11; 95% CI, 0.951-4.66; p = 0.065, χ2 = 3.411). The relationship between XRCC1 194Arg/Trp and acute dermatitis, and mucositis was not found.
Our investigation shows, for the first time, that patients with the XRCC1 399Arg/Gln genotype were more likely to experience severe acute dermatitis and oral mucositis. With further validation, the information can be used to determine personalized radiotherapy strategy.
Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor with antitumor and antiangiogenic activities. To investigate the effects of celecoxib on nasopharyngeal carcinoma (NPC), HNE-1 cells were ...treated with celecoxib at various concentrations. MTT assay, migration assay and invasion assay were performed to observe the inhibitory activity of celecoxib on HNE-1 cells. Additionally, VEGF-A expression and radiation survival of NPC cell were also examined after treatment with celecoxib. Celecoxib treatment presented an anti-proliferation function in a time and dose-dependent manner on HNE-1 cells which highly express COX-2 protein. Celecoxib also displayed an obvious inhibitory activity on invasive capacity of NPC cells. Moreover, the celecoxib's effects to suppress VEGF-A expression and enhance radiosensitivity were detected in HNE-1 cells. These findings implicate that application of celecoxib may be an effective strategy for NPC therapy.
The zinc-fingers and homeoboxes (ZHX) family members have been characterized as master regulators in cancer initiation and development. The present study performed in silico data-mining with publicly ...available datasets and immunohistochemistry to assess the expression status of ZHX factors and the corresponding prognostic implications in liver cancer. Increased ZHX3 mRNA expression was associated with favorable overall survival in patients with liver cancer. Subgroups analyses revealed a significant association between the expression of ZHX factors and outcomes in select patient cohorts. Immunohistochemical analysis supported that ZHX3 expression was an independent prognostic indicator for patient survival. These results suggested that dysregulation of ZHX factors is involved in disease progression and ZHX3 expression may serve as a prognostic biomarker for liver cancer.
Immunogenicity improvement is a valuable strategy for tumor immunotherapy. However, immunosuppressive factors bestow tolerogenic phenotype on tumor-infiltrating DCs, which exhibit weak antigen ...presentation and strong anti-inflammatory cytokines secretion abilities, limiting the effectiveness of tumor immunotherapy even if the tumor has adequate immunogenicity. Herein, we designed a programmable releasing versatile hydrogel platform (PIVOT) to sculpt tumor immunogenicity, increase intratumoral DCs and cDC1s abundance, and reverse the tolerogenic phenotype of DCs, thus promoting their maturation for boosting innate and adaptive immune responses. Responsive to tumoral reactive oxygen species (ROS), the hydrogel splits and promotes the activation of DCs and macrophages. Then, oxaliplatin is first released from PIVOT to sculpt tumor immunogenicity by inducing immunogenic cell death (ICD) and causing tumoral DNA fragments exposure simultaneously. Subsequently, the impaired DNA fragments bind to high mobility group protein 1 (HMGB1) forming the DNA-HMGB1 complex. Moreover, exogenous FMS-like tyrosine kinase 3 ligand (Flt-3L) recruits masses of DCs, especially cDC1s, which will endocytose the complex benefiting from TIM-3 blockade (αTIM3) that can reverse tolerogenic DCs. Finally, the endocytosis activates the cGAS-STING pathway of cDC1s, which promotes the secretion of type I IFN that triggers innate immune responses, and CXCL9 which recruits CD8
effector T cells to initiate the following adaptive immune response against tumor progress. PIVOT achieves nearly 90 % tumor growth inhibition and induces systemic antitumor immune responses. In conclusion, this study focuses on ICD-mediated tumor immunogenicity sculpture and nucleic acid endocytosis-involved tolerogenic DCs reversal, providing a novel paradigm for enhancing DCs-based antitumor immune responses.
Cancer vaccine-based postsurgical immunotherapy is emerging as a promising approach in patients following surgical resection for inhibition of tumor recurrence. However, low immunogenicity and ...insufficient cancer antigens limit the widespread application of postoperative cancer vaccines. Here, we propose a “trash to treasure” cancer vaccine strategy to enhance postsurgical personalized immunotherapy, in which antigenicity and adjuvanticity of purified surgically exfoliated autologous tumors (with whole antigen repertoire) were co-reinforced. In the antigenicity and adjuvanticity co-reinforced personalized vaccine (Angel-Vax), polyriboinosinic: polyribocytidylic acid (pIC) and tumor cells that have undergone immunogenic death are encapsulated in a self-adjuvanted hydrogel formed by cross-linking of mannan and polyethyleneimine. Angel-Vax exhibits an enhanced capacity on antigen-presenting cells stimulation and maturation compared to its individual components in vitro. Immunization with Angel-Vax provokes an efficient systemic cytotoxic T-cell immune response, contributing to the satisfied prophylactic and therapeutic efficacy in mice. Furthermore, when combined with immune checkpoint inhibitors (ICI), Angel-Vax effectively prevented postsurgical tumor recurrence, as evidenced by an increase in median survival of approximately 35% compared with ICI alone. Unlike the cumbersome preparation process of postoperative cancer vaccines, the simple and feasible approach herein may represent a general strategy for various kinds of tumor cell-based antigens in the inhibition of postsurgical tumor relapse by reinforced immunogenicity.
Vascular endothelial growth factor (VEGF) not only serves as an autocrine survival factor for tumor cells themselves, but also stimulates angiogenesis by paracrine pathway. Strategies targeting VEGF ...holds tremendous potential for tumor therapy, however, agents targeting VEGF are limited by intolerable side effects, together with incomplete and temporary blocking of VEGF, resulting in unsatisfactory and unsustained therapeutic outcomes. Herein, hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. After intravenous administration, HUNGER exhibits prolonged blood circulation and hyaluronic acid-CD44 mediated tumor-targeting capability. Subsequently, when matrix metalloproteinase-2 is overexpressed in the tumor microenvironment, the PEG layer will be removed. The cell-penetrating peptide R8 endows HUNGER deep tumor penetration and specific cellular uptake. Upon cellular internalization, HUNGER undergoes hyaluronidase-triggered deshielding in lysosome, lysosomal escape is realized swiftly, and then the loaded CRISPR/Cas9 plasmid (>8 kb) is transported to nucleus efficiently. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. Overall, this work opens a brand-new avenue for anti-VEGF therapy and presents a feasible strategy for in vivo delivery of CRISPR/Cas9 system.
Hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. By hierarchical-unlocking, HUNGER could achieve prolonged blood circulation, tumor-targeting, deep tumor penetration, specific cellular uptake and fast lysosomal escape. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. Display omitted
Cyclin‑dependent kinase 10 (CDK10) has been indicated to be a candidate tumor suppressor in multiple cancer types. However, to the best of the authors' knowledge, its biological and regulatory ...functions in glioma have not been previously reported. In the present study, it was demonstrated that overexpression of CDK10 inhibited glioma cell proliferation and metastasis. By contrast, knockdown of CDK10 expression promoted these malignant phenotypes. It was additionally indicated that dysregulated CDK10 expression was associated with epithelial‑mesenchymal transition (EMT) and that it regulated the expression of zinc finger protein SNAI1 (Snail). Furthermore, silencing Snail expression rescued EMT phenotypes induced by CDK10 knockdown, suggesting that Snail may be involved in the mechanistic association between CDK10 and EMT. The present study illustrated that downregulation of CDK10 expression activated Snail‑driven EMT and consequently promoted glioma metastasis, suggesting that CDK10 may serve as a potential molecular target for glioma therapy.
Summary The B-lymphocyte stimulator (BLyS) is implicated in various pathophysiological processes. The overexpression of BLyS has been observed in some human diseases, including systemic lupus ...erythematosus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis. This feature suggests that BLyS may be a therapeutic target for some human autoimmune diseases. We developed a therapeutic vaccine by coupling a tetanus toxoid T-helper cell epitope with the C-terminal of BLyS (TT-BLyS). This vaccine can induce high titers of neutralizing antibodies against BLyS in an animal model; the antibody has markedly protective effects on experimental autoimmune encephalomyelitis in rats, which is induced by inoculation of spinal cord homogenate. Our data suggest that the BLyS autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with the production of BLyS.
Human vascular endothelia growth factor receptor 3 (VEGFR-3) is up-regulated in a variety of human cancers. It is a potentially rational target for drug delivery. To identify novel ligands with ...specific binding capabilities to VEGFR-3, we screened a phage display peptide library and found a consensus motif of the peptides which is displayed by the positive phages CSDxxHxWC (x is any amino acid). The phage displaying peptide CSDSWHYWC (designated as P1) exhibited the highest affinity to VEGFR-3 in phage ELISA and the chemically synthesized P1 could bind to VEGFR-3 specifically in a dose-dependent manner. In addition, the flow cytometry assay and immunoflourescence showed that the FITC labelled P1 could bind to VEGFR-3 positive carcinoma cells with specificity. Our study suggests that P1 may be a homing peptide for treatment of tumours.
Despite significant advances in the early diagnosis and effective treatment of gastric cancer, it remains the fourth most common cancer and the second leading cause of cancer-related deaths ...worldwide. The zinc-fingers and homeoboxes (ZHX) family of transcriptional repressors has been shown to play a role in multiple types of cancer. However, the prognostic significance of ZHX expression in patients with gastric cancer remains unclear. This work studied the association between differential expression of ZHX mRNA and outcomes in patients with gastric cancer using data from the Oncomine, CCLE, Kaplan-Meier-plotter, and cBioPortal databases. Expression of ZHX3 protein was also measured by immunohistochemistry (IHC) in gastric cancer tissues. We found that increased expression of
ZHX1
mRNA and decreased expression of
ZHX2
and
ZHX3
were correlated with better overall survival (OS) in patients with gastric cancer. Further subgroup analyses identified significant associations between
ZHX1
expression and survival in select gastric cancer patients. IHC staining confirmed that the over-expression of ZHX3 was associated with worse OS, and multivariate analyses identified ZHX3 expression as an independent prognostic factor. These results suggest that the ZHX family members may serve as distinct biomarkers and prognostic factors for patients with gastric cancer.
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