Application prospects of the 2BS cell-adapted China fixed rabies virus vaccine strain 2aG4-B40.

BACKGROUND: Rabies is a fatal zoonotic disease whose pathogenesis has not been fully elucidated, and vaccination is the only effective method for protecting against rabies virus infection. Most inactivated vaccines are produced using Vero cells, which are African green monkey kidney cells, to achieve large-scale production. However, there is a potential carcinogenic risk due to nonhuman DNA contamination. Thus, replacing Vero cells with human diploid cells may be a safer strategy. In this study, we developed a novel 2BS cell-adapted rabies virus strain and analysed its sequence, virulence and immunogenicity to determine its application potential as a human diploid cell inactivated vaccine. METHODS AND RESULTS: The 2BS cell-adapted rabies virus strain 2aG4-B40 was established by passage for 40 generations and selection of plaques in 2BS cells. RNA sequence analysis revealed that mutations in 2BS cell-adapted strains were not located at key sites that regulate the production of neutralizing antibodies or virulence in the aG strain (GQ412744.1). The gradual increase in virulence (remaining above 7.0 logLD50/ml from the 40th to 55th generation) and antigen further indicated that these mutations may increase the affinity of the adapted strains for human diploid cells. Identification tests revealed that the 2BS cell-adapted virus strain was neutralized by anti-rabies serum, with a neutralization index of 19,952. PrEP and PEP vaccination and the NIH test further indicated that the vaccine prepared with the 2aG4-B40 strain had high neutralizing antibody levels (2.24 to 46.67 IU/ml), immunogenicity (protection index 270) and potency (average 11.6 IU/ml). CONCLUSIONS: In this study, a 2BS cell-adapted strain of the 2aG4 rabies virus was obtained by passage for 40 generations. The results of sequencing analysis and titre determination of the adapted strain showed that the mutations in the adaptive process are not located at key sequence regions of the virus, and these mutations may enhance the affinity of the adapted strain for human diploid cells. Moreover, vaccines made from the adapted strain 2aG4-B40 had high potency and immunogenicity and could be an ideal candidate rabies virus strain for inactivated vaccine preparation.

Paclitaxel liposome, cisplatin and 5-fluorouracil-based induction chemotherapy followed by de-escalated intensity-modulated radiotherapy with concurrent cisplatin in stage IVA-IVB childhood nasopharyngeal carcinoma in endemic area: a phase II, single-arm trial.

Background: Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation. Methods: We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60 Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70 Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT). Findings: From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation. Interpretation: Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

The map of bone metastasis in nasopharyngeal carcinoma: A real-world study.

OBJECTIVES: The aim of this study was to compare the metastatic patterns of synchronous bone metastasis (SBM) and metachronous bone metastasis (MBM) in nasopharyngeal carcinoma (NPC). METHODS: This study included bone metastases in NPC patients from 2005 to 2016 in a Chinese hospital. Cohort 1 was collected from 2005 to 2010 for discovery, and Cohort 2 from 2011 to 2016 for validation. The chi-squared test, Wilcoxon rank sum test, and Kaplan-Meier technique were used to compare site, time, and survival between cohorts 1 and 2. Prognostic factors were analyzed using univariate or multivariate Cox regression. RESULTS: Cohort 1 had 112 individuals with SBM and 394 with MBM, and cohort 2 had 328 with SBM and 307 with MBM. The thoracic vertebra was the most frequently affected site of metastasis. Patients with SBM more often had metastasis to the cervical vertebrae compared with patients with MBM (34.5% vs. 22.3%, p < 0.05). Patients with SBM had better overall survival (42.2 months, 95% CI: 33.9-50.7) than patients with MBM (24.9 months, 95% CI: 22.2-28.7). Age at bone metastasis detection, metastasis to other organs, and more bone metastasis locations were associated with worse prognosis. The majority of MBMs occurred at 7 to 18 months after NPC diagnosis. CONCLUSION: Radiotherapy does not modify the metastatic patterns of NPC bone metastases. Patients with SBM tend to have metastasis to the cervical vertebra, which is close to the nasopharynx. Paying more attention to bone metastases during follow-up in the first 2 years after an NPC diagnosis.

The role of post-translational modifications in the regulation of MCL1.

Apoptosis is an evolutionarily conserved form of programed cell death (PCD) that has a vital effect on early embryonic development, tissue homeostasis and clearance of damaged cells. Dysregulation of apoptosis can lead to many diseases, such as Alzheimer's disease, cancer, AIDS and heart disease. The anti-apoptotic protein MCL1, a member of the BCL2 family, plays important roles in these physiological and pathological processes. Its high expression is closely related to drug resistances in the treatment of tumor. This review summarizes the structure and function of MCL1, the types of post-translational modifications of MCL1 and their effects on the functions of MCL1, as well as the treatment strategies targeting MCL1 in cancer therapy. The research on the fine regulation of MCL1 will be favorable to the provision of a promising future for the design and screening of MCL1 inhibitors.

Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues.

PURPOSE: Thyroid carcinoma (TC) is the most common endocrinal malignancy worldwide. Cyclin E2 (CCNE2), a member of the cyclin family, acts as a regulatory subunit of cyclin-dependent kinases (CDKs). It controls the transition of quiescent cells into the cell cycle, regulates the G1/S transition, promotes DNA replication, and activates CDK2. This study explored the role and potential molecular mechanisms of CCNE2 expression in TC tissues. MATERIAL/METHODS: Immunohistochemistry was used to evaluate the CCNE2 protein expression levels in TC. High-throughput data on CCNE2 in TC were obtained from RNA sequencing (RNA-seq), microarray, and literature data. The CCNE2 expression levels in TC were comprehensively assessed through an integrated analysis. Analyses of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPIs) data facilitated the investigation of the relative molecular mechanisms of CCNE2 in TC. RESULTS: The immunohistochemical experiment showed a significant increase in the expression of CCNE2 in the TC tissues. For 505 TC and 59 non-cancerous samples from RNA-seq data, the area under the curve (AUC) was 0.8016 (95% confidence interval [CI] 0.742-0.8612; p<0.001). With another 14 microarrays, the pool standard mean difference [SMD] was 1.01 (95% CI [0.82-1.19]). The pooled SMD of CCNE2 was 1.12 (95% CI [0.60-1.64]), and the AUC was 0.87 (95% CI [0.84-0.90]) for 1157 TC samples and 366 non-cancerous thyroid samples from all possible sources. Nine hub genes were upregulated in TC. CONCLUSIONS: A high expression of CCNE2 may lead to carcinogenesis and the development of TC.

Immunohistochemical basigin expression level in thyroid cancer tissues.

BACKGROUND: Thyroid cancer (TC) is the most common endocrine malignancy; basigin (also known as BSG) plays a crucial role in tumor cell invasion, metastasis, and angiogenesis. This study was designed to identify the change of BSG expression in TC and its possible potential mechanism. METHODS: The BSG expression levels in TC were demonstrated using data collected from in-house immunohistochemical (IHC), RNA-sequencing (RNA-seq), microarrays, and literatures. Integrated analysis was performed to determined BSG expression levels in TC comprehensively. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed with the integration of BSG co-expressed genes and differentially expressed genes (DEGs) in TC tissues to explore the potential mechanisms of BSG in TC. RESULTS: The protein expression level of BSG was significantly higher in TC cases based on the IHC experiments. In addition, the combined SMD for BSG expression was 0.39 (p < 0.0001), the diagnostic odds ratio was 3.69, and the AUC of the sROC curve was 0.6986 using 1182 TC cases and 437 non-cancerous cases from 17 independent datasets. Furthermore, BSG co-expressed genes tended to be enriched in gene terms of the extracellular matrix (ECM), cell adhesion, and cell-cell interactions. The expression levels of nine hub BSG co-expressed genes were markedly upregulated in TC cases. CONCLUSION: BSG expression levels were closely correlated with the progression of TC and may affect the signals of the ECM, cell adhesion, and cell-cell interactions.

Chiral Second-Harmonic Generation from Monolayer WS2/Aluminum Plasmonic Vortex Metalens.

Two-dimensional spiral plasmonic structures have emerged as a versatile approach to generate near-field vortex fields with tunable topological charges. We demonstrate here a far-field approach to observe the chiral second-harmonic generation (SHG) at designated visible wavelengths from a single plasmonic vortex metalens. This metalens comprises an Archimedean spiral slit fabricated on atomically flat aluminum epitaxial film, which allows for precise tuning of plasmonic resonances and subsequent transfer of two-dimensional materials on top of the spiral slit. The nonlinear optical measurements show a giant SHG circular dichroism. Furthermore, we have achieved an enhanced chiral SHG conversion efficiency (about an order of magnitude greater than the bare aluminum lens) from monolayer tungsten disulfide (WS2)/aluminum metalens, which is designed at the C-exciton resonance of WS2. Since the C-exciton is not a valley exciton, the enhanced chiral SHG in this hybrid system originates from the plasmonic vortex field-enhanced SHG under the optical spin-orbit interaction.

Expression level and prospective mechanism of miRNA-99a-3p in head and neck squamous cell carcinoma based on miRNA-chip and miRNA-sequencing data in 1, 167 cases.

BACKGROUND: The role of miR-99a-3p in Head and neck squamous cell carcinoma (HNSCC) has not been reported. Therefore, in this study, we examined the expression level and its molecular mechanisms of miR-99a-3p in HNSCC. MATERIALS AND METHODS: MiR-99a-3p-related miRNA-chip and miRNA-sequencing data were collected. We then carried out meta-analyses to pool the standard mean difference (SMD) value and generate a summarized receiver operating characteristic (sROC) curve. MiR-99a-3p mimic was transfected into FaDu cells and those genes influenced by miR-99a-3p were gathered. The target genes were also predicted from 12 tools through miRwalk2.0, and combined with differentially expressed genes in HNSCC from the The Cancer Genome Atlas and Genotype-Tissue Expression sequencing databases. FunRich and DAVID were used for the pathway signaling analyses for the potential targets of miR-99a-3p in HNSCC. RESULTS: The SMD was -0.30 (95% CI: -0.51, -0.08) in the fixed-effect model and -0.28 (95% CI: -0.67, 0.10) in the random-effect model (I2 = 60%), indicating a reduced expression level of miR-99a-3p in HNSCC tissues based on 1167 cases. In the sROC curve, the area under the curve (AUC) was 0.77 (95% CI: 0.73, 0.81). The 251 potential targets of miR-99a-3p were enriched in several pathways related to cancer, with the "Pathways in cancer" standing at the top. vascular endothelial growth factor A was selected as an example with up-regulated trend in HNSCC tissues. CONCLUSION: MiR-99a-3p exhibits a significant lower expression status in HNSCC, and this reduced or deletion status promotes the malignant progression of HNSCC. However, its molecular mechanism is still unclear and requires further investigation.

Controlled synthesis of novel cyanopropyl polysilsesquioxane hollow spheres loaded with highly dispersed Au nanoparticles for catalytic applications.

The design and synthesis of novel cyanopropyl polysilsesquioxane hollow spheres lead to production of a highly active and stable catalyst in the reduction of 4-nitrophenol catalyzed by Au nanoparticles.

Highly porous, water-soluble, superparamagnetic, and biocompatible magnetite nanocrystal clusters for targeted drug delivery.

Magnetic particles have become very promising materials for drug delivery. However, preparation of magnetite particles with high surface area, biocompatibility, strong magnetic response, and suitable particle size still remains a major challenge. In this report, magnetite nanocrystal clusters with high surface areas were fabricated through a solvothermal process by introducing ammonium acetate as a porogen and trisodium citrate as a surface modification agent. The porosity, which was controlled by the reactant concentration, has been investigated in detail. The surface area of the nanocrystal clusters was as high as 141 m(2) g(-1). Ibuprofen, as a model drug, was entrapped into the magnetite carriers. The interfacial interaction between the carboxylic groups on the drug molecules and the carboxylate groups on the carriers enhanced the loading efficiency. Low cytotoxicity in MCF-7 cell and in vitro constant drug release behavior combined with the high drug loading efficiency and high saturation magnetization values demonstrated the potential of the as-synthesized magnetite materials in targeted drug release systems.

Novel fluorinated polysilsesquioxane hollow spheres: synthesis and application in drug release.

Fluorinated polysilsesquioxane (FPSQ) hollow spheres with a large empty interior were synthesized in an aqueous medium by using (trifluoropropyl)trimethoxysilane as the sole precursor. The drug release applications of these spheres were demonstrated, and the materials have great potential as fluorinated drug release carriers.

Highly ordered three-dimensional large-pore periodic mesoporous organosilica with Im3m symmetry.

Highly ordered three-dimensional Im3m-type periodic mesoporous organosilica with a cavity size of 9.8 nm has been synthesized under strongly acidic media in the presence of inorganic salts using triblock copolymer F127 as the template and 1,2-bis(trimethoxysilyl)ethane as the organically bridged silica source.