Search

Abstract Cancer vaccines, crucial in the immunotherapeutic landscape, are bifurcated into preventive and therapeutic types, both integral to combating oncogenesis. Preventive cancer vaccines, like those against HPV and HBV, reduce the incidence of virus-associated cancers, while therapeutic cancer vaccines aim to activate dendritic cells and cytotoxic T lymphocytes for durable anti-tumor immunity. Recent advancements in vaccine platforms, such as synthetic peptides, mRNA, DNA, cellular, and nano-vaccines, have enhanced antigen presentation and immune activation. Despite the US Food and Drug Administration approval for several vaccines, the full therapeutic potential remains unrealized due to challenges such as antigen selection, tumor-mediated immunosuppression, and optimization of delivery systems. This review provides a comprehensive analysis of the aims and implications of preventive and therapeutic cancer vaccine, the innovative discovery of neoantigens enhancing vaccine specificity, and the latest strides in vaccine delivery platforms. It also critically evaluates the role of adjuvants in enhancing immunogenicity and mitigating the immunosuppressive tumor microenvironment. The review further examines the synergistic potential of combining cancer vaccines with other therapies, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors, to improve therapeutic outcomes. Overcoming barriers such as effective antigen identification, immunosuppressive microenvironments, and adverse effects is critical for advancing vaccine development. By addressing these challenges, cancer vaccines can offer significant improvements in patient outcomes and broaden the scope of personalized cancer immunotherapy. more...

IntroductionThis study aims to identify the therapeutic targets and regulatory mechanisms of the antitumor drug gallic acid (GA) in cervical cancer (CC).MethodsHeLa cells were treated with GA and subjected to RNA-sequencing using the DNBSEQ platform. By combining the results of the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) analysis and RNA-seq, the differentially expressed genes (DEGs), including those upregulated and downregulated genes in CC compared with the normal cervix in the GEO and TCGA database, while expressed reversed after treatment with GA, were identified. Subsequently, the function enrichment analysis and protein–protein interaction of the DEGs were conducted. The candidate genes were identified using the Cytoscape software Gentiscape2.2 and MCODE plug-ins. Furthermore, the upstream microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) of the candidate genes were predicted using the online tools of MirDIP, TarBase, and ENCORI. Finally, the regulatory network was constructed using Cytoscape software.ResultsCC cells are significantly inhibited by GA. Combining the GEO and TCGA databases and RNA-seq analyses, 127 DEGs were obtained and subjected to functional enrichment analysis. This analysis revealed that 221 biological processes, 82 cellular components, 63 molecular functions, and 36 KEGG pathways were employed to identify three therapeutic candidate genes, including CDC20, DLGAP5, and KIF20A. The upstream 13 miRNAs, 4 lncRNA, and 42 circRNAs were detected and used to construct a lncRNA/circRNA-miRNA-mRNA-pathway regulatory network.ConclusionThis study identified candidate genes and the regulatory networks underlying the therapeutic effects of GA on CC using GA data mining methods, thus establishing a theoretical basis for targeted therapy of CC. more...

Abstract Background In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold‑inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). Methods CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. Results Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)‑like population. Moreover, hyperthermia substantially improved the sensitivity of radiation‑resistant NPC cells and CSC‑like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti‑tumor‑killing activity of hyperthermia against NPC cells and CSC‑like cells, whereas ectopic expression of Cirbp compromised tumor‑killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC‑like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. Conclusion Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia. more...

Abstract It is considered a more formidable task to precisely control the self-assembled products containing purely covalent components, due to a lack of intrinsic templates such as transition metals to suppress entropy loss during self-assembly. Here, we attempt to tackle this challenge by using directing groups. That is, the self-assembly products of condensing a 1:2 mixture of a tetraformyl and a biamine can be precisely controlled by slightly changing the substituent groups in the aldehyde precursor. This is because different directing groups provide hydrogen bonds with different modes to the adjacent imine units, so that the building blocks are endowed with totally different conformations. Each conformation favors the formation of a specific product that is thus produced selectively, including chiral and achiral cages. These results of using a specific directing group to favor a target product pave the way for accomplishing atom economy in synthesizing purely covalent molecules without relying on toxic transition metal templates. more...

Abstract Background DTL has been found to be related with multiple cancers. However, comprehensive analyses, which identify the prediction value of DTL in diagnosis, prognosis, immune infiltration and treatment, have rarely been reported so far. Methods Combined with the data online databases, the gene expression, gene mutation, function enrichment and the correlations with the immunity status and clinical indexes of DTL were analyzed. Expression of DTL and the degree of immune cell infiltration were examined by immunofluorescence (IF) and immunohistochemistry (IHC) and analyzed by statistical analysis. Furthermore, the influences of DTL on the cell cycle, cell proliferation and apoptosis were detected by live cell imaging, IF and flow cytometric (FC) analysis. Genomic stability assays were conducted by chromosome slide preparation. Results DTL was widely expressed in various cells and tissues, while it was overexpressed in tumor tissues except acute myeloid leukemia (LAML). Pan-cancer bioinformatics analysis showed that the expression of DTL was correlated with the prognosis, immunotherapy, and clinical indexes in various cancers. In addition, gene set enrichment analysis (GSEA) uncovered that DTL was enriched in oocyte meiosis, pyrimidine metabolism, the cell cycle, the G2M checkpoint, mTORC1 signaling and E2F targets. Furthermore, the overexpression of DTL, and its association with immune cell infiltration and clinical indexes in liver hepatocellular carcinoma (LIHC), bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD) were verified in our study. It was also verified that overexpression of DTL could regulate the cell cycle, promote cell proliferation and cause genomic instability in cultured cells, which may be the reason why DTL plays a role in the occurrence, progression and treatment of cancer. Conclusions Collectively, this study suggested that DTL is of clinical value in the diagnosis, prognosis and treatment of various cancers, and may be a potential biomarker in certain cancers. more...

The self-assembly of molecular knots in water is challenging. Here, authors report the self-assembly of a trefoil knot in water via imine condensation, without relying on external templates; the handedness of the trefoil knot is determined by the chirality of the bisamino precursor. more...

Abstract Background Non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB-DLBCL) has worse clinical outcome than GCB-DLBCL, and some relapsed/refractory non-GCB-DLBCL (R/R non-GCB-DLBCL) are even resistant to CD20 monoclonal antibody (rituximab). Bruton’s tyrosine kinase inhibitors (BTKis) are new drugs for B-cell lymphoma. BTKis can promote apoptosis of DLBCL by inactivating nuclear transcription factor κB (NFκB) signaling pathway. Cylindromatosis (CYLD) is a tumor suppressor and ubiquitinase. CYLD can inactivate NFκB signaling pathway through ubiquitination and regulate the apoptosis of hematological tumors. The ubiquitination of CYLD can be regulated by phosphorylation, suggesting that the regulation of CYLD phosphorylation can be a potential mechanism to promote the apoptosis of hematological tumors. Therefore, we hypothesized that BTKis could promote the apoptosis of non-GCB-DLBCL by regulating the phosphorylation of CYLD, especially in rituximab resistant cases, and we proved this hypothesis through both in vivo and in vitro experiments. Methods The baseline expression levels of CYLD phosphorylation in non-GCB-DLBCL patients and cell lines were detected by Western Blotting. The non-GCB-DLBCL cell lines were treated with BTKis, and apoptosis induced by BTKis treatment was detected by Western blotting, cell viability assay and Annexin V assay. To verify whether the effect of BTKis on apoptosis in non-GCN-DLBCL cells is CYLD dependent, the expression of CYLD was knocked down by lentiviral shRNAs. To verify the effect of BTKis on the phosphorylation of CYLD and the apoptosis in vivo and in rituximab resistant non-GCB-DLBCL, the xeograft model and rituximab resistant non-GCB-DLBCL cells were generated by tumor cell inoculation and escalation of drug concentrations, respectively. Results BTKis induced apoptosis by down-regulating CYLD phosphorylationin in non GCB-DLBCL, xenograft mouse model, and rituximab-resistant cells, and this effect could be enhanced by rituximab. Knocking-down CYLD reversed apoptosis which was induced by BTKis. BTKis induced CYLD-dependent apoptosis in non-GCB-DLBCL including in rituximab-resistant cells. Conclusions The present results indicated that CYLD phosphorylation is a potential clinical therapeutic target for non-GCB-DLBCL, especially for rituximab-resistant relapsed/refractory cases. more...

Summary: Background: Accurate prediction of treatment response to neoadjuvant chemotherapy (NACT) in individual patients with locally advanced gastric cancer (LAGC) is essential for personalized medicine. We aimed to develop and validate a deep learning radiomics nomogram (DLRN) based on pretreatment contrast-enhanced computed tomography (CT) images and clinical features to predict the response to NACT in patients with LAGC. Methods: 719 patients with LAGC were retrospectively recruited from four Chinese hospitals between Dec 1st, 2014 and Nov 30th, 2020. The training cohort and internal validation cohort (IVC), comprising 243 and 103 patients, respectively, were randomly selected from center I; the external validation cohort1 (EVC1) comprised 207 patients from center II; and EVC2 comprised 166 patients from another two hospitals. Two imaging signatures, reflecting the phenotypes of the deep learning and handcrafted radiomics features, were constructed from the pretreatment portal venous-phase CT images. A four-step procedure, including reproducibility evaluation, the univariable analysis, the LASSO method, and the multivariable logistic regression analysis, was applied for feature selection and signature building. The integrated DLRN was then developed for the added value of the imaging signatures to independent clinicopathological factors for predicting the response to NACT. The prediction performance was assessed with respect to discrimination, calibration, and clinical usefulness. Kaplan-Meier survival curves based on the DLRN were used to estimate the disease-free survival (DFS) in the follow-up cohort (n = 300). Findings: The DLRN showed satisfactory discrimination of good response to NACT and yielded the areas under the receiver operating curve (AUCs) of 0.829 (95% CI, 0.739–0.920), 0.804 (95% CI, 0.732–0.877), and 0.827 (95% CI, 0.755–0.900) in the internal and two external validation cohorts, respectively, with good calibration in all cohorts (p > 0.05). Furthermore, the DLRN performed significantly better than the clinical model (p more...

With the development of educational informatization, the information literacy of college teachers is becoming more and more important, so it is necessary to evaluate the information literacy of college teachers quantitatively. Fuzzy comprehensive evaluation method is a method that synthesizes various influencing factors and transforms qualitative evaluation into quantitative evaluation, which is very suitable for the evaluation of information literacy of teachers in colleges and universities. Based on this, this paper uses fuzzy comprehensive evaluation method to conduct a comprehensive evaluation and analysis of college teachers’ information literacy, in order to provide reference for colleges and universities to improve teachers’ information literacy and promote the construction of education informatization. more...

Flash flood in small catchments of hilly area is an extremely complicated nonlinear process affected by catchment properties and rainfall spatio-temporal variation characteristics including many physical-geographical factors, and thus accurate simulation of flash flood is very difficult. Given the fact that hundreds of hydrological models are available in the literature, how to choose a suitable hydrological model remains an unsolved task. In this paper, we selected five widely used hydrological models including three lumped hydrologic models, a semi-distributed hydrological model and a distributed hydrological model for flash flood simulation, and studied their applicability in fourteen typical catchments in hilly areas across China. The results show that the HEC-HMS distributed hydrological model outperforms the other models and is suitable to simulate the flash floods caused by highly intense rainfall. The Dahuofang model (lumped) has higher precision in peak runoff time simulation. However, its performance is quite poor on the flood volume simulation in the small catchments characterized by intense vegetation coverage and highly developed stream network. The Antecedent precipitation index and Xinanjiang models (lumped) can obtain good simulation results in small humid catchments as long as long-term historical precipitation and runoff data are provided. The TOPMODEL also shows good performance in small humid catchments, but it is unable to simulate the flash floods characterized by the rapid rise and recession. Our results could be very beneficial in practice, since these provide a solid foundation in the selection of hydrological model for flash flood simulation in small catchments in hilly area. more...

Background: Population-based studies have consistently showed an increased incidence of coronary heart disease and cardiac mortality in patients with type 2 diabetes mellitus (T2DM). Tongmai Jiangtang capsules (TJC) are Chinese patent medicines that have been approved in China for the treatment of diabetic vascular complications. However, the evidence supporting the efficacy of Tongmai Jiangtang capsules in type 2 diabetic coronary heart disease (T2DM-CHD) remains unclear. Herein, we designed a randomized, parallel-controlled clinical trial to investigate a new complementary therapy for T2DM-CHD patients.Methods: A total of 360 T2DM-CHD subjects (aged 18–75 years) will be randomly assigned to the TJC group or the placebo group at a 2:1 ratio. On the basis of western medicine therapy, all the participants will receive TJC or placebo, orally, three capsules/treatment, three per day for 12 weeks. The primary outcomes will be assessed according to the Canadian Cardiovascular Society (CCS) classification. All statistical analyses will be performed setting a two-sided 0.05 significance level, using SAS 9.4 statistical software.Discussion: The efficacy of TJC for the treatment of T2DM-CHD patients will be evaluated. The study will provide reliable clinical research evidence for application of TJC in treating T2DM-CHD patients.Clinical Trial Registration:https://www.chictr.org.cn/enIndex.aspx, Chinese Clinical Trial Registry ChiCTR2000037491. more...

In view of the high-quality development of cities in the Yangtze River Economic Belt, and in combination with the characteristics of the new development pattern, this paper constructs the evaluation index system of high-quality development of cities in the Yangtze River Economic Belt from five aspects which contain innovative development, coordinated development, green development, open development, and shared development. Firstly, this paper constructs the evaluation model of the high-quality development of the cities in the Yangtze River Economic Belt. Secondly, the paper uses the analytic hierarchy process to determine the weight of the indicators. Thirdly, the paper uses the fuzzy comprehensive evaluation method to establish the evaluation set of the indicators. Finally, it concludes that the high-quality development level of the cities in the Yangtze River Economic Belt is at the middle level. more...

To evaluate the pathological changes of femoral nerves and the levels of caveolin-1 in diabetic foot amputation patients with neuropathy, and evaluate the association between caveolin-1 and neuropathy development. more...

Abstract Neuronal necrosis occurs during early phase of ischemic insult. However, our knowledge of neuronal necrosis is still inadequate. To study the mechanism of neuronal necrosis, we previously established a Drosophila genetic model of neuronal necrosis by calcium overloading through expression of a constitutively opened cation channel mutant. Here, we performed further genetic screens and identified a suppressor of neuronal necrosis, CG17259, which encodes a seryl-tRNA synthetase. We found that loss-of-function (LOF) CG17259 activated eIF2α phosphorylation and subsequent up-regulation of chaperons (Hsp26 and Hsp27) and autophagy. Genetically, down-regulation of eIF2α phosphorylation, Hsp26/Hsp27 or autophagy reduced the protective effect of LOF CG17259, indicating they function downstream of CG17259. The protective effect of these protein degradation pathways indicated activation of a toxic protein during neuronal necrosis. Our data indicated that p53 was likely one such protein, because p53 was accumulated in the necrotic neurons and down-regulation of p53 rescued necrosis. In the SH-SY5Y human cells, tunicamycin (TM), a PERK activator, promoted transcription of hsp27; and necrosis induced by glutamate could be rescued by TM, associated with reduced p53 accumulation. In an ischemic stroke model in rats, p53 protein was also increased, and TM treatment could reduce the p53 accumulation and brain damage. more...

Wave-based methods for acoustic simulations within enclosures suffer the numerical dispersion and then usually have evident dispersion error for problems with high wave numbers. To improve the upper limit of calculating frequency for 3D problems, a hybrid smoothed finite element method (hybrid SFEM) is proposed in this paper. This method employs the smoothing technique to realize the reduction of the numerical dispersion. By constructing a type of mixed smoothing domain, the traditional node-based and face-based smoothing techniques are mixed in the hybrid SFEM to give a more accurate stiffness matrix, which is widely believed to be the ultimate cause for the numerical dispersion error. The numerical examples demonstrate that the hybrid SFEM has better accuracy than the standard FEM and traditional smoothed FEMs under the condition of the same basic elements. Moreover, the hybrid SFEM also has good performance on the computational efficiency. A convergence experiment shows that it costs less time than other comparison methods to achieve the same computational accuracy. more...

As fundamental processes in mitochondrial dynamics, mitochondrial fusion, fission and transport are regulated by several core components, including Miro. As an atypical Rho-like small GTPase with high molecular mass, the exchange of GDP/GTP in Miro may require assistance from a guanine nucleotide exchange factor (GEF). However, the GEF for Miro has not been identified. While studying mitochondrial morphology in Drosophila, we incidentally observed that the loss of vimar, a gene encoding an atypical GEF, enhanced mitochondrial fission under normal physiological conditions. Because Vimar could co-immunoprecipitate with Miro in vitro, we speculated that Vimar might be the GEF of Miro. In support of this hypothesis, a loss-of-function (LOF) vimar mutant rescued mitochondrial enlargement induced by a gain-of-function (GOF) Miro transgene; whereas a GOF vimar transgene enhanced Miro function. In addition, vimar lost its effect under the expression of a constitutively GTP-bound or GDP-bound Miro mutant background. These results indicate a genetic dependence of vimar on Miro. Moreover, we found that mitochondrial fission played a functional role in high-calcium induced necrosis, and a LOF vimar mutant rescued the mitochondrial fission defect and cell death. This result can also be explained by vimar's function through Miro, because Miro's effect on mitochondrial morphology is altered upon binding with calcium. In addition, a PINK1 mutant, which induced mitochondrial enlargement and had been considered as a Drosophila model of Parkinson's disease (PD), caused fly muscle defects, and the loss of vimar could rescue these defects. Furthermore, we found that the mammalian homolog of Vimar, RAP1GDS1, played a similar role in regulating mitochondrial morphology, suggesting a functional conservation of this GEF member. The Miro/Vimar complex may be a promising drug target for diseases in which mitochondrial fission and fusion are dysfunctional. more...

The microRNA miR-101 is downregulated in several cancers, including bladder cancer. However, miR-101's role in the invasion, metastasis, and chemosensitivity of bladder cancer cells remains unclear. This study was conducted to determine miR-101's role on the lymphangiogenic molecule vascular endothelial growth factor C (VEGF-C) and their effects upon bladder cancer cell migration, invasion, and chemosensitivity to cisplatin.Two bladder cancer cell lines (T24 and 5637) and the tool cell line 293T were employed here. Bladder cancer cells were transfected with either a miR-101 overexpression vector or a scrambled-sequence lentivirus, both of which exhibited a high transfection efficiency. Non-transfection was used as a mock negative control. Wound healing and Transwell assays were performed to measure cell migration and invasiveness. A luciferase reporter assay was performed to validate miR-101's interaction with VEGF-C's 3' untranslated region followed by RT-PCR and Western blot confirmation. An MTS assay was used to evaluate the cisplatin sensitivity of the cell lines.miR-101 overexpression significantly inhibited the migration and invasiveness while significantly enhancing cisplatin sensitivity. miR-101 negatively regulated VEGF-C protein expression, and VEGF-C overexpression rescued the effects of miR-101 overexpression, indicating that miR-101 negatively regulates VEGF-C protein expression post-transcriptionally. miR-101 and VEGF-C interference independently enhanced cisplatin cytotoxicity in bladder cancer cells.miR-101 suppresses VEGF-C expression, inhibits cell migration and invasion, and increases cisplatin sensitivity in bladder cancer cells. This study provides new insight into miR-101's role in bladder cancer and shows miR-101's promise as a potential molecular target for bladder cancer. more...