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Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer. However, the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations. Furthermore, monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors. In this study, based on our discovery that spore shell (SS) of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity, we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy, chemodynamic therapy and antitumor immunity for synergistic cancer treatment. In detail, SS is separated from probiotic spores and then attached to the surface of liposome (Lipo) that was loaded with hemoglobin (Hb), glucose oxidase (GOx) and JQ1 to construct SS@Lipo/Hb/GOx/JQ1. In tumor tissue, highly toxic hydroxyl radicals (•OH) are generated via sequential catalytic reactions: GOx catalyzing glucose into H2O2 and Fe2+ in Hb decomposing H2O2 into •OH. The combination of •OH and SS adjuvant can improve tumor immunogenicity and activate immune system. Meanwhile, JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response. In this manner, SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis. To summarize, the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

Objective: To evaluate and compare the image quality of T2-weighted abdominal scans using a respiratory belt trigger (RBT) and frequency-modulated continuous wave (FMCW)-trigger (FT) techniques and to explore the feasibility of FT in abdominal magnetic resonance imaging (MRI).Methods: The study prospectively included 28 subjects, each undergoing abdominal scans with both RBT and FT. The analysis focused on 64 inconsistent trigger segments from the respiratory curves triggered by RBT and FMCW. Parameters such as inconsistent trigger type (ITT), number of inconsistent trigger points (ITPs), ratio of ITP (ITR), and single-segment ITR (SITR) were derived from these curves. Image quality was evaluated by two observers using subjective scoring, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). The assessments classified image quality as either “good” or “poor.” Consistency in image quality assessment between observers was determined using the kappa test and intraclass correlation coefficient (ICC). The chi-square test, Student’s t-test, and the Mann–Whitney U test were employed to compare the categorical and continuous variables between the RBT and FT groups.Results: The observers showed a high level of agreement in image quality assessment. There were no significant differences in ITR, SITR, acquisition time, SNR, and CNR between the RBT and FT groups (all p > 0.05). Both subjective and objective evaluations indicated no notable difference in image quality between the two groups (p > 0.05).Conclusion: The FMCW trigger technique is a viable alternative to the traditional respiratory belt trigger in scenarios of relatively stable breathing. It offers potential benefits, such as reducing operational demands on technicians and improving MRI workflow efficiency.

Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4+ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8+ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

PurposeTo develop and validate multi-parametric MRI (MP-MRI)-based radiomics models for the prediction of biological characteristics in endometrial cancer (EC).MethodsA total of 292 patients with EC were divided into LVSI (n = 208), DMI (n = 292), MSI (n = 95), and Her-2 (n = 198) subsets. Total 2316 radiomics features were extracted from MP-MRI (T2WI, DWI, and ADC) images, and clinical factors (age, FIGO stage, differentiation degree, pathological type, menopausal state, and irregular vaginal bleeding) were included. Intra-class correlation coefficient (ICC), spearman’s rank correlation test, univariate logistic regression, and least absolute shrinkage and selection operator (LASSO) were used to select radiomics features; univariate and multivariate logistic regression were used to identify clinical independent risk factors. Five classifiers were applied (logistic regression, random forest, decision tree, K-nearest neighbor, and Bayes) to construct radiomics models for predicting biological characteristics. The clinical model was built based on the clinical independent risk factors. The combined model incorporating the radiomics score (radscore) and the clinical independent risk factors was constructed. The model was evaluated by ROC curve, calibration curve (H-L test), and decision curve analysis (DCA).ResultsIn the training cohort, the RF radiomics model performed best among the five classifiers for the three subsets (MSI, LVSI, and DMI) according to AUC values (AUCMSI: 0.844; AUCLVSI: 0.952; AUCDMI: 0.840) except for Her-2 subset (Decision tree: AUC=0.714), and the combined model had higher AUC than the clinical model in each subset (MSI: AUCcombined =0.907, AUCclinical =0.755; LVSI: AUCcombined =0.959, AUCclinical =0.835; DMI: AUCcombined = 0.883, AUCclinical =0.796; Her-2: AUCcombined =0.812, AUCclinical =0.717; all P

Abstract The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.

Abstract Breast cancer with bone metastasis accounts for serious cancer‐associated pain which significantly reduces the quality of life of affected patients and promotes cancer progression. However, effective treatment using nanomedicine remains a formidable challenge owing to poor drug delivery efficiency to multiple cancer lesions and inappropriate management of cancer‐associated pain. In this study, using engineered macrophage membrane (EMM) and drugs loaded nanoparticle, we constructed a biomimetic nanoplatform (EMM@DJHAD) for the concurrent therapy of bone metastatic breast cancer and associated pain. Tumor tropism inherited from EMM provided the targeting ability for both primary and metastatic lesions. Subsequently, the synergistic combination of decitabine and JTC801 boosted the lytic and inflammatory responses accompanied by a tumoricidal effect, which transformed the tumor into an ideal decoy for EMM, resulting in prolonged troop migration toward tumors. EMM@DJHAD exerted significant effects on tumor suppression and a pronounced analgesic effect by inhibiting µ‐opioid receptors in bone metastasis mouse models. Moreover, the nanoplatform significantly reduced the severe toxicity induced by chemotherapy agents. Overall, this biomimetic nanoplatform with good biocompatibility may be used for the effective treatment of breast cancer with bone metastasis.

Abstract Objectives To evaluate the therapeutic effect of neoadjuvant therapy (NAT) followed by radical hysterectomy and concurrent chemoradiotherapy (CCRT) in stage IB2 and IIA2 squamous cervical cancer (SCC) and investigate the value of apparent diffusion coefficient (ADC) in outcome evaluation of different treatment strategies in the patients. Methods A total of 149 patients with IB2 and IIA2 SCC who underwent pretreatment MRI and DWI scan were included. Patients were treated with NAT + RH or CCRT. Clinical indices and pathological factors were recorded. The imaging indices were measured including tumor size and tumor ADC values. Intraclass correlation coefficient was employed to evaluate the consistency of the indices measured by two observers. ROC curves were used to evaluate the cutoff values of clinical and imaging indices. Kaplan–Meier and Cox proportional hazard model were used to analyze the independent factors of disease-free survival (DFS). Results The median follow-up period was 42.3 months. SCC-Ag, ADCmax and ADCmin were independent factors for DFS in the entire cohort. SCC-Ag, ADCmin and vascular invasion were independent factors for DFS in NAT + RH group. ADCmax and ADCmin were independent factors for DFS in CCRT group. ADCmin was the strongest independent factor for DFS in NAT + RH group, while ADCmax was that in CCRT group. Conclusion The NAT + RH patients had similar DFS to that of CCRT in IB2 and IIA2 SCC, which could be a potential feasible alternative treatment. ADCmin and ADCmax were more valuable in evaluating the outcome of patients who underwent NAT + RH or CCRT, respectively.

The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes (LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin (SV) adjuvant loaded Au nanocages (AuNCs) as cores (AuNCs/SV) and folic acid modified thermal-sensitive liposomes (FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy (PTT) induced the release of tumor-derived protein antigens (TDPAs) and the shedding of FA-TSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine (AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.

ObjectivesTo investigate the value of amide proton transfer weighted (APTw) imaging combined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting intermediate-risk factors of deep stromal invasion (DSI) and lymphovascular vascular space invasion (LVSI) in cervical cancer.MethodsSeventy patients with cervical cancer who underwent MRI before operation from July 2019 to February 2022 were retrospectively included in this study. Clinical information including age, histologic subtype etc. were recorded for patients. ATPw imaging parameter APTmean and DCE-MRI parameters Ktrans, Kep and Ve were measured and analyzed. The independent-sample t-test, Mann-Whitney U test, or Chi-square test was used to compare the differences of parameters between DSI/LVSI positive and negative groups. Logistic analysis was used to develop a combined predictive model. The receiver operating characteristic curve was for predictive performance. ANOVA and Kruskal-Wallis test were used to compare the differences of consecutive parameters among multiple groups.ResultsKtrans and SCC-Ag were independent factors in predicting DSI; Ktrans+SCC-Ag had the highest AUC 0.819 with sensitivity and specificity of 71.74% and 91.67%, respectively. APTmean and Ktrans were independent factors in predicting LVSI; APTmean+Ktrans had the highest AUC 0.874 with sensitivity and specificity of 92.86% and 75.00%, respectively. Ktrans and Ve could discriminate coexistence of DSI and LVSI from presence of single one, APTmean could discriminate the presence of DSI or LVSI from no risk factor presence.ConclusionThe combination of APTw and DCE-MRI is valuable in predicting intermediate-risk factors of DSI and LVSI in cervical cancer.

Abstract Background Aberrant spliced isoforms are specifically associated with cancer progression and metastasis. The cytoplasmic adaptor CRKL (v-crk avian sarcoma virus CT10 oncogene homolog-like) is a CRK like proto-oncogene, which encodes a SH2 and SH3 (src homology) domain-containing adaptor protein. CRKL is tightly linked to leukemia via its binding partners BCR-ABL and TEL-ABL, upregulated in multiple types of human cancers, and induce cancer cell proliferation and invasion. However, it remains unclear whether signaling adaptors such as CRKL could regulate alternative splicing. Methods We analyzed the expression level of CRKL in 305 cervical cancer tissue samples available in TCGA database, and then selected two groups of cancer samples with CRKL differentially expressed to analyzed potential CRKL-regulated alternative splicing events (ASEs). CRKL was knocked down by shRNA to further study CRKL-regulated alternative splicing and the activity of SR protein kinases in HeLa cells using RNA-Seq and Western blot techniques. We validated 43 CRKL-regulated ASEs detected by RNA-seq in HeLa cells, using RT-qPCR analysis of HeLa cell samples and using RNA-seq data of the two group of clinical cervical samples. Results The expression of CRKL was mostly up-regulated in stage I cervical cancer samples. Knock-down of CRKL led to a reduced cell proliferation. CRKL-regulated alternative splicing of a large number of genes were enriched in cancer-related functional pathways, among which DNA repair and G2/M mitotic cell cycle, GnRH signaling were shared among the top 10 enriched GO terms and KEGG pathways by results from clinical samples and HeLa cell model. We showed that CRKL-regulated ASEs revealed by computational analysis using ABLas software in HeLa cell were highly validated by RT-qPCR, and also validated by cervical cancer clinical samples. Conclusions This is the first report of CRKL-regulation of the alternative splicing of a number of genes critical in tumorigenesis and cancer progression, which is consistent with CRKL reported role as a signaling adaptor and a kinase. Our results underline that the signaling adaptor CRKL might integrate the external and intrinsic cellular signals and coordinate the dynamic activation of cellular signaling pathways including alternative splicing regulation.