IRAK1 deficiency potentiates the efficacy of radiotherapy in repressing cervical cancer development.

IRAK1 has been implicated in promoting development of various types of cancers and mediating radioresistance. However, its role in cervical cancer tumorigenesis and radioresistance, as well as the potential underlying mechanisms, remain poorly defined. In this study, we evaluated IRAK1 expression in radiotherapy-treated cervical cancer tissues and found that IRAK1 expression is negatively associated with the efficacy of radiotherapy. Consistently, ionizing radiation (IR)-treated HeLa and SiHa cervical cancer cells express a lower level of IRAK1 than control cells. Depletion of IRAK1 resulted in reduced activation of the NF-κB pathway, decreased cell viability, downregulated colony formation efficiency, cell cycle arrest, increased apoptosis, and impaired migration and invasion in IR-treated cervical cancer cells. Conversely, overexpressing IRAK1 mitigated the anti-cancer effects of IR in cervical cancer cells. Notably, treatment of IRAK1-overexpressing IR-treated HeLa and SiHa cells with the NF-κB pathway inhibitor pyrrolidine dithiocarbamate (PDTC) partially counteracted the effects of excessive IRAK1. Furthermore, our study demonstrated that IRAK1 deficiency enhanced the anti-proliferative role of IR treatment in a xenograft mouse model. These collective observations highlight IRAK1's role in mitigating the anti-cancer effects of radiotherapy, partly through the activation of the NF-κB pathway. SUMMARY: IRAK1 enhances cervical cancer resistance to radiotherapy, with IR treatment reducing IRAK1 expression and increasing cancer cell vulnerability and apoptosis.

Delta radiomics analysis for prediction of intermediary- and high-risk factors for patients with locally advanced cervical cancer receiving neoadjuvant therapy.

This study aimed to assess the feasibility of using magnetic resonance imaging (MRI)-based Delta radiomics characteristics extrapolated from the Ax LAVA + C series to identify intermediary- and high-risk factors in patients with cervical cancer undergoing surgery following neoadjuvant chemoradiotherapy. A total of 157 patients were divided into two groups: those without any intermediary- or high-risk factors and those with one intermediary-risk factor (negative group; n = 75). Those with any high-risk factor or more than one intermediary-risk factor (positive group; n = 82). Radiomics characteristics were extracted using Ax-LAVA + C MRI sequences. The data was divided into training (n = 126) and test (n = 31) sets in an 8:2 ratio. The training set data features were selected using the Mann-Whitney U test and the Least Absolute Shrinkage and Selection Operator (LASSO) test. The best radiomics features were then analyzed to build a preoperative predictive radiomics model for predicting intermediary- and high-risk factors in cervical cancer. Three models-the clinical model, the radiomics model, and the combined clinic and radiomics model-were developed in this study utilizing the random forest Algorithm. The receiver operating characteristic (ROC) curve, decision curve analysis (DCA), accuracy, sensitivity, and specificity were used to assess the predictive efficacy and clinical benefits of each model. Three models were developed in this study to predict intermediary- and high-risk variables associated with postoperative pathology for patients who underwent surgery after receiving neoadjuvant radiation. In the training and test sets, the AUC values assessed using the clinical model, radiomics model, and combined clinical and radiomics models were 0.76 and 0.70, 0.88 and 0.86, and 0.91 and 0.89, respectively. The use of machine learning algorithms to analyze Delta Ax LAVA + C MRI radiomics features can aid in the prediction of intermediary- and high-risk factors in patients with cervical cancer receiving neoadjuvant therapy.

Nomogram for prognosis of elderly patients with cervical cancer who receive combined radiotherapy.

This retrospective study identified prognostic factors to help guide the clinical treatment of elderly patients (≥ 65 years) with cervical cancer who had undergone radiotherapy. A personalized model to predict 3- and 5-years survival was developed. A review was conducted of 367 elderly women with cervical cancer (staged II-III) who had undergone radiotherapy in our hospital between January 2012 and December 2016. The Cox proportional hazards regression model was used for survival analysis that considered age, hemoglobin, squamous cell carcinoma antigen, pathologic type, stage, pelvic lymph node metastasis status, and others. A nomogram was constructed to predict the survival rates. The median follow-up time was 71 months (4-118 months). The 3- (5-) years overall, progression-free, local recurrence-free, and distant metastasis-free survival rates were, respectively, 91.0% (84.4%), 92.3% (85.9%), 99.18% (99.01%), and 99.18% (97.82%). The following were significant independent prognostic factors for overall survival: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The C-index of the line chart was 0.699 (95% CI 0.652-0.746). The areas under the receiver operating characteristic curves for 3- and 5-years survival were 0.751 and 0.724. The nomogram was in good concordance with the actual survival rates. The independent prognostic factors for overall survival in elderly patients with cervical cancer after radiotherapy were: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The novel prognostic nomogram based on these factors showed good concordance with the actual survival rates and can be used to guide personalized clinical treatment.

Rapid selection of potyviral cross-protection effective mutants from the local lesion host after nitrous acid mutagenesis.

Zucchini yellow mosaic virus (ZYMV) seriously damages cucurbits worldwide. Control of ZYMV by cross-protection has been practised for decades, but selecting useful mild viruses is time-consuming and laborious. Most attenuated potyviruses used for cross-protection do not induce hypersensitive reaction (HR) in Chenopodium quinoa, a local lesion host Chenopodium quinoa. Here, severe ZYMV TW-TN3 tagged with green fluorescent protein (GFP), designated ZG, was used for nitrous acid mutagenesis. From three trials, 11 mutants were identified from fluorescent spots without HR in inoculated C. quinoa leaves. Five mutants caused attenuated symptoms in squash plants. The genomic sequences of these five mutants revealed that most of the nonsynonymous changes were located in the HC-Pro gene. The replacement of individual mutated HC-Pros in the ZG backbone and an RNA silencing suppression (RSS) assay indicated that each mutated HC-Pro is defective in RSS function and responsible for reduced virulence. Four mutants provided high degrees of protection (84%-100%) against severe virus TW-TN3 in zucchini squash plants, with ZG 4-10 being selected for removal of the GFP tag. After removal of the GFP gene, Z 4-10 induced symptoms similar to ZG 4-10 and still provided 100% protection against TW-TN3 in squash, thus is considered not a genetically engineered mutant. Therefore, using a GFP reporter to select non-HR mutants of ZYMV from C. quinoa leaves is an efficient way to obtain beneficial mild viruses for cross-protection. This novel approach is being applied to other potyviruses.

Concurrent Control of Two Aphid-Borne Potyviruses in Cucurbits by Two-in-One Vaccine.

The application of attenuated viruses has been widely practiced for protecting crops from infection by related severe strains of the same species. Papaya ringspot virus W-type (PRSV W) and zucchini yellow mosaic virus (ZYMV) devastate cucurbits worldwide. However, the prevailing of these two viruses in cucurbits cannot be prevented by a single protective virus. In this study, we disclosed that co-infection of horn melon plants by two mild strains, PRSV P-type (PRSV P) HA5-1 and ZYMV-ZAC (a previously developed mild mutant of ZYMV) confers concurrent protection against PRSV P and ZYMV. Consequently, mild mutants of PRSV W were created by site-directed mutagenesis through modifications of the pathogenicity motifs FRNK and PD in helper component-protease (HC-Pro). A stable PRSV W mutant WAC (PRSV-WAC) with R181I and D397N mutations in HC-Pro was generated, inducing mild mottling, followed by symptomless recovery in cucurbits. Horn melon plants pre-infected by PRSV-WAC and ZYMV-ZAC showed no apparent interference on viral accumulation with no synergistic effects on symptoms. An agroinfiltration assay of mixed HC-Pros of WACHC-Pro + ZACHC-Pro revealed no additive effect of RNA silencing suppression. PRSV-WAC or ZYMV-ZAC alone only antagonized a severe strain of homologous virus, while co-infection with these two mild strains provided complete protection against both PRSV W and ZYMV. Similar results were reproduced in muskmelon and watermelon plants, indicating the feasibility of a two-in-one vaccine for concurrent control of PRSV W and ZYMV in cucurbits.

Prognostic value of tumor measurement parameters and SCC-Ag changes in patients with locally-advanced cervical cancer.

OBJECTIVE: To investigate the prognostic relevance of specific measurement parameters such as tumor diameter, tumor volume, tumor volume reduction rate (TVRR), and changes in the squamous cell carcinoma antigen (SCC-Ag) level in patients with locally-advanced cervical cancer (LACC) undergoing concurrent radiotherapy and chemotherapy. METHODS: This was a retrospective study of 203 patients with stage IIA-IVA cervical squamous cell carcinoma who were newly diagnosed at our hospital between January 2011 and March 2015. Clinical data and pre-and post-treatment imaging information were collected and each parameter was calculated using 3DSlicer software. The pre/post-treatment tumor diameter (TDpre/post), tumor volume (TVpre/post), SCC-Ag (SCCpre/post), and TVRR, SCC-Ag reduction rate (SCCRR) were analyzed and their prognostic relevance evaluated. RESULTS: The median follow-up was 69 months. The 5-year overall survival (OS) and disease progression-free survival (PFS) rates were 69.5% and 64.5%, respectively. On univariate analysis, TDpre/post, TVpre/post, TVRR, SCCpre/post and SCCRR showed significant association with OS and PFS (P < 0.05). On multivariate analysis, TDpre [Hazard ratio (HR) = 0.373, P = 0.028], TDpost (HR = 0.376, P = 0.003) and SCCpost (HR = 0.374, P = 0.001) were independent predictors of OS. TVRR (HR = 2.998, P < 0.001), SCCpre (HR = 0.563, P = 0.041), and SCCpost (HR = 0.253, P < 0.001) were independent predictors of PFS. Tumor measurement parameters showed a positive correlation with SCC-Ag (P < 0.05). CONCLUSION: TDpre/post, TVpre/post, TVRR, SCCpre/post, and SCCRR were prognostic factors in LACC. TDpre/post and SCCpost showed the most significant prognostic value. TVRR and SCCpre/post were closely related to disease progression. Further studies should investigate the correlation between measurement parameters of tumor and SCC-Ag.

Novel Biomarker Genes for Prognosis of Survival and Treatment of Glioma.

Glioblastoma multiforme (GBM) is the most aggressive malignant primary central nervous system tumor. Although surgery, radiotherapy, and chemotherapy treatments are available, the 5-year survival rate of GBM is only 5.8%. Therefore, it is imperative to find novel biomarker for the prognosis and treatment of GBM. In this study, a total of 141 differentially expressed genes (DEGs) in GBM were identified by analyzing the GSE12657, GSE90886, and GSE90598 datasets. After reducing the data dimensionality, Kaplan-Meier survival analysis indicated that expression of PTPRN and RIM-BP2 were downregulated in GBM tissues when compared with that of normal tissues and that the expression of these genes was a good prognostic biomarker for GBM (p<0.05). Then, the GSE46531 dataset and the Genomics of Drug Sensitivity in Cancer (GDSC) database were used to examine the relationship between sensitivity radiotherapy (RT) and chemotherapy for GBM and expression of PTPRN and RIM-BP2. The expression of PTPRN was significantly high in RT-resistant patients (p<0.05) but it was not related to temozolomide (TMZ) resistance. The expression level of RIM-BP2 was not associated with RT or TMZ treatment. Among the chemotherapeutic drugs, cisplatin and erlotinib had a significantly good treatment effect for glioma with expression of PTPRN or RIM-BP2 and in lower-grade glioma (LGG) with IDH mutation. (p < 0.05). The tumor mutational burden (TMB) score in the low PTPRN expression group was significantly higher than that in the high PTPRN expression group (p=0.013), with a large degree of tumor immune cell infiltration. In conclusion, these findings contributed to the discovery process of potential biomarkers and therapeutic targets for glioma patients.

miR-566 expression and immune changes in patients with intracranial aneurysm.

OBJECTIVE: Our study aims to investigate the correlations of micro ribonucleic acid (miR)-566 expression with the changes in immune-related indexes and differential genes in patients with intracranial aneurysm (IA). METHODS: Aneurysm wall tissues from a total of 50 IA cases and the corresponding normal arterial wall tissues from 50 individuals were selected. The miR-566 expression, differential gene expression profile, and expression level of differential gene proteins were detected and analyzed by fluorescence quantitative polymerase chain reaction (qPCR), RNAseq technique and western blotting, respectively. RESULTS: The miR-566 level was significantly higher in intracranial aneurysm tissues than that in normal arterial wall tissues (P<0.05). The levels of cluster of differentiation (CD)3+, CD4+, CD8+, CD4+/CD8+ and CD23+ T lymphocytes in the peripheral blood of IA patients significantly declined compared with those in the control group (P<0.05). RNAseq detection showed that there were 16 immune-inflammation-related genes significantly differentially expressed in aneurysm wall tissues compared with normal arterial wall tissues in the control group. The levels of VHL and NIK in aneurysm wall tissues were significantly decreased, while those of VEGF and ALOX5 were obviously increased. Both mRNA and protein levels of these four genes also had significant changes, which had linear relations to the expression of miR-566. CONCLUSION: The abnormal expression of miR-566 affects the immune function, thus promoting the occurrence and deterioration of intracranial aneurysm.

Prognosis of nasopharyngeal carcinoma with insufficient radical dose to the primary site in the intensity-modulated radiotherapy era.

BACKGROUND: It was reported that reduced radiotherapy is feasible for children with nasopharyngeal carcinoma (NPC) and papilloma virus-positive oropharyngeal cancer. Therefore, we performed this study to explore the prognosis of reduced-dose radiation in adult with NPC. METHODS: Between 2004 and 2013, we retrospectively analyzed 19 patients histologically diagnosed with NPC, who received <66 Gy radiation therapy. Ten patients receiving <54 Gy to the primary site were group A. Nine patients receiving ≥54 Gy were group B. RESULTS: Thirteen patients received induction chemotherapy (IC) for two or three cycles. In group A, the 5-year overall survival (OS) was 50.0%. For group B, the 5-year OS, locoregional relapse-free survival, progression-free survival, and distant metastasis-free survival were 88.9%, 100.0%, 88.9%, and 88.9%. Group B had a better prognosis than group A on OS (88.9% vs 50.0%, P = .03). CONCLUSION: Patients receiving ≥54 Gy but <66 Gy with IC achieved good local control and long-term survival.