FAT10 induces immune suppression by upregulating PD-L1 expression in hepatocellular carcinoma.

The upregulation of programmed death ligand 1 (PD-L1) plays a crucial role in facilitating cancer cells to evade immune surveillance through immunosuppression. However, the precise regulatory mechanisms of PD-L1 in hepatocellular carcinoma (HCC) remain undefined. The correlation between PD-L1 and ubiquitin-like molecules (UBLs) was studied using sequencing data from 20 HCC patients in our center, combined with TCGA data. Specifically, the association between FAT10 and PD-L1 was further validated at both the protein and mRNA levels in HCC tissues from our center. Subsequently, the effect of FAT10 on tumor progression and immune suppression was examined through both in vivo and in vitro experiments. Utilizing sequencing data, qPCR, and Western blotting assays, we confirmed that FAT10 was highly expressed in HCC tissues and positively correlated with PD-L1 expression. Additionally, in vitro experiments demonstrated that the overexpression of FAT10 fostered the proliferation, migration, and invasion of HCC cells. Furthermore, the overexpression of FAT10 in HCC cells led to an increase in PD-L1 expression, resulting in the inhibition of T cell proliferation and the enhancement of HCC cell resistance to T cell-mediated cytotoxicity. Moreover, in vivo experiments utilizing the C57BL/6 mouse model revealed that overexpression of FAT10 effectively suppressed the infiltration of CD8 + GZMB + and CD8 + Ki67 + T cells, as well as reduced serum levels of TNF-α and IFN-γ. Mechanistically, we further identified that FAT10 upregulates PD-L1 expression via activating the PI3K/AKT/mTOR pathway, but not in a ubiquitin-like modification. In conclusion, our findings indicate that FAT10 promotes immune evasion of HCC via upregulating PD-L1 expression, suggesting its potential as a novel target to enhance the efficiency of immunotherapy in HCC.

CircNUP54 promotes hepatocellular carcinoma progression via facilitating HuR cytoplasmic export and stabilizing BIRC3 mRNA.

Circular RNAs (circRNAs) have been implicated in tumorigenesis and progression of various cancers. However, the underlying mechanisms of circRNAs in hepatocellular carcinoma (HCC) have not been fully elucidated. Herein, a new oncogenic circRNA, hsa_circ_0070039 (circNUP54), was identified to be significantly upregulated in HCC through circRNA sequencing. As verified in 68 HCC samples, circNUP54 overexpression was correlated with aggressive cancerous behaviors and poor outcomes. Moreover, the function experiments showed that knockdown of circNUP54 inhibited the malignant progression of HCC in vitro and in vivo, whereas overexpression of circNUP54 had the opposite role. Mechanistic investigations carried out by RNA pull-down, RNA immunoprecipitation, and immunofluorescence revealed that circNUP54 interacted with the RNA-binding protein Hu-antigen R (HuR) and promoted its cytoplasmic export. The cytoplasmic accumulation of HuR stabilized the downstream BIRC3 mRNA through its binding to the 3' UTR region. Consequently, the encoded protein of BIRC3, cellular inhibitor of apoptosis 2 (cIAP2), proceeded to activate the NF-κB signal pathway and ultimately contributed to HCC progression. In addition, depletion of BIRC3 rescued the pro-tumorigenic effect of circNUP54 on HCC cells. Overall, this study demonstrated that circNUP54 facilitates HCC progression via regulating the HuR/BIRC3/NF-κB axis, which may serve as a promising therapeutic target for HCC treatment.

A novel risk score system based on immune subtypes for identifying optimal mRNA vaccination population in hepatocellular carcinoma.

PURPOSE: Although mRNA vaccines have shown certain clinical benefits in multiple malignancies, their therapeutic efficacies against hepatocellular carcinoma (HCC) remains uncertain. This study focused on establishing a novel risk score system based on immune subtypes so as to identify optimal HCC mRNA vaccination population. METHODS: GEPIA, cBioPortal and TIMER databases were utilized to identify candidate genes for mRNA vaccination in HCC. Subsequently, immune subtypes were constructed based on the candidate genes. According to the differential expressed genes among various immune subtypes, a risk score system was established using machine learning algorithm. Besides, multi-color immunofluorescence of tumor tissues from 72 HCC patients were applied to validate the feasibility and efficiency of the risk score system. RESULTS: Twelve overexpressed and mutated genes associated with poor survival and APCs infiltration were identified as potential candidate targets for mRNA vaccination. Three immune subtypes (e.g. IS1, IS2 and IS3) with distinct clinicopathological and molecular profiles were constructed according to the 12 candidate genes. Based on the immune subtype, a risk score system was developed, and according to the risk score from low to high, HCC patients were classified into four subgroups on average (e.g. RS1, RS2, RS3 and RS4). RS4 mainly overlapped with IS3, RS1 with IS2, and RS2+RS3 with IS1. ROC analysis also suggested the significant capacity of the risk score to distinguish between the three immune subtypes. Higher risk score exhibited robustly predictive ability for worse survival, which was further independently proved by multi-color immunofluorescence of HCC samples. Notably, RS4 tumors exhibited an increased immunosuppressive phenotype, higher expression of the twelve potential candidate targets and increased genome altered fraction, and therefore might benefit more from vaccination. CONCLUSIONS: This novel risk score system based on immune subtypes enabled the identification of RS4 tumor that, due to its highly immunosuppressive microenvironment, may benefit from HCC mRNA vaccination.

Identification of FOXP1 as a favorable prognostic biomarker and tumor suppressor in intrahepatic cholangiocarcinoma.

BACKGROUND: Forkhead-box protein P1 (FOXP1) has been proposed to have both oncogenic and tumor-suppressive properties, depending on tumor heterogeneity. However, the role of FOXP1 in intrahepatic cholangiocarcinoma (ICC) has not been previously reported. METHODS: Immunohistochemistry was performed to detect FOXP1 expression in ICC and normal liver tissues. The relationship between FOXP1 levels and the clinicopathological characteristics of patients with ICC was evaluated. Finally, in vitro and in vivo experiments were conducted to examine the regulatory role of FOXP1 in ICC cells. RESULTS: FOXP1 was significantly downregulated in the ICC compared to their peritumoral tissues (p < 0.01). The positive rates of FOXP1 were significantly lower in patients with poor differentiation, lymph node metastasis, invasion into surrounding organs, and advanced stages (p < 0.05). Notably, patients with FOXP1 positivity had better outcomes (overall survival) than those with FOXP1 negativity (p < 0.05), as revealed by Kaplan-Meier survival analysis. Moreover, Cox multivariate analysis showed that negative FOXP1 expression, advanced TNM stages, invasion, and lymph node metastasis were independent prognostic risk factors in patients with ICC. Lastly, overexpression of FOXP1 inhibited the proliferation, migration, and invasion of ICC cells and promoted apoptosis, whereas knockdown of FOXP1 had the opposite role. CONCLUSION: Our findings suggest that FOXP1 may serve as a novel outcome predictor for ICC as well as a tumor suppressor that may contribute to cancer treatment.

Gaze Point Tracking Based on a Robotic Body-Head-Eye Coordination Method.

When the magnitude of a gaze is too large, human beings change the orientation of their head or body to assist their eyes in tracking targets because saccade alone is insufficient to keep a target at the center region of the retina. To make a robot gaze at targets rapidly and stably (as a human does), it is necessary to design a body-head-eye coordinated motion control strategy. A robot system equipped with eyes and a head is designed in this paper. Gaze point tracking problems are divided into two sub-problems: in situ gaze point tracking and approaching gaze point tracking. In the in situ gaze tracking state, the desired positions of the eye, head and body are calculated on the basis of minimizing resource consumption and maximizing stability. In the approaching gaze point tracking state, the robot is expected to approach the object at a zero angle. In the process of tracking, the three-dimensional (3D) coordinates of the object are obtained by the bionic eye and then converted to the head coordinate system and the mobile robot coordinate system. The desired positions of the head, eyes and body are obtained according to the object's 3D coordinates. Then, using sophisticated motor control methods, the head, eyes and body are controlled to the desired position. This method avoids the complex process of adjusting control parameters and does not require the design of complex control algorithms. Based on this strategy, in situ gaze point tracking and approaching gaze point tracking experiments are performed by the robot. The experimental results show that body-head-eye coordination gaze point tracking based on the 3D coordinates of an object is feasible. This paper provides a new method that differs from the traditional two-dimensional image-based method for robotic body-head-eye gaze point tracking.

Cross-Attention Based Multi-Resolution Feature Fusion Model for Self-Supervised Cervical OCT Image Classification.

Cervical cancer seriously endangers the health of the female reproductive system and even risks women's life in severe cases. Optical coherence tomography (OCT) is a non-invasive, real-time, high-resolution imaging technology for cervical tissues. However, since the interpretation of cervical OCT images is a knowledge-intensive, time-consuming task, it is tough to acquire a large number of high-quality labeled images quickly, which is a big challenge for supervised learning. In this study, we introduce the vision Transformer (ViT) architecture, which has recently achieved impressive results in natural image analysis, into the classification task of cervical OCT images. Our work aims to develop a computer-aided diagnosis (CADx) approach based on a self-supervised ViT-based model to classify cervical OCT images effectively. We leverage masked autoencoders (MAE) to perform self-supervised pre-training on cervical OCT images, so the proposed classification model has a better transfer learning ability. In the fine-tuning process, the ViT-based classification model extracts multi-scale features from OCT images of different resolutions and fuses them with the cross-attention module. The ten-fold cross-validation results on an OCT image dataset from a multi-center clinical study of 733 patients in China indicate that our model achieved an AUC value of 0.9963 ± 0.0069 with a 95.89 ± 3.30% sensitivity and 98.23 ± 1.36 % specificity, outperforming some state-of-the-art classification models based on Transformers and convolutional neural networks (CNNs) in the binary classification task of detecting high-risk cervical diseases, including high-grade squamous intraepithelial lesion (HSIL) and cervical cancer. Furthermore, our model with the cross-shaped voting strategy achieved a sensitivity of 92.06% and specificity of 95.56% on an external validation dataset containing 288 three-dimensional (3D) OCT volumes from 118 Chinese patients in a different new hospital. This result met or exceeded the average of four medical experts who have used OCT for over one year. In addition to promising classification performance, our model has a remarkable ability to detect and visualize local lesions using the attention map of the standard ViT model, providing good interpretability for gynecologists to locate and diagnose possible cervical diseases.

Identification of a Novel Ferroptosis-Related Gene Signature for Predicting Prognosis and Responsiveness to Immunotherapy in Hepatocellular Carcinoma.

Purpose: Ferroptosis has been reported to regulate multiple biological behaviors. However, the prognostic and oncologic values of ferroptosis-related genes (FRGs) have not been comprehensively elucidated in hepatocellular carcinoma (HCC). Here, we aimed to construct FRGs-associated signature for stratification of the prognosis of HCC patients. Methods: A list of FRGs was generated from FerrDb. Public databases were used to extract expression matrices and clinical information. TCGA cohort was randomly divided into a training set and a validation set. Prognostic signature for Overall Survival (OS) was established in training set and validated in internal cohorts (TCGA validation set and entire set) and external cohort (ICGC cohort). Additionally, the role of signature in HCC was well investigated by analysis of mutations, gene set enrichment analysis (GSEA), analysis of immune infiltrates, and analysis of response to immune checkpoint blockade (ICB) treatment. The oncogenic effects of ZFP69B on HCC were also investigated in vitro. Results: We identified 12 FRGs-based signature for OS with LASSO regression. Patients were partitioned into different risk groups based on the signature. Overall, patients in different groups had different prognosis. The signature independently predicted OS in multivariate Cox regression analyses. Anti-tumor immune cells including activated CD8 T cells, cytolytic activity, and Th1 cells were negatively correlated with risk score in both TCGC and ICGC cohorts. Furthermore, low-risk patients responded better to ICB than high-risk patients. In addition, knockdown of ZFP69B reduced proliferation, migration, and invasion, and promoted erastin-induced ferroptosis of HCC cells. Conclusion: We developed a prognostic signature based on FRGs to predict OS of HCC patients. And the signature may facilitate clinicians in identifying those who are likely to benefit from ICIs. The results also indicated that ZFP69B might regulate the process of ferroptosis and could be used as a novel potential target for HCC.

Convivial cooking: Impacts of an educational intervention on college students' food agency.

Objective: This research examines the effects of educational materials, delivered with "take-home and cook-with-friends" meal kits, on college students' food agency. Participants: In the spring of 2021, 186 students were recruited at a US public university and randomly allocated into either an intervention group that received meal kits and educational materials or a control group that received only meal kits. Methods: Meal kits containing local ingredients were distributed weekly to the participants and surveys were conducted to measure participants' food agency, using the Cooking and Food Provisioning Action Scale (CAFPAS). Hypothesis tests and regression analysis were then conducted to examine the educational intervention's effects on the CAFPAS scores. Results: The educational intervention had a positive and statistically significant effect on students' CAFPAS scores. Conclusions: Educational interventions hold promise in enhancing college students' food agency, at least in the short term.

Identification of LSM Family Members as Novel Unfavorable Biomarkers in Hepatocellular Carcinoma.

Background: Smith-like (LSM) family members play critical roles in multiple oncologic processes in several types of malignancies. The study on LSM family members of HCC might provide new insights into the tumorigenesis and therapeutic strategies of HCC. Methods: The clinical significance and oncologic biological functions of LSM family members were assessed through multiple bioinformatics methods and in vitro studies. The potential correlation between LSM family members and tumor immunity was also investigated using single sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm. Results: LSM family member overexpression in HCC was significantly correlated with poor clinical outcomes such as higher TNM stage, advanced histologic grade, and worse prognosis. A risk score system based on LSM5, LSM10, LSM12, and LSM14B showed a reliable predictive ability for OS of HCC patients. Functional enrichment analysis demonstrated that LSM family members overexpressed were all involved in cell cycle related biological processes. Besides, LSM12, LSM14A, and LSM14B were found to be significantly associated with PI3K-Akt-mTOR and T cell receptor signaling pathways. Tumors with LSM12, LSM14A, and LSM14B overexpression exhibited lower infiltration of activated CD8+ T cells with declined cytolytic activity and immune score, but increased infiltration of Th2 cells and Th2/Th1. LSM12, LSM14A, and LSM14B overexpression is also associated with higher tumor-related immune checkpoints (e.g., PD-L1, B7-H3, and PVR) expression and increased therapeutic insensitivity to immune checkpoint blockade (ICB). Moreover, the knockdown of LSM12, LSM14A, and LSM14B significantly inhibited the proliferation and invasion of HCC cells. Conclusion: This study systematically investigated the expression pattern and biological values of LSM family members in HCC and identified LSM family members as novel therapeutic targets in HCC.

CircLIFR suppresses hepatocellular carcinoma progression by sponging miR-624-5p and inactivating the GSK-3ß/ß-catenin signaling pathway.

Circular RNAs have been reported to play essential roles in the tumorigenesis and progression of various cancers. However, the biological processes and mechanisms involved in hepatocellular carcinoma (HCC) remain unclear. Initial RNA-sequencing data and qRT-PCR results in our cohort showed that hsa_circ_0072309 (also called circLIFR) was markedly downregulated in HCC tissues. Kaplan-Meier analysis indicated that higher levels of circLIFR in HCC patients correlated with favorable overall survival and recurrence-free survival rates. Both in vitro and in vivo experiments indicated that circLIFR inhibited the proliferation and invasion abilities of HCC cells. We therefore conducted related experiments to explore the mechanism of circLIFR in HCC. Fluorescence in situ hybridization results revealed that circLIFR was mainly located in the cytoplasm, and RNA immunoprecipitation assays indicated that circLIFR was significantly enriched by Ago2 protein. These results suggested that circLIFR may function as a sponge of miRNAs to regulate HCC progression. We further conducted bioinformatics prediction as well as dual-luciferase reporter assays, and the results of which showed that circLIFR could sponge miR-624-5p to stabilize glycogen synthase kinase 3ß (GSK-3ß) expression. Loss and gain of function experiments demonstrated that regulation of the expression of miR-624-5p or GSK-3ß markedly affected HCC progression induced by circLIFR. Importantly, we also proved that circLIFR could facilitate the degradation of ß-catenin and prevent its translocation to the nucleus in HCC cells. Overall, our study demonstrated that circLIFR acts as a tumor suppressor in HCC by regulating miR-624-5p and inactivating the GSK-3ß/ß-catenin signaling pathway.

A Novel Guanine Elicitor Stimulates Immunity in Arabidopsis and Rice by Ethylene and Jasmonic Acid Signaling Pathways.

Rice sheath blight (ShB) caused by Rhizoctonia solani is one of the most destructive diseases in rice. Fungicides are widely used to control ShB in agriculture. However, decades of excessive traditional fungicide use have led to environmental pollution and increased pathogen resistance. Generally, plant elicitors are regarded as environmentally friendly biological pesticides that enhance plant disease resistance by triggering plant immunity. Previously, we identified that the plant immune inducer ZhiNengCong (ZNC), a crude extract of the endophyte, has high activity and a strong ability to protect plants against pathogens. Here, we further found that guanine, which had a significant effect on inducing plant resistance to pathogens, might be an active component of ZNC. In our study, guanine activated bursts of reactive oxygen species, callose deposition and mitogen-activated protein kinase phosphorylation. Moreover, guanine-induced plant resistance to pathogens depends on ethylene and jasmonic acid but is independent of the salicylic acid signaling pathway. Most importantly, guanine functions as a new plant elicitor with broad-spectrum resistance to activate plant immunity, providing an efficient and environmentally friendly biological elicitor for bacterial and fungal disease biocontrol.

Cervical optical coherence tomography image classification based on contrastive self-supervised texture learning.

BACKGROUND: Cervical cancer (CC) seriously affects the health of the female reproductive system. Optical coherence tomography (OCT) emerged as a noninvasive, high-resolution imaging technology for cervical disease detection. However, OCT image annotation is knowledge-intensive and time-consuming, which impedes the training process of deep-learning-based classification models. PURPOSE: This study aims to develop a computer-aided diagnosis (CADx) approach to classifying in-vivo cervical OCT images based on self-supervised learning. METHODS: In addition to high-level semantic features extracted by a convolutional neural network (CNN), the proposed CADx approach designs a contrastive texture learning strategy to leverage unlabeled cervical OCT images' texture features. We conducted 10-fold cross-validation on the OCT image dataset from a multicenter clinical study on 733 patients from China. RESULTS: In a binary classification task for detecting high-risk diseases, including high-grade squamous intraepithelial lesion and CC, our method achieved an area-under-the-curve value of 0.9798 ± 0.0157 with a sensitivity of 91.17% ± 4.99% and a specificity of 93.96% ± 4.72% for OCT image patches; also, it outperformed two out of four medical experts on the test set. Furthermore, our method achieved 91.53% sensitivity and 97.37% specificity on an external validation dataset containing 287 three-dimensional OCT volumes from 118 Chinese patients in a new hospital using a cross-shaped threshold voting strategy. CONCLUSIONS: The proposed contrastive-learning-based CADx method outperformed the end-to-end CNN models and provided better interpretability based on texture features, which holds great potential to be used in the clinical protocol of "see-and-treat."

SLC39A1 Overexpression is Associated with Immune Infiltration in Hepatocellular Carcinoma and Promotes Its Malignant Progression.

BACKGROUND: Solute carrier family 39 member 1 (SLC39A1) has been identified as a zinc ion transport protein that possesses oncogenic properties in various types of cancers. However, its potential function in hepatocellular carcinoma (HCC) remains unknown. This study aimed to investigate the expression profile and potential mechanisms of SLC39A1 in HCC. METHODS: SLC39A1 expression was analyzed using multiple databases. The clinical significance and associated biological pathways of SLC39A1 were investigated using bioinformatics analysis. Potential correlations between SLC39A1 expression and tumor immunity in HCC were also evaluated using single-sample gene set enrichment analysis (GSEA). Sixty paired HCC samples were used to verify the expression pattern of SLC39A1. In vitro studies were performed to investigate the oncogenic effects of SLC39A1 in HCC. Western blot analysis was conducted to further investigate the possible involved signaling pathways. RESULTS: The overexpression of SLC39A1 in HCC was determined by bioinformatics analysis and was confirmed in tissues from our center. SLC39A1 overexpression was also significantly correlated with worse prognosis, advanced TNM stage, and histological grade. GSEA analysis demonstrated that SLC39A1 overexpression was involved in various tumor-related pathways, such as the cell cycle and Wnt signaling pathway. SLC39A1 knockdown repressed the proliferation, invasion, and migration abilities of HCC cells. Furthermore, SLC39A1 knockdown decreased the expression of the tumor progression-related proteins (eg, cyclin D1 and MMP2) and Wnt signaling pathway-related proteins (eg, Wnt3A and ß-catenin). In addition, SLC39A1 overexpression may be associated with impaired tumor immunity in HCC, as evidenced by the increased infiltration of Th2 cells and reduced infiltration of cytotoxic cells. CONCLUSION: These findings preliminarily suggested the crucial effect of SLC39A1 overexpression on HCC tumor progression and immunosuppression, suggesting its potential as a novel prognostic and therapeutic target in HCC.

Highly active biostimulant Paecilomyces variotii extracts reduced controlled-release urea application while maintaining rice yield.

BACKGROUND: The high cost of controlled-release urea (CRU) has prompted this study to explore whether the amount of CRU can be reduced by adding biostimulants while maintaining or increasing rice yield. A 2 year field experiment was conducted with CRU at three levels (60%, 80%, and 100% of the recommended nitrogen (N) fertilizer) and a novel biostimulant Paecilomyces variotii extract (ZNC), to investigate their synergistic effects on yield, nitrogen use efficiency (NUE), and net profitability of rice. RESULTS: Controlled-release urea achieved a significantly higher gain yield and NUE than conventional urea with the same N level, which could be attributed to its N supply. Even if the N level of CRU was reduced by 40%, both rice yield and net profit were still significantly higher than for the full amount of urea. Paecilomyces variotii extract sprayed on the surface of CRU at a dose of only 87.5 mL ha-1 exhibited ultra-high effectiveness by increasing the panicles, the N accumulation, and the rice yield. Controlled-release urea enriched by ZNC achieved significantly higher gain yield than CRU alone, increasing the yield by 9.2% and 8.7%, respectively, in 2 years under the full recommended N rate. The combination of 80% CRU and ZNC showed no significant difference in rice yield from treatment with 100% CRU, indicating that the rate of CRU could be reduced by ZNC. The application of ZNC further increased NUE, N partial factor productivity, and net profit. CONCLUSION: The CRU and ZNC combination provided a feasible approach for reducing N input while maintaining rice yield and agricultural sustainability. © 2021 Society of Chemical Industry.

A novel chondroitin sulfate E from Dosidicus gigas cartilage and its antitumor metastatic activity.

Chondroitin sulfate (CS) chains containing GlcUAß1-3GalNAc(4S,6S) (E unit) have been shown to be involved in various physiological and pathological processes. However, commercial E unit-rich CS (CS-E) is difficult to produce on a large scale due to expensive and limited squid cartilage resources. In this study, a novel CS-E (CS-nE) was isolated from the cheap and abundant cartilage of the giant squid Dosidicus gigas. The CS-nE has a surprisingly large molecular mass of 696 kDa and a relatively high E unit proportion (44.5 %). It can interact with various growth factors, including HGF, bFGF, pleiotrophin, and HB-EGF, with high affinity, and exhibits dose-dependent anti-metastatic activity. Furthermore, the E unit-rich decasaccharide selectively prepared from CS-nE has been shown to be the minimal functional domain with the strongest antitumor metastatic activity. Taken together, CS-nE will be a very promising candidate for the development of CS-E-based pharmaceutical products.

Ultrahigh-activity immune inducer from Endophytic Fungi induces tobacco resistance to virus by SA pathway and RNA silencing.

BACKGROUND: Plant viruses cause severe economic losses in agricultural production. An ultrahigh activity plant immune inducer (i.e., ZhiNengCong, ZNC) was extracted from endophytic fungi, and it could promote plant growth and enhance resistance to bacteria. However, the antiviral function has not been studied. Our study aims to evaluate the antiviral molecular mechanisms of ZNC in tobacco. RESULTS: Here, we used Potato X virus (PVX), wild-type tobacco and NahG transgenic tobacco as materials to study the resistance of ZNC to virus. ZNC exhibited a high activity in enhancing resistance to viruses and showed optimal use concentration at 100-150 ng/mL. ZNC also induced reactive oxygen species accumulation, increased salicylic acid (SA) content by upregulating the expression of phenylalanine ammonia lyase (PAL) gene and activated SA signaling pathway. We generated transcriptome profiles from ZNC-treated seedlings using RNA sequencing. The first GO term in biological process was positive regulation of post-transcriptional gene silencing, and the subsequent results showed that ZNC promoted RNA silencing. ZNC-sprayed wild-type leaves showed decreased infection areas, whereas ZNC failed to induce a protective effect against PVX in NahG leaves. CONCLUSION: All results indicate that ZNC is an ultrahigh-activity immune inducer, and it could enhance tobacco resistance to PVX at low concentration by positively regulating the RNA silencing via SA pathway. The antiviral mechanism of ZNC was first revealed in this study, and this study provides a new antiviral bioagent.

WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.

Recently, inhibitor of apoptosis proteins (IAPs) and some IAP antagonists were found to regulate autophagy, but the underlying mechanisms remain unclear. WX20120108 is an analogue of GDC-0152 (a known IAP antagonist) and displays more potent anti-tumor and autophagy-regulating activity in tumor cells, we investigated the regulatory mechanisms underlying WX20120108-induced autophagy. Using molecular docking and fluorescence polarization anisotropy (FPA) competitive assay, we first demonstrated that WX20120108, acting as an IAP antagonist, bound to the XIAP-BIR3, XIAP BIR2-BIR3, cIAP1 BIR3, and cIAP2 BIR3 domains with high affinities. In six cancer cell lines, WX20120108 inhibited the cell proliferation with potencies two to ten-fold higher than that of GDC-0152. In HeLa and MDA-MB-231 cells, WX20120108 induced caspase-dependent apoptosis and activated TNFα-dependent extrinsic apoptosis. On the other hand, WX20120108 induced autophagy in HeLa and MDA-MB-231 cells in dose- and time-dependent manners. We revealed that WX20120108 selectively activated Foxo3, evidenced by Foxo3 nuclear translocation in both gene modified cell line and HeLa cells, as well as the upregulated expression of Foxo3-targeted genes (Bnip3, Pik3c3, Atg5, and Atg4b), which played a key role in autophagy initiation. WX20120108-induced autophagy was significantly suppressed when Foxo3 gene was silenced. WX20120108 dose-dependently increased the generation of reactive oxygen species (ROS) in HeLa cells, and WX20120108-induced Foxo3 activation was completely blocked in the presence of catalase, a known ROS scavenger. However, WX20120108-induced ROS generation was not affected by cIAP1/2 or XIAP gene silencing. In conclusion, WX20120108-induced autophagy relies on activating ROS-Foxo3 pathway, which is independent of IAPs. This finding provides a new insight into the mechanism of IAP antagonist-mediated regulation of autophagy.

Preliminary application of 3D-printed coplanar template for iodine-125 seed implantation therapy in patients with advanced pancreatic cancer.

AIM: To evaluate a 3D-printed coplanar template for iodine-125 seed implantation therapy in patients with pancreatic cancer. METHODS: A retrospective analysis of our database was performed, and a total of 25 patients with pancreatic cancer who underwent iodine-125 seed implantation between January 2014 and November 2017 were analyzed. Of these, 12 implantations were assisted by a 3D-printed coplanar template (group A), and 13 implantations performed freehand were selected as a control group (group B). A 3D coplanar template was designed and printed according to a preoperative CT scan and treatment planning system. The iodine-125 seeds were then implanted using the template as a guide. Dosimetric verification was performed after implantation. Pre- and postoperative D90, V100, and V150 were calculated. The success rate of iodine-125 seed implantation, dosimetric parameters, and complications were analyzed and compared between the two groups. RESULTS: Iodine-125 seed implantation was successfully performed in both groups. In group A, the median pre- and postoperative D90 values were 155.32 ± 8.05 Gy and 154.82 ± 16.43 Gy, respectively; the difference between these values was minimal and not statistically significant (P > 0.05). Postoperative V100 and V150 were 91.05% ± 4.06% and 64.54% ± 13.40%, respectively, which met the treatment requirement. A better dosimetric parameter was observed in group A than in group B, and the difference was statistically significant (V100: 91.05% ± 4.06% vs 72.91% ± 13.78%, P < 0.05). No major procedure-related complications were observed in either group. For group A, mild hemorrhage was observed in 1 patient with a peritoneal local hematoma due to mesenteric vein damage from the iodine-125 seed implantation needle. The hematoma resolved spontaneously without treatment. Postoperative blood amylase levels remained within the normal range for all patients. CONCLUSION: A 3D-printed coplanar template appears to be a safe and effective iodine-125 seed implantation guidance tool to improve implantation accuracy and optimize dosimetric distribution.

Study on patient-induced radioactivity during proton treatment in hengjian proton medical facility.

At present, increasingly more proton medical facilities have been established globally for better curative effect and less side effect in tumor treatment. Compared with electron and photon, proton delivers more energy and dose at its end of range (Bragg peak), and has less lateral scattering for its much larger mass. However, proton is much easier to produce neutron and induced radioactivity, which makes radiation protection for proton accelerators more difficult than for electron accelerators. This study focuses on the problem of patient-induced radioactivity during proton treatment, which has been ignored for years. However, we confirmed it is a vital factor for radiation protection to both patient escort and positioning technician, by FLUKA's simulation and activation formula calculation of Hengjian Proton Medical Facility (HJPMF), whose energy ranges from 130 to 230MeV. Furthermore, new formulas for calculating the activity buildup process of periodic irradiation were derived and used to study the relationship between saturation degree and half-life of nuclides. Finally, suggestions are put forward to lessen the radiation hazard from patient-induced radioactivity.

[Effect of angiotensin II on follicular atresia in mouse].

The effect of angiotensin II (Ang II) on the follicular development was studied by using an animal model of follicular atresia induced by pregnant mare s serum gonadotropin (PMSG). The results showed that: (1) a large number of atretic follicles were found in the ovary of 24-day-old mouse after 6-day treatment of PMSG. Deoxyribonucleic acid (DNA) extracted from granulosa cells clearly showed a ladder band under agarose gel electrophoresis analysis. (2) the contents of Ang II in the ovary extremely increased with the development of follicular atresia. (3) Ang II significantly antagonized the stimulating effect of the follicle-stimulating hormone (FSH) on estradiol (E(2)) generation of granulosa cells. It is suggested that Ang II may be involved in the regulation of follicular atresia in mouse.