Multi­parameter quantitative magnetic resonance imaging in the early assessment of radiation­induced parotid damage in patients with nasopharyngeal carcinoma following intensity­modulated radiotherapy.

The present study aimed to investigate the value of intravoxel incoherent motion imaging (IVIM) and three-dimensional pulsed continuous arterial spin labeling (ASL) in assessing dynamic changes of the parotid gland in patients with nasopharyngeal carcinoma (NPC) following radiotherapy (RT). A total of 18 patients with NPC who underwent intensity-modulated RT were enrolled in the present study. All patients underwent conventional magnetic resonance imaging, plus IVIM and ASL imaging of the bilateral parotid glands within 2 weeks prior to RT, and 1 week (1W) and 3 months (3M) following RT. Pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (F) and blood flow (BF) were analyzed. D and BF values were significantly increased from pre-RT to 1W post-RT [change rate: Median (IQR), ΔD1W%: 39.28% (38.23%) and ΔBF1W%: 60.84% (54.88%)] and continued to increase from 1W post-RT to 3M post-RT [55.44% (40.56%) and ΔBF%: 120.39% (128.74%)]. In addition, the F value was significantly increased from pre-RT to 1W post-RT, [change rate: Median (IQR), ΔF1W%: 28.13% (44.66%)], and this decreased significantly from 1W post-RT to 3M post-RT. However, no significant differences were observed between pre-RT and 3M post-RT. Results of the present study also demonstrated that the D* value was significantly decreased from pre-RT to 1W post-RT and 3M post-RT [change rate: Median (IQR), ΔD*1w%: -41.86% (51.71%) and ΔD*3M: -29.11% (42.67%)]. No significant difference was observed between the different time intervals post-RT. There was a significant positive correlation between percentage change in ΔBF1W and radiation dose (ρ=0.548, P=0.001). Thus, IVIM-diffusion-weighted imaging and ASL may aid in the detection and prediction of radiation-induced parotid damage in the early stages following RT. They may contribute to further understanding the potential association between damage to the parotid glands and patient-/treatment-related variables, through the assessment of individual microcapillary perfusion and tissue diffusivity.

Radiological characteristics predicting early poor drug response in patients with hemifacial spasm.

OBJECTIVES: Patients with hemifacial spasm (HFS) often resort to botulinum toxin injections or microvascular decompression surgery when medication exhibits limited effectiveness. This study aimed to identify MRI and demographic factors associated with poor drug response at an early stage in patients with HFS. METHODS: We retrospectively included patients with HFS who underwent pre-therapeutic MRI examination. The presence, location, severity, and the offending vessels of neurovascular compression were blindly evaluated using MRI. Drug responses and clinical data were obtained from the medical notes or phone follow-ups. Logistic regression analysis was performed to identify potential factors. RESULTS: A total of 116 patients were included, with an average age at the time of first examination of 50.4 years and a median duration of onset of 18 months. Forty-nine (42.2%) patients reported no symptom relief. Thirty-seven (31.9%) patients reported poor symptom relief. Twenty-two (19.0%) patients reported partial symptom relief. Eight (6.9%) patients achieved complete symptom relief. The factors that were statistically significant associated with poor drug responses were contact in the attach segment of the facial nerve and aged 70 and above, with an odds ratio of 7.772 (p = 0.002) and 0.160 (p = 0.028), respectively. CONCLUSIONS: This study revealed that mild compression in the attach segment of the facial nerve in pre-therapeutic MRI increases the risk of poor drug responses in patients with HFS, while patients aged 70 and above showed a decreased risk. These findings may assist clinician to choose optimal treatment at an early stage.

Development and validation of a nomogram based on CT texture analysis for discriminating minimally invasive adenocarcinoma from glandular precursor lesions in sub­centimeter pulmonary ground glass nodules.

In a recent reclassification, adenocarcinoma in situ has been redefined as a glandular precursor lesion (GPL), alongside adenomatous hyperplasia. This updated classification necessitates corresponding adaptations in clinical diagnostic and therapeutic protocols. Consequently, the present study aimed to construct and validate a nomogram utilizing computed tomography (CT) texture features to effectively discriminate between minimally invasive adenocarcinoma (MIA) and GPL within sub-centimeter pulmonary ground glass nodules (GGNs). To achieve this objective, the present study employed rigorous statistical methodologies, including the Mann-Whitney U test and binary logistic regression analysis, to identify distinguishing features and establish predictive models. Subsequently, the diagnostic performance of these models underwent evaluation through receiver operating characteristic (ROC) curves. The area under the curve (AUC) in ROC curves was compared using DeLong's test. Additionally, the nomogram was constructed using R software and its diagnostic performance was validated through calibration curves. Within both the training and validation datasets, the AUCs were observed to be 0.992 [95% confidence interval (CI): 0.980-1.000] and 0.975 (95% CI: 0.935-1.000), respectively. DeLong's test revealed significant disparities in the AUCs between the nomogram and single-parameter models (P<0.001). Furthermore, calibration curves demonstrated concordance between the training and validation datasets. In conclusion, the application of a CT texture-based nomogram model has demonstrated aptitude in differentiating between MIA and GPL within sub-centimeter GGNs. This model streamlines the identification of optimal surgical interventions and enhances the sphere of clinical decision-making and management.

Convolutional neural network for biomarker discovery for triple negative breast cancer with RNA sequencing data.

Triple negative breast cancers (TNBCs) are tumors with a poor treatment response and prognosis. In this study, we propose a new approach, candidate extraction from convolutional neural network (CNN) elements (CECE), for discovery of biomarkers for TNBCs. We used the GSE96058 and GSE81538 datasets to build a CNN model to classify TNBCs and non-TNBCs and used the model to make TNBC predictions for two additional datasets, the cancer genome atlas (TCGA) breast cancer RNA sequencing data and the data from Fudan University Shanghai Cancer Center (FUSCC). Using correctly predicted TNBCs from the GSE96058 and TCGA datasets, we calculated saliency maps for these subjects and extracted the genes that the CNN model used to separate TNBCs from non-TNBCs. Among the TNBC signature patterns that the CNN models learned from the training data, we found a set of 21 genes that can classify TNBCs into two major classes, or CECE subtypes, with distinct overall survival rates (P = 0.0074). We replicated this subtype classification in the FUSCC dataset using the same 21 genes, and the two subtypes had similar differential overall survival rates (P = 0.0490). When all TNBCs were combined from the 3 datasets, the CECE II subtype had a hazard ratio of 1.94 (95% CI, 1.25-3.01; P = 0.0032). The results demonstrate that the spatial patterns learned by the CNN models can be utilized to discover interacting biomarkers otherwise unlikely to be identified by traditional approaches.

Ginsenoside Rk1 attenuates radiation-induced intestinal injury through the PI3K/AKT/mTOR pathway.

Radiation-induced intestinal injury (RIII) frequently occurs during radiotherapy; however, methods for treating RIII are limited. Ginsenoside Rk1 (RK1) is a substance that is derived from ginseng, and it has several biological activities, such as antiapoptotic, antioxidant and anticancer activities. The present study was designed to investigate the potential protective effect of Rk1 on RIII and the potential mechanisms. The results showed that RK1 treatment significantly improved the survival rate of the irradiated rats and markedly ameliorated the structural injury of the intestinal mucosa observed by histology. Treatment with RK1 significantly alleviated radiation-induced intestinal epithelial cell oxidative stress apoptosis. Moreover, RNA-Seq identified 388 differentially expressed genes (DEGs) and showed that the PI3K-AKT pathway might be a key signaling pathway by which RK1 exerts its therapeutic effects on RIII. The western blotting results showed that the p-PI3K, p-AKT and p-mTOR expression levels, which were increased by radiation, were markedly inhibited by Rk1, and these effects were reversed by IGF-1. The present study demonstrates that Rk1 can alleviate RIII and that the mechanism underlying the antiapoptotic effects of RK1 may involve the suppression of the PI3K/Akt/mTOR pathway. This study provides a promising therapeutic agent for RIII.

Low expression of the dynamic network markers FOS/JUN in pre-deteriorated epithelial cells is associated with the progression of colorectal adenoma to carcinoma.

BACKGROUND: Deterioration of normal intestinal epithelial cells is crucial for colorectal tumorigenesis. However, the process of epithelial cell deterioration and molecular networks that contribute to this process remain unclear. METHODS: Single-cell data and clinical information were downloaded from the Gene Expression Omnibus (GEO) database. We used the recently proposed dynamic network biomarker (DNB) method to identify the critical stage of epithelial cell deterioration. Data analysis and visualization were performed using R and Cytoscape software. In addition, Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis was used to identify potential transcription factors, and CellChat analysis was conducted to evaluate possible interactions among cell populations. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analysis (GSVA) analyses were also performed. RESULTS: The trajectory of epithelial cell deterioration in adenoma to carcinoma progression was delineated, and the subpopulation of pre-deteriorated epithelial cells during colorectal cancer (CRC) initialization was identified at the single-cell level. Additionally, FOS/JUN were identified as biomarkers for pre-deteriorated epithelial cell subpopulations in CRC. Notably, FOS/JUN triggered low expression of P53-regulated downstream pro-apoptotic genes and high expression of anti-apoptotic genes through suppression of P53 expression, which in turn inhibited P53-induced apoptosis. Furthermore, malignant epithelial cells contributed to the progression of pre-deteriorated epithelial cells through the GDF signaling pathway. CONCLUSIONS: We demonstrated the trajectory of epithelial cell deterioration and used DNB to characterize pre-deteriorated epithelial cells at the single-cell level. The expression of DNB-neighboring genes and cellular communication were triggered by DNB genes, which may be involved in epithelial cell deterioration. The DNB genes FOS/JUN provide new insights into early intervention in CRC.

Construction and validation of an immune-related genes prognostic index (IRGPI) model in colon cancer.

Background: Though immunotherapy has become one of the standard therapies for colon cancer, the overall effective rate of immunotherapy is very low. Constructing an immune-related genes prognostic index (IRGPI) model may help to predict the response to immunotherapy and clinical outcomes. Methods: Differentially expressed immune-related genes (DEIRGs) between normal tissues and colon cancer tissues were identified and used to construct the co-expression network. Genes in the module with the most significant differences were further analyzed. Independent prognostic immune-related genes (IRGs) were identified by univariate and multivariate cox regression analysis. Independent prognostic IRGs were used to construct the IRGPI model using the multivariate cox proportional hazards regression model, and the IRGPI model was validated by independent dataset. ROC curves were plotted and AUCs were calculated to estimate the predictive power of the IRGPI model to prognosis. Gene set enrichment analysis (GSEA) was performed to screen the enriched KEGG pathways in the high-risk and low-risk phenotype. Correlations between IRGPI and clinical characteristic, immune checkpoint expression, TMB, immune cell infiltration, immune function, immune dysfunction, immune exclusion, immune subtype were analyzed. Results: Totally 680 DEIRGs were identified. Three independent IRGs,NR5A2, PPARGC1A and LGALS4, were independently related to survival. NR5A2, PPARGC1A and LGALS4 were used to establish the IRGPI model. Survival analysis showed that patients with high-risk showed worse survival than patients in the low-risk group. The AUC of the IRGPI model for 1-year, 3-year and 5-year were 0.584, 0.608 and 0.697, respectively. Univariate analysis and multivariate cox regression analysis indicated that IRGPI were independent prognostic factors for survival. Stratified survival analysis showed that patients with IRGPI low-risk and low TMB had the best survival, which suggested that combination of TMB and IRGPI can better predict clinical outcome. Immune cell infiltration, immune function, immune checkpoint expression and immune exclusion were different between IRGPI high-risk and low-risk patients. Conclusion: An immune-related genes prognostic index (IRGPI) was constructed and validated in the current study and the IRGPI maybe a potential biomarker for evaluating response to immunotherapy and clinical outcome for colon cancer patients.

Establishment and Validation of a Novel MRI Radiomics Feature-Based Prognostic Model to Predict Distant Metastasis in Endemic Nasopharyngeal Carcinoma.

Purpose: We aimed to establish a prognostic model based on magnetic resonance imaging (MRI) radiomics features for individual distant metastasis risk prediction in patients with nasopharyngeal carcinoma (NPC). Methods: Regression analysis was applied to select radiomics features from T1-weighted (T1-w), contrast-enhanced T1-weighted (T1C-w), and T2-weighted (T2-w) MRI scans. All prognostic models were established using a primary cohort of 518 patients with NPC. The prognostic ability of the radiomics, clinical (based on clinical factors), and merged prognostic models (integrating clinical factors with radiomics) were identified using a concordance index (C-index). Models were tested using a validation cohort of 260 NPC patients. Distant metastasis-free survival (DMFS) were calculated by using the Kaplan-Meier method and compared by using the log-rank test. Results: In the primary cohort, seven radiomics prognostic models showed similar discrimination ability for DMFS to the clinical prognostic model (P=0.070-0.708), while seven merged prognostic models displayed better discrimination ability than the clinical prognostic model or corresponding radiomics prognostic models (all P<0.001). In the validation cohort, the C-indices of seven radiomics prognostic models (0.645-0.722) for DMFS prediction were higher than in the clinical prognostic model (0.552) (P=0.016 or <0.001) or in corresponding merged prognostic models (0.605-0.678) (P=0.297 to 0.857), with T1+T1C prognostic model (based on Radscore combinations of T1 and T1C Radiomics models) showing the highest C-index (0.722). In the decision curve analysis of the validation cohort for all prognostic models, the T1+T1C prognostic model displayed the best performance. Conclusions: Radiomics models, especially the T1+T1C prognostic model, provided better prognostic ability for DMFS in patients with NPC.

MRI-based radiomics models can improve prognosis prediction for nasopharyngeal carcinoma with neoadjuvant chemotherapy.

BACKGROUND: The purpose of this study was to explore the prognostic value of imaging features and related models in nasopharyngeal carcinoma (NPC) patients that received neoadjuvant chemotherapy. MATERIALS AND METHODS: We systematically reviewed the data of 110 NPC patients who received radiotherapy and neoadjuvant chemotherapy. The patients were randomly divided into the training cohort (n = 88) and the verification cohort (n = 22). The imaging data collected in this study were screened via Pyramidics and used to construct prediction models based on histology and clinical nomographs. The models' accuracy was evaluated via calibration curves and the consistency index (C-index). In addition, we also explored the correlation between radiomics expression patterns, quantitative histological characteristics, and clinical data and then constructed a model to predict the prognosis of NPC. RESULTS: The models that integrated radiomics contours with all the clinical data were superior to those based on the clinical data alone (C-index 0.746 vs. C-index 0.814, respectively) and the calibration curves showed good consistency. The heat map showed that the radiomics expression pattern and selected histological characteristics were correlated with the clinical stage, T stage, and N stage (p < 0.05), and no radiomics feature was associated with lactate dehydrogenase expression, lymphocyte count, or mononuclear cell count. CONCLUSION: MRI-based radiomics can significantly improve the efficacy of traditional TNM staging and clinical data in predicting the progression-free survival (PFS) of patients with advanced NPC, which may provide an opportunity for precision medicine.

Circulating T-Cell Repertoires Correlate With the Tumor Response in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy.

PURPOSE: Neoadjuvant chemotherapy (NAC) has been widely used in patients with breast cancer to minish tumor burden and increase resection rate of cancer. T-cell repertoire has been believed to be able to monitor antitumor immune responses. This study aimed to explore the dynamic change of T-cell repertoire and its clinical value in evaluating the tumor response in patients with breast cancer receiving NAC. MATERIALS AND METHODS: Ninety-four patients who underwent NAC before surgery were recruited, and peripheral blood samples were collected at multiple time points during NAC. High-throughput T-cell receptor (TCR)-ß sequencing was used to characterize the T-cell repertoire of every sample and analyzed the changes in circulating T-cell repertoire during NAC. RESULTS: We found that the diversity of TCR repertoires was associated with age and clinical stage of the patients with breast cancer. The distribution of Vß and Jß genes in TCR repertoires was skewed in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Vß20.1 and Vß30 expression levels before NAC correlate with tumor response after all cycles of NAC in HER2- and HER2+ patients, respectively. Some CDR3 motifs that correlated with clinical response in either HER2+ or HER2- patients were identified. Besides, TCR repertoire evolved during NAC and the diversity of TCR repertoire decreased more after two cycles of NAC in patients with good tumor response after all cycles of NAC (P = .0061). CONCLUSION: Our results demonstrated that TCR repertoire correlated with the characteristics of the tumor, such as the expression status of HER2. Moreover, some characteristics of TCR repertoires that correlated with clinical response were identified and they might provide useful information to tailor therapeutic regimens at the early cycle of NAC.

Machine learning-based multiparametric traditional multislice computed tomography radiomics for improving the discrimination of parotid neoplasms.

Characterization of parotid tumors is important for treatment planning and prognosis, and parotid tumor discrimination has recently been developed at the molecular level. The aim of the present study was to establish a machine learning (ML) predictive model based on multiparametric traditional multislice CT (MSCT) radiomic and clinical data analysis to improve the accuracy of differentiation among pleomorphic adenoma (PA), Warthin tumor (WT) and parotid carcinoma (PCa). A total of 345 patients (200 with WT, 91 with PA and 54 with PCa) with pathologically confirmed parotid tumors were retrospectively enrolled from five independent institutions between January 2010 and May 2019. A total of 273 patients recruited from institutions 1, 2 and 3 were randomly assigned to the training model; the independent validation set consisted of 72 patients treated at institutions 1, 4 and 5. Data were investigated using a linear discriminant analysis-based ML classifier. Feature selection and dimension reduction were conducted using reproducibility testing and a wrapper method. The diagnostic accuracy of the predictive model was compared with histopathological findings as reference results. This classifier achieved a satisfactory performance for the discrimination of PA, WT and PCa, with a total accuracy of 82.1% in the training cohort and 80.5% in the validation cohort. In conclusion, ML-based multiparametric traditional MSCT radiomics can improve the accuracy of differentiation among PA, WT and PCa. The findings of the present study should be validated by multicenter prospective studies using completely independent external data.

The Diagnostic and Prognostic Potential of the B-Cell Repertoire in Membranous Nephropathy.

Membranous nephropathy (MN), an autoimmune glomerular disease, is one of the most common causes of nephrotic syndrome in adults. In current clinical practice, the diagnosis is dependent on renal tissue biopsy. A new method for diagnosis and prognosis surveillance is urgently needed for patients. In the present study, we recruited 66 MN patients before any treatment and 11 healthy control (HC) and analyzed multiple aspects of the immunoglobulin heavy chain (IGH) repertoire of these samples using high-throughput sequencing. We found that the abnormalities of CDR-H3 length, hydrophobicity, somatic hypermutation (SHM), and germ line index were progressively more prominent in patients with MN, and the frequency of IGHV3-66 in post-therapy patients was significantly lower than that in pre-therapy patients. Moreover, we found that the IGHV3-38 gene was significantly related to PLA2R, which is the most commonly used biomarker. The most important discovery was that several IGHV, IGHD transcripts, CDR-H3 length, and SHM rate in pre-therapy patients had the potential to predict the therapeutic effect. Our study further demonstrated that the IGH repertoire could be a potential biomarker for prognosis prediction of MN. The landscape of circulating B-lymphocyte repertoires sheds new light on the detection and surveillance of MN.

Artificial Intelligence in Breast MRI Radiogenomics: Towards Accurate Prediction of Neoadjuvant Chemotherapy Responses.

Neoadjuvant Chemotherapy (NAC) in breast cancer patients has considerable prognostic and treatment potential and can be tailored to individual patients as part of precision medicine protocols. This work reviews recent advances in artificial intelligence so as to enable the use of radiogenomics for accurate NAC analysis and prediction. The work addresses a new problem in radiogenomics mining: How to combine structural radiomics information and non-structural genomics information for accurate NAC prediction. This requires the automated extraction of parameters from structural breast radiomics data, and finding non-structural feature vectors with diagnostic value, which then are combined with genomics data acquired from exocrine bodies in blood samples from a cohort of cancer patients to enable accurate NAC prediction. A self-attention-based deep learning approach, along with an effective multi-channel tumour image reconstruction algorithm of high dimensionality, is proposed. The aim was to generate non-structural feature vectors for accurate prediction of the NAC responses by combining imaging datasets with exocrine body related genomics analysis.

MiRNA-217 accelerates the proliferation and migration of bladder cancer via inhibiting KMT2D.

To uncover the biological function of miRNA-217 in the progression of bladder cancer and the underlying mechanism. Potential miRNAs binding KMT2D were predicted through online bioinformatics. Their expression levels in bladder cancer tissues and adjacent ones were determined. Through Pearson correlation analysis and survival analysis, the most potential miRNA candidate (miRNA-217) that targets and regulates KMT2D in bladder cancer was selected. Subsequently, expression levels of miRNA-217 and KMT2D in non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) were detected. MiRNA-217 level in bladder cancer cell lines was determined as well. The interaction between KMT2D and miRNA-217 was verified by dual-luciferase reporter gene assay. Finally, regulatory effect of miRNA-217 on viability and migration in T24 and UMUC-3 cells were investigated. Five potential candidates that were upstream genes binding KMT2D were searched by bioinformatics. Among them, miRNA-217 was remarkably upregulated in bladder cancer tissues and closely linked to poor prognosis of affected patients. Moreover, dual-luciferase reporter gene assay verified the interaction between miRNA-217 and KMT2D. MiRNA-217 was able to downregulate mRNA and protein levels of KMT2D. Furthermore, knockdown of miRNA-217 attenuated viability and migration in bladder cancer cells. MiRNA-217 accelerates proliferative and migratory abilities in bladder cancer via inhibiting the level of tumor suppressor KMT2D, thereafter leading to the poor prognosis in bladder cancer patients.

Polymorphisms in the APOBEC3G gene of Chinese rhesus macaques affect resistance to ubiquitination and degradation mediated by HIV-2 Vif.

Animal cells have multiple innate effector mechanisms that inhibit viral replication. For the pathogenic retrovirus human immunodeficiency virus 1 (HIV-1), there are widely expressed restriction factors, such as APOBEC3 proteins, tetherin/BST2, SAMHD1 and MX2, as well as TRIM5α. We previously found that the TRIM5α gene clearly affects SIVmac or HIV-2 replication, but the major determinant of the combinatorial effect caused by multiple host restriction factors is still not fully clear. APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G), a host restriction factor that restricts HIV replication by causing cytosine deamination, can be targeted and degraded by the SIV/HIV-1/HIV-2 accessory protein Vif. Although rhesus macaques are widely used in HIV/AIDS research, little is known regarding the impact of APOBEC3G gene polymorphisms on viral Vif-mediated ubiquitin degradation in Chinese-origin rhesus macaques. In this study, we therefore genotyped APOBEC3G in 35 Chinese rhesus macaques. We identified a novel transcript and 27 APOBEC3G polymorphisms, including 20 non-synonymous variants and 7 synonymous mutation sites, of which 10 were novel. According to the predicted structure of the A3G protein, we predicted that the E88K and G212D mutations, both on the surface of the A3G protein, would have a significant effect on Vif-induced A3G degradation. However, an in vitro overexpression assay showed that these mutations did not influence HIV-2-Vif-mediated degradation of APOBEC3G. Unexpectedly, another polymorphism L71R, conferred resistance to Vif-mediated ubiquitin degradation, strongly suggesting that L71R might play an important role in antiviral defense mechanisms.

TCR Repertoire as a Novel Indicator for Immune Monitoring and Prognosis Assessment of Patients With Cervical Cancer.

There is increasing evidence that deep sequencing-based T cell repertoire can sever as a biomarker of immune response in cancer patients; however, the characteristics of T cell repertoire including diversity and similarity, as well as its prognostic significance in patients with cervical cancer (CC) remain unknown. In this study, we applied a high throughput T cell receptor (TCR) sequencing method to characterize the T cell repertoires of peripheral blood samples from 25 CC patients, 30 cervical intraepithelial neoplasia (CIN) patients and 20 healthy women for understanding the immune alterations during the cervix carcinogenesis. In addition, we also explored the signatures of TCR repertoires in the cervical tumor tissues and paired sentinel lymph nodes from 16 CC patients and their potential value in predicting the prognosis of patients. Our results revealed that the diversity of circulating TCR repertoire gradually decreased during the cervix carcinogenesis and progression, but the circulating TCR repertoires in CC patients were more similar to CIN patients than healthy women. Interestingly, several clonotypes uniquely detected in CC patients tended to share similar CDR3 motifs, which differed from those observed in CIN patients. In addition, the TCR repertoire diversity in sentinel lymphatic nodes from CC patients was higher than in tumor tissues. More importantly, less clonotypes in TCR repertoire of sentinel lymphatic node was associated with the poor prognosis of the patients. Overall, our findings suggested that TCR repertoire might be a potential indicator of immune monitoring and a biomarker for predicting the prognosis of CC patients. Although functional studies of T cell populations are clearly required, this study have expanded our understanding of T cell immunity during the development of CC and provided an experimental basis for further studies on its pathogenesis and immunotherapy.

Circulating CD8+ T-cell repertoires reveal the biological characteristics of tumors and clinical responses to chemotherapy in breast cancer patients.

PURPOSE: CD8+ T cells are primarily cytotoxic cells that provide immunological protection against malignant cells. Considerable evidence suggests that the T-cell repertoire is closely associated with the host immune response and the development of cancer. In this study, we explored the characteristics of the circulating CD8+ T-cell repertoire and their potential value in predicting the clinical response of breast cancer patients to chemotherapy. EXPERIMENTAL DESIGN: We applied a high-throughput TCR ß-chain sequencing method to characterize the CD8+ T-cell repertoire of the peripheral blood from 26 breast cancer patients. In addition, changes in the circulating CD8+ T-cell repertoire during chemotherapy were analyzed. RESULTS: We found that the HEC ratios of the CD8+ T-cell repertoires from HER2+ breast cancer patients were significantly higher than those of HER2- patients, suggesting that the HER2 protein is released into circulation where it is targeted by CD8+ T cells. Several Vß and CDR3 motifs preferentially used in HER2+ patients were identified. Besides, we found that the circulating CD8+ T-cell repertoires evolved during chemotherapy and correlated with patient clinical responses to chemotherapy. Increased CD8+ T-cell repertoire heterogeneity during chemotherapy was associated with a better clinical response. CONCLUSIONS: Although functional studies of clonally expanded CD8+ T-cell populations are clearly required, our results suggest that the circulating CD8+ T-cell repertoire reflects the characteristics of the tumor-associated biomolecules released into the blood and correlates with the clinical responses of the patients to chemotherapy which might assist in making treatment decisions.

TCR repertoire profiling of tumors, adjacent normal tissues, and peripheral blood predicts survival in nasopharyngeal carcinoma.

The T-cell immune responses in nasopharyngeal carcinoma patients have been extensively investigated recently for designing adoptive immunotherapy or immune checkpoint blockade therapy. However, the distribution characteristics of T cells associated with NPC pathogenesis are largely unknown. We performed deep sequencing for TCR repertoire profiling on matched tumor/adjacent normal tissue from 15 NPC patients and peripheral blood from 39 NPC patients, 39 patients with other nasopharyngeal diseases, and 33 healthy controls. We found that a lower diversity of TCR repertoire in tumors than paired tissues or a low similarity between the paired tissues was associated with a poor prognosis in NPC. A more diverse TCR repertoire was identified in the peripheral blood of NPC patients relative to the controls; this was related to a significant decrease in the proportion of high-frequency TCR clones in NPC. Higher diversity in peripheral blood of NPC patients was associated with a worse prognosis. Due to the peculiarity of the Vß gene usage patterns in the peripheral blood of NPC patients, 15 Vß genes were selected to distinguish NPC patients from controls by the least absolute shrinkage and selection operator analysis. We identified 11 clonotypes shared by tumors and peripheral blood samples from different NPC patients, defined as "NPC-associated" that might have value in adoptive immunotherapy. In conclusion, we here report the systematic and overall characteristics of the TCR repertoire in tumors, adjacent normal tissues, and peripheral blood of NPC patients. The data obtained may be relevant to future clinical studies in the setting of immunotherapy for NPC patients.

T cell receptor repertoire profiling predicts the prognosis of HBV-associated hepatocellular carcinoma.

Tumor-infiltrating T cell repertoire has been demonstrated to be closely associated with anti-tumor immune response. However, the relationship between T cell repertoire in tumor tissue and prognosis has never been reported in Hepatocellular carcinoma (HCC). We performed the high-throughput T cell receptor (TCR) sequencing to systematically characterize the infiltrating T cell repertoires of tumor and matched adjacent normal tissues from 23 HBV-associated HCC patients. Significant differences on usage frequencies of some Vß, Jß, and Vß-Jß paired genes have been found between the 2 groups of tissue samples, but no significant difference of TCR repertoire diversity could be found. Interestingly, the similarity of TCR repertoires between paired samples or the TNM stage alone could not be helpful to evaluate the prognosis of patients very well, but their combination could serve as an efficient prognostic indicator that the patients with early stage and high similarity showed a better prognosis. This is the first attempt to assess the potential value of TCR repertoire in HCC prognosis, and our findings could serve as a complement for the characterization of TCR repertoire in HCC.

Changes of plasma cytokines and chemokines expression level in nasopharyngeal carcinoma patients after treatment with definitive intensity-modulated radiotherapy (IMRT).

BACKGROUND: Potential clinical application values of certain cytokines and chemokines that participate in the process of tumor growth, invasion, and metastasis have been reported. However, there still lack of biomarkers for a great many of malignancy. This study identified cytokines or chemokines involved in the occurrence and development of nasopharyngeal carcinoma (NPC), which might be a biomarker for noninvasive early diagnosis. METHODS: The plasma levels of 19 cytokines and chemokines were detected by the luminex liquid array-based multiplexed immunoassays in 39 NPC patients before and after treatment by definitive intensity-modulated radiotherapy (IMRT). RESULTS: Plasma levels of almost all of the 19 cytokines and chemokines in NPC patients were higher than healthy controls, while only IFN-γ, IL-1b IL-6, MCP-1, TNF-α, FKN, IL-12P70, IL-2, IL-5 and IP-10 showed significant differences. However, expression levels of most of the 19 cytokines and chemokines decreased after therapy, especially IFN-γ, IL-10, IL-1b, IL-6, IL-8, MCP-1, TNF-α, VEGF, IL-17A, IL-2, IL-5 and MIP-1b, have a dramatic decline. Taking together, plasma levels of IFN-γ, IL-1b, IL-6, MCP-1, TNF-α, IL-2 and IL-5 are significantly increased in NPC patients and dramatically decreased after treatment, suggesting these cytokines and chemokines might play important roles in the progress of NPC. More interestingly, the expression level of MPC-1 is significantly associated with clinical stage. CONCLUSION: MCP-1 might involve in the genesis and development process of NPC, which might serve as a noninvasive biomarker for early diagnosis.