Diaminonaphthalene Boronic Acid (DANBA): New Approach for Peroxynitrite Sensing Site.

Selective detection of reactive oxygen species (ROS) is vital for studying their role in brain diseases. Fluorescence probes can distinguish ONOO- species from other ROS; however, their selectivity toward ONOO- species depends on the ONOO- recognition group. Aryl-boronic acids and esters, which are common ONOO- recognition groups, are not selective for ONOO- over H2O2. In this study, we developed a diaminonaphthalene (DAN)-protected boronic acid as a new ONOO- recognition group that selectively reacts with ONOO- over H2O2 and other ROS. Three DAN-protected boronic acid (DANBA)-based fluorophores that emit fluorescence over visible to near-infrared (NIR) regions, Cou-BN, BVP-BN, and HDM-BN, and their aryl-boronic acid-based counterparts (Cou-BO, BVP-BO, and HDM-BO), were developed. The DANBA-based probes exhibited enhanced selectivity toward ONOO- over that of their control group, as well as universality in MTT assays and in vitro experiments with PC12 cells. The NIR-emissive HDM-BN was optimized to delineate in vivo ONOO- levels in mouse brains with Parkinson's disease. This DAN-protected boronic acid belongs to a new generation of recognition groups for developing ONOO- probes, and this strategy could be extended to other common hydroxyl-containing dyes to detect ONOO- levels in complex biological systems and processes.

Four-gene signature predicting overall survival and immune infiltration in hepatocellular carcinoma by bioinformatics analysis with RT‒qPCR validation.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers, with a poor prognosis. Prognostic biomarkers for HCC patients are urgently needed. We aimed to establish a nomogram prediction system that combines a gene signature to predict HCC prognosis. METHODS: Differentially expressed genes (DEGs) were identified from publicly available Gene Expression Omnibus (GEO) datasets. The Cancer Genome Atlas (TCGA) cohort and International Cancer Genomics Consortium (ICGC) cohort were regarded as the training cohort and testing cohort, respectively. First, univariate and multivariate Cox analyses and least absolute shrinkage and selection operator (LASSO) regression Cox analysis were performed to construct a predictive risk score signature. Furthermore, a nomogram system containing a risk score and other prognostic factors was developed. In addition, a correlation analysis of risk group and immune infiltration was performed. Finally, we validated the expression levels using real-time PCR. RESULTS: Ninety-five overlapping DEGs were identified from four GEO datasets, and we constructed a four-gene-based risk score predictive model (risk score = EZH2 * 0.075 + FLVCR1 * 0.086 + PTTG1 * 0.015 + TRIP13 * 0.020). Moreover, this signature was an independent prognostic factor. Next, the nomogram system containing risk score, sex and TNM stage indicated better predictive performance than independent prognostic factors alone. Moreover, this signature was significantly associated with immune cells, such as regulatory T cells, resting NK cells and M2 macrophages. Finally, RT‒PCR confirmed that the mRNA expressions of four genes were upregulated in most HCC cell lines. CONCLUSION: We developed and validated a nomogram system containing the four-gene risk score, sex, and TNM stage to predict prognosis.

Development and Validation of a Novel Nomogram for Predicting Vessels that Encapsulate Tumor Cluster in Hepatocellular Carcinoma.

BACKGROUND: Vessels that encapsulate tumor cluster (VETC) is associated with poor prognosis in hepatocellular carcinoma (HCC). Vessels that encapsulate tumor cluster estimation before initial treatment is helpful for clinical doctors. We aimed to construct a novel predictive model for VETC, using preoperatively accessible clinical parameters and imagine features. METHODS: Totally, 365 HCC patients who received curative hepatectomy in the Sun Yat-Sen University Cancer Center from 2013 to 2014 were enrolled in this study. Vessels that encapsulate tumor cluster pattern was confirmed by immunochemistry staining. 243 were randomly assigned to the training cohort while the rest was assigned to the validation cohort. Independent predictive factors for VETC estimation were determined by univariate and multivariate logistic analysis. We further constructed a predictive nomogram for VETC in HCC. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curve, and calibration curve. Besides, the decision curve was plotted to evaluate the clinical usefulness. Ultimately, Kaplan-Meier survival curves were utilized to confirm the association between the nomogram and survival. RESULTS: Immunochemistry staining revealed VETC in 87 patients (23.8%). lymphocyte to monocyte ratio (>7.75, OR = 4.06), neutrophil (>7, OR = 4.48), AST to ALT ratio (AAR > .86, OR = 2.16), ALT to lymphocyte ratio index (BLRI > 21.73, OR = 2.57), alpha-fetoprotein (OR = 1.1), and tumor diameter (OR = 2.65) were independent predictive factors. The nomogram incorporating these predictive factors performed well with an area under the curve (AUC) of .746 and .707 in training and validation cohorts, respectively. Calibration curves indicated the predicted probabilities closely corresponded with the actual VETC status. Moreover, the decision curve proved our nomogram could provide clinical benefits with patients. Finally, low probability of VETC group had significantly longer recurrence free survival (RFS) and overall survival (OS) than the high probability of the VETC group (all P < .001). CONCLUSION: A novel predictive nomogram integrating clinical indicators and image characteristics shows strong predictive VETC performance and might provide standardized net clinical benefits.

Construction of a novel immune-related lncRNA signature and its potential to predict the immune status of patients with hepatocellular carcinoma.

BACKGROUND: The accuracy of existing biomarkers for predicting the prognosis of hepatocellular carcinoma (HCC) is not satisfactory. It is necessary to explore biomarkers that can accurately predict the prognosis of HCC. METHODS: In this study, original transcriptome data were downloaded from The Cancer Genome Atlas (TCGA) database. Immune-related long noncoding ribonucleic acids (irlncRNAs) were identified by coexpression analysis, and differentially expressed irlncRNA (DEirlncRNA) pairs were distinguished by univariate analysis. In addition, the least absolute shrinkage and selection operator (LASSO) penalized regression was modified. Next, the cutoff point was determined based on the area under the curve (AUC) and Akaike information criterion (AIC) values of the 5-year receiver operating characteristic (ROC) curve to establish an optimal model for identifying high-risk and low-risk groups of HCC patients. The model was then reassessed in terms of clinicopathological features, survival rate, tumor-infiltrating immune cells, immunosuppressive markers, and chemotherapy efficacy. RESULTS: A total of 1009 pairs of DEirlncRNAs were recognized in this study, 30 of these pairs were included in the Cox regression model for subsequent analysis. After regrouping according to the cutoff point, we could more effectively identify factors such as aggressive clinicopathological features, poor survival outcomes, specific immune cell infiltration status of tumors, high expression level of immunosuppressive biomarkers, and low sensitivity to chemotherapy drugs in HCC patients. CONCLUSIONS: The nonspecific expression level signature involved with irlncRNAs shows promising clinical value in predicting the prognosis of HCC patients.

Expression pattern and prognostic value of N6-methyladenosine RNA methylation key regulators in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is still one of the most common malignancies worldwide. The accuracy of biomarkers for predicting the prognosis of HCC and the therapeutic effect is not satisfactory. N6-methyladenosine (m6A) methylation regulators play a crucial role in various tumours. Our research aims further to determine the predictive value of m6A methylation regulators and establish a prognostic model for HCC. In this study, the data of HCC from The Cancer Genome Atlas (TCGA) database was obtained, and the expression level of 15 genes and survival was examined. Then we identified two clusters of HCC with different clinical factors, constructed prognostic markers and analysed gene set enrichment, proteins' interaction and gene co-expression. Three subgroups by consensus clustering according to the expression of the 13 genes were identified. The risk score generated by five genes divided HCC patients into high-risk and low-risk groups. In addition, we developed a prognostic marker that can identify high-risk HCC. Finally, a novel prognostic nomogram was developed to accurately predict HCC patients' prognosis. The expression levels of 13 m6A RNA methylation regulators were significantly upregulated in HCC samples. The prognosis of cluster 1 and cluster 3 was worse. Patients in the high-risk group show a poor prognosis. Moreover, the risk score was an independent prognostic factor for HCC patients. In conclusion, we reveal the critical role of m6A RNA methylation modification in HCC and develop a predictive model based on the m6A RNA methylation regulators, which can accurately predict HCC patients' prognosis and provide meaningful guidance for clinical treatment.

Lymphocyte-C-reactive protein ratio as a novel prognostic index in intrahepatic cholangiocarcinoma: A multicentre cohort study.

BACKGROUND & AIMS: The lymphocyte-C-reactive protein ratio (LCR) is a novel inflammatory-based score, based solely on the lymphocyte and C-reactive protein. We aimed to clarify the prognostic value of the LCR score in intrahepatic cholangiocarcinoma (ICC) patients after resection. METHODS: We compared the prognostic accuracy of the LCR score with other inflammatory-based scores in this large, multicentre cohort study. The independent variables associated with overall survival (OS) were explored in both the primary (n = 228) and validation cohorts (n = 135). Harrell's concordance index (C-index) was used to compare the predictive ability of all the assessed inflammatory-based scores. RESULTS: The LCR score was differentiated two groups of ICC patients with distinct prognoses (1-, 3-, and 5-year OS rates: 94.4%, 66.3%, and 59.3%; and 66.6%, 45.6%, and 32.7%, respectively) (P < .001). Multivariate analysis showed that the LCR score, as well as the TNM stage and preoperative CA19-9 level, were independently associated with OS. The predictive accuracy of the LCR score (c score: 0.634) was superior to that of the other inflammatory-based scores (c scores: 0.508-0.615). These findings were supported by the external validation cohort. CONCLUSION: The LCR score is stable and consistently the best prognostic score and may offer as a simple, objective and discriminatory method in facilitating the risk stratification of ICC patients.

Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial.

BACKGROUND: Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients. OBJECTIVE: This study aimed to investigate the efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI. METHODS: In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety. RESULTS: Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (n = 63) or FU group (n = 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (p = 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events. CONCLUSIONS: Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI. TRIAL REGISTRATION: Trial number: NCT03192618.

Adjuvant chemoradiotherapy versus radiotherapy alone in high-risk endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: The benefits of adjuvant chemoradiotherapy (CRT) for high-risk endometrial cancer (HREC) in International Federation of Gynecology and Obstetrics (FIGO) stages I-III remain controversial. A systematic review and meta-analysis was conducted to evaluate the clinical effectiveness and safety of postoperative CRT over radiotherapy (RT) alone, exclusively for patients with HREC for the following key endpoints: overall survival (OS), progression-free survival (PFS), the local recurrence rate, the distant metastasis rate, cancer-specific survival (CSS), grade III/IV acute and late toxicities, and the small bowel obstruction rate. METHODS: Five databases, namely, PubMed, EMBASE, Cochrane Library, Web of Science and ClinicalTrials.gov, were systematically explored and supplemented by manual searching to identify relevant studies published before Dec 9, 2017. Only prospective randomized controlled trials (RCTs) conducted for HREC comparing CRT and RT alone after surgery were included. All statistical analyses were performed using RevMan Version 5.3 software. RESULTS: Six eligible trials involving 2105 patients were identified for the final meta-analysis (CRT: n = 1064; RT: n = 1041). No statistically significant differences were evident between the CRT and RT groups regarding OS (n = 2105, RR = 1.02, 95% CI 0.98-1.06, P = 0.40). Additionally, no differences were apparent in terms of the local recurrence rate (n = 690, RR = 0.48, 95% CI 0.19-1.18, P = 0.11) or distant metastasis rate (n = 1445, RR = 0.94, 95% CI 0.72-1.23, P = 0.67). However, CRT significantly prolonged overall five-year PFS (80.2% vs. 74.5%, +5.7%; RR = 1.08, P = 0.005) and five-year CSS (86.1% vs. 79.0%, +7.1%; RR = 1.09, P = 0.03). A higher incidence of grade III/IV toxicities (P < 0.00001) was evident with CRT, while grade III/IV late toxicities and the small bowel obstruction rate were not significantly different between the two groups. CONCLUSIONS: For patients with endometrial cancers with stage I-III risk factors, adjuvant CRT can significantly improve PFS and CSS compared with RT. With the exception of increased acute toxicities, CRT is well accepted and tolerated in HREC patients.

Hyphal editing of the conserved premature stop codon in CHE1 is stimulated by oxidative stress in Fusarium graminearum.

Although genome-wide A-to-I editing mediated by adenosine-deaminase-acting-on-tRNA (ADAT) occurs during sexual reproduction in the presence of stage-specific cofactors, RNA editing is not known to occur during vegetative growth in filamentous fungi. Here we identified 33 A-to-I RNA editing events in vegetative hyphae of Fusarium graminearum and functionally characterized one conserved hyphal-editing site. Similar to ADAT-mediated editing during sexual reproduction, majority of hyphal-editing sites are in coding sequences and nonsynonymous, and have strong preference for U at -1 position and hairpin loops. Editing at TA437G, one of the hyphal-specific editing sites, is a premature stop codon correction (PSC) event that enables CHE1 gene to encode a full-length zinc fingertranscription factor. Manual annotations showed that this PSC site is conserved in CHE1 orthologs from closely-related Fusarium species. Whereas the che1 deletion and CHE1TAA (G438 to A) mutants had no detectable phenotype, the CHE1TGG (A437 to G) mutant was defective in hyphal growth, conidiation, sexual reproduction, and plant infection. However, the CHE1TGG mutant was increased in tolerance against oxidative stress and editing of TA437G in CHE1 was stimulated by H2O2 treatment in F. graminearum. These results indicate that fixation of the premature stop codon in CHE1 has a fitness cost on normal hyphal growth and reproduction but provides a benefit to tolerance against oxidative stress. Taken together, A-to-I editing events, although rare (not genome-wide), occur during vegetative growth and editing in CHE1 plays a role in response to oxidative stress in F. graminearum and likely in other fungal pathogens.

Biphasic co-detection of melanoma aneuploid tumor cells and tumor endothelial cells in guidance of specifying the field cancerized surgical excision margin and administering immunotherapy.

An optimum safety excision margin (EM) delineated by precise demarcation of field cancerization along with reliable biomarkers that enable predicting and timely evaluating patients' response to immunotherapy significantly impact effective management of melanoma. In this study, optimized biphasic "immunofluorescence staining integrated with fluorescence insitu hybridization" (iFISH) was conducted along the diagnosis-metastasis-treatment-cellular MRD axis to longitudinally co-detect a full spectrum of intact CD31- aneuploid tumor cells (TCs), CD31+ aneuploid tumor endothelial cells (TECs), viable and necrotic circulating TCs (CTCs) and circulating TECs (CTECs) expressing PD-L1, Ki67, p16 and Vimentin in unsliced specimens of the resected primary tumor, EM, dissected sentinel lymph nodes (SLNs) and peripheral blood in an early-stage melanoma patient. Numerous PD-L1+ aneuploid TCs and TECs were detected at the conventional safety EM (2 cm), quantitatively indicating the existence of a field cancerized EM for the first time. Contrary to highly heterogeneous PD-L1 expression and degrees of Chr8 aneuploidy in TCs and TECs in the primary lesions as well as CTCs and CTECs in peripheral blood, almost all TCs and TECs in SLNs and EM were homogeneously PD-L1+ haploid cells. Dynamic monitoring and cellular MRD assessment revealed that, in contrast to PD-L1+ CTCs being responsive to the immune checkpoint inhibitor (ICI-anti-PD-1), multiploid (≥pentasomy 8) PD-L1+ and Ki67+ CTECs were respectively resistant to ICI-sensitized T cells. In therapeutically stressed lymphatic and hematogenous metastatic cascades, stratified phenotypic and karyotypic profiling of iFISH tissue and liquid biopsied TCs, TECs, CTCs and CTECs in future large-cohort studies will enable appropriate re-specification of the optimal safety EM and distribution mapping of in-depth characterized, subcategorized target cells to help illustrate their metastatic relevance, ultimately improving risk stratification and clinical intervention of tumor progression, metastases, therapy resistance and cancer relapse.

Unveiling the A-to-I mRNA editing machinery and its regulation and evolution in fungi.

A-to-I mRNA editing in animals is mediated by ADARs, but the mechanism underlying sexual stage-specific A-to-I mRNA editing in fungi remains unknown. Here, we show that the eukaryotic tRNA-specific heterodimeric deaminase FgTad2-FgTad3 is responsible for A-to-I mRNA editing in Fusarium graminearum. This editing capacity relies on the interaction between FgTad3 and a sexual stage-specific protein called Ame1. Although Ame1 orthologs are widely distributed in fungi, the interaction originates in Sordariomycetes. We have identified key residues responsible for the FgTad3-Ame1 interaction. The expression and activity of FgTad2-FgTad3 are regulated through alternative promoters, alternative translation initiation, and post-translational modifications. Our study demonstrates that the FgTad2-FgTad3-Ame1 complex can efficiently edit mRNA in yeasts, bacteria, and human cells, with important implications for the development of base editors in therapy and agriculture. Overall, this study uncovers mechanisms, regulation, and evolution of RNA editing in fungi, highlighting the role of protein-protein interactions in modulating deaminase function.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

A Metabolism-Related Gene Prognostic Index Bridging Metabolic Signatures and Antitumor Immune Cycling in Head and Neck Squamous Cell Carcinoma.

Background: In the era of immunotherapy, predictive or prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC) are urgently needed. Metabolic reprogramming in the tumor microenvironment (TME) is a non-negligible reason for the low therapeutic response to immune checkpoint inhibitor (ICI) therapy. We aimed to construct a metabolism-related gene prognostic index (MRGPI) for HNSCC bridging metabolic characteristics and antitumor immune cycling and identified the immunophenotype, genetic alternations, potential targeted inhibitors, and the benefit of immunotherapy in MRGPI-defined subgroups of HNSCC. Methods: Based on The Cancer Genome Atlas (TCGA) HNSCC dataset (n = 502), metabolism-related hub genes were identified by the weighted gene co-expression network analysis (WGCNA). Seven genes were identified to construct the MRGPI by using the Cox regression method and validated with an HNSCC dataset (n = 270) from the Gene Expression Omnibus (GEO) database. Afterward, the prognostic value, metabolic activities, genetic alternations, gene set enrichment analysis (GSEA), immunophenotype, Connectivity map (cMAP), and benefit of immunotherapy in MRGPI-defined subgroups were analyzed. Results: The MRGPI was constructed based on HPRT1, AGPAT4, AMY2B, ACADL, CKM, PLA2G2D, and ADA. Patients in the low-MRGPI group had better overall survival than those in the high-MRGPI group, consistent with the results in the GEO cohort (cutoff value = 1.01). Patients with a low MRGPI score display lower metabolic activities and an active antitumor immunity status and more benefit from immunotherapy. In contrast, a higher MRGPI score was correlated with higher metabolic activities, more TP53 mutation rate, lower antitumor immunity ability, an immunosuppressive TME, and less benefit from immunotherapy. Conclusion: The MRGPI is a promising indicator to distinguish the prognosis, the metabolic, molecular, and immune phenotype, and the benefit from immunotherapy in HNSCC.

A Multi-Omics Pan-Cancer Analysis of 4EBP1 in Cancer Prognosis and Cancer-Associated Fibroblasts Infiltration.

Background: Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP1) involved in inhibition of protein translation and synthesis. However, the phosphoprotein of 4EBP1 (p-4EBP1) promotes the translation and synthesis of several proteins, including multiple classic oncogenic proteins. The prognostic significance of 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 in Pan-cancer are still unclear. Methods: In this study, we provided a multi-Omics investigation for the prognostic value of 4EBP1 mRNA, 4EBP1 protein, and different 4EBP1 phosphoproteins in a Pan-cancer manner based on the TCGA projects. We explored the correlation between 4EBP1 expression and the cancer-associated fibroblast (CAFs) infiltration, respectively using the EPIC, MCPCOUNTER, and TIDE algorithms. The functional states of 4EBP1 were explored using single-cell sequencing analysis in Pan-Cancer. Immunohistochemistry staining was used to detect and verify the expression of 4EBP1 in several cancers. Results: 4EBP1 mRNA was aberrantly overexpressed in most cancers, and was associated with the poor prognosis in ten cancers. Notably, increased 4EBP1 mRNA expression significantly correlated with tumor staging and worse prognosis in BRCA, KIRC, and KIRP, while having the opposite effect in STAD. 4EBP1 expression was associated with the CAFs infiltration level in ten cancer types. Interestingly, the correlation between 4EBP1 and CAFs infiltration had pronounced heterogeneity in digestive system tumors and urinary system tumors. In BLCA, KIRC, and ACC as well as BRCA, 4EBP1 was significantly positively correlated with CAFs infiltration and was associated with a poor prognosis. In STAD and COAD, 4EBP1 is negatively correlated with CAFs infiltration and was associated with a better prognosis. Lastly, the expression and prognostic significance of 4EBP1 protein and different p-4EBP1 varied enormously among cancers. Conclusion: Our multi-omics study indicates that 4EBP1-driven CAFs infiltration is associated with cancer prognosis and 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 proteins may serve as potential prognostic biomarkers and therapeutic targets in diverse cancer.

Real-world outcomes of patients with advanced intrahepatic cholangiocarcinoma treated with programmed cell death protein-1-targeted immunotherapy.

OBJECTIVE: There is a lack of effective treatment to improve the prognosis of intrahepatic cholangiocarcinoma (ICC). Programmed cell death protein-1 (PD-1)-targeted immunotherapy has shown promising results in a variety of malignant tumours. However, in patients with advanced ICC, the safety and efficacy of anti-PD-1 agents remain unclear. METHODS: Forty-two advanced ICC patients treated with anti-PD-1 agents from August 2018 to December 2020 were retrospectively analyzed. Tumour response, overall survival (OS), progression-free survival (PFS), and time to tumour progression (TTP) were evaluated. Adverse events were also recorded. RESULTS: The median duration of follow-up was 12.1 months, and the median time of treatment was 6.7 months for all patients. The median OS, median PFS, and median TTP for the whole cohort were 19.3 months, 11.6 months, and 11.6 months, respectively. The overall response rate (ORR) and disease control rate (DCR) for the whole cohort were 23.8% and 85.7%, respectively. Of the 42 evaluable individuals, two (4.8%) had hyperprogressive disease. The most common adverse events (AEs) were pain (n = 6; 14.3%), anorexia (n = 4; 9.5%), hypertension (n = 4; 9.5%), pyrexia (n = 3; 7.1%), cough (n = 3; 7.1%), and hypothyroidism (n = 3; 7.1%). The median OS of patients with albumin-bilirubin (ALBI) grade 1 was longer than that of patients with ALBI grade 2 (19.3 months vs. 14.7 months). The median PFS did not show a significant difference between ALBI grade 1 and grade 2 patients (13.6 months vs. 6.9 months). CONCLUSIONS: PD-1-targeted immunotherapy showed promising efficacy and safety in advanced ICC patients.Key messagesPD-1-targeted immunotherapy is a safe and effective treatment for advanced ICC patients.This study provides therapeutic strategy for advanced ICC patients.

Transarterial Infusion Chemotherapy with FOLFOX Could be an Effective and Safe Treatment for Unresectable Intrahepatic Cholangiocarcinoma.

Background: Transarterial infusion (TAI) chemotherapy with the FOLFOX regimen has shown good efficacy and safety in the treatment of hepatocellular carcinoma (HCC). However, it has not been reported in intrahepatic cholangiocarcinoma (ICC). Methods: The data of consecutive patients with unresectable ICC who underwent TAI with the FOLFOX regimen from November 2016 to September 2019 were retrospectively analyzed. Treatment effectiveness and safety were evaluated and compared using the Kaplan-Meier method, log-rank test, Cox regression models, and χ 2 test. Results: Twenty-nine patients were included in the study. The median overall survival (OS) was 16.2 months (95% CI, 13.0-19.4). The median progression-free survival (PFS) was 8.7 months (95% CI, 6.2-11.1). Twenty-seven patients were included in the efficacy analysis. There were 0, 10, 13, and 4 patients with CR, PR, SD, and PD, respectively, based on mRECIST criteria. The ORR was 37.0%, and the DCR was 85.2%. There were 27 patients (93.1%) who experienced grade 1-2 AEs, while only 1 patient experienced grade 3 AEs. Conclusion: TAI with the FOLFOX regimen could be an effective and safe treatment for unresectable ICC.

Plasmon Coupling and Efficient Charge Transfer in Rough-Surfaced Au Nanotriangles/MXene Hybrids as an Ultrasensitive Surface-Enhanced Raman Scattering Platform.

The rational design of Raman substrate materials with prominent electromagnetic enhancement and charge transfer is quite important for surface-enhanced Raman scattering (SERS). Herein, an efficient SERS substrate based on two-dimensional ultrathin Ti3C2T x MXene and rough-surfaced Au nanotriangles (NTs) was successfully prepared for efficient detection of organic molecules due to the synthetic effect of an optimized electromagnetic field and charge transfer. Uniform Au NTs with tunable surface roughness were controllably prepared by selectively depositing of Au on the smooth Au NTs. Due to the large surface area, tunable plasmon resonance, and abundant hotspots on the planar surface, the modified Au NTs showed much better SERS performance than initial Au NTs. By combination of the rough-surfaced Au NTs with MXene, the Ti3C2T x /Au NT hybrids exhibited much better SERS performance than initial Au NTs and Au NTs with a rough surface. The detection limit is down to 10-12 M, and the analytical enhancement factors reach 3.6 × 109 (at 1174 cm-1) on detecting crystal violet excited at 785 nm. This is because the strong plasmon coupling between the in-plane resonance of Au NTs and transversal plasmon resonance of Ti3C2T x MXene around 785 nm can generate an intense interfacial electromagnetic field for amplifying SERS signals. Additionally, the efficient charge transfer between Au NTs, MXene, and molecules also plays an important role in enhancing the SERS performance. This work presents a new insight to develop high-performance SERS substrates based on plasmon.

Uncovering Cis-Regulatory Elements Important for A-to-I RNA Editing in Fusarium graminearum.

Adenosine-to-inosine (A-to-I) RNA editing independent of adenosine deaminase acting on RNA (ADAR) enzymes was discovered in fungi recently, and shown to be crucial for sexual reproduction. However, the underlying mechanism for editing is unknown. Here, we combine genome-wide comparisons, proof-of-concept experiments, and machine learning to decipher cis-regulatory elements of A-to-I editing in Fusarium graminearum. We identified plenty of RNA primary sequences and secondary structural features that affect editing specificity and efficiency. Although hairpin loop structures contribute importantly to editing, unlike in animals, the primary sequences have more profound influences on editing than secondary structures. Nucleotide preferences at adjacent positions of editing sites are the most important features, especially preferences at the -1 position. Unexpectedly, besides the number of positions with preferred nucleotides, the combination of preferred nucleotides with depleted ones at different positions are also important for editing. Some cis-sequence features have distinct importance for editing specificity and efficiency. Machine learning models built from diverse sequence and secondary structural features can accurately predict genome-wide editing sites but not editing levels, indicating that the cis-regulatory principle of editing efficiency is more complex than that of editing specificity. Nevertheless, our model interpretation provides insights into the quantitative contribution of each feature to the prediction of both editing sites and levels. We found that efficient editing of FG3G34330 transcripts depended on the full-length RNA molecule, suggesting that additional RNA structural elements may also contribute to editing efficiency. Our work uncovers multidimensional cis-regulatory elements important for A-to-I RNA editing in F. graminearum, helping to elucidate the fungal editing mechanism. IMPORTANCE A-to-I RNA editing is a new epigenetic phenomenon that is crucial for sexual reproduction in fungi. Deciphering cis-regulatory elements of A-to-I RNA editing can help us elucidate the editing mechanism and develop a model that accurately predicts RNA editing. In this study, we discovered multiple RNA sequence and secondary structure features important for A-to-I editing in Fusarium graminearum. We also identified the cis-sequence features with distinct importance for editing specificity and efficiency. The potential importance of full-length RNA molecules for editing efficiency is also revealed. This study represents the first comprehensive investigation of the cis-regulatory principles of A-to-I RNA editing in fungi.

Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway.

BACKGROUND: Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response. METHODS: The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment. RESULTS: TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo. CONCLUSIONS: Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.