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. Keywords: Hepatocellular carcinoma, Signature, Nomogram, Prognosis, Immune infiltration
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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.
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).
PD-1-targeted immunotherapy showed promising efficacy and safety in advanced ICC patients.
Key messages
PD-1-targeted immunotherapy is a safe and effective treatment for advanced ICC patients.
This study provides therapeutic strategy for advanced ICC patients.
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.
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.
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.
Iron deficiency anemia （IDA） is a common type of anemia in childhood caused by iron deficiency due to varying causes, which can result in a decline in the synthesis of hemoglobin. IDA will adversely ...affect the growth and development of children. Hepcidin exerts a negative regulatory effect on iron metabolism. Recent studies have shown that hepcidin can be used as one of the biomarkers for early diagnosis of IDA and the response evaluation. Vitamin D exerts a direct or indirect inhibitory effect upon hepcidin. Lack of vitamin D is one of the common triggers for anemia in children, and the degree of vitamin D deficiency is positively correlated with the degree of anemia. Combined therapy of vitamin D and iron exerts preventive and therapeutic effect on IDA. In this article, the correlation between the hepcidin and vitamin D levels in IDA children and their significance in the diagnosis and treatment of IDA were reviewed, aiming to provide novel diagnostic and therapeutic ideas for the clinical management of ped
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.
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.
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.
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Non-Hermitian skin effect (NHSE), where huge modes are accumulated at system boundaries, offers new possibility for steering the transport and localization of light by non-Hermiticity. Here, the ...direction-dependent NHSE is proposed in a photonic waveguide array
via
spatially complex modulation, where the skin modes tend to localize at different boundaries for opposite propagation directions. We utilize complex modulation to arouse anisotropic coupling between symmetric and anti-symmetric modes in multimode waveguides and further match the refractive index of adjacent waveguides. In this way, a non-Hermitian Su–Schrieffer–Heeger (SSH) lattice that supports NHSE is achieved. In particular, the anisotropic coupling is highly unidirectional. For forward direction, it allows mode conversion from antisymmetric modes to symmetric modes. However, the process is forbidden for backward direction. As a result, the skin modes tend to locate at lower boundary for forward propagation but the localization direction is reversed for backward injection. Our results provide a potential platform to investigate NHSE on photonic chips and may find applications in non-magnetic unidirectional devices.
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