Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer.

Identifying biomarkers for predicting radiotherapy efficacy is crucial for optimizing personalized treatments. We previously reported that rs1553867776 in the miR-4274 seed region can predict survival in patients with rectal cancer receiving postoperative chemoradiation therapy. Hence, to investigate the molecular mechanism of the genetic variation and its impact on the radiosensitivity of colorectal cancer (CRC), in this study, bioinformatics analysis is combined with functional experiments to confirm peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-4274. The miR-4274 rs1553867776 variant influences the binding of miR-4274 and PEX5 mRNA, which subsequently regulates PEX5 protein expression. The interaction between PEX5 and Ku70 was verified by co-immunoprecipitation and immunofluorescence. A xenograft tumor model was established to validate the effects of miR-4274 and PEX5 on CRC progression and radiosensitivity in vivo. The overexpression of PEX5 enhances radiosensitivity by preventing Ku70 from entering the nucleus and reducing the repair of ionizing radiation (IR)-induced DNA damage by the Ku70/Ku80 complex in the nucleus. In addition, the enhanced expression of PEX5 is associated with increased IR-induced ferroptosis. Thus, targeting this mechanism might effectively increase the radiosensitivity of CRC. These findings offer novel insights into the mechanism of cancer radioresistance and have important implications for clinical radiotherapy.

Understanding the molecular pathway of triclosan-induced ADHD-like behaviour: Involvement of the hnRNPA1-PKM2-STAT3 feedback loop.

Triclosan (TCS) is an environmental pollutant. In recent years, there has been increasing level of concern regarding the potential toxicity of TCS in animals and humans, especially its effects on the nervous system. However, whether TCS induces ADHD-like behaviour and the mechanism by which it affects neural function are unclear. The impact of 60 days of continuous exposure to TCS on the behaviour of offspring rats was assessed in this research. According to the results of this study, TCS exposure led to ADHD-like behaviour in offspring rats and activated microglia in the prefrontal cortex (PFC), inducing inflammatory factor release. In vitro studies showed that TCS increased the levels of inflammatory cytokines, including interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α, in HMC3 cells. More importantly, we found that TCS regulated the STAT3 pathway by upregulating PKM2 via hnRNPA1. In summary, this study suggested that TCS can induce ADHD-like behaviour in offspring rats and continuously activate HMC3 microglia through the hnRNPA1-PKM2-STAT3 feedback loop, promoting inflammatory cytokine secretion.

Targeted Delivery of Macrophage Membrane Biomimetic Liposomes Through Intranasal Administration for Treatment of Ischemic Stroke.

Purpose: Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration. Methods: MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated. Results: Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life. Conclusion: MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.

Identification of molecular characteristics of hepatocellular carcinoma with microvascular invasion based on deep targeted sequencing.

BACKGROUND: As an indicator of tumor invasiveness, microvascular invasion (MVI) is a crucial risk factor for postoperative relapse, metastasis, and unfavorable prognosis in hepatocellular carcinoma (HCC). Nevertheless, the genetic mechanisms underlying MVI, particularly for Chinese patients, remain mostly uncharted. METHODS: We applied deep targeted sequencing on 66 Chinese HCC samples. Focusing on the telomerase reverse transcriptase (TERT) promoter (TERTp) and TP53 co-mutation (TERTp+/TP53+) group, gene set enrichment analysis (GSEA) was used to explore the potential molecular mechanisms of the TERTp+/TP53+ group on tumor progression and metastasis. Additionally, we evaluated the tumor immune microenvironment of the TERTp+/TP53+ group in HCC using multiplex immunofluorescence (mIF) staining. RESULTS: Among the 66 HCC samples, the mutated genes that mostly appeared were TERT, TP53, and CTNNB1. Of note, we found 10 cases with TERTp+/TP53+, of which nine were MVI-positive and one was MVI-negative, and there was a co-occurrence of TERTp and TP53 (p < 0.05). Survival analysis demonstrated that patients with the TERTp+/TP53+ group had lower the disease-free survival (DFS) (p = 0.028). GSEA results indicated that telomere organization, telomere maintenance, DNA replication, positive regulation of cell cycle, and negative regulation of immune response were significantly enriched in the TERTp+/TP53+ group (all adjusted p-values (p.adj) < 0.05). mIF revealed that the TERTp+/TP53+ group decreased CD8+ T cells infiltration (p = 0.25) and enhanced PDL1 expression (p = 0.55). CONCLUSIONS: TERTp+/TP53+ was significantly enriched in MVI-positive patients, leading to poor prognosis for HCC patients by promoting proliferation of HCC cell and inhibiting infiltration of immune cell surrounding HCC. TERTp+/TP53+ can be utilized as a potential indicator for predicting MVI-positive patients and poor prognosis, laying a preliminary foundation for further exploration of co-mutation in HCC with MVI and clinical treatment.

Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

BACKGROUND: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

The Optimization Design of Macrophage Membrane Camouflaging Liposomes for Alleviating Ischemic Stroke Injury through Intranasal Delivery.

Ischemic stroke is associated with a high mortality rate, and effective treatment strategies are currently lacking. In this study, we aimed to develop a novel nano delivery system to treat ischemic stroke via intranasal administration. A three-factor Box-Behnken experimental design was used to optimize the formulation of liposomes co-loaded with Panax notoginseng saponins (PNSs) and Ginsenoside Rg3 (Rg3) (Lip-Rg3/PNS). Macrophage membranes were coated onto the surface of the optimized liposomes to target the ischemic site of the brain. The double-loaded liposomes disguised by macrophage membranes (MM-Lip-Rg3/PNS) were spherical, in a "shell-core" structure, with encapsulation rates of 81.41% (PNS) and 93.81% (Rg3), and showed good stability. In vitro, MM-Lip-Rg3/PNS was taken up by brain endothelial cells via the clathrin-dependent endocytosis and micropinocytosis pathways. Network pharmacology experiments predicted that MM-Lip-Rg3/PNS could regulate multiple signaling pathways and treat ischemic stroke by reducing apoptosis and inflammatory responses. After 14 days of treatment with MM-Lip-Rg3/PNS, the survival rate, weight, and neurological score of middle cerebral artery occlusion (MCAO) rats significantly improved. The hematoxylin and eosin (H&E) and TUNEL staining results showed that MM-Lip-Rg3/PNS can reduce neuronal apoptosis and inflammatory cell infiltration and protect the ischemic brain. In vivo biological experiments have shown that free Rg3, PNS, and MM-Lip-Rg3/PNS can alleviate inflammation and apoptosis, especially MM-Lip-Rg3/PNS, indicating that biomimetic liposomes can improve the therapeutic effects of drugs. Overall, MM-Lip-Rg3/PNS is a potential biomimetic nano targeted formulation for ischemic stroke therapy.

Integrated plasma proteomics and N-glycoproteomics reveals alterations in the N-glycosylation in Chinese hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a life-threatening disease that presents diagnostic challenges due to the absence of reliable biomarkers. Recently, plasma proteomics and glycoproteomics have emerged as powerful tools for identifying potential diagnostic biomarkers for various diseases. In this study, we conducted a comprehensive proteomic and glycoproteomic analysis of plasma samples from 11 HCC patients and 11 healthy control (HC) individuals. We identified 20 differentially expressed (DE) proteins and 32 DE intact glycosylated peptides (IGPs) that can effectively differentiate between HCC patients and HC samples. Our findings demonstrate that IGP profiles had better predictive power than protein profiles for screening HCC. Pathways associated with DE proteins and IGPs were identified. It was reported that the protein expression level of galectin 3 binding protein (LGALS3BP) and its N-linked glycosylation at the N398 and N551 sites might serve as valuable candidates for HCC diagnosis. These results highlight the importance of N-glycoproteomics in advancing our understanding of HCC and suggest possible candidates for the future diagnosis of this disease.

Predictors of Gleason Grading Group Upgrading in Low-Risk Prostate Cancer Patients From Transperineal Biopsy After Radical Prostatectomy.

RATIONALE AND OBJECTIVES: To investigate the predictors of Gleason Grading Group (GGG) upgrading in low-risk prostate cancer (Gleason score=3 + 3) from transperineal biopsy after radical prostatectomy (RP). MATERIALS AND METHODS: The clinical data of 160 patients who underwent transperineal biopsy and RP from January 2017 to December 2022 were retrospectively analyzed. First, univariate and multivariate logistic regression analysis were used to obtain independent predictors of postoperative GGG upgrading. Then receiver operating characteristic curve was used to evaluate the diagnostic efficacy of predictors. Finally, Linear-by-Linear Association test was used to analyze the risk trends of patients in different predictor groups in the postoperative GGG. RESULTS: In this study, there were 81 cases (50.6%) in the GGG concordance group and 79 cases (49.4%) in the GGG upgrading group. Univariate analysis showed age, free/total prostate-specific antigen (f/tPSA), proportion of positive biopsies, positive target of magnetic-resonance imaging (MRI) and positive target of contrast-enhanced ultrasound had significant effects on GGG upgrading (all P < .05). In multivariate logistic regression analysis, age (odds ratio [OR]=1.066, 95%CI=1.007-1.127, P = .027), f/tPSA (OR=0.001, 95%CI=0-0.146, P = .001) and positive target of MRI (OR=3.005, 95%CI=1.353-76.674, P = .007) were independent predictors. The prediction model (area under curve=0.751 P < .001) had higher predictive efficacy than all independent predictors. The proportion of patients in exposed group of different GGG increased with the level of GGG, but decreased in nonexposed group, and the linear trend was significantly different (all P < .001). CONCLUSION: Age, f/tPSA, and positive target of MRI were independent predictors of postoperative GGG upgrading. The predictive model constructed had the best diagnostic efficacy.

High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) is a malignancy-associated gene that plays a critical role in the regulation of chromosome separation and cell division. However, the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma (HCC) has not been fully elucidated. AIM: To investigate the molecular mechanisms underlying the role of SKA3 in HCC. METHODS: SKA3 expression, clinicopathological, and survival analyses were performed using multiple public database platforms, and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples. Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC. Furthermore, the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC. The response to chemotherapeutic drugs was evaluated by the R package "pRRophetic". RESULTS: We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC. Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival. GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair. Moreover, patients with high SKA3 expression had significantly decreased ratios of CD8+ T cells, natural killer cells, and dendritic cells. Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib, sunitinib, paclitaxel, doxorubicin, gemcitabine, and vx-680. CONCLUSION: High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

Machine learning-based on cytotoxic T lymphocyte evasion gene develops a novel signature to predict prognosis and immunotherapy responses for kidney renal clear cell carcinoma patients.

Background: Immunotherapy resistance has become a difficult point in treating kidney renal clear cell carcinoma (KIRC) patients, mainly because of immune evasion. Currently, there is no effective signature to predict immunotherapy. Therefore, we use machine learning algorithms to construct a signature based on cytotoxic T lymphocyte evasion genes (CTLEGs) to predict the immunotherapy responses of patients, so as to screen patients effective for immunotherapy. Methods: In public data sets and our in-house cohort, we used 10 machine learning algorithms to screen the optimal model with 89 combinations under the cross-validation framework, and 101 published signatures were collected. The relationship between the CTLEG signature (CTLEGS) and clinical variables was analyzed. We analyzed the role of CTLES in other types of cancer by pan-cancer analysis. The immune cell infiltration and biological characteristics were evaluated. Moreover, the response to immunotherapy and drug sensitivity of different risk groups were investigated. The key gene closely related to the signature was identified by WGCNA. We also conducted cell functional experiments and clinical tissue validation of key gene. Results: In public data sets and our in-house cohort, the CTLEGS shows good prediction performance. The CTLEGS can be regard as an independent risk factor for KIRC. Compared with 101 published models, our signature shows considerable superiority. The high-risk group has abundant infiltration of immunosuppressive cells and high expression of T cell depletion markers, which are characterized by immunosuppressive phenotype, minimal benefit from immunotherapy, and resistance to sunitinib and sorafenib. The CTLEGS was also strongly correlated with immunity in pan-cancer. Immunohistochemistry verified that T cell depletion marker LAG3 is highly expressed in high-risk groups in the clinical in-house cohort. The key CTLEG STAT2 can promote the proliferation, migration and invasion of KIRC cell. Conclusions: CTLEGS can accurately predict the prognosis of patients and their response to immunotherapy. It can provide guidance for the precise treatment of KIRC and help clinicians identify patients who may benefit from immunotherapy.

Autophagy and biotransformation affect sorafenib resistance in hepatocellular carcinoma.

As sorafenib is a first-line drug for treating advanced hepatocellular carcinoma, sorafenib resistance has historically attracted attention. However, most of this attention has been focused on a series of mechanisms related to drug resistance arising after sorafenib treatment. In this study, we used proteomic techniques to explore the potential mechanisms by which pretreatment factors affect sorafenib resistance. The degree of redundant pathway PI3K/AKT activation, biotransformation capacity, and autophagy level in hepatocellular carcinoma patients prior to sorafenib treatment might affect their sensitivity to sorafenib, in which ADH1A and STING1 are key molecules. These three factors could interact mechanistically to promote tumor cell survival, might be malignant features of tumor cells, and are associated with hepatocellular carcinoma prognosis. Our study suggests possible avenues of therapeutic intervention for patients with sorafenib-resistance and the potential application of immunotherapy with the aim of improving the survival of such patients.

MiR-590-5p promotes cisplatin resistance via targeting hMSH2 in ovarian cancer.

OBJECTIVE: The mechanisms of ovarian cancer generate chemotherapy resistance are still unclear. This study aimed to explore the role of microRNA (miR)-590-5p in regulating hMSH2 expression and cisplatin resistance in ovarian cancer. METHODS: MiR-590-5p was identified as a regulator of hMSH2 with miRDB database and Target Scan database. Then cisplatin sensitive cell line (SKOV3) and resistant cell line (SKOV3-DDP) of ovarian cancer were cultured for cell functional assay and molecular biology assay. The expression levels of MiR-590-5p and hMSH2 were compared between the two cell lines. Dual luciferase reporter assay was used to verify the targeted regulatory relationship between miR-590-5p and hMSH2. CCK-8 assay and cell apoptosis assay were utilized to assess the role of MiR-590-5p and hMSH2 in cell viability under cisplatin. RESULTS: The expression of hMSH2 was significantly decreased, and miR-590-5p was significantly up-regulated in SKOV3-DDP. Up-regulation of hMSH2 weakened the viability of SKOV3 and SKOV3-DDP cell under cisplatin. Transfection with miR­590-5p mimics reduced the expression of hMSH2 and enhanced the viability of ovarian cancer cells under cisplatin, whereas inhibition of miR­590-5p increased the expression of hMSH2, and decreased ovarian cancer cells' viability under cisplatin. Furthermore, luciferase reporter assay showed that hMSH2 was a direct target of miR-590-5p. CONCLUSION: The present study demonstrates that miR­590-5p promotes cisplatin resistance of ovarian cancer via negatively regulating hMSH2 expression. Inhibition of miR­590-5p decreases ovarian cancer cells' viability under cisplatin. Thus miR­590-5p and hMSH2 may serve as therapeutic targets for cisplatin resistant ovarian cancer.

Anlotinib as Monotherapy or Combination Therapy for Recurrent High-Grade Glioma: A Retrospective Study.

Background: Anlotinib is a multi-target anti-angiogenic agent. The retrospective study was conducted to evaluate the safety and effectiveness of anlotinib as monotherapy or combination therapy for the treatment of recurrent high-grade gliomas. Methods: In this retrospective study, patients with recurrent high-grade glioma (according to the 2021 World Health Organization classification as levels III-IV) at Sichuan Cancer Hospital from June 2019 to June 2022 were included. The patients were divided into an anlotinib-monotherapy group and an anlotinib-combination group, and received oral anlotinib 8 to 12 mg once a day, with 2 weeks on/1 week off. The primary endpoint was progression-free survival (PFS). The Secondary endpoints included overall survival (OS), 6-month PFS rate, objective response rate (ORR), and disease control rate (DCR). Also, adverse events were evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE version 5.0). Results: A total of 29 patients (including 20 glioblastomas, 1 diffuse midline glioma, 5 anaplastic astrocytoma, and 3 anaplastic oligodendroglioma) were included in this study. Of these, 34.48% of the patients were treated with anlotinib alone and 65.52% with anlotinib combination therapy. The median follow-up time was 11.6 months (95% confidence interval [CI]: 9.4-15.7). The median PFS was 9.4 months (95% CI: 6.5-12.3), and the 6-month PFS rate was 62.1%. The median OS was 12.7 months (95% CI: 9.7-15.7), and the 12-month OS rate was 48.3%. Evaluation of treatment response was performed according to RANO (response assessment in neuro-oncology, RANO) criteria, including 21 partial response, 6 stable disease, and 2 PFS events. The ORR and DCR were 72.4%, and 93.1%, respectively. Grade III AEs occurred in 2 patients, and the others were less than grade III. The most common AE was thrombocytopenia, with an incidence rate of 31.0%. All AEs were alleviated and controlled by symptomatic treatment. No treatment-related deaths occurred. Conclusion: Anlotinib had a low incidence of AEs and good safety in the treatment of recurrent high-grade glioma. Moreover, it showed good short-term effectiveness and significantly prolonged the PFS of patients, which may become a promising therapeutic option for recurrent high-grade glioma and lay a foundation for further clinical studies.

YAP nuclear translocation facilitates radiation resistance in nasopharyngeal carcinoma cells.

OBJECTIVES: Investigate the role of the Hippo-YAP signaling pathway in radioresistant Nasopharyngeal Carcinoma (NPC). METHODS: Establishment of radioresistant CNE-1 cells (CNE-1-RR) by gradually increasing ionizing radiation (IR) doses, and identifying the apoptosis of CNE-1-RR by flow cytometry. We employed immunoblot and immunofluorescence staining to detect the expression of YAP in both CNE-1-RR and control group cells. Moreover, we validated the role of YAP in CNE-1-RR by inhibiting its nuclear translocation. RESULTS: In contrast to the control group, radioresistant NPC cells demonstrated significant YAP dephosphorylation and nuclear translocation. CNE-1-RR cells exhibited enhanced activation of γ-H2AX (Ser139) upon exposure to IR and greater recruitment of double-strand breaks (DSBs) repair-related proteins. Additionally, inhibiting YAP nuclear translocation in radioresistant CNE-1-RR cells significantly increased their sensitivity to radiotherapy. CONCLUSIONS: The present investigation has unveiled the intricate mechanisms and physiological roles of YAP in CNE-1-RR cells exhibiting resistance to IR. Based on our findings, it can be inferred that a combinational therapeutic strategy involving radiotherapy and inhibitors that impede the nuclear translocation of YAP holds promising potential for treating radioresistant NPC.

Clinical Benefits of Neoadjuvant Radiotherapy on the Postoperative Recurrence of Centrally Located Hepatocellular Carcinoma: A Real-World Evidence Based on Phase II Clinical Trial.

Objective: Although surgical resection is one of the most effective way to treat liver cancer, its efficacy and safety in treatment of centrally located hepatocellular carcinoma (HCC) remains elusive. Therefore, it is very important to find a comprehensive treatment mode, such as radical resection combined with neoadjuvant radiotherapy (neoRT). Methods: The centrally located HCC patients who underwent radical resection from July 2015 to April 2021 were enrolled. According to whether the neoRT was implemented or not, these patients were allocated into neoadjuvant radiotherapy combined with liver resection (neoRT+LR) and liver resection alone (LR) group. The research method used propensity-score analysis and Cox proportional-hazards regression models. We generated an E-value to assess the sensitivity to unmeasured confounding. This study is a real-world, retrospective study based on phase II clinical trial. Results: A total of 168 patients were enrolled, including 38 patients treating with neoRT+LR and 130 patients with LR. The 1-, 3-, 5-year disease free survival (DFS) rates were 74%, 55% and 39% in the neoRT+LR group, and 44%, 28%, and 24% in the LR group, respectively. Neoadjuvant radiotherapy was an independent prognostic factor for postoperative recurrence ([HR]0.42, 95% CI [0.25, 0.69]). There was significant association between neoRT+LR and longer disease-free survival (Match, [HR] 0.43, 95% CI [0.24, 0.76]; GenMatch, [HR] 0.32, 95% CI [0.23, 0.43]; Adjusted for propensity score, [HR] 0.41, 95% CI [0.23, 0.73]; Inverse probability weighting, [HR] 0.38, 95% CI [0.22, 0.65], respectively). DFS before and after matching analysis was statistically different in two groups (p-value=0.005, p-value=0.0024, respectively). Neoadjuvant radiotherapy can significantly reduce the postoperative early recurrence (p-value <0.05). E-value analysis suggested robustness to unmeasured confounding. Conclusion: Liver resection combined with neoadjuvant radiotherapy was effective and safe for treatment of centrally located HCC patients, which improved the prognosis of patients and reduced the incidence of early recurrence.

LncRNA CAI2 contributes to poor prognosis of glioma through the PI3K-AKt signaling pathway.

AIMS: We aim to explore new potential therapeutic targets and markers in human glioma. BACKGROUND: Gliomas are the most common malignant primary tumor in the brain. OBJECTIVE: In the present research, we evaluated the effect of CAI2, a long non-coding RNA, on the biological behaviors of glioma and explored the related molecular mechanism. METHOD: The expression of CAI2 was analyzed using qRT-PCR in 65 cases of glioma patients. The cell proliferation was determined with MTT and colony formation assays, and the PI3K-AKt signaling pathway was analyzed using western blot. RESULT: CAI2 was upregulated in human glioma tissue compared with the matched, adjacent nontumor tissue and was correlated with WHO grade. Survival analyses proved that the overall survival of patients with high CAI2 expression was poor compared to that of patients with low CAI2 expression. High CAI2 expression was an independent prognostic factor in glioma. The absorbance values in the MTT assay after 96 h were .712 ± .031 for the si-control and .465 ± .018 for the si-CAI2-transfected cells, and si-CAI2 inhibited colony formation in U251 cells by approximately 80%. The levels of PI3K, p-AKt, and AKt in si-CAI2-treated cells were decreased. CONCLUSION: CAI2 may promote glioma growth through the PI3K-AKt signaling pathway. This research provided a novel potential diagnostic marker for human glioma.

Diagnostic performance of artificial intelligence-based computer-aided diagnosis system in longitudinal and transverse ultrasonic views for differentiating thyroid nodules.

Objective: To evaluate the diagnostic performance of different ultrasound sections of thyroid nodule (TN) using computer-aided diagnosis system based on artificial intelligence (AI-CADS) in predicting thyroid malignancy. Materials and methods: This is a retrospective study. From January 2019 to July 2019, patients with preoperative thyroid ultrasound data and postoperative pathological results were enrolled, which were divided into two groups: lower risk group (ACR TI-RADS 1, 2 and 3) and higher risk group (ACR TI-RADS 4 and 5). The malignant risk scores (MRS) of TNs were obtained from longitudinal and transverse sections using AI-CADS. The diagnostic performance of AI-CADS and the consistency of each US characteristic were evaluated between these sections. The receiver operating characteristic (ROC) curve and the Cohen κ-statistic were performed. Results: A total of 203 patients (45.61 ± 11.59 years, 163 female) with 221 TNs were enrolled. The area under the ROC curve (AUC) of criterion 3 [0.86 (95%CI: 0.80~0.91)] was lower than criterion 1 [0.94 (95%CI: 0.90~ 0.99)], 2 [0.93 (95%CI: 0.89~0.97)] and 4 [0.94 (95%CI: 0.90, 0.99)] significantly (P<0.001, P=0.01, P<0.001, respectively). In the higher risk group, the MRS of transverse section was higher than longitudinal section (P<0.001), and the agreement of extrathyroidal extension and shape was moderate and fair (κ =0.48, 0.31 respectively). The diagnostic agreement of other ultrasonic features was substantial or almost perfect (κ >0.60). Conclusion: The diagnostic performance of computer-aided diagnosis system based on artificial intelligence (AI-CADS) in longitudinal and transverse ultrasonic views for differentiating thyroid nodules (TN) was different, which was higher in the transverse section. It was more dependent on the section for the AI-CADS diagnosis of suspected malignant TNs.

Overexpression of RtSYP121 confers cadmium colerance by promoting vesicle trafficking, maintaining ion homeostasis, and alleviating photosynthetic inhibition in Arabidopsis.

Cadmium (Cd) is a toxic heavy metal in soil that seriously threatens crop production, food security, and human health. Syntaxins, a prototype family of Soluble N-ethyl-maleimide-associated protein receptors (SNAREs) involved in vesicle trafficking, are implicated in resistance to abiotic stresses, including Cd stress, but the molecular mechanisms underlying the involvement of syntaxins in Cd tolerance in plants are unclear. In this study, we isolated and functionally characterized the syntaxin gene RtSYP121 from Reaumuria trigyna to evaluate its potential for phytoremediation. RtSYP121 resides in the plasma membrane. The transcriptional level of RtSYP121 was strongly increased by salt, drought, and Cd stress. Overexpression of RtSYP121 significantly enhanced the Cd tolerance of transgenic Arabidopsis. The Cd tolerance of transgenic plants mainly depended on elevated vesicle trafficking, which increased the content of K+ and Ca2+ and thus decreased the accumulation of Cd2+ by regulating the delivery or activity of ion transporters, channels, and pumps. Moreover, overexpression of RtSYP121 in Arabidopsis ameliorated Cd stress-induced phytotoxic effects, including growth inhibition, ROS burst, photosynthetic impairment, and cell death. Therefore, we suggest that RtSYP121 plays multiple roles in the plant response to Cd stress by promoting vesicle trafficking, maintaining ion homeostasis, and alleviating photosynthetic inhibition.