Circular RNA hsa_circ_0000467 promotes colorectal cancer progression by promoting eIF4A3-mediated c-Myc translation.

BACKGROUND: Colorectal cancer (CRC) is the second most common malignant tumor worldwide, and its incidence rate increases annually. Early diagnosis and treatment are crucial for improving the prognosis of patients with colorectal cancer. Circular RNAs are noncoding RNAs with a closed-loop structure that play a significant role in tumor development. However, the role of circular RNAs in CRC is poorly understood. METHODS: The circular RNA hsa_circ_0000467 was screened in CRC circRNA microarrays using a bioinformatics analysis, and the expression of hsa_circ_0000467 in CRC tissues was determined by in situ hybridization. The associations between the expression level of hsa_circ_0000467 and the clinical characteristics of CRC patients were evaluated. Then, the role of hsa_circ_0000467 in CRC growth and metastasis was assessed by CCK8 assay, EdU assay, plate colony formation assay, wound healing assay, and Transwell assay in vitro and in a mouse model of CRC in vivo. Proteomic analysis and western blotting were performed to investigate the effect of hsa_circ_0000467 on c-Myc signaling. Polysome profiling, RT‒qPCR and dual-luciferase reporter assays were performed to determine the effect of hsa_circ_0000467 on c-Myc translation. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to assess the effect of hsa_circ_0000467 on eIF4A3 distribution. RESULTS: In this study, we found that the circular RNA hsa_circ_0000467 is highly expressed in colorectal cancer and is significantly correlated with poor prognosis in CRC patients. In vitro and in vivo experiments revealed that hsa_circ_0000467 promotes the growth and metastasis of colorectal cancer cells. Mechanistically, hsa_circ_0000467 binds eIF4A3 to suppress its nuclear translocation. In addition, it can also act as a scaffold molecule that binds eIF4A3 and c-Myc mRNA to form complexes in the cytoplasm, thereby promoting the translation of c-Myc. In turn, c-Myc upregulates its downstream targets, including the cell cycle-related factors cyclin D2 and CDK4 and the tight junction-related factor ZEB1, and downregulates E-cadherin, which ultimately promotes the growth and metastasis of CRC. CONCLUSIONS: Our findings revealed that hsa_circRNA_0000467 plays a role in the progression of CRC by promoting eIF4A3-mediated c-Myc translation. This study provides a theoretical basis and molecular target for the diagnosis and treatment of CRC.

Assessing the efficiency of eligibility criteria for low-dose computed tomography lung screening in China according to current guidelines.

BACKGROUND: Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population. METHODS: Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP). RESULTS: Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45-49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35-39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P < 0.001). CONCLUSIONS: The I-ELCAP guideline has the highest eligibility rate for both males and females. But its actual efficiency ratio for those deemed eligible by the guideline was the lowest. Whereas the NCCN guideline has the highest ERe value for those deemed eligible by the guideline.

Sensitive fluorescence ELISA for the detection of zearalenone based on self-assembly DNA nanocomposites and copper nanoclusters.

Zearalenone (ZEN), produced by Fusarium species, is a potential risk to human health. Traditional enzyme-linked immunosorbent assay (ELISA) is restricted due to low sensitivity for the detection of ZEN. Herein, enzyme nanocomposites (ALP-SA-Bio-ssDNA, ASBD) were prepared with the self-assembly strategy based on streptavidin-labeled alkaline phosphatase (SA-ALP) and dual-biotinylated ssDNA (B2-ssDNA). The enzyme nanocomposites improved the loading amount of ALP and catalyzed more ascorbic acid 2-phosphate to generate ascorbic acid (AA). Subsequently, Cu2+ could be reduced to copper nanoclusters (CuNCs) having strong fluorescence signal by AA with poly T. Benefiting from the high enzyme load of nanocomposites and the strong signal of CuNCs, the fluorescence ELISA was successfully established for the detection of ZEN. The proposed method exhibited lower limit of detection (0.26 ng mL-1) than traditional ELISA (1.55 ng mL-1). The recovery rates ranged from 92.00% to 108.38% (coefficient of variation < 9.50%) for the detection of zearalenone in corn and wheat samples. In addition, the proposed method exhibited no cross reaction with four other mycotoxins. This proposed method could be used in trace detection for food safety.

The impact of PD-1 inhibitors on prognosis in unresectable hepatocellular carcinoma treated with TACE and lenvatinib: a retrospective study.

Our aim was to explore whether programmed death receptor-1 (PD-1) inhibitors would improve the prognosis of unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) plus lenvatinib. In this single-center retrospective study, patients with unresectable HCC who underwent TACE and were administered lenvatinib with or without PD-1 inhibitors were enrolled and divided into the TACE + lenvatinib group and TACE + lenvatinib + PD-1 group. Overall survival (OS), progression-free survival (PFS) and tumor response were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1 and mRECIST). Treatment-related adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). In total, 35 eligible patients with unresectable HCC were included; 82.9% of patients had Hepatitis B virus (HBV) infection, and 88.6% of patients had liver cirrhosis. A total of 88.6% of patients had multiple tumors, and the median diameter of the largest tumor was 10.1 cm. A total of 14.3% of patients had extrahepatic metastasis, and 51.4% of patients had portal vein tumor thrombus. The percentages of BCLC stages A, B and C were 5.7%, 28.6% and 65.7%, respectively. There were 16 patients in the TACE + lenvatinib group and 19 patients in the TACE + lenvatinib + PD-1 group. The median follow-up time was 7.7 months (ranging from 1.7 to 31.6 months). Neither group reached the median overall survival. Under RECIST v1.1 criteria, the median PFS was 10.4 and 7.9 months in the TACE + lenvatinib and TACE + lenvatinib + PD-1 groups (HR, 1.13; 95% CI 0.45-2.84; p = 0.80), the objective response rates (ORR) were 31.3% and 31.6% (p > 0.05), and the disease control rates (DCR) were 93.8% and 78.9% (p > 0.05), respectively. Under mRECIST criteria, the median PFS was 10.4 and 10.1 months (HR, 0.98; 95% CI 0.38-2.54, p = 0.97), the ORR was 62.5% and 63.2% (p > 0.05), and the DCR was 93.8% and 73.7% (p > 0.05), respectively. Overall, AEs were relatively similar between the two groups. PD-1 inhibitors did not improve the PFS and tumor response of unresectable HCC treated with TACE plus lenvatinib. Hepatitis B infection, liver cirrhosis, portal vein tumor thrombus, multiple tumors and large tumor diameter may be potential factors that affect the efficacy of PD-1 inhibitors but need further validation.

Case report on postoperative coagulation abnormalities.

RATIONALE: Intracranial aneurysm (IA) is defined as a localized dilation of cerebral arteries. With the continuous development of modern medical technology, surgery is still one of the main treatment methods. Although there are various postoperative complications, abnormal coagulation function is rare, especially those caused by lupus antibodies after surgery. The patient not only experienced postoperative abnormalities in coagulation function, but also discovered the presence of lupus anticoagulants in their body. Is the patient suffering from coagulation dysfunction caused by lupus anticoagulants, how is lupus anticoagulant produced, and what's special about treatment. With these questions in mind, we reviewed the entire treatment process of the patient. PATIENT CONCERNS: A 69-year-old woman presented with "headache and dizziness with neck pain" and was eventually diagnosed with IA hemorrhage. The patient underwent craniotomy under general anesthesia, and provided targeted support and treatment. Postoperative symptoms such as coma and intermittent fever occurred, and coagulation indicators were generally normal. After symptomatic support treatment, such as anti-infection treatment, the patient's temperature was gradually controlled. However, the abnormal clotting index and the efficacy of symptomatic therapeutic support, such as supplementation with coagulation factors, were not good. After further examination, the lupus anticoagulant was found, which provided us with a new treatment idea. DIAGNOSES: Coagulation disorders, postoperative IA, hypertension grade 3 (extremely high risk), coronary atherosclerotic atheropathy, and type 2 diabetes. INTERVENTIONS: The patient developed abnormal coagulation function after craniotomy, and symptomatic support treatment with coagulation factor supplementation and plasma infusion was ineffective. Finally, the lupus anticoagulant was found after a series of relevant examinations. After timely adjustment of the treatment plan, the patient's coagulation indices gradually improved. OUTCOMES: In this report, we present the case of a patient with abnormal coagulation function caused by the lupus anticoagulant after IA surgery. LESSONS: The coagulation function of the patient was abnormal after craniocerebral operation. After coagulation factor supplementation, the coagulation index of the patient was still not well improved. After further examination, the lupus anticoagulant was found. The treatment plan was actively adjusted, and the patient's condition gradually improved. Early recognition can allow doctors to provide appropriate therapy to patients.

Integration of a biocompatible metal-phenolic network and fluorescence microspheres as labels for sensitive and stable detection of carbendazim with a lateral flow immunoassay.

High fluorescence intensity microspheres such as aggregation-induced emission fluorescence microspheres (AIEFM) have improved the sensitivity of lateral flow immunoassay (LFIA). The preparation of immune probes in LFIA usually adopts the chemical coupling strategy with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide for antibody coupling, which has the problems of low coupling efficiency, tedious coupling process, and poor repeatability. A biocompatible metal-phenolic network (MPN), which contains large amounts of phenols and galloyl groups, could easily, quickly, and stably couple with antibodies. Herein, we proposed a strategy based on MPN modification on ultrabright AIEFM surface as a novel label for the rapid detection of carbendazim. The limit of detection of AIEFM@MPN-LFIA was 0.019 ng/mL, which was 4.9 times lower than that of AIEFM-LFIA. In spiked samples, the average recoveries of AIEFM@MPN-LFIA ranged from 80% to 118% (coefficient of variation <13.45%). Therefore, AIEFM@MPN was a promising signal label that could improve the detection performance of LFIA.

HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor.

Human papillomavirus (HPV) is a class of envelope-free double-stranded DNA virus. HPV infection has been strongly associated with the development of many malignancies, such as cervical, anal and oral cancers. The viral oncoproteins E6 and E7 perform central roles on HPV-induced carcinogenic processes. During tumor development, it usually goes along with the activation of abnormal signaling pathways. E6 and E7 induces changes in cell cycle, proliferation, invasion, metastasis and other biological behaviors by affecting downstream tumor-related signaling pathways, thus promoting malignant transformation of cells and ultimately leading to tumorigenesis and progression. Here, we summarized that E6 and E7 proteins promote HPV-associated tumorigenesis and development by regulating the activation of various tumor-related signaling pathways, for example, the Wnt/ß-catenin, PI3K/Akt, and NF-kB signaling pathway. We also discussed the importance of HPV-encoded E6 and E7 and their regulated tumor-related signaling pathways for the diagnosis and effective treatment of HPV-associated tumors.

Cellular metabolism: A key player in cancer ferroptosis.

Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron-dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.

Opportunistic lung cancer screening with low-dose computed tomography in National Cancer Center of China: The first 14 years' experience.

BACKGROUND: In China, over 50% of lung cancer cases occur in nonsmokers. Thus, identifying high-risk individuals for targeted lung cancer screening is crucial. Beyond age and smoking, determining other risk factors for lung cancer in the Asian population has become a focal point of research. Using 30,000 participants in the prospectively enrolled cohort at China's National Cancer Center (NCC) over the past 14 years, we categorized participants by risk, with an emphasis on nonsmoking females. MATERIALS AND METHODS: Between November 2005 and December 2019, 31,431 individuals voluntarily underwent low-dose computed tomography (LDCT) scans for lung cancer screening at the NCC. We recorded details like smoking history, exposure to hazards, and family history of malignant tumors. Using the 2019 NCCN criteria, participants were categorized into high-, moderate-, and low-risk groups. Additionally, we separated non-high-risk groups into female never smokers (aged over 40) exposed to second-hand smoke (SHS) and others. Any positive results from initial scans were monitored per the I-ELCAP protocol (2006), and suspected malignancies were addressed through collaborative decisions between patients and physicians. We analyzed and compared the detection rates of positive results, confirmed lung cancers, and cancer stages across risk, age, and gender groups. RESULTS: Out of 31,431 participants (55.9% male, 44.1% female), 3695 (11.8%) showed positive baseline LDCT scans with 197 (0.6%; 106 females, 91 males) confirmed as lung cancer cases pathologically. Malignancy rate by age was 0.1% among those aged under 40 years, 0.4% among those aged 40-49 years, 0.8% among those aged 50-59 years, and 1.2% among those aged 60 years and older. From the 25,763 participants (56.9% male, 43.1% female) who completed questionnaires, 1877 (7.3%) were categorized as high risk, 6500 (25.2%) as moderate risk, and 17,386 (67.5%) as low risk. Of the 23,886 in the non-high-risk category, 8041 (33.7%) were females over 40 years old exposed to SHS. The high-risk group showed the highest lung cancer detection rate at 1.4%. However, females exposed to SHS had a notably higher detection rate than the rest of the non-high-risk group (1.1% vs. 0.5%; p < 0.0001). In this cohort, 84.8% of the detected lung cancers were at an early stage. CONCLUSIONS: In our study, using LDCT for lung cancer screening proved significant for high-risk individuals. For non-high-risk populations, LDCT screening could be considered for nonsmoking women with exposure to SHS.

Diallyl disulfide induces DNA damage and growth inhibition in colorectal cancer cells by promoting POU2F1 ubiquitination.

Previous studies have demonstrated that diallyl disulfide (DADS) exhibits potent anti-tumor activity. However, the pharmacological actions of DADS in inhibiting the growth of colorectal cancer (CRC) cells have not been clarified. Herein, we show that DADS treatment impairs the activation of the pentose phosphate pathway (PPP) to decrease PRPP (5-phosphate ribose-1-pyrophosphate) production, enhancing DNA damage and cell apoptosis, and inhibiting the growth of CRC cells. Mechanistically, DADS treatment promoted POU2F1 K48-linked ubiquitination and degradation by attenuating the PI3K/AKT signaling to up-regulate TRIM21 expression in CRC cells. Evidently, TRIM21 interacted with POU2F1, and induced the K272 ubiquitination of POU2F1. The effects of DADS on the enhanced K272 ubiquitination of POU2F1, the PPP flux, PRPP production, DNA damage and cell apoptosis as well as the growth of CRC tumors in vivo were significantly mitigated by TRIM21 silencing or activating the PI3K signaling in CRC cells. Conversely, the effects of DADS were enhanced by TRIM21 over-expression or inhibiting the PI3K/AKT signaling in CRC cells. Collectively, our findings reveal a novel mechanism by which DADS suppresses the growth of CRC by promoting POU2F1 ubiquitination, and may aid in design of novel therapeutic intervention of CRC.

Endoplasmic reticulum stress-a key guardian in cancer.

Endoplasmic reticulum stress (ERS) is a cellular stress response characterized by excessive contraction of the endoplasmic reticulum (ER). It is a pathological hallmark of many diseases, such as diabetes, obesity, and neurodegenerative diseases. In the unique growth characteristic and varied microenvironment of cancer, high levels of stress are necessary to maintain the rapid proliferation and metastasis of tumor cells. This process is closely related to ERS, which enhances the ability of tumor cells to adapt to unfavorable environments and promotes the malignant progression of cancer. In this paper, we review the roles and mechanisms of ERS in tumor cell proliferation, apoptosis, metastasis, angiogenesis, drug resistance, cellular metabolism, and immune response. We found that ERS can modulate tumor progression via the unfolded protein response (UPR) signaling of IRE1, PERK, and ATF6. Targeting the ERS may be a new strategy to attenuate the protective effects of ERS on cancer. This manuscript explores the potential of ERS-targeted therapies, detailing the mechanisms through which ERS influences cancer progression and highlighting experimental and clinical evidence supporting these strategies. Through this review, we aim to deepen our understanding of the role of ER stress in cancer development and provide new insights for cancer therapy.

The association of psychological stress with metabolic syndrome and its components: cross-sectional and bidirectional two-sample Mendelian randomization analyses.

Background: Metabolic syndrome (MetS) is a group of co-occurring conditions that increase the risk of cardiovascular disease, which include the conditions of hypertension, overweight or obesity, hyperglycemia, and dyslipidemia. Psychological stress is gradually being taken seriously, stemming from the imbalance between environmental demands and individual perceptions. However, the potential causal relationship between psychological stress and MetS remains unclear. Method: We conducted cross-sectional and bidirectional Mendelian randomization (MR) analyses to clarify the potential causal relationship of psychological stress with MetS and its components. Multivariable logistic regression models were used to adjust for potential confounders in the cross-sectional study of the Chinese population, including 4,933 individuals (70.1% men; mean age, 46.13 ± 8.25). Stratified analyses of sexual characteristics were also performed. Bidirectional MR analyses were further carried out to verify causality based on summary-level genome-wide association studies in the European population, using the main analysis of the inverse variance-weighted method. Results: We found that higher psychological stress levels were cross-sectionally associated with an increased risk of hypertension in men (odds ratio (OR), 1.341; 95% confidence interval (CI), 1.023-1.758; p = 0.034); moreover, higher levels of hypertension were cross-sectionally associated with an increased risk of psychological stress in men and the total population (men: OR, 1.545 (95% CI, 1.113-2.145); p = 0.009; total population: OR, 1.327 (95% CI, 1.025-1.718); p = 0.032). Genetically predicted hypertension was causally associated with a higher risk of psychological stress in the inverse-variance weighted MR model (OR, 2.386 (95% CI, 1.209-4.710); p = 0.012). However, there was no association between psychological stress and MetS or the other three risk factors (overweight or obesity, hyperglycemia, and dyslipidemia) in cross-sectional and MR analyses. Conclusion: Although we did not observe an association between psychological stress and MetS, we found associations between psychological stress and hypertension both in cross-sectional and MR studies, which may have implications for targeting hypertension-related factors in interventions to improve mental and metabolic health. Further study is needed to confirm our findings.

Characterization of AhLea-3 and its enhancement of salt tolerance in transgenic peanut plants

BACKGROUND: Late embryogenesis abundant (LEA) proteins were reported to be related to adversity stress and drought tolerance. Lea-3 from Arachis hypogaea L. (AhLea-3) was previously found to be related to salt tolerance according to the result of transcriptome profiling and digital gene expression analysis. So, AhLea-3 was cloned and the salt tolerance was validated by transgenic peanut plants. RESULTS: AhLea-3 was isolated from M34, a salt-resistant mutant of peanut, with its cDNA as the template. AhLea-3 contains one intron and two extrons, and the full-length cDNA sequence contains 303 bp. AhLea3 was ligated to pCAMBIA1301 to obtain the overexpression vector pCAMBIA1301-AhLea-3, which was then transferred into peanut variety Huayu23. The expression level of AhLea-3, as determined by qRTPCR analysis, was >10 times higher in transgenic than in non-transgenic plants. Five days after they were irrigated with 250 mM NaCl, the transgenic plants showed less severe leaf wilting, higher activities of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase), and lower malonic dialdehyde content than non-transgenic plants. Relative to non-transgenic plants, the transgenic plants had a higher photosynthetic net rate, stomatal conductance, and transpiration rate, and a lower intercellular CO2 concentration after salt stress treatment (250 mM NaCl). CONCLUSIONS: These results indicate that overexpression of AhLea-3 increased the salt tolerance of transgenic peanut plants. AhLea-3 might become a useful gene resource for the variety breeding of salinity tolerance in peanut.