miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Salicylic Acid Spray Delays Sand Pear Fruit Senescence during Room Temperature Shelf Life by Regulating Antioxidant Capacity and Senescence-Related Genes.

'Whangkeumbae' (Pyrus pyrifolia) is a variety of sand pear fruit well-known for its smooth surface and good taste. However, the fruit quality is adversely affected by postharvest ethylene production. Therefore, improving postharvest shelf life by regulating fruit senescence is critical to promoting the 'Whangkeumbae' fruit industry. Here, we investigated the effect of salicylic acid (SA) spray on fruit senescence in sand pears during room temperature shelf life. Exogenous SA reduced polyphenol oxidase (PPO) activity and malondialdehyde (MDA) content during room temperature shelf life. Additionally, SA effectively maintained the fruit skin coloration and increased the activity of antioxidant enzymes, such as superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX). SA treatment inhibited PpPPO1 expression and upregulated PpSOD1, PpAPX6, and PpGST2 expression. Furthermore, SA application downregulated the expression of PpACO2, PpEIN3a, PpNCED1, and PpAOC2, while upregulating PpNPR-1, PpTAR2, and PpCOMT1 during room temperature shelf life. SA treatment also influenced cell wall metabolism and modification genes by inhibiting PpPG1, PpPME2, and PpCEL3 and inducing PpPGIP1 expression. Additionally, SA treatment affected sugar and acid metabolism genes and increased the expression of PpSPS1, PpSUS1, PpSOT1, PpTMT4, PpSWEET15, and PpcyNAD-MDH, but suppressed the expression of PpcyNADP-ME. The Pearson correlation analysis indicated that PPO activity and MDA content were positively correlated with the expression of PpPPO1, PpACO2, PpEIN3a, PpNCED1, PpAOC2, PpPG1, PpPME2, PpCEL3, and PpcyNDA-MDH. Conversely, these factors were negatively associated with the activities of SOD, POD, CAT, and APX, as well as the expression levels of PpSOD1, PpPOD1, PpCAT1, PpAPX6, PpGST2, PpNPR-1, PpTAR2, PpCOMT1, PpPGIP1, PpSPS1, PpSUS1, PpSOT1, PpTMT4, PpSWEET15, and PpcyNAD-MDH. Our results reveal that exogenous SA could delay fruit senescence in sand pear fruit by regulating various biochemical and molecular mechanisms and can be used to effectively extend fruit shelf life during room temperature storage. However, further research is necessary to determine whether the fruits sprayed with SA are suitable for direct human consumption.

Correlation between preoperative systemic immune inflammation index, nutritional risk index, and prognosis of radical resection of liver cancer.

BACKGROUND: Radical surgery is the most commonly used treatment for hepatocellular carcinoma (HCC). However, the surgical effect remains not ideal, and prognostic evaluation is insufficient. Furthermore, clinical intervention is rife with uncertainty and not conducive to prolonging patient survival. AIM: To explore correlations between the systemic immune inflammatory index (SII) and geriatric nutritional risk index (GNRI) and HCC operation prognosis. METHODS: This retrospective study included and collected follow up data from 100 HCC. Kaplan-Meier survival curves were used to analyze the correlation between SII and GNRI scores and survival. SII and GNRI were calculated as follows: SII = neutrophil count × platelet count/lymphocyte count; GNRI = [1.489 × albumin (g/L) + 41.7 × actual weight/ideal weight]. We analyzed the predictive efficacy of the SII and GNRI in HCC patients using receiver operating characteristic (ROC) curves, and the relationships between the SII, GNRI, and survival rate using Kaplan-Meier survival curves. Cox regression analysis was utilized to analyze independent risk factors influencing prognosis. RESULTS: After 1 year of follow-up, 24 patients died and 76 survived. The area under the curve (AUC), sensitivity, specificity, and the optimal cutoff value of SII were 0.728 (95% confidence interval: 0.600-0.856), 79.2%, 63.2%, and 309.14, respectively. According to ROC curve analysis results for predicting postoperative death in HCC patients, the AUC of SII and GNRI combination was higher than that of SII or GNRI alone, and SII was higher than that of GNRI (P < 0.05). The proportion of advanced differentiated tumors, tumor maximum diameter (5-10 cm, > 10 cm), lymph node metastasis, and TNM stage III-IV in patients with SII > 309.14 was higher than that in patients with SII ≤ 309.14 (P < 0.05). The proportion of patients aged > 70 years was higher in patients with GNRI ≤ 98 than that in patients with GNRI > 98 (P < 0.05). The 1-year survival rate of the SII > 309.14 group (compared with the SII ≤ 309.14 group) and GNRI ≤ 98 group (compared with the GNRI > 98 group) was lower (P < 0.05). CONCLUSION: The prognosis after radical resection of HCC is related to the SII and GNRI and poor in high SII or low GNRI patients.

miR-30c-2-3p suppresses the proliferation of human renal cell carcinoma cells by targeting TOP2A.

Background: The ambiguity of renal cell carcinoma (RCC) symptoms hinders early diagnosis, thereby contributing to high mortality rates. By attaching to the 3'-untranslated region (UTR) of the target gene, microRNAs (miRNAs) exert significant control over the expression of genes. Objectives: To investigate the influence of miR-30c-2-3p and DNA topoisomerase II alpha (TOP2A) on RCC growth and the mechanisms underlying the regulation of its expression. Methods: The expression of miRNA-30c-2-3p and TOP2A in RCC cells was examined using quantitative real-time polymerase chain reaction (qRT-PCR). MiR-30c-2-3p mimics, its inhibitors, and controls, as well as TOP2A short hairpin RNA (shRNA) and controls, were used to transfect the human RCC cell lines 786-O, Caki-1, and ACHN. Additionally, the roles of miRNA-30c-2-3p and TOP2A in the growth of RCC were evaluated using the cell counting kit (CCK)-8 test, colony formation assay, apoptosis analysis, and Western blotting. Meanwhile, binding of miRNA-30c-2-3p and TOP2A was verified using dual-luciferase reporter assays and Western blotting. Results: miR-30c-2-p is underexpressed in RCC cells. Overexpression of miR-30c-2-p promotes apoptosis and inhibits proliferation of ACHN, Caki-1, and 786-O cells. miR-30c-2-3p targets TOP2A, which is elevated in RCC tissues and cells, whereas TOP2A silencing inhibits the proliferation ability of RCC cells. The miRNA-30c-2-3p inhibitor compromises TOP2A shRNA-induced apoptosis of RCC. RCC cells cotransfected with miRNA-30c-2-3p inhibitors and TOP2A shRNAs have a higher proliferation rate than those transfected with only TOP2A shRNAs. Conclusions: Collectively, our results verify that miRNA-30c-2-3p has a tumor suppressor property. miRNA-30c-2-3p inhibits the proliferation of RCC through regulation of TOP2A. The data provide a viable therapeutic target for RCC.

ADAMDEC1 induces EMT and promotes colorectal cancer cells metastasis by enhancing Wnt/ß-catenin signaling via negative modulation of GSK-3ß.

Colorectal cancer (CRC) is a highly invasive malignant tumor with pronounced proliferation capacity and is prone to epithelial-mesenchymal transition (EMT) and subsequent metastasis. A disintegrin and metalloproteinase domain-like decysin 1 (ADAMDEC1) is a proteolytically active metzincin metalloprotease that is involved in extracellular matrix remodeling, cell adhesion, invasion, and migration. However, the effects of ADAMDEC1 on CRC are unclear. This study was conducted to investigate the expression and biological role of ADAMDEC1 in CRC. We found that ADAMDEC1 was differentially expressed in CRC. Further, ADAMDEC1 was found to enhance CRC proliferation, migration, and invasion while inhibiting apoptosis. Exogenous ADAMDEC1 overexpression elicited EMT in CRC cells, as evidenced by alterations in E-cadherin, N-cadherin, and vimentin expression. In ADAMDEC1 knockdown or ADAMDEC1 overexpressed CRC cells, the western blotting analysis revealed that Wnt/ß-catenin signaling pathway-related proteins were down-regulated or up-regulated. Furthermore, an inhibitor of the Wnt/ß-catenin pathway (FH535) partially negated the effect of ADAMDEC1 overexpression on EMT and CRC cell proliferation. Further mechanistic research suggested that ADAMDEC1 knockdown may upregulate GSK-3ß and inactivate the Wnt/ß-catenin pathway, accompanied by suppressing the expression of ß-catenin. Additionally, the blocker of GSK-3ß (CHIR-99021) markedly abolished the inhibitory effect of ADAMDEC1 knockdown on Wnt/ß-catenin signaling. Our results indicate that ADAMDEC1 promotes CRC metastasis by negatively regulating GSK-3ß, activating the Wnt/ß-catenin signaling pathway, and inducing EMT, presenting its potential as a therapeutic target for the treatment of metastatic CRC.

Inhibition of STAT3 signaling as critical molecular event in HUC-MSCs suppressed Glioblastoma Cells.

Objective: We investigated the effect of human umbilical cord mesenchymal stem cells (HUC-MSCs) supernatants on proliferation, migration, invasion, and apoptosis in glioblastoma (GBM) cell lines RG-2, U251, U87-MG, and LN-428, as well as their apoptosis and autophagy-mediated through IL-6/JAK2/STAT3 signaling pathway to explore the molecular mechanisms. Methods: In this study, RG-2, U251, U87-MG, and LN-428 cells were treated with 9 mg/ml HUC-MSCs supernatants. Their responses to HUC-MSCs supernatants treatment and the status of STAT3 signaling were analyzed by multiple experimental approaches to elucidate the importance of HUC-MSCs supernatants for GBM. Results: The results demonstrated that after treatment with HUC-MSCs supernatants, in vitro proliferation of RG-2, U251, U87-MG, and LN-428 cells were inhibited, and their sustained growth was also blocked. RG-2, U251, and U87-MG cells showed significant S phase accumulation, while LN-428 cells were blocked in G0/G1 phase. Their migratory invasive capacities were inhibited, and their apoptosis and autophagy ratios were increased. These effects were mediated through the IL-6/JAK2/STAT3 and its downstream signaling pathway. Conclusion: Our data showed that HUC-MSCs supernatants had anti-tumor effects on GBM cells. It inhibited the proliferation, migration, and invasion of GBM cells and promoted their apoptosis. Negative regulation of the IL-6/JAK2/STAT3 signaling pathway enhanced apoptosis and autophagy in tumor cells, thereby improving the therapeutic effect on GBM.

Factors associated with lack of tracheal sealing by a cuff inflated to more than 30 cmH2O during mechanical ventilation: A cross-sectional study.

Objectives: The cuff pressures > 30 cmH2O may create a seal in the trachea. The objective of this study was to identify risk factors associated with lack of tracheal sealing by an endotracheal cuff inflated to > 30 cmH2O in patients undergoing mechanical ventilation. Methods: This prospective cross-sectional study was conducted from 2019 to 2020 in the cardiothoracic intensive care unit and respiratory medical care unit of a Hospital in Nantong, China. Patients aged >16 years undergoing cardiothoracic surgery with mechanical ventilation using endotracheal intubation were included. Patient characteristics and ventilator parameters were analyzed. Cuff pressure was maintained with the minimum leak technique (MLT) and measured with a cuff pressure gauge. Cuff pressure was measured for 30 seconds when ventilation was accompanied by no leak, simultaneously detected by the ventilator or auscultation with a stethoscope. Result: Of 352 patients undergoing mechanical ventilation, 51 patients (14.5%) had a cuff pressure of >30 cmH2O. Multivariable analysis showed that cuff manufacturer (Guangzhou Weili) and nasal endotracheal intubation significantly increased the risk of an unsealed trachea. Peak inspiratory pressure, cuff diameter and male sex had a strong inverse association with an unsealed trachea. Conclusions: These findings suggest that an endotracheal cuff pressure of 20 to 30 cmH2O is adequate for most patients, but lack of a tracheal seal still occurs in a small number of people. An unsealed trachea is most likely because cuff and tracheal diameters do not match. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx Unique identifier: ChiCTR-COC-15006459.

RPL11 promotes non-small cell lung cancer cell proliferation by regulating endoplasmic reticulum stress and cell autophagy.

BACKGROUND: Abnormal biogenesis and ribosome free function of ribosomal proteins (RPs) is important for tumorgenesis and development. Ribosomal protein L11 (RPL11) is a component of ribosomal 60 S large subunit with different roles in different cancers. Here, we aimed to unravel the role of RPL11 in non-small cell lung cancer (NSCLC), especially those affecting cell proliferation. METHODS: RPL11 expression in NCI-H1650, NCI-H1299, A549 and HCC827 and normal lung bronchial epithelial cells HBE was detected using western blotting. The function of RPL11 in NSCLC cells were determined by investigating cell viablity, colony formation and cell migration. Mechanism expoloration of RPL11 effect on NSCLC cells proliferation was explored using flow cytometry, and the effect on autophagy was investigated by the additon of autophagy inhibitor chloroquine (CQ) and endoplasmic reticulum stress (ERS) inhibitor tauroursodeoxycholic acid (TUDCA). RESULTS: RPL11 was highly expressed in NSCLC cells. Extopic expression of RPL11 promoted NCI-H1299 and A549 cells proliferation, and migration, and promoted the transition from the G1 phase to the S phase of the cell cycle. Small RNA interference of RPL11 (siRNA) suppressed NCI-H1299 and A549 cells proliferation and migration and arrested the cell cycle in G0/G1 phase. Moreover, RPL11 promoted NSCLC cell proliferation by modulating autophagy and ERS. Expression levels of autophagy and ERS markers were induced by RPL11 overexpression and inhibited by siRPL11. CQ partially suppressed RPL11-induced A549 and NCI-H1299 proliferation: CQ addition reduced RPL11-induced cells viability and clone numbers and reversed the cell cycle process. ERS inhibitor (TUDCA) partially reversed RPL11-induced autophagy. CONCLUSION: Taken together, RPL11 has a tumor-promoting role in NSCLC. It promotes the cell proliferation of NSCLC cells by regulating ERS and autophagy.

Bow Hunter's syndrome combined with ipsilateral vertebral artery dissection/pseudoaneurysm: case study and literature review.

BACKGROUND: Bow hunter's syndrome (BHS), also known as rotational vertebral artery occlusion syndrome, is rare. Occasionally, it combines with dissection/pseudoaneurysm of the ipsilateral VA. METHODS: We report a case of BHS combined with ipsilateral VA dissection/pseudoaneurysm and review eight similar cases reported in the literature. Their aetiology, clinical and imaging features, treatment, and prognosis were analysed. RESULTS: Nine patients (seven male, two female; average age 22.0 ± 4.5 years) were enrolled. Visual symptoms comprised the most common clinical finding (66.7%, 7/9). Clinical symptoms were not related to neck rotation in seven patients (77.8%). Eight patients (88.9%) had multiple, scattered, new and old infarctions of the posterior circulation revealed on computed tomography/magnetic resonance imaging (CT/MRI) scans. Dissection/pseudoaneurysm was found in the ipsilateral VA - usually subtle and localised in the atlas, axis, and occipital bone - in all nine patients. Seven patients (66.7%) had special causes for the syndrome (i.e. congenital bone dysplasia). Altogether, 87.5% (7/8) experienced recurrence with cerebral infarction after antithrombotic therapy alone. Aetiologically targeted treatment, including surgical decompression or vertebral fixation, was performed in seven patients (77.8%). CONCLUSION: Young patients presenting with cryptogenic stroke in the posterior circulation and localised, subtle dissection/pseudoaneurysm of the ipsilateral VA around the atlanto-axial joint should undergo carotid ultrasonography with a neck rotation test or dynamic CT angiography/MR angiography/digital subtraction angiography, if necessary, to rule out/diagnose BHS.

Development and validation of a model for predicting the risk of suicide in patients with cancer.

OBJECTIVE: The objective of this study was to establish a nomogram model to predict SI in patients with cancer and further evaluate its performance. METHOD: This study was performed among 390 patients in oncology departments of Affiliated Hospital of Nantong University from April 2020 to January 2021. Of these, eligible patients who were diagnosed with cancer were split into training and validation cohorts according the ratio of 2:1 randomly. In the training cohort, multivariate regression was performed to determine the independent variables related to SI. A nomogram was built incorporating these variables. The model performance was evaluated by an independent validation cohort. RESULTS: The prevalence of SI in patients with cancer was 22.31% and 19.23% in training and validation cohorts, respectively. The nomogram model suggested independent variables for SI, including depression, emotional function, time after diagnosis, family function and educational status. The area under the curve (AUC) was 0.93 (95%CI, 0.90-0.97) and 0.82 (95%CI, 0.74-0.90) in training and validation cohorts respectively, which indicated good discrimination of the nomogram in predicting SI in cancer patients. The p-value of the goodness of fit (GOF) test was 0.197 and 0.974 in training and validation cohorts respectively, suggesting our nomogram model has acceptable calibration power, and the calibration curves further indicated good calibration power. CONCLUSION: In conclusion, the nomogram model for predicting individualized probability of SI could help clinical caregivers estimate the risk of SI in patients with cancer and provide appropriate management.

Bioinformatics analysis of prognostic value and immunological role of MeCP2 in pan-cancer.

Methyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and colorectal cancer. So far, no pan-cancer analysis has been reported. Therefore, this study aims to explore pan-cancer's prognostic value, immune infiltration pattern, and biological function. We used bioinformatics methods to analyze the expression and prognostic significance of MeCP2, and the relationship between MeCP2 and clinicopathological parameters, genetic variation, methylation, phosphorylation, immune cell infiltration, and biological function in pan-cancer from using a public database. The results showed that expression of MeCP2 was up-regulated in 8 cancers and down-regulated in 2 cancers, which was remarkably correlated with the prognosis, pathological stage, grade and subtype of cancers. The promoter methylation level of MeCP2 DNA was decreased in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), liver hepatocellular carcinoma (LIHC), prostate adenocarcinoma (PRAD), uterine corpus endometrial carcinoma (UCEC), testicular germ cell tumors (TGCT), and stomach adenocarcinoma (STAD);decreased phosphorylation of S25, S90, S92, S241, S286, S325 and S435 was found in MeCP2, such as UCEC, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), colon adenocarcinoma (COAD), and kidney renal clear cell carcinoma (KIRC). Furthermore, MeCP2 expression was significantly associated with multiple immunomodulators and immune cell infiltration levels across most tumors. Therefore, our pan-cancer explored the prognostic markers and immunotherapeutic value of MeCP2 in different cancers.

Ribosomal protein RPL5 regulates colon cancer cell proliferation and migration through MAPK/ERK signaling pathway.

BACKGROUND: Abnormal expression of ribosomal proteins has an important regulatory effect on the progression of cancer. RPL5 is involved in the progression of various malignancies, however, the role of RPL5 in colon cancer remains is still unclear. METHODS: Data from TCGA and GTEx databases were used to analyze the RPL5 expression in pan-cancer. The expression level of RPL5 in clinical colon cancer tissue samples and human colon cancer cell lines was detected by western blotting; siRNA targeting RPL5 was designed, and its interference efficiency was verified by western blotting and RT-qPCR; CCK8 assay, clone formation assay, cell cycle assay, and cell scratch assay were used to observe the effect of RPL5 on colon cancer cell proliferation and migration; the changes of proteins related to MAPK/ERK signaling pathway were also detected using western blotting. RESULTS: The expression level of RPL5 in colon cancer tissues and cell lines was significantly higher than that in adjacent tissues and NCM460 cells, respectively, and its expression level was higher in HCT116 cells and RKO cells. Knockdown of RPL5 significantly inhibited the proliferation and migration of HCT16 and RKO cells, and arrested the cell cycle in G0/G1 phase. Mechanistic studies revealed that the expression of p-MEK1/2, p-ERK, c-Myc were down-regulated, and the expression of FOXO3 was up-regulated after down-regulation of RPL5, ERK activator (TBHQ) could partially reverse the above-mentioned effects caused by siRPL5. Moreover, TBHQ could partially reverse the inhibitory effect of siRPL5 on the proliferation and migration of colon cancer cells. Collectively, RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway. CONCLUSION: RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

Distinct clinicopathological features of ovarian endometriosis after long-term exposure to mifepristone.

OBJECTIVE: Mifepristone has been used to treat endometriosis, but it can cause a constellation of endometrial alterations. Our study investigated the effects of long-term mifepristone on ovarian endometriosis. METHODS: We retrospectively analyzed the clinicopathological changes of ovarian endometriosis in 11 Chinese patients after long-term low-dose mifepristone therapy and compared these alterations with those observed in eutopic endometrium and adenomyosis side-by-side. Immunohistochemistry was applied to investigate estrogen receptor (ER), progesterone receptor (PR), and Ki67 expression in eutopic and ectopic endometrium. RESULTS: Nearly all patients had a pelvic mass and elevated serum CA125 levels. The ovarian lesions were grossly solid, cystic-solid, or cystic. They had a grayish-reddish appearance and a fleshy, honeycomb-like cut surface. The ovarian lesions shared morphological features with the uterine endometrium, and they were characterized by dilated, crowding endometrial glands with non-physiological changes. Immunostaining revealed consistent staining for ER and PR and a low Ki67 index in both eutopic and ectopic endometrium. CONCLUSIONS: Our findings suggest that ovarian endometriosis can mimic an endometrioid borderline tumor after long-term mifepristone administration. Careful histological assessment and related clinical information are critical for the correct interpretation of these rare entities.

Pilot study of peripheral blood chemokines as biomarkers for atrial fibrillation-related thromboembolism and bleeding in elderly patients.

Background: The scoring systems currently used to identify the potential for thrombosis and bleeding events in high-risk atrial fibrillation patients have certain limitations. The aim of this pilot study was to identify inflammatory chemokines with potential utility as sensitive biomarkers for the risk of thrombosis and bleeding in elderly patients with non-valvular atrial fibrillation. Methods: From January 1, 2014, to December 31, 2017, 200 consecutive elderly patients with atrial fibrillation (average age: 87.6 ± 7.7 years) were enrolled and followed up for 2 years to observe thromboembolic (arterial and venous) and bleeding events. Serum was collected upon enrollment, and the baseline levels of 27 chemokines were analyzed. During the 2-year follow-up, 12 patients were lost to follow-up. Among the 188 patients, there were 32 cases (17.0%) of AF-related thrombosis, 36 cases (19.1%) of arterial thrombosis, and 35 cases (18.6%) of major bleeding events. Results: Among 188 patients, 30 patients without clinical events (control group), 23 with arterial thrombosis, 15 with atrial fibrillation-related venous thromboembolism, and 12 with major bleeding were selected and randomly matched to compare chemokine levels. The baseline levels of interleukin-6, interleukin-10, vascular cell adhesion molecule-1, chemokine C-C-motif ligand, B-lymphocyte chemoattractant 1, interleukin-4, E-selectin, fractalkine, C-X-C motif chemokine 12, and granulocyte chemotactic protein 2 were found to differ statistically among the four groups (p < 0.05). Compared with that in the control group, the level of interleukin-4 in patients with atrial fibrillation-related thrombosis, arterial thrombosis, or major bleeding increased by 53-fold (0.53 vs. 0.01 pg/ml), 17-fold (0.17 vs. 0.01 pg/ml), and 19-fold (0.19 vs. 0.01 pg/ml), respectively. Compared with that in the control group, the level of interleukin-6 in patients with arterial thrombosis increased by six-fold (39.78 vs. 4.98 pg/ml). Conclusions: Among elderly patients with atrial fibrillation at high risk of thromboembolism and bleeding, the baseline levels of interleukin-6, interleukin-4, and E-selectin were significantly increased in those that experienced thrombosis and bleeding events during the 2-year follow-up, indicating that these chemokines may serve as potential biomarkers for an increased risk of thrombosis and bleeding in this population. Clinical trial registration number: ChiCTR-OCH-13003479.

Mixture toxicity of cadmium and acetamiprid to the early life stages of zebrafish (Danio rerio).

Aquatic organisms are often exposed to contaminants that occur in the natural environment. Nevertheless, the toxic effects of chemical combinations on aquatic animals and their underlying toxic mechanisms for dealing with such exposures are still not fully understood. In this study, we investigated the combined effects of cadmium (Cd) and acetamiprid (ACE) on zebrafish (Danio rerio) using various endpoints. Cd exhibited a 96-h LC50 value of 4.77 mg a.i. L-1 against zebrafish embryos, which was lower than that of ACE (152.6 mg a.i. L-1). In contrast, the 96-h LC50 value of the mixture of Cd and ACE was 157.4 mg a.i. L-1. The mixture of Cd and ACE had a synergetic effect on the organisms. The activities of T-SOD, POD, and CarE were significantly changed in most exposures compared with the control group. In addition, five genes (TRα, crh, Tnf, IL, and P53) involved in oxidative stress, cellular apoptosis, the immune system, and the endocrine system exhibited more remarkable changes when exposed to chemical mixtures relative to their individual counterparts, demonstrating variations in the cellular and mRNA expression levels induced by the mixture exposure of ACE and Cd during the embryonic development of zebrafish. Therefore, these results indicated that the combined pollution of ACE and Cd could be a potentially hazardous factor, and further investigation is necessary for the safety evaluation and application of ACE. Moreover, further investigation on the combined toxicities of various chemicals must be performed to determine the chemical mixtures with synergistic responses.

Cytology, High-Risk Human Papillomavirus Testing and Serum CA19-9 in a Large Cohort of Patients with Invasive Cervical Adenocarcinomas: Correlation with a New Pathogenetic Classification.

AIMS: This study aims to investigate the screening value of cytology, high-risk human papillomavirus (hrHPV) testing and serum CA19-9 in cervical adenocarcinomas. MATERIALS AND METHODS: We employed HPV RNA in situ hybridization and immunohistochemistry to reclassify 209 cervical adenocarcinomas according to the International Endocervical Adenocarcinoma Criteria and Classification (IECC). We analyzed the diagnostic value of cytology, hrHPV testing and serum CA19-9 in these tumors and their detection variance among IECC histotypes. RESULTS: We found that the sensitivity of cytology or hrHPV test alone was 74.1% (129/174) or 72% (131/182), respectively. Non-HPV related adenocarcinoma showed a lower detection rate of cytology (60%, 27/45 vs. 79.1%, 102/129, p=0.017) or hrHPV testing (9.8%, 4/41 vs. 90.1%, 127/141, p<0.0001), compared to HPV-related adenocarcinomas. The cytology and hrHPV co-testing significantly demonstrated a higher sensitivity (151/165, 91.5%) than single test alone (p<0.001). Nevertheless, the sensitivity of co-testing was substantially lower for gastric-type adenocarcinoma (GAC) (74.1%, 20/27) than that for non-GAC (94.9%, 131/138) (p=0.001). Serum CA19-9 (>40 U/mL) identified 44.1% (15/34) GACs including 75% (6/8) that were missed by co-testing, much higher than for non-GACs (10.7%, 19/177; p<0.001). The combination of cytology, hrHPV test and serum CA19-9 enhanced the detection rate of GACs (92.9%, 26/28). CONCLUSION: We conclude that cytology and hrHPV co-testing is not very effective for non-HPV related adenocarcinoma, particularly for GAC. As such, additional serum CA19-9 should be given in women with potential cancer risks.

Independent validation of distinct clinicopathological features and prognosis among usual-type, mucinous-type and gastric-type endocervical adenocarcinoma categorised by new WHO classification (2020).

The new World Health Organization (WHO) classification of tumours of the female genital tract (2020) divides endocervical adenocarcinoma (EAC) into human papilloma virus (HPV)-related adenocarcinoma (HPVA) and HPV-independent adenocarcinoma (HPVI) to underscore the morphological and pathogenetic correlation. It may be potentially prognostic. In this study, we appraised the new WHO classification in an independent, single institution-based EAC cohort from China to assess the clinicopathological features and prognostic value among tumour types. Our study cohort contained 402 consecutive, surgically excised EACs consisting of 298 (74.1%) HPVA, 88 (21.9%) HPVI and 16 (4%) adenocarcinomas not otherwise specified (NOS). Usual-type (55.7%) and gastric-type adenocarcinoma (GAC) (18.2%) was the most common type in HPVA and HPVI, respectively. Block p16 staining (94.7% vs 24.4%) and HPV mRNA signal (89.4% vs 0) were more common in HPVA than in HPVI (p<0.001). HPVI or GAC were more frequently associated with prognostically adverse variables including old age, large tumour size, deep invasion of the cervical wall, high tumour stage, spread of the upper genital tract, lymphovascular invasion, and mutant-type p53 expression, compared to HPVA or mucinous/usual-type HPVA, respectively (all p<0.001). In univariate survival analysis, HPVI had a worse overall survival and higher tumour recurrence compared to HPVA (p<0.05). Mucinous-type HPVA showed a worse prognosis than usual-type HPVA, but better than GAC (p<0.001). Multivariate survival analysis demonstrated that HPVI was independently associated with a worse overall survival and tumour recurrence (p<0.05) while GAC was an adverse prognostic factor independently of FIGO stage (p<0.05). Our findings validate the value of the new WHO classification in prognostic stratification and pathogenetic correlation in EAC and its subtypes.

Role of MRI in characterizing serous borderline ovarian tumor and its subtypes: Correlation of MRI features with clinicopathological characteristics.

PURPOSE: This study aimed to investigate the diagnostic value of MRI in serous borderline ovarian tumor (SBOT), and to determine the MRI features of SBOT and their correlations with clinicopathological characteristics. MATERIALS AND METHODS: A total of 121 patients suspected of SBOT by preoperative MRI and then underwent surgery at our hospital were retrospectively reviewed. The accuracy of MRI in diagnosing SBOT was assessed. MRI features of the SBOT subtypes were compared and their correlations with clinicopathological characteristics were evaluated. RESULTS: SBOT was confirmed by postoperative pathology in 95 patients, including 77 patients with conventional SBOT (SBOT-C) and 18 patients with micropapillary SBOT (SBOT-MP). The accuracy of MRI in diagnosing SBOT was 87.6%. Three MRI morphological patterns of SBOT were identified: (i) mainly solid, (ii) mainly cystic, and (iii) mixed. Branching papillary architecture and internal branching (PA&IB) structures corresponding to multiple branching papillary projections and internal fibrous stalks in tumors were observed in 69.7% of SBOTs on T2-weighted images. MRI findings were consistent with postoperative pathology. Compared with SBOT-C, patients with SBOT-MP were more likely to display elevated cancer antigen 125, bilateral tumors, peritoneal implantation, lymph node metastasis, and advanced tumor staging. No significant differences were observed in MRI features between SBOT-C and SBOT-MP groups. CONCLUSION: MRI has good performance in diagnosing SBOT. MRI findings of SBOT are consistent with clinicopathological characteristics. The PA&IB structure is the characteristic MRI finding of SBOT. Compared to SBOT-C, SBOT-MP tends to display more aggressive clinical behavior, but their MRI features are similar.

Grading of endocervical adenocarcinoma: a novel prognostic system based on tumor budding and cell cluster size.

A novel 3-tiered grading system based on tumor budding activity and cell nest size has been validated to be highly prognostic in organ-wide squamous cell carcinomas. In this study, we applied a similar grading system with slight modification to assess the prognostic value in an institutional cohort of well annotated endocervical adenocarcinomas (EAC) consisting of 398 consecutive cases with surgical resection, no neoadjuvant chemotherapy, and higher than stage pT1a. Each case was reviewed by the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and Silva pattern classification, and scored on tumor budding activity and cell cluster size to form the basis of a novel grading system. High budding activity, small tumor cell cluster size, and novel grade 3 were more frequently associated with a decreased overall survival time and tumor recurrence time (p < 0.001), and several other clinicopathologic factors including HPV-independent adenocarcinoma, lymphovascular invasion, lymph node metastasis, advanced FIGO stage, and Silva pattern C (p < 0.05). Moreover, the novel grading system was helpful in stratifying overall survival in HPV-associated adenocarcinoma (p = 0.036) and gastric-type adenocarcinoma (p = 0.033). On multivariate analysis, novel grade 3 was an adverse indicator for overall survival and tumor recurrence independently of age and FIGO stage (p < 0.05). By comparison, Silva pattern C was only associated with tumor relapse (p = 0.020) in HPV-associated adenocarcinomas whereas the conventional FIGO system was not associated with overall survival and tumor recurrence in EAC (p > 0.05). In conclusion, our study demonstrates that the grading system based on tumor budding activity and cell cluster size is robust in prognostic assessment that outperforms the conventional FIGO grading and Silva pattern classification in EAC. The novel grading system, if further validated, could be applicable in routine pathologic descriptions of EAC by providing useful information in clinical decision-making.