Overexpression of long noncoding RNA DUXAP8 inhibits ER-phagy through activating AKT/mTOR signaling and contributes to preeclampsia.

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.

[Aqueous extract of Epimedium sagittatum mitigates pulmonary fibrosis in mice].

This study aims to investigate the intervention effect of the aqueous extract of Epimedium sagittatum Maxim on the mouse model of bleomycin(BLM)-induced pulmonary fibrosis, so as to provide data support for the clinical treatment of pulmonary fibrosis. Ninety male C57BL/6N mice were randomized into normal(n=10), model(BLM, n=20), pirfenidone(PFD, 270 mg·kg~(-1), n=15), and low-, medium-, and high-dose E. sagittatum extract(1.67 g·kg~(-1), n=15; 3.33 g·kg~(-1), n=15; 6.67 g·kg~(-1), n=15) groups. The model of pulmonary fibrosis was established by intratracheal instillation of BLM(5 mg·kg~(-1)) in the other five groups except the normal group, which was treated with an equal amount of normal saline. On the day following the modeling, each group was treated with the corresponding drug by gavage for 21 days. During this period, the survival rate of the mice was counted. After gavage, the lung index was calculated, and the morphology and collagen deposition of the lung tissue were observed by hematoxylin-eosin(HE) and Masson staining, respectively. The levels of reactive oxygen species(ROS) in lung cell suspensions were measured by flow cytometry. The levels of glutathione peroxidase(GSH-Px), total superoxide dismutase(T-SOD), and malondialdehyde(MDA) the in lung tissue were measured. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling(TUNEL) was employed to examine the apoptosis of lung tissue cells. The content of interleukin-6(IL-6), chemokine C-C motif ligand 2(CCL-2), matrix metalloproteinase-8(MMP-8), transforming growth factor-beta 1(TGF-ß1), alpha-smooth muscle actin(α-SMA), E-cadherin, collagen Ⅰ, and fibronectin in the lung tissue was measured by enzyme-linked immunosorbent assay(ELISA). The expression levels of F4/80, Ly-6G, TGF-ß1, and collagen Ⅰ in the lung tissue were determined by immunohistochemistry. The mRNA levels of CCL-2, IL-6, and MMP-7 in the lung tissue were determined by qRT-PCR. The content of hydroxyproline(HYP) in the lung tissue was determined by alkaline hydrolysation. The expression of α-SMA and E-cadherin was detected by immunofluorescence, and the protein levels of α-SMA, vimentin, E-cadherin in the lung tissue were determined by Western blot. The results showed the aqueous extract of E. sagittatum increased the survival rate, decreased the lung index, alleviated the pathological injury, collagen deposition, and oxidative stress in the lung tissue, and reduced the apoptotic cells. Furthermore, the aqueous extract of E. sagittatum down-regulated the protein levels of F4/80 and Ly-6G and the mRNA levels of CCL-2, IL-6, and MMP-7 in the lung tissue, reduced the content of IL-6, CCL-2, and MMP-8 in the alveolar lavage fluid. In addition, it lowered the levels of HYP, TGF-ß1, α-SMA, collagen Ⅰ, fibronectin, and vimentin, and elevated the levels of E-cadherin in the lung tissue. The aqueous extract of E. sagittatum can inhibit collagen deposition, alleviate oxidative stress, and reduce inflammatory response by regulating the expression of the molecules associated with epithelial-mesenchymal transition, thus alleviating the symptoms of bleomycin-induced pulmonary fibrosis in mice.

Added value of CE-CT radiomics to predict high Ki-67 expression in hepatocellular carcinoma.

BACKGROUND: This study aimed to develop a computed tomography (CT) model to predict Ki-67 expression in hepatocellular carcinoma (HCC) and to examine the added value of radiomics to clinico-radiological features. METHODS: A total of 208 patients (training set, n = 120; internal test set, n = 51; external validation set, n = 37) with pathologically confirmed HCC who underwent contrast-enhanced CT (CE-CT) within 1 month before surgery were retrospectively included from January 2014 to September 2021. Radiomics features were extracted and selected from three phases of CE-CT images, least absolute shrinkage and selection operator regression (LASSO) was used to select features, and the rad-score was calculated. CE-CT imaging and clinical features were selected using univariate and multivariate analyses, respectively. Three prediction models, including clinic-radiologic (CR) model, rad-score (R) model, and clinic-radiologic-radiomic (CRR) model, were developed and validated using logistic regression analysis. The performance of different models for predicting Ki-67 expression was evaluated using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis (DCA). RESULTS: HCCs with high Ki-67 expression were more likely to have high serum α-fetoprotein levels (P = 0.041, odds ratio [OR] 2.54, 95% confidence interval [CI]: 1.04-6.21), non-rim arterial phase hyperenhancement (P = 0.001, OR 15.13, 95% CI 2.87-79.76), portal vein tumor thrombus (P = 0.035, OR 3.19, 95% CI: 1.08-9.37), and two-trait predictor of venous invasion (P = 0.026, OR 14.04, 95% CI: 1.39-144.32). The CR model achieved relatively good and stable performance compared with the R model (AUC, 0.805 [95% CI: 0.683-0.926] vs. 0.678 [95% CI: 0.536-0.839], P = 0.211; and 0.805 [95% CI: 0.657-0.953] vs. 0.667 [95% CI: 0.495-0.839], P = 0.135) in the internal and external validation sets. After combining the CR model with the R model, the AUC of the CRR model increased to 0.903 (95% CI: 0.849-0.956) in the training set, which was significantly higher than that of the CR model (P = 0.0148). However, no significant differences were found between the CRR and CR models in the internal and external validation sets (P = 0.264 and P = 0.084, respectively). CONCLUSIONS: Preoperative models based on clinical and CE-CT imaging features can be used to predict HCC with high Ki-67 expression accurately. However, radiomics cannot provide added value.

Radiomics nomogram for the prediction of microvascular invasion of HCC and patients' benefit from postoperative adjuvant TACE: a multi-center study.

OBJECTIVES: To evaluate the performance of a radiomics nomogram developed based on gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) MRI for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC), and to identify patients who may benefit from the postoperative adjuvant transarterial chemoembolization (PA-TACE). METHODS: A total of 260 eligible patients were retrospectively enrolled from three hospitals (140, 65, and 55 in training, standardized external, and non-standardized external validation cohort). Radiomics features and image characteristics were extracted from Gd-EOB-DTPA MRI image before hepatectomy for each lesion. In the training cohort, a radiomics nomogram which incorporated the radiomics signature and radiological predictors was developed. The performance of the radiomics nomogram was assessed with respect to discrimination calibration, and clinical usefulness with external validation. A score (m-score) was constructed to stratify the patients and explored whether it could accurately predict patient who benefit from PA-TACE. RESULTS: A radiomics nomogram integrated with the radiomics signature, max-D(iameter) > 5.1 cm, peritumoral low intensity (PTLI), incomplete capsule, and irregular morphology had favorable discrimination in the training cohort (AUC = 0.982), the standardized external validation cohort (AUC = 0.969), and the non-standardized external validation cohort (AUC = 0.981). Decision curve analysis confirmed the clinical usefulness of the novel radiomics nomogram. The log-rank test revealed that PA-TACE significantly decreased the early recurrence in the high-risk group (p = 0.006) with no significant effect in the low-risk group (p = 0.270). CONCLUSIONS: The novel radiomics nomogram combining the radiomics signature and clinical radiological features achieved preoperative non-invasive MVI risk prediction and patient benefit assessment after PA-TACE, which may help clinicians implement more appropriate interventions. CLINICAL RELEVANCE STATEMENT: Our radiomics nomogram could represent a novel biomarker to identify patients who may benefit from the postoperative adjuvant transarterial chemoembolization, which may help clinicians to implement more appropriate interventions and perform individualized precision therapies. KEY POINTS: • The novel radiomics nomogram developed based on Gd-EOB-DTPA MRI achieved preoperative non-invasive MVI risk prediction. • An m-score based on the radiomics nomogram could stratify HCC patients and further identify individuals who may benefit from the PA-TACE. • The radiomics nomogram could help clinicians to implement more appropriate interventions and perform individualized precision therapies.

[Protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism]. / ç¯ç›èŠ±ç´ å¯¹å®«å† ç‚Žç—‡è‡´æ—©äº§å¤§é¼ è„‘æŸä¼¤çš„ä¿æŠ¤ä½œç”¨åŠå ¶æœºåˆ¶æŽ¢è®¨.

OBJECTIVES: To study the protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism. METHODS: A preterm rat model of brain injury caused by intrauterine inflammation was prepared by intraperitoneal injections of lipopolysaccharide in pregnant rats. The pregnant rats and preterm rats were respectively randomly divided into 5 groups: control, model, low-dose breviscapine (45 mg/kg), high-dose breviscapine (90 mg/kg), and high-dose breviscapine (90 mg/kg)+ML385 [a nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, 30 mg/kg] (n=10 each). The number and body weight of the live offspring rats were measured for each group. Hematoxylin-eosin staining was used to observe the pathological morphology of the uterus and placenta of pregnant rats and the pathological morphology of the brain tissue of offspring rats. Immunofluorescent staining was used to measure the co-expression of ionized calcium binding adaptor molecule-1 (IBA-1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in the cerebral cortex of offspring rats. ELISA was used to measure the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß) in the brain tissue of offspring rats. Western blotting was used to measure the expression of Nrf2 pathway-related proteins in the brain tissue of offspring rats. RESULTS: Pathological injury was found in the uterus, and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, and severe microglia pyroptosis occurred in the cerebral cortex of the offspring rats in the model group. Compared with the control group, the model group had significant reductions in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and heme oxygenase-1 (HO-1) in the brain tissue of the offspring rats (P<0.05), but significant increases in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1ß, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats (P<0.05). Compared with the model group, the breviscapine administration groups showed alleviated pathological injury of the uterus and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, significant increases in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and HO-1 in the brain tissue of the offspring rats (P<0.05), and significant reductions in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1ß, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats (P<0.05). The high-dose breviscapine group had a significantly better effect than the low-dose breviscapine (P<0.05). ML385 significantly inhibited the intervention effect of high-dose breviscapine (P<0.05). CONCLUSIONS: Breviscapine can inhibit inflammatory response in brain tissue of preterm rats caused by intrauterine inflammation by activating the Nrf2 pathway, and it can also inhibit microglial pyroptosis and alleviate brain injury.

Preoperative determination of pathological grades of primary single HCC: development and validation of a scoring model.

PURPOSE: This study aimed to establish a reliable diagnostic score model for the preoperative determination of pathological grade in HCC based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced MRI and biochemical indicators. METHODS: In this retrospective study, we analyzed 139 patients with HCC who underwent Gd-EOB-DTPA MRI between 2014 and 2020, including an establishment cohort of 76 patients and a validation cohort of 63 patients. Based on the imaging features demonstrated on Gd-EOB-DTPA MRI images and biochemical indicators of the establishment cohort, a scoring model based on logistic regression was developed, and compared with postoperative pathological findings in terms of effective determination of pathological grade. The validity of the scoring model was assessed by ROC curves and an independent external validation cohort. RESULTS: Three parameters related to pathological grades were identified, including maximum diameter of the tumor, peritumoral hypointensity in the hepatobiliary phase, and [alkaline phosphatase (U/L) + gamma glutamyl transpeptidase (U/L)]/ lymphocyte count (× 109/L) (AGLR) ratios. Based on these three parameters, a scoring model was developed. ROC curve showed that a score of > 5 was set as the threshold for determining pathological grades with accuracy, sensitivity, specificity, PPV, and NPV of 89.5%, 75.0%, 95.1%, 85.7%, and 90.7%, respectively. CONCLUSION: The study provided the groundwork for a promising and easily implementable scoring model for preoperative determination of HCC pathological grades, for which further validation should be pursued.

Deep learning image reconstruction in pediatric abdominal and chest computed tomography: a comparison of image quality and radiation dose.

Background: Studies on the application of deep learning image reconstruction (DLIR) in pediatric computed tomography (CT) are limited and have so far been mostly based on phantom. The purpose of this study was to compare the image quality and radiation dose of DLIR with that of adaptive statistical iterative reconstruction-Veo (ASiR-V) during abdominal and chest CT for the pediatric population. Methods: A pediatric phantom was used for the pilot study, and 20 children were recruited for clinical verification. The preset scan parameter noise index (NI) was 5, 8, 11, 13, 15, and 18 for the phantom study, and 8 and 13 for the clinical pediatric study. We reconstructed CT images with ASiR-V 30%, ASiR-V 70%, DLIR-M (medium) and DLIR-H (high). The regions of interest (ROI) were marked on the organs of the abdomen (liver, kidney, and subcutaneous fat) and the chest (lung, mediastinum, and spine). The CT dose index volume (CTDIvol), CT value, image noise (N), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured and calculated. The subjective image quality was assessed by 3 radiologists blindly using a 5-point scale. The dose reduction efficiency of DLIR was estimated. Results: In the phantom study, the interobserver assessment of the data measurement demonstrated good agreement [intraclass correlation coefficient (ICC) =0.814 for abdomen, 0.801 for chest]. Within the same dose level, the N, SNR, and CNR were statistically different among reconstructions, while the CT value remained the same. The N increased and SNR decreased as the radiation dose decreased. The DLIR-H performed better than ASiR-V when the radiation dose was reduced, without sacrificing image quality. In the patient study, the interobserver assessment of the data measurement demonstrated good agreement (ICC =0.774 for abdomen, 0.751 for chest). DLIR-H had the highest subjective and objective scores in the abdomen. Conclusions: Application of DLIR could help to reduce radiation dose without sacrificing the image quality of pediatric CT scans. Further clinical validation is required.

An updated view on the centrosome as a cell cycle regulator.

The centrosome is a multifunctional organelle that is known primarily for its microtubule organising function. Centrosomal defects caused by changes in centrosomal structure or number have been associated with human diseases ranging from congenital defects to cancer. We are only beginning to appreciate how the non-microtubule organising roles of the centrosome are related to these clinical conditions. In this review, we will discuss the historical evidence that led to the proposal that the centrosome participates in cell cycle regulation. We then summarize the body of work that describes the involvement of the mammalian centrosome in triggering cell cycle progression and checkpoint signalling. Then we will highlight work from the fission yeast model organism, revealing the molecular details that explain how the spindle pole body (SPB, the yeast functional equivalent of the centrosome), participates in these cell cycle transitions. Importantly, we will discuss some of the emerging questions from recent discoveries related to the role of the centrosome as a cell cycle regulator.

Prediction of microvascular invasion in HCC by a scoring model combining Gd-EOB-DTPA MRI and biochemical indicators.

OBJECTIVES: This study aimed to establish a reliable diagnostic scoring model for the preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biochemical indicators. METHODS: This retrospective study included 129 patients with HCC at our hospital from 2014 to 2020. Based on the intratumoral and peritumoral features on Gd-EOB-DTPA MRI and biochemical indicators, a scoring model was developed for preoperative prediction of MVI, and examined for diagnostic efficacy according to postoperative pathological results. The scoring model was further externally validated in an independent cohort of 63 HCC patients. RESULTS: Logistic regression analysis was performed to identify five parameters related to MVI, including maximum tumor diameter, peritumoral low intensity in the hepatobiliary phase, incomplete capsule, apparent diffusion coefficient (ADC), and [alkaline phosphatase (ALP) (U/L) + gamma-glutamyl transpeptidase (GGT) (U/L)] / lymphocyte count (× 109/L) ratio (AGLR). Based on these five parameters, a scoring model was developed, and the accuracy, sensitivity, specificity, PPV, and NPV in predicting MVI were 93.6%, 94.7%, 93.2%, 85.7%, and 97.6%, respectively, with a score > 8 set as the threshold. CONCLUSION: The scoring model based on Gd-EOB-DTPA MRI and biochemical indicators provides a reliable tool for preoperative prediction of MVI in HCC patients. KEY POINTS: • The scoring model based on Gd-EOB-DTPA MRI and biochemical indicators is practical for preoperative prediction of MVI in HCC patients. • AGLR is an independent risk factor for MVI. • The scoring model could help implement more appropriate interventions, potentially leading to precise and individualized treatments based on the biological characteristics of the tumor.

L-Tetrahydropalmatine enhances the sensitivity of human ovarian cancer cells to cisplatin via microRNA-93/PTEN/Akt cascade.

PURPOSE: Το evaluate the effect of L-Tetrahydropalmatine (L-THP) on the sensitivity of a cisplatin resistant ovarian cancer (OC) cell line. As miR-93 is reported to be overexpressed in OC and cisplatin resistance, we also evaluated its pathway in OC. METHODS: The levels of miR-93 were evaluated using RT-PCR and Luciferase assay was performed to confirm the target of miR-93. The extent of apoptosis was evaluated by Annexin V and propidium iodide (PI) staining, whereas Hoechst 33258 staining was done for identifying the number of apoptotic cells. RESULTS: The cisplatin-resistant A2780/DDP cell line showed lower survival rate compared to control when incubated with L-THP along with cisplatin. L-THP caused G0/G1 cell cycle arrest and increased the sensitivity to cisplatin. Furthermore, we found that the levels of miR-93 in cisplatin-resistant cells were highly expressed compared to parental cells. L-THP suppressed the expression of miR-93 and increased the levels of PTEN, a crucial tumor suppressor in OC. It was further observed that the cells transfected with PTEN siRNA showed increased survival compared with the control group and this phenomenon could be reversed by the AKT inhibitor Triciribine. The A2780 cells treated with PTEN siRNA showed similar survival rate to the cells with miR-93 overexpression. CONCLUSION: The findings of this study suggested L-THP increased the sensitivity of ovarian cancer cells to cisplatin via modulating miR-93/PTEN/AKT pathway in A2780/DDP ovarian cancer cell line.

ABO blood group and the risk of hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B.

BACKGROUND: Studies have observed an association between the ABO blood group and risk of certain malignancies. However, no studies of the association with hepatocellular carcinoma (HCC) risk are available. We conducted this hospital-based case-control study to examine the association with HCC in patients with chronic hepatitis B (CHB). METHODS: From January 2004 to December 2008, a total of 6275 consecutive eligible patients with chronic hepatitis B virus (HBV) infection were recruited. 1105 of them were patients with HBV-related HCC and 5,170 patients were CHB without HCC. Multivariate logistic regression models were used to investigate the association between the ABO blood group and HCC risk. RESULTS: Compared with subjects with blood type O, the adjusted odds ratio (AOR) for the association of those with blood type A and HCC risk was 1.39 [95% confidence interval (CI), 1.05-1.83] after adjusting for age, sex, type 2 diabetes, cirrhosis, hepatitis B e antigen, and HBV DNA. The associations were only statistically significant [AOR (95%CI) = 1.56(1.14-2.13)] for men, for being hepatitis B e antigen positive [AOR (95%CI) = 4.92(2.83-8.57)], for those with cirrhosis [AOR (95%CI), 1.57(1.12-2.20)], and for those with HBV DNA≤10(5)copies/mL [AOR (95%CI), 1.58(1.04-2.42)]. Stratified analysis by sex indicated that compared with those with blood type O, those with blood type B also had a significantly high risk of HCC among men, whereas, those with blood type AB or B had a low risk of HCC among women. CONCLUSIONS: The ABO blood type was associated with the risk of HCC in Chinese patients with CHB. The association was gender-related.

Type 2 diabetes and hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B.

Type 2 diabetes has been suggested as an independent risk factor for the development of hepatocellular carcinoma (HCC). However, the role of Type 2 diabetes on the development of HCC in the presence of chronic hepatitis B (CHB) remains inconclusive. We conducted this hospital-based case-control study to evaluate the roles of Type 2 diabetes in HCC development in patients with CHB. From January 2004 to December 2008, a total of 6,275 eligible consecutive patients with chronic hepatitis B virus (HBV) infection were recruited. A total of 1,105 of them were patients with HBV-related HCC and 5,170 patients were CHB but without HCC. We used multivariate logistic regression models to investigate the association between Type 2 diabetes and HCC risk. The prevalence of Type 2 diabetes is higher among HCC patients without cirrhosis than among those with cirrhosis (12.1% vs. 6.7%, p=0.003). Type 2 diabetes was associated with a significantly high risk of HCC in female patients after adjusting for age, family history of HCC, city of residence, hepatitis B e antigen and cirrhosis with an odds ratio (95% confidence interval, CI) of 1.9 (1.1-3.4). Restricted analyses among female patients without cirrhosis indicated that Type 2 diabetes was strongly associated with HCC risk with adjusted odds ratio (95% CI) of 5.6 (2.2-14.1). In conclusion, Type 2 diabetes is independently associated with the increased risk of HCC in female CHB patients. Female CHB patients with Type 2 diabetes are of a high HCC risk population and should be considered for HCC close surveillance program.