Ultra-low-dose rituximab is effective for the treatment of patients with minimal change disease - A retrospective study.

BACKGROUND PURPOSE: Rituximab (RTX),an anti-CD20 monoclonal antibody can effectively treat minimal change disease (MCD),with low toxicity and a reduced steroid dosage. The optimal dosage of RTX for treating MCD remains unclear. This study aimed to investigate the efficacy of an ultra-low-dose regimen of RTX (100 mg per week for 4 weeks) for treating MCD. METHODS: We retrospectively analyzed clinical data from 31 patients with MCD who received RTX. Seventeen patients received ultra-low-dose RTX (ULD-RTX) therapy, and 14 patients received standard-dose RTX (SD-RTX) therapy (500 mg weekly for 4 weeks). All patients were followed up for at least 6 months. RESULTS: Both groups showed significant increases in the serum albumin levels and notable decreases in the urinary protein levels in the 1st and 6th months after RTX therapy. There were no significant differences in the plasma albumin or urinary protein levels between the groups (p > 0.05). B-cell depletion was observed in all patients after 1 month of RTX administration. At 6 months after RTX treatment, the remission rate was 93% in the SD-RTX group and 88% in the ULD-RTX group (p > 0.05). The ULD-RTX therapy incurred lower costs than did the SD-RTX therapy. One patient in the SD-RTX group developed community-acquired pneumonia. CONCLUSION: Ultra-low-dose RTX is effective at inducing remission in patients with MCD at a lower cost.

The use of SNAP and T1-weighted VISTA in cervical artery dissection.

BACKGROUND AND PURPOSE: Some cervical artery dissection (CAD) can't be easily confirmed by commonly used angiography techniques in clinical practice. We aimed to compare the abilities of the vessel wall magnetic resonance imaging (MRI) techniques including simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) sequence and T1-weighted volumetric isotropic turbo spin echo acquisition (T1-w VISTA) sequence alone for evaluating CAD. MATERIALS AND METHODS: From July 2017 to October 2020, 59 patients underwent MRI examinations including SNAP and T1-w VISTA sequences for cervical artery pathologies. SNAP and T1-w VISTA images were retrospectively and independently reviewed to evaluate their diagnostic performances of CAD by using the final diagnosis as the reference standard which was established by clinical history, physical examination, and all available images. The agreement between T1-w VISTA and SNAP in the identification of the imaging features of CAD, including intramural hematoma (IMH), intimal flap, and double lumen, were compared. The IMH-wall contrasts by T1-w VISTA and SNAP were also compared. RESULTS: CAD was confirmed in 43 of the 59 patients. T1-w VISTA and SNAP showed the same diagnostic performance, and their consistencies with the final diagnosis were good (κ = 0.776, p < 0.001). The sensitivity and specificity in CAD diagnosis were 0.978 and 0.750 for T1-w VISTA and SNAP. The IMH, intimal flap, and double lumen observed on SNAP were also determined by T1-w VISTA (κ = 1.000, p < 0.001 for all). The SNAP sequence showed higher IMH-wall contrast than T1-w VISTA (7.34 ± 4.56 vs. 3.12 ± 1.17, p < 0.001). CONCLUSIONS: SNAP and T1-w VISTA sequences had the same performance in CAD diagnosis, thus they were both recommended. In addition, SNAP showed better IMH-wall contrast than T1-w VISTA.

Detection of mild cognitive impairment in type 2 diabetes mellitus based on machine learning using privileged information.

Type 2 diabetes mellitus (T2DM) patients may develop into mild cognitive impairment (MCI) or even dementia. However, there is lack of reliable machine learning model for detection MCI in T2DM patients based on machine learning method. In addition, the brain network changes associated with MCI have not been studied. The aim of this study is to develop a machine learning based algorithm to help detect MCI in T2DM. There are 164 participants were included in this study. They were divided into T2DM-MCI (n = 56), T2DM-nonMCI (n = 49), and normal controls (n = 59) according to the neuropsychological evaluation. Functional connectivity of each participant was constructed based on resting-state magnetic resonance imaging (rs-fMRI). Feature selection was used to reduce the feature dimension. Then the selected features were set into the cascaded multi-column random vector functional link network (RVFL) classifier model using privileged information. Finally, the optimal model was trained and the classification performance was obtained using the testing data. The results show that the proposed algorithm has outstanding performance compared with classic methods. The classification accuracy of 73.18 % (T2DM-MCI vs NC) and 79.42 % (T2DM-MCI vs T2DM-nonMCI) were achieved. The functional connectivity related to T2DM-MCI mainly distribute in the frontal lobe, temporal lobe, and central region (motor cortex), which could be used as neuroimaging biomarkers to recognize MCI in T2DM patients. This study provides a machine learning model for diagnosis of MCI in T2DM patients and has potential clinical significance for timely intervention and treatment to delay the development of MCI.

Intraplacental T2-hypointense bands may help predict placental invasion depth and postpartum hemorrhage in placenta accrete spectrum disorders in high-risk gravid patients.

INTRODUCTION: Accurate noninvasive prenatal diagnosis of placenta accreta spectrum (PAS) disorder is critical for delivery management. PURPOSE: To evaluate the diagnostic ability of MRI features in predicting the PAS, invasive depth and postpartum hemorrhage (PPH) in high-risk gravid patients. MATERIALS AND METHODS: Between February 2019 and November 2020, women with ultrasound (US)-suspected PAS were enrolled. With the exclusion criteria, 80 women were included in the study. Two experienced genitourinary radiologists reviewed and recorded the MRI features. The chi square test was used to compare the effectiveness of MRI features. Relative risk ratios were computed to test the association of intraplacental T2-hypointense bands with poor outcomes of cesarean section. Receiver operating characteristic (ROC) analyses based on the number and area of intraplacental T2-hypointense bands were used to predict PAS, invasion depth, and PPH. RESULTS: PAS was diagnosed in 56 of 80 women (70%). At delivery, 24 of 80 women (30%) experienced PPH (≥1000 mL). Intraplacental T2-hypointense bands were detected at MRI in 28 of 56 women with PAS (50%). The relative risk ratio of intraplacental T2-hypointense bands was 1.51 for PAS, 3.17 for depth of PAS invasiveness and 4.74 for PPH. The largest areas of intraplacental T2-hypointense bands for predicting PAS, invasion depth and PPH were 0.66 cm2, 1.68 cm2 and 1.99 cm2, respectively. DISCUSSION: The appearance of intraplacental T2-hypointense bands has important diagnostic value for PAS, its invasion depth and PPH. The area of the largest T2-hypointense band in the placenta can predict poor outcomes of cesarean section.

Humanization of Yeasts for Glycan-Type End-Products.

Yeasts are often considered microorganisms for producing human therapeutic glycosylated end-products at an industrial scale. However, the products with non-humanized glycans limited their usage. Therefore, various methods to develop humanized glycosylated end-products have been widely reported in yeasts. To make full use of these methods, it is necessary to summarize the present research to find effective approaches to producing humanized products. The present research focuses on yeast species selection, glycosyltransferase deletion, expression of endoglycosidase, and expression of proteins with galactosylated and or sialylated glycans. Nevertheless, the yeasts will have growth defects with low bioactivity when the key enzymes are deleted. It is necessary to express the corresponding repairing protein. Compared with N-glycosylation, the function of yeast protein O-glycosylation is not well-understood. Yeast proteins have a wide variety of O-glycans in different species, and it is difficult to predict glycosylation sites, which limits the humanization of O-glycosylated yeast proteins. The future challenges include the following points: there are still many important potential yeasts that have never been tried to produce glycosylated therapeutic products. Their glycosylation pathway and related mechanisms for producing humanized glycosylated proteins have rarely been reported. On the other hand, the amounts of key enzymes on glycan pathways in human beings are significantly more than those in yeasts. Therefore, there is still a challenge to produce a large body of humanized therapeutic end-products in suitable yeast species, especially the protein with complex glycans. CRISPR-Cas9 system may provide a potential approach to address the important issue.

HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization.

Increased aneurysm wall permeability colocalized with low wall shear stress in unruptured saccular intracranial aneurysm.

Aneurysm wall permeability has recently emerged as an in vivo marker of aneurysm wall remodeling. We sought to study the spatial relationship between hemodynamic forces derived from 4D-flow MRI and aneurysm wall permeability by DCE-MRI in a region-based analysis of unruptured saccular intracranial aneurysms (IAs). We performed 4D-flow MRI and DCE-MRI on patients with unruptured IAs of ≥ 5 mm to measure hemodynamic parameters, including wall shear stress (WSS), oscillatory shear index (OSI), WSS temporal (WSSGt) and spatial (WSSGs) gradient, and aneurysm wall permeability (Ktrans) in different sectors of aneurysm wall defined by evenly distributed radial lines emitted from the aneurysm center. The spatial association between Ktrans and hemodynamic parameters measured at the sector level was evaluated. Thirty-one patients were scanned. Ktrans not only varied between aneurysms but also demonstrated spatial heterogeneity within an aneurysm. Among all 159 sectors, higher Ktrans was associated with lower WSS, which was seen in both Spearman's correlation analysis (rho = - 0.18, p = 0.025) and linear regression analysis using generalized estimating equation to account for correlations between multiple sectors of the same aneurysm (regression coefficient = - 0.33, p = 0.006). Aneurysm wall permeability by DCE-MRI was shown to be spatially heterogenous in unruptured saccular IAs and associated with local WSS by 4D-flow MRI.

Construction of a novel radiomics nomogram for the prediction of aggressive intrasegmental recurrence of HCC after radiofrequency ablation.

OBJECTIVES: To construct a precise prediction model of preoperative magnetic resonance imaging (MRI)-based nomogram for aggressive intrasegmental recurrence (AIR) of hepatocellular carcinoma (HCC) patients treated with radiofrequency ablation (RFA). METHODS: Among 891 patients with HCC treated by RFA, 22 patients with AIR and 36 patients without AIR (non-AIR) were finally enrolled in our study, and each patient was followed up for more than 6 months to determine the occurrence of AIR. The laboratory indicators and MRI features were compared and assessed. Preoperative contrast-enhanced T1-weighted images (CE-T1WI) were used for radiomics analysis. The selected clinical indicators and texture features were finally screened out to generate the novel prediction nomogram. RESULTS: Tumor shape, ADC Value, DWI signal intensity and ΔSI were selected as the independent factors of AIR by univariate and multivariate logistic regression analysis. Meanwhile, two radiomics features were selected from 396 candidate features by LASSO (P < 0.05), which were further used to calculate the Rad-score. The selected clinical factors were further integrated with the Rad-score to construct the predictive model, and the AUCs were 0.941 (95% CI: 0.876-1.000) and 0.818 (95% CI: 0.576-1.000) in the training (15 AIR and 25 non-AIR) and validation cohorts (7 AIR and 11 non-AIR), respectively. The AIR predictive model was further converted into a novel radiomics nomogram, and decision curve analysis showed good agreement. CONCLUSIONS: The predictive nomogram integrated with clinical factors and CE-T1WI -based radiomics signature could accurately predict the occurrence of AIR after RFA, which could greatly help individualized evaluation before treatment.

USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bß via deubiquitinating EGLN3.

BACKGROUND: Cholangiocarcinoma represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades. Cholangiocarcinoma silent nature limits early diagnosis and prevents efficient treatment. METHODS: Immunoblotting and immunohistochemistry were used to assess the expression profiling of USP9X and EGLN3 in cholangiocarcinoma patients. ShRNA was used to silence gene expression. Cell apoptosis, cell cycle, CCK8, clone formation, shRNA interference and xenograft mouse model were used to explore biological function of USP9X and EGLN3. The underlying molecular mechanism of USP9X in cholangiocarcinoma was determined by immunoblotting, co-immunoprecipitation and quantitative real time PCR (qPCR). RESULTS: Here we demonstrated that USP9X is downregulated in cholangiocarcinoma which contributes to tumorigenesis. The expression of USP9X in cholangiocarcinoma inhibited cell proliferation and colony formation in vitro as well as xenograft tumorigenicity in vivo. Clinical data demonstrated that expression levels of USP9X were positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that USP9X was involved in the deubiquitination of EGLN3, a member of 2-oxoglutarate and iron-dependent dioxygenases. USP9X elicited tumor suppressor role by preventing degradation of EGLN3. Importantly, knockdown of EGLN3 impaired USP9X-mediated suppression of proliferation. USP9X positively regulated the expression level of apoptosis pathway genes de through EGLN3 thus involved in apoptosis of cholangiocarcinoma. CONCLUSION: These findings help to understand that USP9X alleviates the malignant potential of cholangiocarcinoma through upregulation of EGLN3. Consequently, we provide novel insight into that USP9X is a potential biomarker or serves as a therapeutic or diagnostic target for cholangiocarcinoma.

Corrigendum: LncRNA PCAT6 Induces M2 Polarization of Macrophages in Cholangiocarcinoma via Modulating miR-326 and RhoA-ROCK Signaling Pathway.

[This corrects the article DOI: 10.3389/fonc.2020.605877.].

Sialic acid-engineered mesoporous polydopamine dual loaded with ferritin gene and SPIO for achieving endogenous and exogenous synergistic T2-weighted magnetic resonance imaging of HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Magnetic resonance imaging (MRI) is one of the most effective imaging methods for the early diagnosis of HCC. However, the current MR contrast agents are still facing challenges in the early diagnosis of HCC due to their relatively low sensitivity and biosafety. Thus, the development of effective MR agents is highly needed for the early diagnosis of HCC. RESULTS: Herein, we fabricated an HCC-targeted nanocomplexes containing SPIO-loaded mesoporous polydopamine (MPDA@SPIO), sialic acid (SA)-modified polyethyleneimine (SA-PEI), and alpha-fetoprotein regulated ferritin gene (AFP-Fth) which was developed for the early diagnosis of HCC. It was found that the prepared nanocomplexes (MPDA@SPIO/SA-PEI/AFP-Fth) has an excellent biocompatibility towards the liver cells. In vivo and in vivo studies revealed that the transfection of AFP-Fth gene in hepatic cells significantly upregulated the expression level of ferritin, thereby resulting in an enhanced contrast on T2-weighted images via the formed endogenous MR contrast. CONCLUSIONS: The results suggested that MPDA@SPIO/SA-PEI/AFP-Fth had a superior ability to enhance the MR contrast of T2-weighted images of tumor region than the other preparations, which was due to its HCC-targeted ability and the combined T2 contrast effect of endogenous ferritin and exogenous SPIO. Our study proved that MPDA@SPIO/SA-PEI/AFP-Fth nanocomplexes could be used as an effective MR contrast agent to detect HCC in the early stage.

3.0 T Magnetic Resonance Functional Imaging Quantitative Parameters for Differential Diagnosis of Benign and Malignant Lesions of the Breast.

Objective: To investigate value of quantitative dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters and apparent diffusion coefficient (ADC) value in differential diagnosis of breast benign and malignant lesions, and their correlation with prognostic factors of breast cancer. Methods: The study collected MRI images and clinical data from 232 female patients suspected of breast cancer. Philips INGENIA 3.0T superconducting magnetic resonance scanner was used for imaging examination. Complete pathological data of patients were collected, and the expression of ER, PR, HER-2, and Ki-67 were further investigated. Results: Kep was higher in malignant breast lesion group than that in benign breast lesion group, and ADC value was lower in the former group than that in the latter group (both p < 0.05). The areas under the receiver operating characteristic curves for Kep, ADC, and extravascular volume fraction (Ve) were 0.904 (95% confidence interval [CI]: 0.863-0.945), 0.813 (95% CI: 0.752-0.875), and 0.774 (95% CI: 0.707-0.841), respectively. Furthermore, according to the maximum Youden index, the specificity of Kep and the sensitivity of ADC were high, which were 97.20% and 96.00%, respectively, with a cutoff value of 0.314 and 0.151, respectively. Kep value in ER-positive expression group was significantly higher than that in ER-negative expression group (p < 0.05). Kep value in PR-positive expression group was significantly higher than that in PR-negative expression group (p < 0.05). There was positive correlation between Kep and expression of Ki-67 (p < 0.05). ADC value was negatively correlated with Ki-67 expression (p < 0.05). Conclusion: Quantitative parameters Kep and ADC of 3.0 T MR functional imaging can be used as reference indexes for differential diagnosis of benign and malignant breast lesions and for biological behavior evaluation, indicating potential clinical value for noninvasive preoperative evaluation of breast cancer.

Multifunctional Microspheres Dual-Loaded with Doxorubicin and Sodium Bicarbonate Nanoparticles to Introduce Synergistic Trimodal Interventional Therapy.

Lactic acid in the tumor microenvironment is highly correlated with the prognosis of tumor chemoembolization, but there are limited clinical strategies to deal with it. To improve the efficacy, NaHCO3 nanoparticles are innovatively introduced into drug-loaded microspheres to neutralize lactic acid in the tumor microenvironment. Here we showed that multifunctional ethyl cellulose microspheres dual-loaded with doxorubicin (DOX) and NaHCO3 nanoparticles (DOX/NaHCO3-MS) presented excellent antitumor effects by improving the pH of the tumor microenvironment. The homeostasis of the tumor microenvironment was continuously disturbed due to the sustained release of NaHCO3 nanoparticles, which also led to a significant increase in tumor cell apoptosis (compared with the control and DOX-MS groups). We also showed that the administration of DOX/NaHCO3-MS via the hepatic artery in a rabbit model of VX2 orthotopic liver cancer resulted in optimal antitumor efficacy, and the area of tumor necrosis at the embolization site was significantly increased and the proliferation of tumor cells was significantly weakened. The designed DOX/NaHCO3-MS exhibited strong synergistic antitumor effects of embolization, chemotherapy, and tumor microenvironment improvement. The present microspheres provided a strategy for the enhancement of the chemoembolization of hepatocellular carcinoma, which could also be extended to other clinical embolization treatments for blood-rich solid tumors.

CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway.

BACKGROUND: Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. METHODS: The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. RESULTS: In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. CONCLUSION: The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

Non-invasive evaluation for benign and malignant subcentimeter pulmonary ground-glass nodules (≤1 cm) based on CT texture analysis.

OBJECTIVES: To investigate potential diagnostic model for predicting benign or malignant status of subcentimeter pulmonary ground-glass nodules (SPGGNs) (≤1 cm) based on CT texture analysis. METHODS: A total of 89 SPGGNs from 89 patients were included; 51 patients were diagnosed with adenocarcinoma, and 38 were diagnosed with inflamed or infected benign SPGGNs. Analysis Kit software was used to manually delineate the volume of interest of lesions and extract a total of 396 quantitative texture parameters. The statistical analysis was performed using R software. The SPGGNs were randomly divided into a training set (n = 59) and a validation set (n = 30). All pre-normalized (Z-score) feature values were subjected to dimension reduction using the LASSO algorithm,and the most useful features in the training set were selected. The selected imaging features were then combined into a Rad-score, which was further assessed by ROC curve analysis in the training and validation sets. RESULTS: Four characteristic parameters (ClusterShade_AllDirection_offset4_SD, ShortRunEmphasis_angle45_offset1, Maximum3DDiameter, SurfaceVolumeRatio) were further selected by LASSO (p < 0.05). As a cluster of imaging biomarkers, the above four parameters were used to form the Rad-score. The AUC for differentiating between benign and malignant SPGGNs in the training set was 0.792 (95% CI: 0.671, 0.913), and the sensitivity and specificity were 86.10 and 65.20%, respectively. The AUC in the validation set was 72.9% (95% CI: 0.545, 0.913), and the sensitivity and specificity were 86.70 and 60%, respectively. CONCLUSION: The present diagnostic model based on the cluster of imaging biomarkers can preferably distinguish benign and malignant SPGGNs (≤1 cm). ADVANCES IN KNOWLEDGE: Texture analysis based on CT images provide a new and credible technique for accurate identification of subcentimeter pulmonary ground-glass nodules.

Gadolinium-loaded calcium phosphate nanoparticles for magnetic resonance imaging of orthotopic hepatocarcinoma and primary hepatocellular carcinoma.

The development of magnetic resonance imaging (MRI) contrast agents with high sensitivity and good biocompatibility is of great value for the diagnosis of primary hepatocellular carcinoma (HCC). Here, a novel MRI contrast agent based on calcium phosphate (CaP) nanoparticles modified with a liver cancer cell targeting peptide A54 (A54-CaP) was fabricated. The T1-positive contrast agent Gd-DTPA was encapsulated inside the nanoparticles (A54-CaPNPs), with a mean diameter of 30 nm and a high encapsulation efficiency of 92.73%. The A54-CaPNP solution exhibited higher longitudinal relaxivity (6.07 mM-1 s-1) than that of the clinically used MRI contrast agent Gd-DTPA (3.56 mM-1 s-1). A much higher accumulation of the nanoparticles in the liver cells was observed, which was directed by the A54 targeting peptide. Furthermore, the MRI diagnostic efficiency of A54-CaPNPs was systematically investigated in an orthotopic liver cancer model and primary HCC model. In vivo MRI experiments showed that A54-CaPNPs had higher sensitivity in the BEL-7402 orthotopic liver cancer model with a more remarkable contrast enhancement and a longer imaging time compared to those without A54 modification. Moreover, the experiments on primary HCC models suggested that A54-CaPNPs showed greatly enhanced MR imaging performance in comparison with Gd-DTPA. These results suggest that A54-CaPNPs possess great potential to enable the non-invasive early diagnosis of primary HCC for timely surgical resection.

Long Non-Coding RNA PCAT6 Induces M2 Polarization of Macrophages in Cholangiocarcinoma via Modulating miR-326 and RhoA-ROCK Signaling Pathway.

LncRNAs can act crucial roles in multiple tumors including cholangiocarcinoma (CCA). M2 polarization of macrophages is crucial for their biological roles in immunologic tolerance, which is able to induce tumorigenesis. Given that increasing evidence have suggested that lncRNAs could participate in modulating immune cell differentiation and function. Our current study was aimed to identify the underlying mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in CCA progression via regulating M2 macrophage polarization. PCAT6 has been reported as an oncogene in many cancers. In our work, we observed increased expression of PCAT6 in CCA patients. PCAT6 expression in various types of immune cells derived from CCA patients was tested by quantitative real-time PCR (qRT-PCR). It was revealed that PCAT6 was highly expressed in macrophages, which indicated that PCAT6 might regulate the function of macrophages to promote CCA progression. Then, via establishing CCA xenograft mouse model, we found loss of PCAT6 obviously triggered the immune response and reduced the in vivo tumor growth. In addition, overexpression of PCAT6 led to the M2 polarization of THP-1-differentiated macrophages. Moreover, miR-326 was predicted and proved as a target for PCAT6. In addition, down-regulation of PCAT6 repressed M2 polarization of macrophages, which was reversed by miR-326 inhibitors. The increase of PCAT6 induced the accumulation of ROS, mitochondrial and metabolic dysfunction in macrophages and mimics of miR-326 exhibited an opposite process. RohA has been recognized as a significant regulator of immune cell function. In our current work, we observed that RohA function as a downstream target for miR-326. In conclusion, our study highlighted a significant role of PCAT6/miR-326/RohA in immune response of macrophages in CCA and indicated PCAT6 as a potential target of immunotherapy in CCA.

Grading of hepatocellular carcinoma using 3D SE-DenseNet in dynamic enhanced MR images.

BACKGROUND: Clinical histological grading of hepatocellular carcinoma (HCC) differentiation is of great significance in clinical diagnoses, treatments, and prognoses. However, it is challenging for radiologists to evaluate HCC gradings from medical images. PURPOSE: In this study, a novel deep neural network was developed by combining the squeeze-and-excitation networks (SENets) in a three-dimensional (3D) densely connected convolutional network (DenseNet), which is referred to as a 3D SE-DenseNet, for the classification of HCC grading using enhanced clinical magnetic resonance (MR) images obtained from two different clinical centers. METHOD: In the proposed architecture, the SENet was added as an additional layer between the dense blocks of the 3D DenseNet, to mitigate the impact of feature redundancy. For the HCC grading task, the 3D SE-DenseNet was trained after data augmentation, and it outperformed the 3D DenseNet based on the clinical dataset. RESULTS: The quantitative evaluations of the 3D SE-DenseNet on a two-class HCC grading task were conducted based on the dataset, which included 213 samples of the dynamic enhanced MR images. The proposed 3D SE-DenseNet demonstrated an accuracy of 83%, when compared with the 72% accuracy of the 3D DenseNet. CONCLUSION: Owing to the advantage of useful automatic feature learning by the SE layer, the 3D SE-DenseNet can simultaneously handle useful feature enhancement and superfluous feature suppression. The quantitative experiments confirm the excellent performance of the 3D SE-DenseNet in the evaluation of the HCC grading.

Characterization and subcellular localization of histone deacetylases and their roles in response to abiotic stresses in soybean.

BACKGROUND: Histone deacetylases (HDACs) function as key epigenetic factors in repressing the expression of genes in multiple aspects of plant growth, development and plant response to abiotic or biotic stresses. To date, the molecular function of HDACs is well described in Arabidopsis thaliana, but no systematic analysis of this gene family in soybean (Glycine max) has been reported. RESULTS: In this study, 28 HDAC genes from soybean genome were identified, which were asymmetrically distributed on 12 chromosomes. Phylogenetic analysis demonstrated that GmHDACs fall into three major groups previously named RPD3/HDA1, SIR2, and HD2. Subcellular localization analysis revealed that YFP-tagged GmSRT4, GmHDT2 and GmHDT4 were predominantly localized in the nucleus, whereas GmHDA6, GmHDA13, GmHDA14 and GmHDA16 were found in both the cytoplasm and nucleus. Real-time quantitative PCR showed that GmHDA6, GmHDA13, GmHDA14, GmHDA16 and GmHDT4 were broadly expressed across plant tissues, while GmHDA8, GmSRT2, GmSRT4 and GmHDT2 showed differential expression across various tissues. Interestingly, we measured differential changes in GmHDACs transcripts accumulation in response to several abiotic cues, indicating that these epigenetic modifiers could potentially be part of a dynamic transcriptional response to stress in soybean. Finally, we show that the levels of histone marks previously reported to be associated with plant HDACs are modulated by cold and heat in this legume. CONCLUSION: We have identified and classified 28 HDAC genes in soybean. Our data provides insights into the evolution of the HDAC gene family and further support the hypothesis that these genes are important for the plant responses to environmental stress.