Reversal of liver failure using a bioartificial liver device implanted with clinical-grade human-induced hepatocytes.

Liver resection is the first-line treatment for primary liver cancers, providing the potential for a cure. However, concerns about post-hepatectomy liver failure (PHLF), a leading cause of death following extended liver resection, have restricted the population of eligible patients. Here, we engineered a clinical-grade bioartificial liver (BAL) device employing human-induced hepatocytes (hiHeps) manufactured under GMP conditions. In a porcine PHLF model, the hiHep-BAL treatment showed a remarkable survival benefit. On top of the supportive function, hiHep-BAL treatment restored functions, specifically ammonia detoxification, of the remnant liver and facilitated liver regeneration. Notably, an investigator-initiated study in seven patients with extended liver resection demonstrated that hiHep-BAL treatment was well tolerated and associated with improved liver function and liver regeneration, meeting the primary outcome of safety and feasibility. These encouraging results warrant further testing of hiHep-BAL for PHLF, the success of which would broaden the population of patients eligible for liver resection.

Transcription factor AP-2α activates RNA polymerase III-directed transcription and tumor cell proliferation by controlling expression of c-MYC and p53.

Deregulation of transcription factor AP2 alpha (TFAP2A) and RNA polymerase III (Pol III) products is associated with tumorigenesis. However, the mechanism underlying this event is not fully understood and the connection between TFAP2A and Pol III-directed transcription has not been investigated. Here, we report that TFAP2A functions as a positive factor in the regulation of Pol III-directed transcription and cell proliferation. We found TFAP2A is also required for the activation of Pol III transcription induced by the silencing of filamin A, a well-known cytoskeletal protein and an inhibitor in Pol III-dependent transcription identified previously. Using a chromatin immunoprecipitation technique, we showed TFAP2A positively modulates the assembly of Pol III transcription machinery factors at Pol III-transcribed gene loci. We found TFAP2A can activate the expression of Pol III transcription-related factors, including BRF1, GTF3C2, and c-MYC. Furthermore, we demonstrate TFAP2A enhances expression of MDM2, a negative regulator of tumor suppressor p53, and also inhibits p53 expression. Finally, we found MDM2 overexpression can rescue the inhibition of Pol III-directed transcription and cell proliferation caused by TFAP2A silencing. In summary, we identified that TFAP2A can activate Pol III-directed transcription by controlling multiple pathways, including general transcription factors, c-MYC and MDM2/p53. The findings from this study provide novel insights into the regulatory mechanisms of Pol III-dependent transcription and cancer cell proliferation.

Early Growth Response 1 Strengthens Pol-III-Directed Transcription and Transformed Cell Proliferation by Controlling PTEN/AKT Signalling Activity.

RNA polymerase III (Pol III) products play essential roles in ribosome assembly, protein synthesis, and cell survival. Deregulation of Pol-III-directed transcription is closely associated with tumorigenesis. However, the regulatory pathways or factors controlling Pol-III-directed transcription remain to be investigated. In this study, we identified a novel role of EGR1 in Pol-III-directed transcription. We found that Filamin A (FLNA) silencing stimulated EGR1 expression at both RNA and protein levels. EGR1 expression positively correlated with Pol III product levels and cell proliferation activity. Mechanistically, EGR1 downregulation dampened the occupancies of Pol III transcription machinery factors at the loci of Pol III target genes. Alteration of EGR1 expression did not affect the expression of p53, c-MYC, and Pol III general transcription factors. Instead, EGR1 activated RhoA expression and inhibited PTEN expression in several transformed cell lines. We found that PTEN silencing, rather than RhoA overexpression, could reverse the inhibition of Pol-III-dependent transcription and cell proliferation caused by EGR1 downregulation. EGR1 could positively regulate AKT phosphorylation levels and is required for the inhibition of Pol-III-directed transcription mediated by FLNA. The findings from this study indicate that EGR1 can promote Pol-III-directed transcription and cell proliferation by controlling the PTEN/AKT signalling pathway.

Diagnosis of Lung Cancer by FTIR Spectroscopy Combined With Raman Spectroscopy Based on Data Fusion and Wavelet Transform.

Lung cancer is a fatal tumor threatening human health. It is of great significance to explore a diagnostic method with wide application range, high specificity, and high sensitivity for the detection of lung cancer. In this study, data fusion and wavelet transform were used in combination with Fourier transform infrared (FTIR) spectroscopy and Raman spectroscopy to study the serum samples of patients with lung cancer and healthy people. The Raman spectra of serum samples can provide more biological information than the FTIR spectra of serum samples. After selecting the optimal wavelet parameters for wavelet threshold denoising (WTD) of spectral data, the partial least squares-discriminant analysis (PLS-DA) model showed 93.41% accuracy, 96.08% specificity, and 90% sensitivity for the fusion data processed by WTD in the prediction set. The results showed that the combination of FTIR spectroscopy and Raman spectroscopy based on data fusion and wavelet transform can effectively diagnose patients with lung cancer, and it is expected to be applied to clinical screening and diagnosis in the future.

Transcription factor GATA4 drives RNA polymerase III-directed transcription and transformed cell proliferation through a filamin A/GATA4/SP1 pathway.

RNA polymerase III (pol III) products play fundamental roles in a variety of cellular processes, including protein synthesis and cancer cell proliferation. In addition, dysregulation of pol III-directed transcription closely correlates with tumorigenesis. It is therefore of interest to identify novel pathways or factors governing pol III-directed transcription. Here, we show that transcription factor (TF) GATA binding protein 4 (GATA4) expression in SaOS2 cells was stimulated by the silencing of filamin A (FLNA), a repressor of pol III-directed transcription, suggesting that GATA4 is potentially associated with the regulation of pol III-directed transcription. Indeed, we show that GATA4 expression positively correlates with pol III-mediated transcription and tumor cell proliferation. Mechanistically, we found that GATA4 depletion inhibits the occupancies of the pol III transcription machinery factors at the loci of pol III target genes by reducing expression of both TFIIIB subunit TFIIB-related factor 1 and TFIIIC subunit general transcription factor 3C subunit 2 (GTF3C2). GATA4 has been shown to activate specificity factor 1 (Sp1) gene transcription by binding to the Sp1 gene promoter, and Sp1 has been confirmed to activate pol III gene transcription by directly binding to both Brf1 and Gtf3c2 gene promoters. Thus, the findings from this study suggest that GATA4 links FLNA and Sp1 signaling to form an FLNA/GATA4/Sp1 axis to modulate pol III-directed transcription and transformed cell proliferation. Taken together, these results provide novel insights into the regulatory mechanism of pol III-directed transcription.

Deep Learning for Accurate Diagnosis of Liver Tumor Based on Magnetic Resonance Imaging and Clinical Data.

Background: Early-stage diagnosis and treatment can improve survival rates of liver cancer patients. Dynamic contrast-enhanced MRI provides the most comprehensive information for differential diagnosis of liver tumors. However, MRI diagnosis is affected by subjective experience, so deep learning may supply a new diagnostic strategy. We used convolutional neural networks (CNNs) to develop a deep learning system (DLS) to classify liver tumors based on enhanced MR images, unenhanced MR images, and clinical data including text and laboratory test results. Methods: Using data from 1,210 patients with liver tumors (N = 31,608 images), we trained CNNs to get seven-way classifiers, binary classifiers, and three-way malignancy-classifiers (Model A-Model G). Models were validated in an external independent extended cohort of 201 patients (N = 6,816 images). The area under receiver operating characteristic (ROC) curve (AUC) were compared across different models. We also compared the sensitivity and specificity of models with the performance of three experienced radiologists. Results: Deep learning achieves a performance on par with three experienced radiologists on classifying liver tumors in seven categories. Using only unenhanced images, CNN performs well in distinguishing malignant from benign liver tumors (AUC, 0.946; 95% CI 0.914-0.979 vs. 0.951; 0.919-0.982, P = 0.664). New CNN combining unenhanced images with clinical data greatly improved the performance of classifying malignancies as hepatocellular carcinoma (AUC, 0.985; 95% CI 0.960-1.000), metastatic tumors (0.998; 0.989-1.000), and other primary malignancies (0.963; 0.896-1.000), and the agreement with pathology was 91.9%.These models mined diagnostic information in unenhanced images and clinical data by deep-neural-network, which were different to previous methods that utilized enhanced images. The sensitivity and specificity of almost every category in these models reached the same high level compared to three experienced radiologists. Conclusion: Trained with data in various acquisition conditions, DLS that integrated these models could be used as an accurate and time-saving assisted-diagnostic strategy for liver tumors in clinical settings, even in the absence of contrast agents. DLS therefore has the potential to avoid contrast-related side effects and reduce economic costs associated with current standard MRI inspection practices for liver tumor patients.

Single and dual target inhibitors based on Bcl-2: Promising anti-tumor agents for cancer therapy.

B-cell lymphoma-2 (Bcl-2) proteins family is an essential checkpoint in apoptosis. Extensive evidences suggested that overexpression of anti-apoptotic Bcl-2 proteins can be observed in multiple cancer cell lines and primary tumor biopsy samples, which is an important reason for tumor cells to evade apoptosis and further acquire drug resistance for chemotherapy. Hence, down-regulation of anti-apoptotic Bcl-2 proteins is effective for the treatment of cancers. In view that Bcl-2 inhibitors and some other anti-tumor agents, such as HDAC inhibitors and Mdm2 inhibitors, exert synergy effects in tumor cells, it is pointed out that dual-targeting therapies based on these targets are regarded as rational strategies to enhance the effectiveness of single target agents for cancer treatment. This review briefly introduces the apoptosis, the structure of Bcl-2 family proteins, and focuses on the current status and recent advances of Bcl-2 inhibitors and the corresponding SARs of them. Moreover, we discuss the synergisms between Bcl-2 and other anti-tumor targets, and summarize the current dual-target agents.

One DNA circle capture probe with multiple target recognition domains for simultaneous electrochemical detection of miRNA-21 and miRNA-155.

In this work, a novel DNA circle capture probe with multiple target recognition domains was designed to develop an electrochemical biosensor for ultrasensitive detection of microRNA-21 (miRNA-21) and miRNA-155 simultaneously. The DNA circle capture probe was anchored at the top of the tetrahedron DNA nanostructure (TDN) to simultaneously recognize miRNA-21 and miRNA-155 through multiple target recognition domains under the assistance of Helper strands, which could trigger mimetic proximity ligation assay (mPLA) for capturing the beacons ferrocene (Fc)-A1 and methylene blue (MB)-A2 to achieve multiple miRNAs detection. In this way, the local reaction concentration could be enhanced and avoid the interference of various capture probes compared with the traditional multiplexed electrochemical biosensor with the use of different capture probes, resulting in the significantly improvement of detection sensitivity. As a result, this proposed biosensor showed wide linearity ranging from 0.1 fM to 10 nM with detection limits of miRNA-21 and miRNA-155 as 18.9 aM and 39.6 aM respectively, which also could be applied in the simultaneously detection of miRNA-21 and miRNA-155 from cancer cell lysates. The present strategy paved a new path in the design of capture probes for achieving more efficient and sensitive multiple biomarkers detections and possessed the potential applications in clinical diagnostic of diseases.

Paeonol Derivatives and Pharmacological Activities: A Review of Recent Progress.

Paeonol, 2-hydroxy-4-methoxy acetophenone, is one of the main active ingredients of traditional Chinese medicine such as Cynanchum paniculatum, Paeonia suffruticosa Andr and Paeonia lactiflora Pall. Modern medical research has shown that paeonol has a wide range of pharmacological activities. In recent years, a large number of studies have been carried out on the structure modification of paeonol and the mechanism of action of paeonol derivatives has been studied. Some paeonol derivatives exhibit good pharmacological activities in terms of antibacterial, anti-inflammatory, antipyretic analgesic, antioxidant and other pharmacological effects. Herein, the research progress on paeonol derivatives and their pharmacological activities were systematically reviewed.

Simply Constructed and Highly Efficient Classified Cargo-Discharge DNA Robot: A DNA Walking Nanomachine Platform for Ultrasensitive Multiplexed Sensing.

In this work, a classified cargo-discharge DNA robot with only two DNA strands was designed and driven by an analogous proximity ligation assay (aPLA)-based enzyme cleaving for fast walk to construct a novel electrochemical biosensor for simultaneously ultrasensitive detection of microRNA-155 (miRNA-155) and miRNA-21. Compared with traditional DNA nanomachines, the multifunctional DNA robot possessed simple structure, high self-assembling efficiency and walking efficiency. Once it interacted with target miRNAs, this DNA robot could walk fast on the electrode surface and realize the classified cargoes discharging including beacons methylene blue (MB) and ferrocene (Fc), respectively labeled in the double-stranded DNA (A1-A2) for ultrasensitive detection of multiple miRNAs simultaneously. As a result, the wide linearity ranging from 100 aM to 100 pM and low detection limits of 42.7 and 51.1 aM were obtained for miRNA-155 and miRNA-21 detection, respectively. As a proof of concept, the present strategy initiates a novel and highly efficient walking platform to realize the ultrasensitive detection of biomarkers and possesses potential applications in the clinical diagnosis of disease.

Three new cucurbitane triterpenoids from Hemsleya penxianensis and their cytotoxic activities.

Two new cucurbitane glycosides, hemslepenside A (1) and 16,25-O-diacetyl-cucurbitacin F-2-O-ß-d-glucopyranoside (3), one new cucurbitacin, 16-O-acetyl-cucurbitacin F (2), along with three known cucurbitane compounds, were isolated from the roots of Hemsleya penxianensis. The structures of 1-6 were established on the basis of extensive spectroscopic and chemical methods. The isolated compounds were evaluated for their cytotoxic activities against different three human cancer cell lines, with IC50 values in the low microgram range.

A gravity-induced flow injection system for surface plasmon resonance biosensor.

A number of portable surface plasmon resonance (SPR) devices have been developed for point-of-care (POC) testing. Meanwhile, micropumps have been fabricated to be integrated into these devices for flow injection analysis (FIA). However, the (micro) pumps, the tubes and their external control units were space-consuming. Here we developed a power-free flow injection analysis (FIA) method for SPR detection based on a gravity-induced flow injection (gFI) system. The gFI system was tubeless and did not need to be controlled. The fluid was driven into the detection areas by its own gravitational force. A transition channel was used to increase the liquid-level difference between the inlet reservoir and the outlet reservoir. After a liquid sample was placed in the inlet reservoir, the flow rate of the liquid sample was increased in the transition channel. Before it arrived at the sensing surface, the flow rate of the sample was steady (with an error of less than 10%). The fluctuation of the flow rate had an influence on the SPR response signal, which was successfully denoised using an internal reference. With the gFI system, the SPR imaging biosensor was able to perform real-time detection manually. The SPR responses of DNA hybridization and protein immobilization were successfully obtained.