Efficacy and Safety of Chinese Herbal Medicine in Patients with Acute Intracerebral Hemorrhage: Protocol for a Randomized Placebo-Controlled Double-Blinded Multicenter Trial.

INTRODUCTION: The popular traditional Chinese medicine (TCM) compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) through effects on brain edema, hematoma absorption, and the immune system. This study is to assess whether FYTF-919 is safe and effective as compared to matching placebo treatment in patients with acute ICH. METHODS: The ongoing Chinese Herbal medicine in patients with Acute INtracerebral hemorrhage (CHAIN) is a multicenter, prospective, randomized, double-blind placebo-controlled trial of FYTF-919 in patients with acute ICH at 20-30 hospital sites in China. Eligible ICH patients presenting within 48 h after symptom onset are randomly allocated to receive either FYTF-919 (100 mL per day × 28 d, oral) or matching placebo. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) to detect a ≥20% improvement in average utility-weight scores on the modified Rankin scale (UW-mRS) assessed at 90 days, with 6% non-adherence and 10% lost to follow-up. The primary efficacy outcome is UW-mRS at 90 days. Secondary outcomes include binary measures of the mRS, neurological impairment on the National Institute of Health Stroke Scale, and health-related quality of life on the EuroQol EQ-5D-5L scale at different time points over 6 months of follow-up. The key safety measure is serious adverse events. CONCLUSION: CHAIN is on schedule to provide reliable evidence over the benefits of a popular herbal TCM for the treatment of acute ICH.

TM4SF1 promotes glioma malignancy through multiple mechanisms.

Transmembrane-4 L Six Family member 1 (TM4SF1) belongs to a family of integral membrane proteins implicated in cell growth and tumor progression. Glioma is the most common and aggressive malignant brain tumor in adults. In this study, we showed that TM4SF1 was highly expressed in glioma tumor tissues and cell lines. The expression levels of TM4SF1 were negatively correlated with patients' survival rates. Silencing TM4SF1 by RNA interference inhibited the proliferation, migration, and invasion of glioma cells. Moreover, TM4SF1 silencing induced glioma cell cycle arrest and early apoptosis. In contrast, overexpression of TM4SF1 in glioma cells exhibited the opposite effects. Mechanistically, we found that loss of TM4SF1 reduced phospho-ATK, Cyclin D1, Bcl-2, and MMP-9 levels in glioma cells. Taken together, these findings provide novel insights into glioma pathogenesis and suggest that TM4SF1 may represent a novel target for glioma intervention.

GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis.

Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell-autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma.

Portal hypertension predicts short-term and long-term outcomes after hepatectomy in hepatocellular carcinoma patients.

BACKGROUND AND AIMS: The impact of portal hypertension (PH) on postoperative short-term outcomes and long-term survival in hepatocellular carcinoma (HCC) patients has lately been discussed controversially. This study aimed to explore the influence of PH on postoperative outcomes in HCC patients undergoing surgical resection. METHODS: Patients undergoing hepatectomy for HCC from 2010 to 2014 were enrolled. The impact of PH on postoperative complications, posthepatectomy liver failure (PHLF) and overall survival (OS) was evaluated. RESULTS: A total of 355 HCC patients were enrolled; 129 (36.3%) experienced postoperative complications and 21 (5.9%) developed PHLF. PH was identified as an independent predictor of PHLF. Patients with PH experienced a higher incidence of complications and PHLF than patients without PH. On the Cox proportional hazards regression model, PH was verified as a risk factor of OS for BCLC stage 0/A and B patients. Patients without PH had significantly better long-term survival compared to patients with PH both in the total cohort and in cirrhosis subgroup. CONCLUSION: Liver resection in HCC patients with PH showed a significantly increased postoperative complications and PHLF, and revealed a decreasing long-term survival than non-PH patients. Besides, tumor burden also played an important role in determining the OS. However, due to the improvement in surgical technique and perioperative management, surgery was feasible in carefully selected HCC patients with PH.

Room-temperature Cu-catalyzed N-arylation of aliphatic amines in neat water.

A room-temperature and PTC-free copper-catalyzed N-arylation of aliphatic amines in neat water has been developed. Using a combination of CuI and 6,7-dihydroquinolin-8(5H)-one oxime as the catalyst and KOH as the base, a wide range of aliphatic amines are arylated with various aryl and heteroaryl halides to give the corresponding products in up to 95% yield.

A non-genetic approach to labelling acute myeloid leukemia and bone marrow cells with quantum dots.

The difficulty in manipulation of leukemia cells has long hindered the dissection of leukemia pathogenesis. We have introduced a non-genetic approach of marking blood cells, using quantum dots. We compared quantum dots complexed with different vehicles, including a peptide Tat, cationic polymer Turbofect and liposome. Quantum dots-Tat showed the highest efficiency of marking hematopoietic cells among the three vehicles. Quantum dots-Tat could also label a panel of leukemia cell lines at varied efficiencies. More uniform intracellular distributions of quantum dots in mouse bone marrow and leukemia cells were obtained with quantum dots-Tat, compared with the granule-like formation obtained with quantum dots-liposome. Our results suggest that quantum dots have provided a photostable and non-genetic approach that labels normal and malignant hematopoietic cells, in a cell type-, vehicle-, and quantum dot concentration-dependent manner. We expect for potential applications of quantum dots as an easy and fast marking tool assisting investigations of various types of blood cells in the future.

A rare condition similar to inguinal hernia in pregnancy: A case of bilateral varicose veins of round ligament of uterus.

Round ligament varicosities (RLV) are a very rare cause of an inguinal mass, which is very similar to an inguinal hernia, and should be taken seriously by women, especially in mid-pregnancy. Ultrasound can confirm the diagnosis of the RLV and can prevent unnecessary interventions. We report a case of a patient with bilateral RLV: the primigravida was 31 years old, G1P0, gestation 30+2w. The patient presented to the clinic 1 month ago due to the discovery of bilateral inguinal masses. After the diagnosis was confirmed by ultrasound, this patient received regular reviews during labor and delivery and is currently in good maternal condition. The patient came to the clinic 1 month after the discovery of bilateral inguinal area masses for 1 month.

Design of Spectrum Processing Chiplet Based on FFT Algorithm.

With the rapid development of electronic information and computer science, the fast Fourier transform (FFT) has played an increasingly important role in digital signal processing (DSP). This paper presented a spectrum processing chiplet design method to solve slow speed, low precision, and low resource utilization in spectrum processing of general-purpose spectrum chips and field programmable gate array (FPGA). To realize signal processing, the Radix-2 4096-point FFT algorithm with pipeline structure is used to process spectral signals extracted from the time domain. To reduce the harm caused by spectrum leakage, a windowing module is added to optimize the input data, and the clock gating unit (CGU) is used to perform low-power management on the entire clock reset. The result shows the chiplet takes 0.368 ms to complete a 4096-point frequency sweep under a clock frequency of 61.44 MHz. The chiplet significantly improves speed and accuracy in spectrum processing, which has great application potential in wireless communication.

Application and Prospect of Artificial Intelligence Methods in Signal Integrity Prediction and Optimization of Microsystems.

Microsystems are widely used in 5G, the Internet of Things, smart electronic devices and other fields, and signal integrity (SI) determines their performance. Establishing accurate and fast predictive models and intelligent optimization models for SI in microsystems is extremely essential. Recently, neural networks (NNs) and heuristic optimization algorithms have been widely used to predict the SI performance of microsystems. This paper systematically summarizes the neural network methods applied in the prediction of microsystem SI performance, including artificial neural network (ANN), deep neural network (DNN), recurrent neural network (RNN), convolutional neural network (CNN), etc., as well as intelligent algorithms applied in the optimization of microsystem SI, including genetic algorithm (GA), differential evolution (DE), deep partition tree Bayesian optimization (DPTBO), two stage Bayesian optimization (TSBO), etc., and compares and discusses the characteristics and application fields of the current applied methods. The future development prospects are also predicted. Finally, the article is summarized.

The impairment of one-trial passive avoidance learning in chicks caused by prenatal aluminum exposure.

Prenatal aluminum exposure may affect the development of the embryo and alter the capacity for learning and memory in adults. The chick embryo is a good experimental model to study the effect of prenatal toxin exposure on cognitive defects in offspring, because it eliminates maternal confounding variables. In the present study, we applied a one-trial passive avoidance-learning task in day-old chicks to examine the effects of prenatal aluminum chloride injections (2, 20, and 200 mM in 200 µl per egg, daily over a period of 4 successive days) on memory consolidation. The data suggest that chicks injected with aluminum chloride (20 mM) daily from E12 to E15 had significantly impaired short-term memory, intermediate-term memory, and long-term memory (LTM) after training (p < .05) but chicks injected with aluminum chloride (2 mM) had impaired LTM only.

Architecture of Computing System based on Chiplet.

Computing systems are widely used in medical diagnosis, climate prediction, autonomous vehicles, etc. As the key part of electronics, the performance of computing systems is crucial in the intellectualization of the equipment. The conflict between performance, efficiency, and cost can be solved by choosing an appropriate computing system architecture. In order to provide useful advice and instructions for the designers to fabricate high-performance computing systems, this paper reviews the Chiplet-based computing system architectures, including computing architecture and memory architecture. Firstly, the computing architecture used for high-performance computing, mobile, and PC is presented and summarized. Secondly, the memory architecture based on mainstream memory and emerging non-volatile memory used for data storing and processing are introduced, and the key parameters of memory are compared and discussed. Finally, this paper is concluded, and the future perspectives of computing system architecture based on Chiplet are presented.

Predictive Equations for Adult Pulmonary Function in Zhejiang Province, China.

Background: Accurate interpretation of lung function tests requires appropriate spirometry reference values derived from large-scale population-specific epidemiological surveys. The aim of this cross-sectional study was to establish normal spirometric values for the population of healthy, nonsmoking Han Chinese adults residing in Zhejiang province, China. Methods: We measured lung function parameters such as forced expiratory volume in 1 s, forced vital capacity, peak expiratory flow, maximal midexpiratory flow, and diffusion capacity for carbon monoxide and considered age, height, and weight as independent factors that may modify these parameters. The clinical data were divided into the study arm and validation group. The study arms were used to construct predictive equations using stepwise multiple linear regression, and data from the validation group were used to assess the robustness of the equations. Results: The 3866 participants were randomized into a study arm (n = 1,949) and a validation arm (n = 1,917). Lung function parameters had a negative association with age and a positive association with height. Data from the two groups were similar. Predictive equations were constructed from the study arm, and the validation group was used to test the feasibility of the reference equations. Conclusions: The reference values we derived can be used to evaluate lung function in this cohort in both epidemiological studies and clinical practice.

Membrane protein-chimeric liposome-mediated delivery of triptolide for targeted hepatocellular carcinoma therapy.

Triptolide (TPL) is a diterpenoid triepoxide with broad antitumor efficacy, while lack of mechanism of action, severe systemic toxicity, and poor water solubility of TPL limited its usage. To unveil the mechanism of action and improve the pharmaceutical properties of TPL, here we explored the molecular mechanism of TPL and then fabricated TPL-loaded membrane protein-chimeric liposomes (TPL@MP-LP) and tested its anticancer efficacy against hepatocellular carcinoma (HCC). CCK8 assay, colony formation assay, EdU assay, and flow cytometry were used to examine the activity of TPL. RNA sequence and gain-and-loss of function assays were used to explore the molecular mechanisms. TPL@MP-LP was characterized by size, zeta potential, polydispersity index, and transmission electron microscopy. Cellular uptake and cell viability assay were performed to evaluate the internalization and anticancer efficacy of TPL@MP-LP in vitro. Biodistribution and in vivo antitumor efficacy of TPL@MP-LP were evaluated on orthotopic HCC mice models. TPL robustly inhibited HCC cells by inducing cell proliferation arrest, apoptosis via the mitochondrial pathway, and necroptosis via RIPK1/RIPK3/MLKL signaling. TPL was successfully loaded into MP-LP, with a drug-loading capacity of 5.62 ± 0.80%. MP-LP facilitated TPL internalization and TPL@MP-LP exerted enhanced anticancer efficacy against Huh7 cells. TPL@MP-LP showed targeting ability to the tumor site. More importantly, TPL@MP-LP treatment suppressed tumor growth but showed minimal damage to liver and renal functions. TPL exerted anticancer effects on HCC via inducing cell proliferation arrest, apoptosis, and necroptosis, and the MP-LP might be a promising delivery strategy to improve the antitumor efficacy while mitigating toxicity of TPL for HCC therapy.

Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment.

BACKGROUND AND AIM: Pancreatic cancer is one of the most malignant tumors worldwide. Zuojin pills (ZJP), a traditional Chinese medicine (TCM) formula, which can treat a variety of cancers. However, the active compounds present in ZJP and the potential mechanisms through which ZJP acts against pancreatic cancer have not been thoroughly investigated. METHODS: Data on pancreatic cancer-related genes, bioactive compounds, and potential targets of ZJP were downloaded from public databases. Bioinformatics analysis, including protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, was conducted to identify important components, potential targets, and signaling pathways through which ZJP affects pancreatic cancer. The results of this analysis were verified by in vitro experiments. RESULTS: The network pharmacology analysis results showed that 41 compounds and 130 putative target genes of ZJP were associated with anti-pancreatic cancer effects. ZJP may exert its inhibitory effects against pancreatic cancer by acting on key targets such as JUN, TP53, and MAPK1. Moreover, KEGG analysis indicated that the anti-pancreatic cancer effect of ZJP was mediated by multiple pathways, such as the PI3K-AKT, IL-17, TNF, HIF-1, and P53 signaling pathways. Among these, the PI3K-AKT signaling pathway, which included the highest number of enriched genes, may play a more important role in treating pancreatic cancer. The in vitro results showed that ZJP significantly inhibits the cell cycle and cell proliferation through the PI3K/AKT/caspase pathway and that it can induce apoptosis of pancreatic cancer cells, consistent with the results predicted by network pharmacological methods. CONCLUSION: This study preliminarily investigated the pharmacological effects of ZJP, which appear to be mediated by multiple compounds, targets and pathways, and its potential therapeutic effect on pancreatic cancer. Importantly, our work provides a promising approach for the identification of compounds in TCM and the characterization of therapeutic mechanisms.

GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway.

Guanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.

Sulfasalazine Sensitizes Polyhematoporphyrin-Mediated Photodynamic Therapy in Cholangiocarcinoma by Targeting xCT.

Cholangiocarcinoma (CCA), which is highly malignant, shows a relatively poor prognosis, due to the insensitivity of the tumour to chemotherapy and radiotherapy. Photodynamic therapy (PDT) has become a promising palliative therapeutic option for patients with unresectable cholangiocarcinoma (CCA), while the functional amount of ROS is limited by intracellular redox systemen. Sulfasalazine (SASP), a well-known anti-inflammatory agent, which also acts as an inhibitor of the amino acid transport system xc (xCT), decreases the intracellular glutathione (GSH) level, thus weakening the antioxidant defence of the cell by inhibition of the antiporter. However, the combination of SASP and PDT remains unexplored. We have reported that polyhematoporphyrin (PHP)-mediated PDT inhibits the cell viability of CCA cells and organoids. Furthermore, in PHP-enriched HCCC-9810 and TFK-1CCA cells, SASP enhances the sensitivity to PHP-mediated PDT through a GSH-dependent mechanism. We found that PHP-PDT can up-regulate xCT expression to promote cells against overloaded ROS, while SASP reduces GSH levels. After the combination of SASP and PHP-PDT, cell viability and GSH levels were significantly inhibited. xCT was also observed to be inhibited by SASP in human organoid samples. Our findings suggest that, in combination with PDT, SASP has potential as a promising approach against CCA.

miR-7112-3p targets PERK to regulate the endoplasmic reticulum stress pathway and apoptosis induced by photodynamic therapy in colorectal cancer CX-1 cells.

BACKGROUND: Colorectal cancer (CRC) is the third most common malignant tumor worldwide. Photodynamic therapy (PDT) is an emerging modality for the treatment of solid tumors. Sinoporphyrin sodium (DVDMS) is a new photosensitizer with good therapeutic killing effects on cancer cells. Recent findings have shown that microRNAs play important roles in many biological processes. However, the functions of microRNAs in DVDMS-induced PDT remain largely unclear. MATERIALS AND METHODS: Proteins involved in endoplasmic reticulum (ER) stress and apoptosis of CX-1 cells treated with DVDMS-PDT were examined by Western blotting and cell viability assays. 15 candidate miRNAs targeting RNA-dependent protein kinase-like ER kinase (PERK) were screened and verified using the TargetScan, miRWalk and miRDB databases. The downstream pathways of candidate miRNAs with high scores were studied by cell transfection, qRT-PCR, Western blotting and dual-luciferase reporter assays. The subcellular location of DVDMS was confirmed by laser confocal microscopy. RESULTS: DVDMS-PDT induced apoptosis via elevated ER stress and activation of the PERK/ATF4/CHOP/caspase cascade pathway in CX-1 cells. The endoplasmic reticulum was involved in the subcellular accumulation of DVDMS in CX-1 cells. Dual-luciferase reporting experiment confirmed that a direct crosslinking between miR-7112-3p and PERK. In addition, miR-7112-3p was highly expressed in CRC tissues compared with peripheral tissues. CONCLUSION: Our work showed that miR-7112-3p directly targeted PERK and further regulated PERK/ATF4/CHOP/caspase cascade pathway, resulting in enhanced apoptosis in CX-1 cells treated with DVDMS-PDT.

Transcriptomic Analysis of circRNAs in the Peripheral Blood of Nonarteritic Anterior Ischemic Optic Neuropathy.

The aim of the study is to explore the expression profile variation of circular RNAs (circRNAs) in the peripheral blood of subjects with nonarteritic anterior ischemic optic neuropathy (NAION) and without NAION, to analyze the differential expression results, and to predict the role of circRNAs in disease development, providing novel ideas and methods for treatment and diagnosis. High-throughput sequencing to explore the expression profiles of RNAs in the peripheral blood of 6 NAION patients and 5 healthy controls was applied. Quality control obtained the advanced data from the original data by ticking out the unqualified data. Then, cluster analysis, volcano plot, coexpression network, and protein-protein interaction network (PPI) were performed. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used to analyze the whole expressed genes. Lastly, the quantitative real-time Polymerase Chain Reaction (qRT-PCR) was used to verify those significantly differentially expressed circRNAs and do some bioinformatics analysis and prediction in 12 NAION patients and 12 controls. There were significant differences in the expression of 49 circRNAs in the peripheral blood of NAION patients, in which there were 24 upregulations and 25 downregulations (variation folds > 2 and P < 0.05), and it was confirmed that hsa_circ_0005583, hsa_circ_0003922, hsa_circ_0002021, and hsa_circ_0000462 were significantly downregulated (variation folds > 2 and P < 0.05), especially hsa_circ_0005583 which was the most significantly changed one (P < 0.001), and are related to processes such as neurodegeneration, oxidative stress, immunity, and metabolism. The expression profile of circRNAs in the peripheral blood of NAION patients is significantly changed, enriching our understanding of the disease.

Application of photodynamic therapy for liver malignancies.

Liver malignancies include primary and metastatic tumors. Limited progress has been achieved in improving the survival rate of patients with advanced stage liver cancer and who are unsuitable for surgery. Apart from surgery, chemoradiotherapy, trans-arterial chemoembolization and radiofrequency ablation, a novel therapeutic modality is needed for the clinical treatment of liver cancer. Photodynamic therapy (PDT) is a novel strategy for treating patients with advanced cancers; it uses a light-triggered cytotoxic photosensitizer and a laser light. PDT provides patients with a potential treatment approach with minimal invasion and low toxicity, that is, the whole course of treatment is painless, harmless, and repeatable. Therefore, PDT has been considered an effective palliative treatment for advanced liver cancers. To date, PDT has been used to treat hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma and liver metastases. Clinical outcomes reveal that PDT can be considered a promising treatment modality for all liver cancers to improve the quality and quantity of life of patients. Despite the advances achieved with this approach, several challenges still impede the application of PDT to liver malignancies. In this review, we focus on the recent advancements and discuss the future prospects of PDT in treating liver malignancies.

GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway.

Guanylate-binding protein 2 (GBP2) is an interferon-inducible large GTPase which is crucial to the protective immunity against microorganisms. However, its biological function in cancer remains largely unknown. Glioblastoma multiforme (GBM) is the most common and deadly brain tumor in adults. Here we show that GBP2 expression is highly elevated in GBM tumor and cell lines, particularly in those of the mesenchymal subtype. High GBP2 expression is associated with poor prognosis. GBP2 overexpression significantly promotes GBM cell migration and invasion in vitro, and GBP2 silencing by RNA interference exhibits opposite effects. We further show that fibronectin (FN1) is dramatically induced by GBP2 expression at both mRNA and protein levels, and FN1 is essential for GBP2-promoted GBM invasiveness. Inhibition of Stat3 pathway prevents GBP2-promoted FN1 induction and cell invasion. Consistently, GBP2 dramatically promotes GBM tumor growth and invasion in mice and significantly reduces the survival time of the mice with tumor. Taken together, these findings establish the role of GBP2/Stat3/FN1 signaling cascade in GBM invasion and suggest GBP2 may serve as a potential therapeutic target for inhibiting GBM invasion.