JCcirc: circRNA full-length sequence assembly through integrated junction contigs.

Recent studies have shed light on the potential of circular RNA (circRNA) as a biomarker for disease diagnosis and as a nucleic acid vaccine. The exploration of these functionalities requires correct circRNA full-length sequences; however, existing assembly tools can only correctly assemble some circRNAs, and their performance can be further improved. Here, we introduce a novel feature known as the junction contig (JC), which is an extension of the back-splice junction (BSJ). Leveraging the strengths of both BSJ and JC, we present a novel method called JCcirc (https://github.com/cbbzhang/JCcirc). It enables efficient reconstruction of all types of circRNA full-length sequences and their alternative isoforms using splice graphs and fragment coverage. Our findings demonstrate the superiority of JCcirc over existing methods on human simulation datasets, and its average F1 score surpasses CircAST by 0.40 and outperforms both CIRI-full and circRNAfull by 0.13. For circRNAs below 400 bp, 400-800 bp, 800 bp-1200 bp and above 1200 bp, the correct assembly rates are 0.13, 0.09, 0.04 and 0.03 higher, respectively, than those achieved by existing methods. Moreover, JCcirc also outperforms existing assembly tools on other five model species datasets and real sequencing datasets. These results show that JCcirc is a robust tool for accurately assembling circRNA full-length sequences, laying the foundation for the functional analysis of circRNAs.

Design, in silico evaluation, and in vitro verification of new bivalent Smac mimetics with pro-apoptotic activity.

Bivalent Smac mimetics have been shown to possess binding affinity and pro-apoptotic activity similar to or more potent than that of native Smac, a protein dimer able to neutralize the anti-apoptotic activity of an inhibitor of caspase enzymes, XIAP, which endows cancer cells with resistance to anticancer drugs. We design five new bivalent Smac mimetics, which are formed by various linkers tethering two diazabicyclic cores being the IAP binding motifs. We built in silico models of the five mimetics by the TwistDock workflow and evaluated their conformational tendency, which suggests that compound 3, whose linker is n-hexylene, possess the highest binding potency among the five. After synthesis of these compounds, their ability in tumour cell growth inhibition and apoptosis induction displayed in experiments with SK-OV-3 and MDA-MB-231 cancer cell lines confirms our prediction. Among the five mimetics, compound 3 displays promising pro-apoptotic activity and deserves further optimization.

Differential requirement for DICER1 activity during the development of mitral and tricuspid valves.

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. Here, we specifically inactivated Dicer1 in the endocardium during cardiogenesis and found that Dicer1 deletion caused congenital mitral valve stenosis and regurgitation, whereas it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. We thus reveal miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.

High-throughput computational materials screening of transition metal peroxides.

Semiconductor materials of abnormal stoichiometric ratio often exhibit unique properties, yet it is still a challenge to determine the structures of such materials in an efficient way. Herein, we propose a method for structurally biased screening according to the coordination numbers and the numbers of Wyckoff positions, balancing the atom local environment and the global symmetry of structures. Based on first-principles calculations, we have predicted two metastable peroxides P21/c-ScO2 and Pmmn-TiO3 with more than six coordination points. For these two structures, the most stable intrinsic defect is the oxygen vacancy (VO) at the peroxide anion (O2-2), which induces the absence of antibonding orbital formed by O2-2 near the valence band maximum. With the introduction of VO, the decrease of coordination numbers leads to charge recombination, and results in the appearance of an ordered phase TiO2.5 with stronger Ti-O orbital hybridization. The proposed method presents a promising and feasible approach for the screening of novel compounds.

Hidden blood loss and its risk factors in percutaneous vertebroplasty surgery for osteoporotic vertebral compression fractures.

OBJECTIVES: Percutaneous vertebroplasty (PVP) is a percutaneous interventional procedure for osteoporotic vertebral compression fractures (OVCFs). However, hidden blood loss (HBL) during the surgery is easily disregarded. This study aimed to evaluate HBL and its possible risk factors in the patients following PVP for OVCFs. METHODS: Patients with OVCFs who underwent PVP surgery between January 2019 and November 2022 at our hospital were retrospectively analyzed. Patients' demographics, laboratory data, and imaging and clinical date were also collected. Preoperative and postoperative hematocrit were recorded, the hidden blood loss was calculated according to Sehat formula, and the risk factors were analyzed by multivariate linear regression analysis. RESULTS: One hundred and fifty-five patients (26 males and 129 females) were retrospectively enrolled in this study. 85.2% of patients had one segment vertebral fracture and the mean surgical time was 30.5 ± 11.0 min. No intraspinal cement leakage occurred. The mean HBL was 204.0 ± 89.6 ml. Multivariate linear regression analysis revealed that HBL was positively associated with number of fracture segments (P = 0.001), degree of vertebral height restoration (P = 0.001), surgical time (P = 0.000), number of puncture (P = 0.002), and cement leakage (P = 0.038). CONCLUSIONS: Multiple vertebral fractures, higher degree of vertebral height restoration, longer surgical time, more number of puncture, and cement leakage are independent risk factors for HBL. Therefore, HBL should not be neglected in the patients with OVCFs undergoing PVP surgery, especially in those with poor preoperative physical condition and presence of anemia.

[Efficacy and safety of low-dose rituximab in treatment of pediatric nephrotic syndrome: a prospective randomized controlled trial]. / ä½Žå‰‚é‡åˆ©å¦¥æ˜”å•æŠ—æ²»ç–—å„¿ç«¥è‚¾ç— ç»¼åˆå¾ç–—æ•ˆåŠå®‰å ¨æ€§çš„å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To study the efficacy and safety of repeated application of rituximab (RTX) at a low dose (200 mg/m2) versus the recommended dose (375 mg/m2) for remission maintenance in frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). METHODS: A randomized controlled trial was conducted for 29 children with FRNS/SDNS who received systemic treatment in the Department of Nephrology, Anhui Provincial Children's Hospital, from September 2020 to December 2021. These children were divided into a recommended dose group (n=14) and a low dose group (n=15) using a random number table. The two groups were compared in terms of general characteristics, changes in CD19 expression after RTX treatment, number of relapses, glucocorticoid dose, adverse reactions of RTX, and hospital costs. RESULTS: After RTX treatment, both the low dose group and the recommended dose group achieved B-lymphocyte depletion and had significant reductions in the number of relapses and glucocorticoid dose (P<0.05). The low dose group had a comparable clinical effect to the recommended dose group after RTX treatment (P>0.05), and the low dose group had a significant reduction in hospital costs for the second, third, and fourth times of hospitalization (P<0.05). There were no serious adverse reactions in either group during RTX treatment and late follow-up, and there was no significant difference in adverse reactions between the two groups (P>0.05). CONCLUSIONS: Repeated RTX treatment at a low dose has comparable clinical efficacy and safety to that at the recommended dose and can significantly reduce the number of FRNS/SDNS relapses and the amount of glucocorticoids used, with little adverse effect throughout the treatment cycle. Therefore, it holds promise for clinical application.

Reconstruction of Full-Length circRNA Sequences Using Chimeric Alignment Information.

Circular RNAs (circRNAs) are RNA molecules formed by joining a downstream 3 splice donor site and an upstream 5 splice acceptor site. Several recent studies have identified circRNAs as potential biomarker for different diseases. A number of methods are available for the identification of circRNAs. The circRNA identification methods cannot provide full-length sequences. Reconstruction of the full-length sequences is crucial for the downstream analyses of circRNA research including differential expression analysis, circRNA-miRNA interaction analysis and other functional studies of the circRNAs. However, a limited number of methods are available in the literature for the reconstruction of full-length circRNA sequences. We developed a new method, circRNA-full, for full-length circRNA sequence reconstruction utilizing chimeric alignment information from the STAR aligner. To evaluate our method, we used full-length circRNA sequences produced by isocirc and ciri-long using long-reads RNA-seq data. Our method achieved better reconstruction rate, precision, sensitivity and F1 score than the existing full-length circRNA sequence reconstruction tool ciri-full for both human and mouse data.

A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/ß-catenin signaling pathway to promote gastric cancer progression.

BACKGROUND: Circular RNA (circRNA), a subclass of non-coding RNA, plays a critical role in cancer tumorigenesis and metastasis. It has been suggested that circRNA acts as a microRNA sponge or a scaffold to interact with protein complexes; however, its full range of functions remains elusive. Recently, some circRNAs have been found to have coding potential. METHODS: To investigate the role of circRNAs in gastric cancer (GC), parallel sequencing was performed using five paired GC samples. Differentially expressed circAXIN1 was proposed to encode a novel protein. FLAG-tagged circRNA overexpression plasmid construction, immunoblotting, mass spectrometry, and luciferase reporter analyses were applied to confirm the coding potential of circAXIN1. Gain- and loss-of-function studies were conducted to study the oncogenic role of circAXIN1 and AXIN1-295aa on the proliferation, migration, invasion, and metastasis of GC cells in vitro and in vivo. The competitive interaction between AXIN1-295aa and adenomatous polyposis coli (APC) was investigated by immunoprecipitation analyses. Wnt signaling activity was observed using a Top/Fopflash assay, real-time quantitative RT-PCR, immunoblotting, immunofluorescence staining, and chromatin immunoprecipitation. RESULTS: CircAXIN1 is highly expressed in GC tissues compared with its expression in paired adjacent normal gastric tissues. CircAXIN1 encodes a 295 amino acid (aa) novel protein, which was named AXIN1-295aa. CircAXIN1 overexpression enhances the cell proliferation, migration, and invasion of GC cells, while the knockdown of circAXIN1 inhibits the malignant behaviors of GC cells in vitro and in vivo. Mechanistically, AXIN1-295aa competitively interacts with APC, leading to dysfunction of the "destruction complex" of the Wnt pathway. Released ß-catenin translocates to the nucleus and binds to the TCF consensus site on the promoter, inducing downstream gene expression. CONCLUSION: CircAXIN1 encodes a novel protein, AXIN1-295aa. AXIN1-295aa functions as an oncogenic protein, activating the Wnt signaling pathway to promote GC tumorigenesis and progression, suggesting a potential therapeutic target for GC.

miR-142 downregulation alleviates rat PTSD-like behaviors, reduces the level of inflammatory cytokine expression and apoptosis in hippocampus, and upregulates the expression of fragile X mental retardation protein.

BACKGROUND: FMRP is a selective mRNA-binding protein that regulates protein synthesis at synapses, and its loss may lead to the impairment of trace fear memory. Previously, we found that FMRP levels in the hippocampus of rats with post-traumatic stress disorder (PTSD) were decreased. However, the mechanism underlying these changes remains unclear. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into four groups. The experimental groups were treated with the single-prolonged stress (SPS) procedure and injected with a lentivirus-mediated inhibitor of miR-142-5p. Behavior test as well as morphology and molecular biology experiments were performed to detect the effect of miR-142 downregulation on PTSD, which was further verified by in vitro experiments. RESULTS: We found that silence of miRNA-142 (miR-142), an upstream regulator of FMRP, could alleviate PTSD-like behaviors of rats exposed to the SPS paradigm. MiR-142 silence not only decreased the levels of proinflammatory mediators, such as interleukin-1ß, interleukin-6, and tumor necrosis factor-α, but also increased the expressive levels of synaptic proteins including PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We further detected that miR-142 silence also downregulated the transportation of nuclear factor kappa-B (NF-κB) into the nuclei of neurons and might further affect the morphology of neurons. CONCLUSIONS: The results revealed miR-142 downregulation could alleviate PTSD-like behaviors through attenuating neuroinflammation in the hippocampus of SPS rats by binding to FMRP.

miR-132 Regulates PTSD-like Behaviors in Rats Following Single-Prolonged Stress Through Fragile X-Related Protein 1.

Fragile X-related protein 1 (FXR1) is a member of the fragile X family of RNA-binding proteins, which regulates a number of neurological and neuropsychiatric disorders such as fragile X syndrome, and is expected as a novel therapeutic target for some psychiatric diseases. However, it is unknown how FXR1 changes and functions in post-traumatic stress disorder (PTSD), a common mental disorder related to trauma and stressor. In this study, we characterized the expression pattern of FXR1 in the pathophysiological process of PTSD and further investigated the possible mechanism underlying these changes by finding an upstream regulator, namely miRNA-132 (miR-132). Furthermore, we verified whether miR-132 silence had an effect on the PTSD-like behaviors of single prolonged stress (SPS) rats through open field test, forced swimming test, and water maze test. At last, we examined the expression levels of PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We showed that the levels of FXR1 and fragile X mental retardation protein (FMRP), an autosomal homolog of FXR1, were decreased in the hippocampus of PTSD rats, but the levels of PSD95 and synapsin I were increased, which could be reversed by downregulation of miR-132. The results revealed that miR-132 could modulate PTSD-like behaviors in rats following SPS through regulating FXR1 and FMRP.

A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008µM and 9.453 µM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.

Identification of Potential Long Non-Coding RNA Candidates that Contribute to Triple-Negative Breast Cancer in Humans through Computational Approach.

Breast cancer (BC) is the most frequent malignancy identified in adult females, resulting in enormous financial losses worldwide. Owing to the heterogeneity as well as various molecular subtypes, the molecular pathways underlying carcinogenesis in various forms of BC are distinct. Therefore, the advancement of alternative therapy is required to combat the ailment. Recent analyses propose that long non-coding RNAs (lncRNAs) perform an essential function in controlling immune response, and therefore, may provide essential information about the disorder. However, their function in patients with triple-negative BC (TNBC) has not been explored in detail. Here, we analyzed the changes in the genomic expression of messenger RNA (mRNA) and lncRNA in standard control in response to cancer metastasis using publicly available single-cell RNA-Seq data. We identified a total of 197 potentially novel lncRNAs in TNBC patients of which 86 were differentially upregulated and 111 were differentially downregulated. In addition, among the 909 candidate lncRNA transcripts, 19 were significantly differentially expressed (DE) of which three were upregulated and 16 were downregulated. On the other hand, 1901 mRNA transcripts were significantly DE of which 1110 were upregulated and 791 were downregulated by TNBCs subtypes. The Gene Ontology (GO) analyses showed that some of the host genes were enriched in various biological, molecular, and cellular functions. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that some of the genes were involved in only one pathway of prostate cancer. The lncRNA-miRNA-gene network analysis showed that the lncRNAs TCONS_00076394 and TCONS_00051377 interacted with breast cancer-related micro RNAs (miRNAs) and the host genes of these lncRNAs were also functionally related to breast cancer. Thus, this study provides novel lncRNAs as potential biomarkers for the therapeutic intervention of this cancer subtype.

SEMA6D regulates perinatal cardiomyocyte proliferation and maturation in mice.

Cardiomyocytes undergo dramatic changes during the fetal to neonatal transition stage to adapt to the new environment. The molecular and genetic mechanisms regulating these changes remain elusive. In this study, we showed Sema6D as a novel signaling molecule regulating perinatal cardiomyocyte proliferation and maturation. SEMA6D is a member of the Semaphorin family of signaling molecules. To reveal its function during cardiogenesis, we specifically inactivated Sema6D in embryonic cardiomyocytes using a conditional gene deletion approach. All mutant animals showed hypoplastic myocardial walls in neonatal hearts due to reduced cell proliferation. We further revealed that expression of MYCN and its downstream cell cycle regulators is impaired in late fetal hearts in which Sema6D is deleted, suggesting that SEMA6D acts through MYCN to regulate cardiomyocyte proliferation. In early postnatal mutant hearts, expression of adult forms of sarcomeric proteins is increased, while expression of embryonic forms is decreased. These data collectively suggest that SEMA6D is required to maintain late fetal/early neonatal cardiomyocytes at a proliferative and less mature status. Deletion of Sema6D in cardiomyocytes led to reduced proliferation and accelerated maturation. We further examined the consequence of these defects through echocardiographic analysis. Embryonic heart deletion of Sema6D significantly impaired the cardiac contraction of male adult hearts, while having a minor effect on female mutant hearts, suggesting that the effect of Sema6D-deletion in adult hearts is sex dependent.

miRNA-192 and -215 activate Wnt/ß-catenin signaling pathway in gastric cancer via APC.

Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.

A novel machine learning based approach for iPS progenitor cell identification.

Identification of induced pluripotent stem (iPS) progenitor cells, the iPS forming cells in early stage of reprogramming, could provide valuable information for studying the origin and underlying mechanism of iPS cells. However, it is very difficult to identify experimentally since there are no biomarkers known for early progenitor cells, and only about 6 days after reprogramming initiation, iPS cells can be experimentally determined via fluorescent probes. What is more, the ratio of progenitor cells during early reprograming period is below 5%, which is too low to capture experimentally in the early stage. In this paper, we propose a novel computational approach for the identification of iPS progenitor cells based on machine learning and microscopic image analysis. Firstly, we record the reprogramming process using a live cell imaging system after 48 hours of infection with retroviruses expressing Oct4, Sox2 and Klf4, later iPS progenitor cells and normal murine embryonic fibroblasts (MEFs) within 3 to 5 days after infection are labeled by retrospectively tracing the time-lapse microscopic image. We then calculate 11 types of cell morphological and motion features such as area, speed, etc., and select best time windows for modeling and perform feature selection. Finally, a prediction model using XGBoost is built based on the selected six types of features and best time windows. Our model allows several missing values/frames in the sample datasets, thus it is applicable to a wide range of scenarios. Cross-validation, holdout validation and independent test experiments show that the minimum precision is above 52%, that is, the ratio of predicted progenitor cells within 3 to 5 days after viral infection is above 52%. The results also confirm that the morphology and motion pattern of iPS progenitor cells is different from that of normal MEFs, which helps with the machine learning methods for iPS progenitor cell identification.

Oxidation of Sodium Deoxycholate Catalyzed by Gold Nanoparticles and Chiral Recognition Performances of Bile Salt Micelles.

Au nanoparticles (NPs) were prepared by UV light irradiation of a mixed solution of HAuCl4 and sodium deoxycholate (NaDC) under alkaline condition, in which NaDC served as both reducing agent and capping agent. The reaction was monitored by circular dichroism (CD) spectra, and it was found that the formed gold NPs could catalyze the oxidation of NaDC. A CD signal at ~283 nm in the UV region was observed for the oxidation product of NaDC. The intensity of the CD signal of the oxidation product was enhanced gradually with the reaction time. Electrospray ionization (ESI) mass spectra and nuclear magnetic resonance (NMR) spectra were carried out to determine the chemical composition of the oxidation product, revealing that NaDC was selectively oxidized to sodium 3-keto-12-hydroxy-cholanate (3-KHC). The chiral discrimination abilities of the micelles of NaDC and its oxidation product, 3-KHC, were investigated by using chiral model molecules R,S-1,1'-Binaphthyl-2,2'-diyl hydrogenphosphate (R,S-BNDHP). Compared with NaDC, the micelles of 3-KHC displayed higher binding ability to the chiral model molecules. In addition, the difference in binding affinity of 3-KHC micelles towards R,S-isomer was observed, and S-isomer was shown to preferentially bind to the micelles.

Arenobufagin induces MCF-7 cell apoptosis by promoting JNK-mediated multisite phosphorylation of Yes-associated protein.

BACKGROUND: It has been demonstrated that bufadienolides exert potent anti-cancer activity in various tumor types. However, the mechanisms that underlie their anti-cancer properties remain unclear. Yes-associated protein, a key effector of Hippo signaling, functions as a transcription coactivator, plays oncogenic and tumor suppressor roles under different conditions. Here, we report that arenobufagin (ABF), a representative bufadienolide, induced breast cancer MCF-7 cells to undergo apoptosis, which occurred through the JNK-mediated multisite phosphorylation of YAP. METHODS: Cytotoxicity was examined using an MTT assay. ABF-induced apoptosis was measured with a TUNEL assay and Annexin V-FITC/PI double staining assay. Western blotting, immunofluorescence, qRT-PCR and coimmunoprecipitation were employed to assess the expression levels of the indicated molecules. Lose-of-function experiments were carried out with siRNA transfection and pharmacological inhibitors. ABF-induced phosphopeptides were enriched with Ti4+-IMAC chromatography and further subjected to reverse-phase nano-LC-MS/MS analysis. RESULTS: ABF significantly reduced the viability of MCF-7 cells and increased the percentage of early and late apoptotic cells in a concentration- and time-dependent manner. Following ABF treatment, YAP accumulated in the nucleus and bound to p73, which enhanced the transcription of the pro-apoptotic genes Bax and p53AIP1. YAP knock-down significantly attenuated ABF-induced apoptotic cell death. Importantly, we found that the mobility shift of YAP was derived from its phosphorylation at multiple sites, including Tyr357. Moreover, mass spectrometry analysis identified 19 potential phosphorylation sites in YAP, with a distribution of 14 phosphoserine and 5 phosphothreonine residues. Furthermore, we found that the JNK inhibitor SP600125 completely diminished the mobility shift of YAP and its phosphorylation at Tyr357, the binding of YAP and p73, the transcription of Bax and p53AIP1 as well as the apoptosis induced by ABF. These data indicate that ABF induced YAP multisite phosphorylation, which was associated with p73 binding, and that apoptosis was mediated by the JNK signaling pathway. CONCLUSIONS: Our data demonstrate that ABF suppresses MCF-7 breast cancer proliferation by triggering the pro-apoptotic activity of YAP, which is mediated by JNK signaling-induced YAP multisite phosphorylation as well as its association with p73. The present work not only provides additional information on the use of ABF as an anti-breast cancer drug, but also offers evidence that the induction of the tumor suppressor role of YAP may be a therapeutic strategy.

[Clinical effect and mechanism of hemoperfusion in treatment of children with severe abdominal Henoch-Schönlein purpura].

OBJECTIVE: To study the clinical effect and mechanism of hemoperfusion (HP) in the treatment of children with severe abdominal Henoch-Schönlein purpura (HSP). METHODS: A total of 24 children with severe abdominal HSP were divided into two groups: conventional treatment and HP (n=12 each). Ten healthy children who underwent physical examination were enrolled as the control group. Before and after treatment, chemiluminescence was used to measure the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); thiobarbituric acid colorimetry was used to measure the plasma level of malondialdehyde (MDA); the hydroxylamine method was used to measure the plasma level of superoxide dismutase (SOD); chemical colorimetry was used to measure the plasma level of total anti-oxidant capability (T-AOC). RESULTS: Compared with the control group, the conventional treatment and HP groups had significantly higher IL-6, TNF-α, and MDA levels and significantly lower SOD and T-AOC levels before treatment (P<0.05), but there were no significant differences between the conventional treatment and HP groups (P>0.05). After treatment, the conventional treatment and HP groups had significant reductions in IL-6, TNF-α, and MDA levels and significant increases in SOD and T-AOC levels (P<0.05). The HP group had significantly greater changes than the conventional treatment group; however, there were still significant differences in these indices between the HP and control groups (P<0.05). Compared with the HP group, the conventional treatment group had a significantly lower percentage of children with disappearance of digestive tract symptoms at 4 days after treatment and significantly longer time to disappearance of rash and digestive tract symptoms (P<0.05). Compared with the conventional treatment group, the HP group had a significantly lower amount of glucocorticoid used during treatment and a significantly lower percentage of children who experienced hematuria and/or proteinuria within 6 months of the disease course (P<0.05). There were no significant differences between the two groups in length of hospital stay and recurrence rates of rash and abdominal pain within 6 months of the disease course. CONCLUSIONS: HP can reduce the amount of glucocorticoid used during treatment and the incidence rate of kidney injury in children with severe abdominal HSP, possibly by eliminating IL-6, TNF-α, and MDA.

Cisplatin and photodynamic therapy exert synergistic inhibitory effects on small-cell lung cancer cell viability and xenograft tumor growth.

Lung cancer is the leading cause of cancer death worldwide. Small-cell lung cancer (SCLC) is an aggressive type of lung cancer that shows an overall 5-year survival rate below 10%. Although chemotherapy using cisplatin has been proven effective in SCLC treatment, conventional dose of cisplatin causes adverse side effects. Photodynamic therapy, a form of non-ionizing radiation therapy, is increasingly used alone or in combination with other therapeutics in cancer treatment. Herein, we aimed to address whether low dose cisplatin combination with PDT can effectively induce SCLC cell death by using in vitro cultured human SCLC NCI-H446 cells and in vivo tumor xenograft model. We found that both cisplatin and PDT showed dose-dependent cytotoxic effects in NCI-H446 cells. Importantly, co-treatment with low dose cisplatin (1 µM) and PDT (1.25 J/cm2) synergistically inhibited cell viability and cell migration. We further showed that the combined therapy induced a higher level of intracellular ROS in cultured NCI-H446 cells. Moreover, the synergistic effect by cisplatin and PDT was recapitulated in tumor xenograft as revealed by a more robust increase in the staining of TUNEL (a marker of cell death) and decrease in tumor volume. Taken together, our findings suggest that low dose cisplatin combination with PDT can be an effective therapeutic modality in the treatment of SCLC patients.

α(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction.

Accumulation of amyloid ß (Aß) peptides in the brain is the key pathogenic factor driving Alzheimer's disease (AD). Endocytic sorting of amyloid precursor protein (APP) mediated by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and Aß generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the α(2A) adrenergic receptor (α(2A)AR). Genetic deficiency of the α(2A)AR significantly reduces, whereas stimulation of this receptor enhances, Aß generation and AD-related pathology. Activation of α(2A)AR signaling disrupts APP interaction with a Vps10 family receptor, sorting-related receptor with A repeat (SorLA), in cells and in the mouse brain. As a consequence, activation of α(2A)AR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by ß secretase. The α(2A)AR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. α(2A)AR-promoted Aß generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests α(2A)AR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the α(2A)AR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical α(2A)R antagonists would be an effective therapeutic strategy for AD.