Matrix Metalloproteinase and Aortic Aneurysm: A Two-sample Mendelian Randomization Study.

BACKGROUND: Studies have linked matrix metalloproteinases (MMPs) to both thoracic aortic aneurysm and abdominal aortic aneurysm (TAA and AAA). The precise MMPs entailed in this procedure, however, were still unknown. This study used a two-sample Mendelian randomization (MR) analysis to look into the causal relationship between MMPs and the risk of TAA and AAA. METHODS: Eight MMPs, including MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13, were found among people of European ancestry with accessible Genome-Wide Association Studies (GWAS). We employed the findings from Genome-Wide Association Studies (GWAS) for 8 MMPs, and TAA and AAA from the FinnGen consortiums (3,201 cases and 317,899 controls, respectively) were used in a two-sample MR analysis. The primary method of analysis for MR was the inverse variance weighted (IVW) method, along with analyses of heterogeneity and horizontal pleiotropy. 31 single-nucleotide polymorphisms connected to MMP were retrieved. RESULTS: IVW demonstrated a negative causal association between TAA and AAA and serum MMP-12 levels. The incidence of TAA decreased by 1.031% for every 1 ng/mL increase in serum MMP-12 [odds ratio (OR) = 0.897, 95% confidence interval (CI): 0.831-0.968, P = 0.005]. The incidence of AAA fell by 1.653% (OR = 0.835, 95% CI: 0.752-0.926, P = 0.001) for every 1 ng/mL increase in serum MMP-12. There was no horizontal pleiotropy or heterogeneity in the MR data (P > 0.05). CONCLUSIONS: The levels of TAA and AAA and serum MMP-12 are causally related. MMP-12 is a factor that reduces the risk of AAA and TTA. Our study suggested that MMP-12 level is causally associated with a decreased risk of TAA and AAA.

"Bioelectricity in Development, Regeneration, and Cancers" Cell Bio 2023: A Joint Meeting of the American Society of Cell Biology and European Molecular Biology Organization December 2-6, 2023, in Boston, MA, USA.

Cell Bio conferences-organized jointly by the American Society of Cell Biology (ASCB) and European Molecular Biology Organization (EMBO)-showcase a diverse global community of the brightest researchers in Cell Biology and in emerging interdisciplinary topics, including bioelectricity. In this report, we briefly overview the Cell Bio 2023 subgroup meeting "Bioelectricity in Development, Regeneration, and Cancers." This subgroup meeting featured 12 talks (7 Principal Investigators and 5 junior scientists) exploring the role of bioelectricity in endogenous and diseased states in model systems ranging from cells in culture to single-cell organisms such as yeast all the way to mammalian systems (including tools and technology developed for exploring bioelectricity and electrotaxis in cells and tissues). The subgroup meeting concluded with a discussion on the current challenges and opportunities for the field of bioelectricity.

Evolution of two-pore domain potassium channels and their gene expression in zebrafish embryos.

BACKGROUND: The two-pore domain potassium (K2P) channels are a major type of potassium channels that maintain the cell membrane potential by conducting passive potassium leak currents independent of voltage change. They play prominent roles in multiple physiological processes, including neuromodulation, perception of pain, breathing and mood control, and response to volatile anesthetics. Mutations in K2P channels have been linked to many human diseases, such as neuronal and cardiovascular disorders and cancers. Significant progress has been made to understand their protein structures, physiological functions, and pharmacological modifiers. However, their expression and function during embryonic development remain largely unknown. RESULTS: We employed the zebrafish model and identified 23 k2p genes using BLAST search and gene cloning. We first analyzed vertebrate K2P channel evolution by phylogenetic and syntenic analyses. Our data revealed that the six subtypes of the K2P genes have already evolved in invertebrates long before the emergence of vertebrates. Moreover, the vertebrate K2P gene number increased, most likely due to two whole-genome duplications. Furthermore, we examined zebrafish k2p gene expression during early embryogenesis by in situ hybridization. Each subgroup's genes showed similar but distinct gene expression domains with some exceptions. Most of them were expressed in neural tissues consistent with their known function of neural excitability regulation. However, a few k2p genes were expressed temporarily in specific tissues or organs, suggesting that these K2P channels may be needed for embryonic development. CONCLUSIONS: Our phylogenetic and developmental analyses of K2P channels shed light on their evolutionary history and potential roles during embryogenesis related to their physiological functions and human channelopathies.

Enhancement of mucosal innate and adaptive immunity following intranasal immunization of mice with a bovine adenoviral vector.

Introduction: Nonhuman adenoviral (AdV) gene delivery platforms have significant value due to their ability to elude preexisting AdV vector immunity in most individuals. Previously, we have demonstrated that intranasal (IN) immunization of mice with BAd-H5HA, a bovine AdV type 3 (BAdV3) vector expressing H5N1 influenza virus hemagglutinin (HA), resulted in enhanced humoral and cell-mediated immune responses. The BAd-H5HA IN immunization resulted in complete protection following the challenge with an antigenically distinct H5N1 virus compared to the mouse group similarly immunized with HAd-H5HA, a human AdV type 5 (HAdV5) vector expressing HA. Methods: Here, we attempted to determine the activation of innate immune responses in the lungs of mice inoculated intranasally with BAd-H5HA compared to the HAd-H5HA-inoculated group. Results: RNA-Seq analyses of the lung tissues revealed differential expression (DE) of genes involved in innate and adaptive immunity in animals immunized with BAd-H5HA. The top ten enhanced genes were verified by RT-PCR. Consistently, there were transient increases in the levels of cytokines (IL-1α, IL-1ß, IL-5, TNF- α, LIF, IL-17, G-CSF, MIP-1ß, MCP-1, MIP-2, and GM-CSF) and toll-like receptors in the lungs of the group inoculated with BAdV vectors compared to that of the HAdV vector group. Conclusion: These results demonstrate that the BAdV vectors induce enhanced innate and adaptive immunity-related factors compared to HAdV vectors in mice. Thus, the BAdV vector platform could be an excellent gene delivery system for recombinant vaccines and cancer immunotherapy.

Estrogen inhibits colonic smooth muscle contractions by regulating BKß1 signaling.

The estrogen inhibits colonic smooth muscle contractions, which may lead to constipation. However, the mechanisms of inhibition are poorly understood. Therefore, the present study examined the effect of estrogen on rat colonic smooth muscle contractions and its potential association with the large-conductance Ca2+-activated K+ channels ß1 (BKß1) subunit. Twenty-four female Sprague Dawley rats were randomly assigned to 4 groups. After 2 weeks of intervention, the contraction activity of isolated colonic smooth muscle and the expression of BKß1 in colonic smooth muscle of rats were detected. Additionally, in order to investigate the effects of estrogen on BKß1 expression and calcium mobilization, in vitro experiments were conducted using rat and human colonic smooth muscle cells (SMCs). BKß1 shRNA was used to investigate whether calcium mobilization is affected by BKß1 in colonic SMCs. To explore the relationship between ERß and BKß1, serial deletions, site-directed mutagenesis, a dual-luciferase reporter assay, and chromatin immunoprecipitation assays were employed. In response to E2, colonic smooth muscle strips showed a decrease in tension, while IBTX exposure transiently increased tension. Furthermore, in these muscle tissues, BKß1 and α-SMA were found to be co-expressed. The E2 group showed significantly higher BKß1 expression. In cultured colonic SMCs, the expression of BKß1 was found to increase in the presence of E2 or DPN. E2 treatment reduced Ca2+ concentrations, while BKß1 shRNA treatment increased Ca2+ concentrations relative to the control. ERß-initiated BKß1 expression appears to occur via binding to the BKß1 promoter. These results indicated that E2 may upregulate BKß1 expression via ERß and inhibit colonic smooth muscle contraction through ERß by directly targeting BKß1.

Bioelectricity in Developmental Patterning and Size Control: Evidence and Genetically Encoded Tools in the Zebrafish Model.

Developmental patterning is essential for regulating cellular events such as axial patterning, segmentation, tissue formation, and organ size determination during embryogenesis. Understanding the patterning mechanisms remains a central challenge and fundamental interest in developmental biology. Ion-channel-regulated bioelectric signals have emerged as a player of the patterning mechanism, which may interact with morphogens. Evidence from multiple model organisms reveals the roles of bioelectricity in embryonic development, regeneration, and cancers. The Zebrafish model is the second most used vertebrate model, next to the mouse model. The zebrafish model has great potential for elucidating the functions of bioelectricity due to many advantages such as external development, transparent early embryogenesis, and tractable genetics. Here, we review genetic evidence from zebrafish mutants with fin-size and pigment changes related to ion channels and bioelectricity. In addition, we review the cell membrane voltage reporting and chemogenetic tools that have already been used or have great potential to be implemented in zebrafish models. Finally, new perspectives and opportunities for bioelectricity research with zebrafish are discussed.

Research on the Carbon Credit Exchange Strategy for Scrap Vehicles Based on Evolutionary Game Theory.

In this article, we construct a game model that uses government regulators and scrap vehicle owners as the main parties to investigate the carbon credit exchange strategy of scrap vehicles using evolutionary game theory. The results were validated using Matlab simulation analysis to reveal the dynamic evolution process of the strategy of both sides of the game. A sensitivity analysis of the key parameters was conducted to explore the influence of each parameter on the evolution process and the stabilization trends. The study shows that (1) The time for the game system to reach a steady state is inversely related to the size of the initial willingness of the parties to cooperate. (2) In the mixed steady-state scenario, when the overall return differential between the positive and negative regulatory verification by government departments is positive, the steady state is participation and positive scrapping. (3) When the probability of the government verifying and being successful in verifying the punishment of the owner's negative scrapping behavior increases, both parties of the game will eventually choose the strategy of participation and positive scrapping. When the cost of the government participation strategy and the cost of the government verification strategy increase, both sides of the game will eventually choose the strategy combination of no participation and positive scrapping. (4) When the owner's reward for cooperating with the strategy, the owner's cost of scrapping the vehicle, and the benefits of the owner's negative cooperation strategy change, they will not change the strategy stability results but will affect the time it takes for the game system to reach a stable state. This study has theoretical implications for government policies in the scrapping industry and how to guide vehicle owners to actively scrap their vehicles.

DANet: Semi-supervised differentiated auxiliaries guided network for video action recognition.

Video Action Recognition (ViAR) aims to identify the category of the human action observed in a given video. With the advent of Deep Learning (DL) techniques, noticeable performance breakthroughs have been achieved in this study. However, the success of most existing DL-based ViAR methods heavily relies on the existence of a large amount of annotated data, i.e., videos with corresponding action categories. In practice, obtaining such a desired number of annotations is often difficult due to expensive labeling costs, which may lead to significant performance degradation for these methods. To address this issue, we propose an end-to-end semi-supervised Differentiated Auxiliary guided Network (DANet) to best use a few annotated videos. Except for the common supervised learning on a few annotated videos, the DANet also involves the knowledge of multiple pre-trained auxiliary networks to optimize the ViAR network in a self-supervised way on the unannotated data by removing the annotations. Considering the tight connection between video action recognition and classical static image-based visual tasks, the abundant knowledge from the pre-trained static image-based models can be used for training the ViAR model. Specifically, the DANet is a two-branch architecture, which includes a target branch of the ViAR network, and an auxiliary branch of multiple auxiliary networks (i.e., referring to diverse off-the-shelf models of relevant image tasks). Given a limited number of annotated videos, we train the target ViAR network end-to-end in a semi-supervised way, namely, with both the supervised cross-entropy loss on annotated videos, and the per-auxiliary weighted self-supervised contrastive losses on the same videos but without using annotations. Besides, we further explore different weighted guidance of the auxiliary networks to the ViAR network to better reflect different relationships between the image-based models and the ViAR model. Finally, we conduct extensive experiments on several popular action recognition benchmarks in comparison with existing state-of-the-art methods, and the experimental results demonstrate the superiority of DANet over most of the compared methods. In particular, the DANet obviously suppresses state-of-the-art ViAR methods even with very fewer annotated videos.

Target-aware transformer tracking with hard occlusion instance generation.

Visual tracking is a crucial task in computer vision that has been applied in diverse fields. Recently, transformer architecture has been widely applied in visual tracking and has become a mainstream framework instead of the Siamese structure. Although transformer-based trackers have demonstrated remarkable accuracy in general circumstances, their performance in occluded scenes remains unsatisfactory. This is primarily due to their inability to recognize incomplete target appearance information when the target is occluded. To address this issue, we propose a novel transformer tracking approach referred to as TATT, which integrates a target-aware transformer network and a hard occlusion instance generation module. The target-aware transformer network utilizes an encoder-decoder structure to facilitate interaction between template and search features, extracting target information in the template feature to enhance the unoccluded parts of the target in the search features. It can directly predict the boundary between the target region and the background to generate tracking results. The hard occlusion instance generation module employs multiple image similarity calculation methods to select an image pitch in video sequences that is most similar to the target and generate an occlusion instance mimicking real scenes without adding an extra network. Experiments on five benchmarks, including LaSOT, TrackingNet, Got10k, OTB100, and UAV123, demonstrate that our tracker achieves promising performance while running at approximately 41 fps on GPU. Specifically, our tracker achieves the highest AUC scores of 65.5 and 61.2% in partial and full occlusion evaluations on LaSOT, respectively.

Microstructure and Mechanical Properties of MIG Welds between 6252 Armor Steel and Q550D HSLA Steel.

The microstructure and mechanical properties of the welded joints of 6252 armor steel and Q550D high-strength low-alloy (HSLA) steel welded by MIG welding were studied. ER70S-G and ER140S-G were used as fillers to obtain welded joints with good formation and no faults. The joint microstructure (OM) analysis showed that a large Widmanstätten structure was observed at the fusion line on the Q550D side, and the apparent grain sizes changed on the 6252 side. Cylindrical ferrite growth along the bainite grain boundary was observed in the ER70S-G filler weld zone, while the ER140S-G filler weld zone was occupied by lower bainite structures. The XRD phase analysis showed that more Fe-Ni-Cr compounds and less ferrite were formed in the ER140S-G filler weld. The hardness test showed that the hardness of the HAZ on the 6252 side was significantly higher than that of the BM and the WZ, and the welded joint obtained by the ER140S-G filler had a higher hardness. The tensile strength test showed that WZ (>772 MPa) had a higher strength than Q550D BM, and the tensile fracture (SEM) was primarily a ductile fracture. The impact test results showed that the welded joint had better impact resistance at room temperature, but the impact absorption energy of the weld and the heat-affected zone was strongly affected by changes in temperature, and brittle fracture occurred easily at low temperatures.

Zebrafish Embryos Display Characteristic Bioelectric Signals during Early Development.

Bioelectricity is defined as endogenous electrical signaling mediated by the dynamic distribution of charged molecules. Recently, increasing evidence has revealed that cellular bioelectric signaling is critical for regulating embryonic development, regeneration, and congenital diseases. However, systematic real-time in vivo dynamic electrical activity monitoring of whole organisms has been limited, mainly due to the lack of a suitable model system and voltage measurement tools for in vivo biology. Here, we addressed this gap by utilizing a genetically stable zebrafish line, Tg (ubiquitin: ASAP1), and ASAP1 (Accelerated sensor of action potentials 1), a genetically encoded voltage indicator (GEVI). With light-sheet microscopy, we systematically investigated cell membrane potential (Vm) signals during different embryonic stages. We found cells of zebrafish embryos showed local membrane hyperpolarization at the cleavage furrows during the cleavage period of embryogenesis. This signal appeared before cytokinesis and fluctuated as it progressed. In contrast, whole-cell transient hyperpolarization was observed during the blastula and gastrula stages. These signals were generally limited to the superficial blastomere, but they could be detected within the deeper cells during the gastrulation period. Moreover, the zebrafish embryos exhibit tissue-level cell Vm signals during the segmentation period. Middle-aged somites had strong and dynamic Vm fluctuations starting at about the 12-somite stage. These embryonic stage-specific characteristic cellular bioelectric signals suggest that they might play a diverse role in zebrafish embryogenesis that could underlie human congenital diseases.

miR-22 Suppresses EMT by Mediating Metabolic Reprogramming in Colorectal Cancer through Targeting MYC-Associated Factor X.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal cancers. MicroRNAs (miRNAs) have been proved to be unusually expressed in CRC progression and thus alter multiple pathological processes in CRC cells. However, the specific roles and mechanisms of miR-22 in CRC have not been clearly reported. MicroRNA-22 (miR-22) and MYC-associated factor X (MAX) expressions were determined by RT-qPCR in CRC tissues and cells. The targeted regulatory effects of miR-22 and MAX were confirmed by luciferase reporter and coimmunoprecipitation assays. Also, gain- and loss-of-function and rescue experiments were used to elucidate the function and mechanism of miR-22 and MAX in CRC cells and the mouse xenograft model. We discovered that miR-22 was hypermethylated and downregulated, while MAX was upregulated in CRC. miR-22 markedly inhibited migration, invasion, glycolysis, and cancer stem cell transcription factors in CRC cells. In addition, it was found that miR-22 can directly target MAX. Additional functional experiments confirmed that MAX overexpression can rescue the effects of miR-22 on the behavior of CRC cells. This study suggested that miR-22, as a cancer suppressor, participates in CRC progression by targeting MAX, which might provide basic information for therapeutic targets for CRC.

Zinc finger protein 384 enhances colorectal cancer metastasis by upregulating MMP2.

Zinc finger proteins (ZNFs) serve key roles in tumor formation and progression; however, the functions and underlying mechanisms of dysregulated ZNF384 in colorectal cancer (CRC) are yet to be fully elucidated. Therefore, the present study initially aimed to investigate the expression levels of ZNF384 in CRC samples. Moreover, lentiviral ZNF384 overexpression and ZNF384 knockdown models were established in CRC cells. Transwell, wound healing and in vivo tail vein metastasis assays were carried out to evaluate the effects of ZNF384 on CRC cell metastasis. Furthermore, reverse transcription­quantitative PCR, western blotting, serial deletion, site­directed mutagenesis, dual­luciferase reporter and chromatin immunoprecipitation assays were conducted to investigate the potential underlying mechanisms. The results of the present study demonstrated that ZNF384 expression was markedly increased in CRC samples and this was associated with a poor prognosis. Notably, ZNF384 overexpression increased the levels of CRC cell invasion and migration, whereas ZNF384 knockdown inhibited CRC development. Moreover, the results of the present study demonstrated that ZNF384 mediated the expression of MMP2. MMP2 knockdown inhibited ZNF384­mediated CRC cell invasion and migration, whereas MMP2 overexpression ameliorated ZNF384 knockdown­induced inhibition of CRC progression. In addition, the results of the present study demonstrated that hypoxia­inducible factor 1α (HIF­1α) had the ability to bind to the ZNF384 promoter, thereby initiating ZNF384 expression. In human­derived CRC samples, the expression levels of ZNF384 were positively correlated with both MMP2 and HIF­1α expression. Collectively, these findings highlighted that ZNF384 may act as a prognostic marker and regulator of CRC metastasis.

Evolution of inwardly rectifying potassium channels and their gene expression in zebrafish embryos.

BACKGROUND: Inwardly rectifying potassium channels are essential for normal potassium homeostasis, maintaining the cellular resting membrane potential, and regulating electrolyte transportation. Mutations in Kir channels have been known to cause debilitating diseases ranging from neurological abnormalities to renal and cardiac failures. Many efforts have been made to understand their protein structures, physiological functions, and pharmacological modifiers. However, their expression and functions during embryonic development remain largely unknown. RESULTS: Using zebrafish as a model, we identified and renamed 31 kir genes. We also analyzed Kir gene evolution by phylogenetic and syntenic analyses. Our data indicated that the four subtypes of the Kir genes might have already evolved out in chordates. These vertebrate Kir genes most likely resulted from both whole-genome duplications and tandem duplications. In addition, we examined zebrafish kir gene expression during early embryogenesis. Each subgroup's genes showed similar but distinct gene expression domains. The gene expression of ohnologous genes from teleost-specific whole-genome duplication indicated subfunctionalization. Varied temporal gene expression domains suggest that Kir channels may be needed for embryonic patterning or regulation. CONCLUSIONS: Our phylogenetic and developmental analyses of Kir channels shed light on their evolutionary history and potential functions during embryogenesis related to congenital diseases and human channelopathies.

Online stereo vision measurement based on correction of sensor structural parameters.

Vibration can easily affect the structure of long baseline binocular vision sensors, resulting in changes in the external parameters of the binocular calibration model and the failure of measurement method. This paper presents an online stereo vision measurement based on correction of sensor structural parameters. The flexible structure model based on calibration model and iterative gradient descent nonlinear optimization model based on 3D redundant information are established. The optimal estimation of external parameters and object position measurement are realized according to multi-information constraints. Experiments show that this method can effectively solve the measurement failure caused by vibration in stereo vision measurement.

MicroRNA-23b-3p targets non-SMC condensing I complex subunit G to promote proliferation and inhibit apoptosis of colorectal cancer cells via regulation of the PI3K/AKT signaling pathway.

Colorectal cancer (CRC) is one of the most common types of malignancy worldwide and has a poor prognosis. Non-SMC condensing I complex subunit G (NCAPG) has been reported to be upregulated in numerous types of malignant tumor. However, to the best of our knowledge, its clinicopathological and biological significance in CRC remain to be elucidated. The results of the present study revealed that NCAPG expression levels were upregulated in human CRC tissues and cell lines. The upregulated expression of NCAPG was positively associated with patient clinicopathological characteristics, such as differentiation and tumor size, and independently associated with poor survival. Consistent with the clinical observations, NCAPG was discovered to promote the proliferation and inhibit the apoptosis of CRC cells. Moreover, NCAPG-knockdown inhibited CRC cell proliferation by regulating the PI3K/AKT signaling pathway. Furthermore, NCAPG was identified as a potential target of microRNA (miR)-23b-3p, which was subsequently demonstrated to negatively regulate NCAPG expression. In conclusion, the findings of the current study indicated that the miR-23b-3p/NCAPG/PI3K/AKT signaling axis may play an important role in CRC carcinogenesis, and the status of the molecule may represent a promising prognostic marker for the disease.

Glutamate receptor, ionotropic, N­methyl D­aspartate­associated protein 1 promotes colorectal cancer cell proliferation and metastasis, and is negatively regulated by miR­296­3p.

N­methyl D­aspartate receptors (NMDARs) are closely associated with the development, growth and metastasis of cancer. Glutamate receptor, ionotropic, N­methyl D­aspartate­associated protein 1 (GRINA) is a member of the of the NMDAR family, and its aberrant expression is associated with gastric cancer. However, the role of GRINA in colorectal cancer (CRC) is not completely understood. In the present study, expression profiles of GRINA in several CRC databases were obtained and further verified using clinical CRC samples. The effects of GRINA overexpression on CRC progression both in vivo and in vitro were assessed. Briefly, cell proliferation was detected using MTT assay, and cell migration and invasion ability were evaluated by wound healing and Transwell assay. In addition, the molecular mechanism underlying the upregulated expression of GRINA in CRC was investigated. The regulatory association between GRINA and miR­296­3p was detected by luciferase assay, reverse transcription­quantitative PCR and western blotting. The results demonstrated that GRINA expression levels were significantly increased in tumor samples compared with those in healthy samples, and upregulated expression of GRINA was associated with a less favorable prognostic outcome in patients with CRC. GRINA overexpression significantly increased CRC cell proliferation, invasion and migration. Additionally, it was determined that GRINA was post­transcriptionally regulated by microRNA (miR)­296­3p. Together, the results of the present study suggested the potential importance of the miR­296­3p/GRINA axis and highlighted potential novel targets for the management of CRC.

Evaluation of Lipoprotein-Associated Phospholipase A2 as a Prognostic Biomarker in Chronic Kidney Disease.

BACKGROUND: The leading cause of death in patients with chronic kidney disease (CKD) is atherosclerosis (AS). Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a biomarker of atherosclerotic plaque stability. The aim of our study was to analyze the association of Lp-PLA2 with CKD complicated with carotid atherosclerotic stenosis (CAS). METHODS: Serum specimens were collected from 77 CKD patients and 39 healthy controls. Laboratory examination results including glucose, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and Lp-PLA2 were measured. Receiver operating characteristic (ROC) was drawn and the area under the curve (AUC) was calculated. RESULTS: Multivariate logistic regression analysis showed that age, gender, glucose, and Lp-PLA2 were considered as risks for CKD-CAS with odds ratios (OR) of 1.111 (95% CI: 1.055, 1.170), 5.123 (95% CI: 1.482, 17.714), 1.679 (95% CI: 1.123, 2.512), and 1.023 (95% CI: 1.008, 1.037), respectively. The AUC for Lp-PLA2 and glucose was 0.618 (p = 0.014) and 0.592 (p = 0.057), respectively. The best diagnostic value was archived by Lp-PLA2 with the cutoff value of 201.06 ng/mL. CONCLUSIONS: Lp-PLA2 is a potential prognostic and diagnostic biomarker for CKD-CAS.

Loss of smarcad1a accelerates tumorigenesis of malignant peripheral nerve sheath tumors in zebrafish.

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of sarcoma that generally originates from Schwann cells. The prognosis for this type of malignancy is relatively poor due to complicated genetic alterations and the lack of specific targeted therapy. Chromosome fragment 4q22-23 is frequently deleted in MPNSTs and other human tumors, suggesting tumor suppressor genes may reside in this region. Here, we provide evidence that SMARCAD1, a known chromatin remodeler, is a novel tumor suppressor gene located in 4q22-23. We identified two human homologous smarcad1 genes (smarcad1a and smarcad1b) in zebrafish, and both genes share overlapping expression patterns during embryonic development. We demonstrated that two smarcad1a loss-of-function mutants, sa1299 and p403, can accelerate MPNST tumorigenesis in the tp53 mutant background, suggesting smarcad1a is a bona fide tumor suppressor gene for MPNSTs. Moreover, we found that DNA double-strand break (DSB) repair might be compromised in both mutants compared to wildtype zebrafish, as indicated by pH2AX, a DNA DSB marker. In addition, both SMARCAD1 gene knockdown and overexpression in human cells were able to inhibit tumor growth and displayed similar DSB repair responses, suggesting proper SMARCAD1 gene expression level or gene dosage is critical for cell growth. Given that mutations of SMARCAD1 sensitize cells to poly ADP ribose polymerase inhibitors in yeast and the human U2OS osteosarcoma cell line, the identification of SMARCAD1 as a novel tumor suppressor gene might contribute to the development of new cancer therapies for MPNSTs.

Activation of AMPK sensitizes medulloblastoma to Vismodegib and overcomes Vismodegib-resistance.

Vismodegib, a Smoothened antagonist, is clinically approved for treatment of human basal cell carcinoma (BCC), in the clinical trials of medulloblastoma (MB) and other cancers. However, a significant proportion of these tumors fail to respond to Vismodegib after a period of treatment. Here, we find that AMPK agonists, A769662, and Metformin, can inhibit GLI1 activity and synergize with Vismodegib to suppress MB cell growth in vitro and in vivo. Furthermore, combination of AMPK agonists with Vismodegib is effective in overcoming Vismodegib-resistant MB. This is the first report demonstrating that combining AMPK agonist (Metformin) and SHH pathway inhibitor (Vismodegib) confers synergy for MB treatment and provides an effective chemotherapeutic regimen that can be used to overcome resistance to Vismodegib in SHH-driven cancers.