Proteomic Characterization Identifies Clinically Relevant Subgroups of Gastrointestinal Stromal Tumors.

BACKGROUND & AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities. METHODS: Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models. RESULTS: Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis. CONCLUSIONS: Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.

MiR-122 knockdown regulates vascular smooth muscle cells phenotypic switching through enhanced FOXO3 expression.

Vascular smooth muscle cells (VSMCs) phenotypic switching is identified as enhanced dedifferentiation, proliferation, and migration ability of VSMCs, in which microRNAs have been identified as important regulators of the process. The present study is aimed to explore the pathophysiological effect of miR-122 on VSMC phenotypic modulation. Here, the result showed that the decreased miR-122 expression was found in VSMCs subjected to platelet-derived growth factor-BB (PDGF-BB) treatment. Next, we investigated the response of miR-122 knockdown in VSMCs with PDGF-BB stimulation. MiR-122 silencing showed increased proliferation and migration capability, whereas attenuated the differentiation markers expression. The above results were reversed by miR-122 overexpression. Finally, we further demonstrated that FOXO3 was an important target for miR-122. Collectively, we demonstrated that miR-122 silencing promoted VSMC phenotypic modulation partially through upregulated FOXO3 expression that indicated miR-122 may be a novel therapeutic target for neointimal formation.

COVID-19 vaccine uptake and hesitation among men and women preparing for pregnancy: a cross-section survey based on the theory of planned behavior.

BACKGROUND: Given the accelerated speed of COVID-19 vaccine research and administration, the main barriers to herd immunity appear to be concerns about safety and efficacy. Men and women preparing for pregnancy may have the same concerns about COVID-19 vaccination, but few studies have focused on COVID-19 vaccine uptake and hesitation among them. METHODS: A cross-sectional study was conducted among men and women who were preparing for pregnancy in Southwest China. The questionnaire was designed based on the theory of planned behavior (TPB). Multiple logistic regression was used to explore the determinants of the behaviors of COVID-19 vaccination. RESULTS: A total of 2878 participants completed the survey. A total of 53.89% of participants received at least one dose of the COVID-19 vaccine. A total of 45.21% of participants would receive the COVID-19 vaccine in the future. A total of 0.90% of participants never thought about receiving the COVID-19 vaccine. Multiple logistic regression model 1 showed that female participants (OR:5.497, 95%CI: 4.292-7.041), participants who never received influenza vaccine (OR:2.664, 95%CI: 1.908-3.718), participants who had never been tested for COVID-19 (OR:2.244, 95%CI:1.504-3.349), participants who had higher score of negative attitude (OR:1.448, 95%CI: 1.219-1.719), participants who had lower scores of injunctive norms (OR:0.440, 95%CI: 0.360-0.537) and descriptive norms (OR:0.105, 95%CI: 0.088-0.126) were more likely to delay COVID-19 vaccination. Model 2 showed that participants who had lower scores for positive attitude (OR: 0.406, 95% CI: 0.230-0.716), injunctive norms (OR: 0.283, 95% CI: 0.130-0.614) and descriptive norms (OR: 0.060, 95% CI: 0.038-0.094) were more likely to refuse COVID-19 vaccination. CONCLUSIONS: The COVID-19 vaccination rate of men and women preparing for pregnancy was significantly lower than the average vaccination rate of China. Gender, protective health behaviors, vaccination attitudes, and subjective norms had effects on the vaccination behaviors of couples preparing for pregnancy.

Environmentally relevant concentrations of mercury inhibit the growth of juvenile silver carp (Hypophthalmichthys molitrix): Oxidative stress and GH/IGF axis.

Mercury (Hg) is a global environmental contaminant, and excessive mercury levels in water can adversely affect the growth of fish. Silver carp (Hypophthalmichthys molitrix) is one of the important freshwater aquaculture fish in China, and its natural resources have been critically declining. However, the effects of Hg2+ exposure on the growth hormone/insulin-like growth factor (GH/IGF) axis and its toxic mechanism are still unclear. In this study, we systematically evaluated the bioaccumulation, histomorphology, antioxidant status, hormone levels, and GH/IGF axis toxicity of juvenile silver carp after exposure to environmental-related concentrations of Hg2+ (0, 0.05, 0.5, 5, and 50 µg/L) for 28 days. Results showed that the Hg2+ bioaccumulation in the liver increased with a rise in Hg2+ concentration and time of exposure. The body length (BL), body weight (BW), weight growth rate (WGR) and specific growth rate (SGR) all decreased after Hg2+ exposure. The serum levels of growth hormones (GH and IGF) and thyroid hormones (T3 and T4) were significantly decreased, and the expressions of GH/IGF axis-related genes were significantly downregulated after 7, 14, and 28 days of Hg2+ exposure. Correlations between the growth parameters and growth hormones or expression of genes in GH/IGF axis further suggested that environmentally relevant concentrations of Hg2+ could have adverse effects on growth. In addition, with increasing Hg2+ exposure, superoxide activities of dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST)and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were significantly increased, whereas the activity of glutathione peroxidase (GPx) significantly decreased and oxidative stress-related gene significantly changed. Liver lesions were mainly characterized by inflammatory cell infiltration, hepatocyte necrosis and fat vacuolation after exposure to Hg2+. Taken together, the results indicate that Hg2+ exposure leads to growth inhibition and oxidative stress in juvenile silver.

Environmentally relevant concentrations of tris (1,3-dichloro-2-propyl) phosphate induce growth inhibition and oxidative stress in silver carp (Hypophthalmichthys molitrix) larvae.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP), widely applied as flame retardant into a variety of products, can be physically leached out to the aquatic environment. Measurable values of TDCIPP have been found in the environment and within biota. Many toxicological assessments have shown that TDCIPP could cause developmental toxicity and oxidative stress in fish. In this study, we focused on the effects of TDCIPP on the growth and oxidative stress of an important commercial fish species in China, silver carp (Hypophthalmichthys molitrix). Fish larvae was exposed to environmentally relevant concentrations (0.05, 0.5, 5 and 50 µg/L) of TDCIPP for 7, 14 and 28 days. Simultaneously, the transcription levels of genes associated with the growth hormone/insulin-like growth factor (GH/IGF) axis and the antioxidative enzymes were examined. The body length and body mass of silver carp larvae decreased significantly only under exposure to 5 and 50 µg/L of TDCIPP at 14 days compared with the control group, while differences on those paraments were observed at 0.05, 0.5, 5 and 50 µg/L when larvae were exposed for 28 days. The observation evidenced the time- and dose- dependent growth inhibitions caused by TDCIPP on silver carp larvae. Exposure to TDCIPP also decreased the contents of GH and IGF1 in fish attended by significant down-regulation of gh and igf1. Moreover, TDCIPP up-regulated the expression of cat, sod1 and gstt followed by an increase of the activities of catalase (CAT) and superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) and glutathione (GSH), but the activities of glutathione peroxidase (GPX) were decreased. These results suggested that growth inhibition and oxidative stress co-occurred in silver carp larvae after exposure to environmentally relevant concentrations of TDCIPP accompanied by the abnormal expression of genes which associated with the GH/IGF axis and antioxidative enzymes.

Simultaneous determination of Acetaminophen and dopamine based on a water-soluble pillar[6]arene and ultrafine Pd nanoparticle-modified covalent organic framework nanocomposite.

While numerous sensing strategies have been applied in the determination of Acetaminophen (AP), dopamine (DA), and ascorbic acid (AA), the selectivity is always a critical challenge based on their similar structure and function. Accordingly, the development of a highly selective sensing method is not only necessary but also crucial. In this study, a novel electrochemical sensing platform for the simultaneous determination of AP and DA has been successfully constructed based on a multifunctional nanocomposite (WP6-Pd-COF) of water-soluble pillar[6]arene (WP6), ultrafine Pd nanoparticles, and triethylene glycol-modified covalent organic framework (COF). Pd nanoparticles with an average size of 4.2 nm are prepared by reducing K2PdCl4 under the stabilization of oxygen-rich COF, which shows superior catalytic activity in electrochemical detection. A supramolecular host-guest recognition system introduced between WP6 and analytes (AP, DA, and AA) can effectively recognize AP and DA, implying the simultaneous determination of AP and DA by this approach. The electrode, best operated at a working potential range from -0.2 to 0.8 V (vs. Hg/Hg2Cl2), works in the concentration ranges of 0.2-8 µM for DA and 0.1-7.5 µM for AP, and has a detection limit of 0.06 µM for DA and 0.03 µM for AP (S/N = 3). Therefore, this study presents potential application values in sensing, catalysis, and other fields.

Lead impaired immune function and tissue integrity in yellow catfish (Peltobargus fulvidraco) by mediating oxidative stress, inflammatory response and apoptosis.

Lead (Pb) widely exists in the water environment and has severe toxic effects on aquatic organisms. The yellow catfish (Pelteobagrus fulvidraco) is one of the most important commercial species in China, and moreover, its natural populations are declining with the degradation of environmental water quality. However, little is known about the toxic effects of Pb on its immune organs. This study was performed to determine waterborne Pb exposure on bioaccumulation, histomorphology, antioxidant status, apoptotic and immune response in the head kidney and spleen of yellow catfish. Experimental fish were randomly allocated into twelve tanks (3 tanks per group), and the Pb concentrations of the four groups were 0, 5, 50, and 500 µg/L, respectively. The results reflected that the Pb bioaccumulation of the head kidney and spleen increased with increasing Pb exposure dose and time. Severe histological alterations in the head kidney and spleen were observed at concentration 500 ug/L. With increasing Pb exposure concentrations, the plasma activity of superoxide dismutase (SOD) and catalase (CAT) significantly increased after exposure 7 days and 14 days, and the levels significantly decreased after exposure 28 days. The change trend of glutathione (GSH) levels was opposite to that of SOD and CAT at corresponding exposure time. The plasma malondialdehyde (MDA) levels together with the activities of plasma alkaline phosphatase (AKP) and acid phosphatase (ACP) increased significantly with the increasing Pb concentrations. In contrast, the levels of lysozyme (LYZ), complement 3 (C3) and immunoglobulin M (IgM) decreased significantly with increasing Pb concentrations. Moreover, Pb exposure induced transcriptional upregulation of heat shock protein 70 (hsp70), metallothionein (mt), sod, cat, interleukin-10 (il-10), transforming growth factor-ß (tgf-ß), and tumor necrosis factor-α (tnf-α), bcl-2-associated X protein (bax), and cysteinyl aspartate specific proteinase -9 (caspase-9), genes in the head kidney and spleen tissues, while downregulating the levels of the lyz, c3, igm and B-cell lymphoma-2 (bcl-2) genes. Our data provide evidence that Pb impaired immune function and tissue integrity in yellow catfish through oxidative stress, inflammatory and apoptosis, and the results can serve as reference data to better protect water environments from Pb eco-toxicants.

LncRNA IGFL2-AS1 functions as a ceRNA in regulating ARPP19 through competitive binding to miR-802 in gastric cancer.

Gastric cancer (GC) is one of the most common malignancies of the digestive system worldwide. Multiple long noncoding RNAs (lncRNAs) participate in the regulation of GC development and metastasis. In this study, we aimed to elucidate the expression and function of lncRNA IGFL2-AS1 in GC. We found that IGFL2-AS1 was highly expressed in GC tissues and cell lines. Knockdown of IGFL2-AS1 suppressed GC cell proliferation, migration, and invasion in vitro. Furthermore, we identified that IGFL2-AS1 exerted its function as a molecular sponge of miR-802. MiR-802 was demonstrated to be a tumor suppressor, and overexpression of miR-802 suppressed GC cell growth, migration, and invasion. Mechanistically, we revealed that the cAMP-regulated phosphoprotein 19 (ARPP19) was a direct target of miR-802 and could reverse the inhibitory function of miR-802. Moreover, our results confirmed that knockdown of IGFL2-AS1 inhibited GC tumor development in an in vivo GC tumor xenograft model. In summary, our data suggest that the IGFL2-AS1/miR-802/ARPP19 axis plays a critical role in the progression and metastasis of GC. Therapies targeting the IGFL2-AS1/miR-802/ARPP19 axis can potentially improve GC treatment.

Nanocomposite Based on Organic Framework-Loading Transition-Metal Co Ion and Cationic Pillar[6]arene and Its Application for Electrochemical Sensing of l-Ascorbic Acid.

In this study, we constructed a highly sensitive and selective electrochemical sensing strategy for l-ascorbic acid (AA) based on a covalent organic framework (COF)-loading non-noble transition metal Co ion and macrocyclic cationic pillar[6]arene (CP6) nanocomposite (CP6-COF-Co). The COF plays a crucial role in anchoring the Co ion according to its crystalline porous and multiple coordination sites and has an outstanding performance for building an electrochemical sensing platform based on a unique two-dimensional structure. Accordingly, the transition-metal Co ion can be successfully anchored on the framework of COF and shows strong catalytic activity for the determination of AA. Moreover, introduction of host-guest recognition based on CP6 and AA can bring new properties for enhancing selectivity, sensitivity, and practical application in real environment. Host-guest interactions between CP6 and AA were evaluated by the 1H NMR spectrum. When compared with other literatures, our method displayed a lower determination limit and broader linear range. To the best of our knowledge, this is the first study carried out for the non-noble transition-metal Co ion, COF, and pillar[6]arene hybrid material in sensing field, which has a potential value in sensing, catalysis, and preparation of advanced multifunction materials.

[Correlation between differential expression of microRNA and quality of embryos].

OBJECTIVE: To explore the correlation between microRNA (miRNA) differential expression and quality of embryo. METHODS: The miRNA expression profiles of 8 blastocysts were detected by a TaqMan microRNA array, and miRNAs with a stable expression were selected. Additional blastocysts were selected, and the candidate miRNA was detected by real-time PCR. Meanwhile, chromosomal abnormalities of the embryos were detected by using next-generation sequencing, and the results were compared. RESULTS: The expression of mir-720, mir-372, mir-886-3p and mir-512-3p was higher than that of miR-145, which suggested that mir-720, mir-372, mir-886-3p and mir-512-3p are related to early embryo development. The expression of miR-145 and mir-886-3p were significantly lower in the normal chromosome group. With the threshold values of above 9 and 3 for the relative expression of miR-145 and mir-886-3p, respectively, there was no embryo without a chromosomal abnormality. CONCLUSION: There is a correlation between the expression level of specific miRNA and chromosomal abnormalities of embryos, which may be used as a novel biomarker for embryo selection.