Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2.

Multiple tyrosine kinase inhibitors (TKIs) are often developed for the same indication. However, their relative overall efficacy is frequently incompletely understood and they may harbor unrecognized targets that cooperate with the intended target. We compared several ROS1 TKIs for inhibition of ROS1-fusion-positive lung cancer cell viability, ROS1 autophosphorylation and kinase activity, which indicated disproportionately higher cellular potency of one TKI, lorlatinib. Quantitative chemical and phosphoproteomics across four ROS1 TKIs and differential network analysis revealed that lorlatinib uniquely impacted focal adhesion signaling. Functional validation using pharmacological probes, RNA interference, and CRISPR-Cas9 knockout uncovered a polypharmacology mechanism of lorlatinib by dual targeting ROS1 and PYK2, which form a multiprotein complex with SRC. Rational multi-targeting of this complex by combining lorlatinib with SRC inhibitors exhibited pronounced synergy. Taken together, we show that systems pharmacology-based differential network analysis can dissect mixed canonical/non-canonical polypharmacology mechanisms across multiple TKIs enabling the design of rational drug combinations.

sPLA2GIB Promotes PGD2 and IL-13 Production in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps.

OBJECTIVE: Secreted phospholipase A2 Group IB (sPLA2GIB) regulates the release of arachidonic acid, prostaglandins, and other inflammatory lipid mediators. Although it has been well involved in extensive inflammatory diseases, its specific mechanism in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. In this study, we investigated the role of sPLA2GIB in the pathophysiology of CRSwNP. METHODS: Quantitative PCR, immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to analyze the expression of sPLA2s, phospholipase A2 receptor (PLA2R), and prostaglandin D2 (PGD2) in nasal samples. Human nasal epithelial cells (HNECs) were cultured at an air-liquid interface (ALI) and stimulated with various cytokines. The human mast cell line HMC-1 was stimulated with sPLA2GIB, and the expression of PGD2 and cytokines in the culture supernatant was detected by ELISA. RESULTS: The mRNA and protein levels of sPLA2GIB were significantly higher in eosinophilic CRSwNP than in control tissues. sPLA2GIB was predominantly expressed in the nasal epithelial cells. PLA2R mRNA and protein levels were upregulated in both eosinophilic and non-eosinophilic CRSwNP compared with the control groups. IL-4, IL-13, TNF-α, and IL-1ß upregulated the expression of sPLA2GIB in ALI-cultured HNECs. sPLA2GIB induced PGD2 and IL-13 production in HMC-1 cells in a hydrolytic activity-independent manner. PGD2 protein expression was elevated in tissue homogenates of eosinophilic CRSwNP, and PGD2 upregulated the expression of IL-13 in HMC-1 cells. CONCLUSION: Increased secretion of sPLA2GIB by epithelial cells may promote eosinophilic inflammation in CRSwNP by enhancing PGD2 and IL-13 production in mast cells via binding to PLA2R. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1107-1117, 2024.

Erratum: Genome-wide target interactome profiling reveals a novel EEF1A1 epigenetic pathway for oncogenic lncRNA MALAT1 in breast cancer.

[This corrects the article on p. 714 in vol. 9, PMID: 31105998.].

The alleviating effect of ellagic acid on DSS-induced colitis via regulating gut microbiomes and gene expression of colonic epithelial cells.

The anti-inflammatory effect of ellagic acid (EA) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mouse chronic colonic inflammation were studied. It was observed that EA administration significantly alleviated the colonic inflammation phenotypes, including decreasing the disease activity index (DAI), enhancing the body weight loss, and improving the shortened length of the colon and pathological damage of colon tissue. Additionally, EA reshaped the constitution of the gut microbiota by elevating the ratio of Bacteroidetes along with Bacteroides and Muribaculaceae, while decreasing the proportion of Firmicutes. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) revealed that the metabolic function of the gut microbiota was also changed. Furthermore, mouse colon transcriptome analysis showed that the tight junction and peroxisome proliferator-activated receptor (PPAR) signaling pathways were activated and the expressions of related genes were upregulated after EA intervention. These results showed that EA could remodel the gut bacterial composition, change the intestinal epithelial cell gene expressions in mice, and consequently improve the colonic inflammatory symptoms.

Multi-factor correlation analysis of the effect of root-promoting practices on tobacco rhizosphere microecology in growth stages.

Some agronomic practices not only promote the development of crop roots and increase overall plant performance but also affect colonisation by rhizosphere microorganisms. However, the composition and temporal dynamics of the tobacco rhizosphere microbiota under different root-promoting practices are poorly understood. Here, we characterised the tobacco rhizosphere microbiota at the knee-high, vigorous growing, and maturity stages under the application of potassium fulvic acid (PFA), γ-Polyglutamic acid (PGA), soymilk root irrigation (SRI), and conventional fertilization (CK) and its correlation with root characteristics and soil nutrients. The results showed that three root-promoting practices notably improved the dry and fresh root weights. Total nitrogen and phosphorus, available phosphorus and potassium, and organic matter contents in the rhizosphere markedly increased at the vigorous growing stage. The rhizosphere microbiota was changed through root-promoting practices. However, with tobacco growth, the change of rhizosphere microbiota showed a pattern of slow first and then fast and the microbiota of different treatments gradually approached. SRI reduced plant-pathogenic fungi but increased chemoheterotrophic and phototrophic bacteria, and arbuscular mycorrhizal fungi. PFA and PGA markedly increased arbuscular mycorrhizal and ectomycorrhizal fungi at the knee-high stage, which benefitted tobacco nutrient absorption. The correlation between rhizosphere microorganisms and environmental factors varied at different growth stages. Notably, the rhizosphere microbiota was more sensitive to environmental factors at the vigorous growing stage, and the interactions were more complex than in other stages. Furthermore, a variance partitioning analysis showed that the influence of root-soil interaction on the rhizosphere microbiota increased with tobacco growth. Overall, all three root-promoting practices could improve root characteristics, rhizosphere nutrient, and rhizosphere microbiota to varying degrees and increase the tobacco biomass, among which PGA had the most obvious effect and most suitable for tobacco cultivation. Our findings revealed the role of root-promoting practices in shaping the rhizosphere microbiota during plant growth and elucidated the assembly patterns and environmental drivers of crop rhizosphere microbiota driven by the application of root-promoting practices in agricultural production.

Abbreviated Versus Full-Protocol MRI for Breast Cancer Neoadjuvant Chemotherapy Response Assessment: Diagnostic Performance by General and Breast Radiologists.

BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually (p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.

IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are often linked to drug resistance. Here, we found that coculture with CAFs or culture in CAF-conditioned medium unexpectedly induced drug sensitivity in certain lung cancer cell lines. Gene expression and secretome analyses of CAFs and normal lung-associated fibroblasts (NAFs) revealed differential abundance of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs), which promoted or inhibited, respectively, signaling by the receptor IGF1R and the kinase FAK. Similar drug sensitization was seen in gefitinib-resistant, EGFR-mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Conversely, drug sensitivity was decreased by recombinant IGFs or conditioned medium from CAFs in which IGFBP5 or IGFBP6 was silenced. Phosphoproteomics and receptor tyrosine kinase (RTK) array analyses indicated that exposure of PC9GR cells to CAF-conditioned medium also inhibited compensatory IGF1R and FAK signaling induced by the EGFR inhibitor osimertinib. Combined small-molecule inhibition of IGF1R and FAK phenocopied the CAF-mediated effects in culture and increased the antitumor effect of osimertinib in mice. Cells that were osimertinib resistant and had MET amplification or showed epithelial-to-mesenchymal transition also displayed residual sensitivity to IGFBPs. Thus, CAFs promote or reduce drug resistance in a context-dependent manner, and deciphering the relationship between the differential content of CAF secretomes and the signaling dependencies of the tumor may reveal effective combination treatment strategies.

[Effect of Organic Material Amendments on Soil Respiration in Tobacco Fields of Central Henan].

A field experiment was conducted to study the effects of different organic material amendments on soil respiration in a flue-cured tobacco field. Five treatments were set up:no fertilizer (NF), chemical fertilizer (NPK), chemical fertilizer+ryegrass (NPKG), chemical fertilizer+wheat straw (NPKS), and chemical fertilizer+tobacco straw biochar (NPKB). The results showed that:① Compared with that under NPK, NPKG and NPKS decreased the temperature sensitivity (Q10) of total soil respiration and heterotrophic respiration, whereas NPKB increased the Q10 of heterotrophic respiration. The two-factor fitting model of soil respiration and soil hydrothermal factors accounted for 50%-80% of the variation in soil respiration. ② The addition of organic materials significantly increased the content of soil soluble organic carbon (DOC) and root dry matter. Soil heterotrophic respiration(Rh) was significantly positively correlated with DOC content, and soil autotrophic respiration(Ra) was significantly parabolically correlated with root biomass, with an R2 of 0.327-0.634. ③ Soil respiration increased first and then decreased during the tobacco growth period. Compared with that under the NF treatment, the NPK treatment significantly promoted soil respiration and its components. Compared with those of the NPK treatment, Rsrates were significantly increased by 20.08%, 10.32%, and 9.88% under the NPKG, NPKS, and NPKB treatments, respectively; Rh rate increased by 24.21%, 16.51%, and 11.68% respectively, and Ra rate was increased by 15.12% in the NPKG treatment. In summary, straw returning and biochar addition significantly increased Rh by increasing soil DOC, thereby promoting Rs. Incorporation of ryegrass not only increased the Rh but also increased Ra by promoting the growth and development of roots and therefore the Rs.

Functional Restoration of BRCA1 Nonsense Mutations by Aminoglycoside-Induced Readthrough.

BRCA1 is a major tumor suppressor that functions in the accurate repair of DNA double-strand breaks via homologous recombination (HR). Nonsense mutations in BRCA1 lead to inactive truncated protein products and are associated with high risk of breast and ovarian cancer. These mutations generate premature termination codons (PTCs). Different studies have shown that aminoglycosides can induce PTC suppression by promoting stop codon readthrough and restoring full-length (FL) protein expression. The use of these compounds has been studied in clinical trials for genetic diseases such as cystic fibrosis and Duchenne muscular dystrophy, with encouraging results. Here we show proof-of-concept data demonstrating that the aminoglycoside G418 can induce BRCA1 PTC readthrough and restore FL protein synthesis and function. We first demonstrate that G418 treatment restores BRCA1 FL protein synthesis in HCC1395, a human breast tumor cell line carrying the R1751X mutation. HCC1395 cells treated with G418 also recover HR DNA repair and restore cell cycle checkpoint activation. A set of naturally occurring BRCA1 nonsense variants encoding different PTCs was evaluated in a GFP C-terminal BRCA1 construct model and BRCA1 PTC readthrough levels vary depending on the stop codon context. Because PTC readthrough could generate FL protein carrying pathogenic missense mutations, variants representing the most probable acquired amino acid substitutions in consequence of readthrough were functionally assessed by a validated transcription activation assay. Overall, this is the first study that evaluates the readthrough of PTC variants with clinical relevance in the breast and ovarian cancer-predisposing gene BRCA1.

Case Analysis and Literature Review of Thirteen Patients with Autoimmune Encephalitis.

OBJECTIVE: To investigate the clinical manifestations, laboratory and imaging examinations, and the treatment outcomes of autoimmune encephalitis (AE). METHODS: The clinical data of 13 patients with autoimmune encephalitis who were hospitalized in the department of neurology, Liaocheng People's Hospital from July 2016 to August 2018 were retrospectively analyzed. RESULTS: The average age of onset of the 13 patients was 45 years, including 6 cases (46%) of anti-NMDAR encephalitis, 3 cases (23%) of anti-GABAB receptor encephalitis, and 4 cases (30%) of anti-LG11 encephalitis, and 4 of them showed abnormal signals of brain MRI (30%). 13 patients (100%) had cognitive impairment and psychiatric symptoms; seizures occurred in 12 patients (92%); lung cancer was found in 1 patient (7%). One case was given up because of the treatment of lung cancer, the other was controlled obviously in epilepsy, and cognitive impairment and abnormal mental behavior were also significantly improved. CONCLUSION: Patients with AE still need to be diagnosed early to avoid missed diagnosis and receive early immunosuppressive therapy, which could effectively reduce mortality and morbidity. A detailed history, clinical manifestations, and positive results for specific NSAbs tests can confirm the diagnosis, and the treatment is mainly done by immunosuppressive therapy.

Thymol improves salinity tolerance of tobacco by increasing the sodium ion efflux and enhancing the content of nitric oxide and glutathione.

BACKGROUND AND OBJECTIVE: Salt stress is one of the most important abiotic stresses affecting the yield and quality of tobacco (Nicotiana tabacum). Thymol (a natural medicine) has been widely used in medical research because of its antibacterial and anti-inflammatory activities. However, the influence of thymol on the root growth of tobacco is not fully elucidated. In this study, the regulatory effects of different concentrations of thymol were investigated. METHODOLOGY: Here, histochemical staining and biochemical methods, non-invasive micro-test technology (NMT), and qPCR assay were performed to investigate the effect of thymol and mechanism of it improving salinity tolerance in tobacco seedlings. RESULTS: In this study, our results showed that thymol rescued root growth from salt stress by ameliorating ROS accumulation, lipid peroxidation, and cell death. Furthermore, thymol enhanced contents of NO and GSH to repress ROS accumulation, further protecting the stability of the cell membrane. And, thymol improved Na+ efflux and the expression of SOS1, HKT1, and NHX1, thus protecting the stability of Na+ and K+. CONCLUSION: Our study confirmed the protecting effect of thymol in tobacco under salt stress, and we also identified the mechanism of it, involving dynamic regulation of antioxidant system and the maintenance of Na+ homeostasis. It can be a new method to improve salinity tolerance in plants.

Subjective cognitive decline symptoms and its association with socio-demographic characteristics and common chronic diseases in the southern Chinese older adults.

BACKGROUND: Subjective cognitive decline (SCD) may be the first symptomatic manifestation of Alzheimer's disease, but information on its health correlates is still sparse in Chinese older adults. This study aimed to estimate SCD symptoms and its association with socio-demographic characteristics, common chronic diseases among southern Chinese older adults. METHODS: Participants aged 60 years and older from 7 communities and 2 nursing homes in Guangzhou were recruited and interviewed with standardized assessment tools. Pittsburgh Sleep Quality Index (PSQI), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were used to measure poor sleep quality, depression symptoms and anxiety symptoms. The SCD symptoms were measured by SCD questionnaire 9 (SCD-Q9) which ranged from 0 to 9 points, with a higher score indicating increased severity of the SCD. Participants were divided into low score group (SCD-Q9 score ≤ 3) and higher score group (SCD-Q9 score > 3). Chi-square tests and multivariate logistic regression analysis were used for exploring the influences of different characteristics of socio-demographic and lifestyle factors on SCD symptoms. Univariate and multivariate logistic regression analysis were applied to explore the association between SCD symptoms with common chronic diseases. RESULTS: A total of 688 participants were included in our analysis with a mean age of 73.79 (SD = 8.28, range: 60-101), while 62.4% of the participants were females. The mean score of the SCD-Q9 was 3.81 ± 2.42 in the whole sample. A total of 286 participants (41.6%) were defined as the low score group (≤3 points), while 402 participants (58.4%) were the high score group (> 3 points). Multivariate logistic regression analysis revealed that female (OR = 1.99, 95%CI: 1.35-2.93), primary or lower education level (OR = 2.58, 95%CI: 1.38-4.83), nursing home (OR = 1.90, 95%CI: 1.18-3.05), napping habits (OR = 1.59, 95%CI: 1.06-2.40), urolithiasis (OR = 2.72, 95%CI: 1.15-6.40), gout (OR = 2.12, 95%CI: 1.14-3.93), poor sleep quality (OR = 1.93, 95%CI: 1.38-2.71), depression symptoms (OR = 3.01, 95%CI: 1.70-5.34) and anxiety symptoms (OR = 3.11, 95%CI: 1.29-7.46) were independent positive related to high SCD-Q9 score. On the other hand, tea-drinking habits (OR = 0.64, 95%CI: 0.45-0.92), current smoking (OR = 0.46, 95%CI: 0.24-0.90) were independent negative related to high SCD-Q9 score. CONCLUSIONS: Worse SCD symptoms were closely related to common chronic diseases and socio-demographic characteristics. Disease managers should pay more attention to those factors to early intervention and management for SCD symptoms among southern Chinese older adults.

Extrafollicular PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production in nasal polyps.

BACKGROUND: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). OBJECTIVE: Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. METHODS: The localization, abundance, and phenotype of CD4+ T-cell subsets were studied by immunofluorescence, flow cytometry, and single-cell RNA sequencing. Purified nasal T-cell subsets were cultured with autologous peripheral naive B cells to explore their function. Programmed death ligand 1 and programmed death ligand 2 expression in NPs was investigated by immunofluorescence staining and flow cytometry. RESULTS: Accumulation of PD-1highCXCR5-CD4+ T cells outside lymphoid aggregates was found in NPs. Nasal PD-1highCXCR5-CD4+ T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1-/intCXCR5- and CXCR5+ CD4+ T cells in NPs as well as PD-1highCXCR5highCD4+ follicular helper T cells in tonsils. Compared with the frequencies of PD-1highCXCR5-CD4+ T cells and their IFN-γ+, IL-17A+, and IL-21+ subsets in the control inferior turbinate tissues, the frequencies of these cells and their subsets were increased in both eosinophilic and noneosinophilic NPs, whereas the frequencies of the IL-4+ and IL-4+IL-21+ subsets were increased only in eosinophilic NPs. Nasal PD-1highCXCR5-CD4+ T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1highCXCR5-CD4+ T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1highCXCR5-CD4+ T cells, and their levels were reduced in NPs. PD-1highCXCR5-CD4+ T-cell abundance was associated with the postsurgical relapse of NPs. CONCLUSION: PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production independent of eLTs in NPs.

The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors.

PARP inhibitors (PARPis) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determine the differential efficacy of multiple clinical PARPis in SCLC cells. Compared with the other PARPis rucaparib, olaparib, and niraparib, talazoparib displays the highest potency across SCLC, including SLFN11-negative cells. Chemical proteomics identifies PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition. Drug combination screening reveals talazoparib synergy with the WEE1/PLK1 inhibitor adavosertib. Global phosphoproteomics identifies disparate effects on cell-cycle and DNA damage signaling thereby illustrating underlying mechanisms of synergy, which is more pronounced for talazoparib than olaparib. Notably, silencing PARP16 further reduces cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib's overall mechanism of action and constitutes an actionable target in SCLC.

Two distinct mechanisms underlie estrogen-receptor-negative breast cancer susceptibility at the 2p23.2 locus.

Genome wide-association studies (GWAS) have established over 400 breast cancer risk loci defined by common single nucleotide polymorphisms (SNPs), including several associated with estrogen-receptor (ER)-negative disease. Most of these loci have not been studied systematically and the mechanistic underpinnings of risk are largely unknown. Here we explored the landscape of genomic features at an ER-negative breast cancer susceptibility locus at chromosome 2p23.2 and assessed the functionality of 81 SNPs with strong evidence of association from previous fine mapping. Five candidate regulatory regions containing risk-associated SNPs were identified. Regulatory Region 1 in the first intron of WDR43 contains SNP rs4407214, which showed allele-specific interaction with the transcription factor USF1 in in vitro assays. CRISPR-mediated disruption of Regulatory Region 1 led to expression changes in the neighboring PLB1 gene, suggesting that the region acts as a distal enhancer. Regulatory Regions 2, 4, and 5 did not provide sufficient evidence for functionality in in silico and experimental analyses. Two SNPs (rs11680458 and rs1131880) in Regulatory Region 3, mapping to the seed region for miRNA-recognition sites in the 3' untranslated region of WDR43, showed allele-specific effects of ectopic expression of miR-376 on WDR43 expression levels. Taken together, our data suggest that risk of ER-negative breast cancer associated with the 2p23.2 locus is likely driven by a combinatorial effect on the regulation of WDR43 and PLB1.

Growth arrest-specific 5 (GAS5) insertion/deletion polymorphism and cancer susceptibility in Asian populations: A meta-analysis.

BACKGROUND: Previous studies have reported the association of an insertion/deletion (Ins/Del) polymorphism (rs145204276 AGGCA/-) in the promoter region of growth arrest-specific 5 (GAS5) with the risk of cancer, such as breast cancer, gastric cancer, and hepatocellular carcinoma. However, the results are still controversial. We aimed to clarify the association of GAS5 rs145204276 polymorphism with cancer risk by meta-analysis. METHODS: PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang, and Cochrane Library were searched for studies concerning GAS5 and cancer published up to November 25, 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate cancer risk. RESULTS: A total of 12 case-control studies with 8729 cases and 10,807 controls were included in this meta-analysis. We found that the GAS5 rs145204276 polymorphism was not significantly associated with cancer risk (Del vs Ins: OR = 0.96, 95% CI: 0.81-1.13; Del/Del vs Ins/Ins: OR = 1.00, 95% CI: 0.70-1.43; Ins/Del vs Ins/Ins: OR = 0.92, 95% CI: 0.78-1.08; Ins/Del and Del/Del vs Ins/Ins: OR = 0.93, 95% CI: 0.76-1.13; Del/Del vs Ins/Del and Ins/Ins: OR = 1.04, 95% CI: 0.78-1.38). In the stratified analyses, significant effects on gastric cancer were found (Del vs Ins: OR = 0.79, 95% CI: 0.72-0.86; Del/Del vs Ins/Ins: OR = 0.65, 95% CI: 0.52-0.82; Ins/Del vs Ins/Ins: OR = 0.76, 95% CI: 0.68-0.86; Ins/Del + Del/Del vs Ins/Ins: OR = 0.74, 95% CI: 0.66-0.83; Del/Del vs Ins/Ins + Ins/Del: OR = 0.74, 95% CI: 0.59-0.91). CONCLUSION: Our meta-analysis showed that GAS5 rs145204276 polymorphisms were not related to overall cancer risk. However, the GAS5 rs145204276 polymorphism may be a protective factor for gastric cancer in the stratification analyses.

Inflammatory Endotypes and Tissue Remodeling Features in Antrochoanal Polyps.

PURPOSE: The pathogenic mechanisms of antrochoanal polyps (ACPs) remain largely unknown. This study aimed to characterize inflammatory patterns and tissue remodeling features in ACPs. METHODS: Inflammatory cell infiltration and tissue edema severity as well as fibrin deposition in ACPs and bilateral eosinophilic and noneosinophilic nasal polyps (NPs) were studied with immunohistochemical and immunofluorescence staining. Cytokine levels in sinonasal tissues were detected with the Bio-Plex assay. The expression of coagulation and fibrinolytic markers was measured using reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assays. RESULTS: Compared to control tissues and bilateral eosinophilic and noneosinophilic NPs, ACPs had higher levels of neutrophil infiltration and expression of myeloperoxidase (MPO), interleukin (IL)-8 and interferon (IFN)-γ. In total, 94.4% of ACPs demonstrated an eosinophil cationic protein/MPO ratio of < 1, compared to 79.0% of noneosinophilic and 26% of eosinophilic NPs. Principle component and multiple correspondence analyses revealed a neutrophilic and type 1 inflammation pattern in ACPs. Compared to control tissues, edema scores and fibrin deposition were increased, whereas d-dimer and tissue plasminogen activator (tPA) levels were decreased in ACPs and bilateral NPs, with more prominent changes in ACPs even than in eosinophilic NPs. The tPA levels were negatively correlated with IFN-γ, IL-8, and MPO levels in ACPs. Neutrophils were the major cellular source of IFN-γ in ACPs, and the number of IFN-γ+ neutrophils was elevated in ACPs than in control tissues and bilateral eosinophilic and noneosinophilic NPs. CONCLUSIONS: ACPs are characterized by the neutrophilic and type 1 inflammation endotype. Neutrophil-derived IFN-γ is associated with reduced tPA production in ACPs.

Comparative analysis of the effects of opioids in angiogenesis.

BACKGROUND: Angiogenesis, the formation of blood vessel from pre-existing ones, plays an important role in many pathophysiological diseases, such as cancer. Opioids are often used in clinic for the management of chronic pain in cancer patients at terminal phases. Here, we investigated and compared the effects and mechanisms of four opioids on angiogenesis. METHODS: We performed angiogenesis assays on human umbilical vein endothelial cells (HUVEC) that represent an in vitro model to assess the toxicity of drugs to endothelium. RESULTS: Morphine and oxycodone at 0.1 µM to 100 µM dose-dependently increased endothelial cell tube formation and proliferation. We observed the same in endothelial cells exposed to fentanyl at 0.1 µM to 10 µM but there was a gradual loss of stimulation by fentanyl at 100 µM and 1000 µM. Morphine and fentanyl reduced endothelial cell apoptosis-induced by serum withdrawal whereas oxycodone did not display anti-apoptotic effect, via decreasing Bax level. Oxycodone at the same concentrations was less potent than morphine and fentanyl. Different from other three opioids, codeine at all tested concentrations did not affect endothelial cell tube formation, proliferation and survival. Mechanism studies demonstrated that opioids acted on endothelial cells via µ-opioid receptor-independent pathway. Although we observed the increased phosphorylation of mitogen-activated protein kinase (MAPK) in cells exposed to morphine, fentanyl and oxycodone, the rescue studies demonstrated that the stimulatory effects of morphine but not fentanyl nor oxycodone were reversed by a specific MAPK inhibitor. CONCLUSION: Our work demonstrates the differential effects and mechanisms of opioids on angiogenesis.

Synthesis of a Reactive Template-Induced Core-Shell PZS@ZIF-67 Composite Microspheres and Its Application in Epoxy Composites.

Developing superior properties of epoxy resin composites with high fire resistance, light smoke, and low toxicity has been the focus of the research in the flame-retardant field. In particular, it is essential to decrease the emissions of toxic gases and smoke particles generated during the thermal decomposition of epoxy resin (EP) to satisfy the industrial requirements for environmental protection and safety. Consequently, the PZS@ZIF-67 composite was designed and synthesized by employing the hydroxyl group-containing polyphosphazene (poly(cyclotriphosphazene-co-4,4'-dihydroxydiphenylsulfone), PZS) as both the interfacial compatibility and an in situ template and the ZIF-67 nanocrystal as a nanoscale coating and flame-retardant cooperative. ZIF-67 nanocrystal with multidimensional nanostructures was uniformly wrapped on the surface of PZS microspheres. Subsequently, the acquired PZS@ZIF-67 composite was incorporated into the epoxy resin to prepare composite samples for the study of their fire safety, toxicity suppression, and mechanical performance. Herein, the EP/5% PZS@ZIF-67 passed the V-0 rating in a UL-94 test with a 31.9% limit oxygen index value. More precisely, it is endowed with a decline of 51.08%, 28.26%, and 37.87% of the peak heat release rate, the total heat release, and the total smoke production, respectively. In addition, the unique structure of PZS@ZIF-67 microsphere presented a slight impact on the mechanical properties of EP composites at low loading. The PZS@ZIF-67 possible flame-retardant mechanism was speculated based on the analysis of the condensed phase and the gas phase of EP composites.

Dynamic expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor beta (PDGFRß) in diabetic brain contributes to cognitive dysfunction.

BACKGROUND: Cognitive dysfunction is increasingly recognized as an important complication of diabetes mellitus (DM). Accumulating evidence indicates that the abnormality of cerebrovascular structure and function plays an essential role in diabetic cognitive impairment (DCI), however, changes in cerebrovascular factors have been blurred during the development of diabetes. OBJECTIVE: To evaluate the changes in the structure and function of cerebrovascular in DCI mice and to investigate the changes of cerebral angiogenesis and stability factors during the development of DM. METHODS: Diabetes was induced by feeding with high-fat diet combined with intraperitoneal injection of streptozotocin (STZ,120 mg/kg). Cognitive function was evaluated at different stages of DM, cerebral neovascularization, blood-brain barrier (BBB) permeability and hippocampal neurons were measured of DCI mice, and the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor ß (PDGFRß) in hippocampus was detected during the development of DM. RESULTS: With the progress of diabetes, the learning and memory ability of mice gradually decreased, and DCI mice showed neuronal degeneration, increased BBB permeability and pathological cerebral neovascularization. Moreover, the expression of VEGF in the hippocampus increased first and then decreased at DM+8week, PDGFRß decreased continuously with the development of diabetes. CONCLUSIONS: Our results demonstrate that DCI may be attributed to the dynamic expression of VEGF/PDGFRß in diabetic hippocampus, and pathological cerebral neovascularization, increased BBB permeability and neuronal degeneration are the key links.