Pathogenesis of chronic enteropathy associated with the SLCO2A1 gene: Hypotheses and conundrums.

Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss. This review explores the potential mechanisms underlying the pathogenesis of CEAS, focusing on the role of SLCO2A1-encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2 (PGE2) levels. Studies have suggested that elevated PGE2 levels contribute to mucosal damage, inflammation, and disruption of the intestinal barrier. The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality, as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS. Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel, targeted therapies.

In Situ Photogenerated Radicals of Hydroxyl Substituted Pyrene-Based Triphenylamines with Enhanced Transport and Free Doping/Post-Oxidation for Efficient Perovskite Solar Cells.

The high-performance hole transporting material (HTM) is one of the most important components for the perovskite solar cells (PSCs) in promoting power conversion efficiency (PCE). However, the low conductivity of HTMs and their additional requirements for doping and post-oxidation greatly limits the device performance. In this work, three novel pyrene-based derivatives containing methoxy-substituted triphenylamines units (PyTPA, PyTPA-OH and PyTPA-2OH) are designed and synthesized, where different numbers of hydroxyl groups are connected at the 2- or 2,7-positions of the pyrene core. These hydroxyl groups at the 2- or 2,7-positions of pyrene play a significantly role to enhance the intermolecular interactions that are able to generate in situ radicals with the assistance of visible light irradiation, resulting in enhanced hole transferring ability, as well as an enhanced conductivity and suppressed recombination. These pyrene-core based HTMs exhibit excellent performance in PSCs, which possess a higher PCE than those control devices using the traditional spiro-OMeTAD as the HTM. The best performance can be found in the devices with PyTPA-2OH. It has an average PCE of 23.44% (PCEmax = 23.50%), which is the highest PCE among the reported PSCs with the pyrene-core based HTMs up to date. This research offers a novel avenue to design a dopant-free HTM by the combination of the pyrene core, methoxy triphenylamines, and hydroxy groups.

Gastroesophageal reflux disease with 6 neurodegenerative and psychiatric disorders: Genetic correlations, causality, and potential molecular mechanisms.

The comorbidities between gastroesophageal reflux disease (GERD) and various neurodegenerative and psychiatric disorders have been widely reported. However, the genetic correlations, causal relationships, and underlying mechanisms linking GERD to these disorders remain largely unknown. Here, we conducted a bidirectional Mendelian randomization (MR) analysis to determine the causality between GERD and 6 neurodegenerative and psychiatric disorders. Sensitivity analyses and multivariable MR were performed to test the robustness of our findings. Linkage disequilibrium score regression was used to assess the genetic correlation between these diseases as affected by heredity. Multiple bioinformatics tools combining two machine learning algorithms were applied to further investigate the potential mechanisms underlying these diseases. We found that genetically predicted GERD significantly increased the risk of Alzheimer's disease, major depressive disorder, and anxiety disorders. There might be a bidirectional relationship between GERD and insomnia. GERD has varying degrees of genetic correlations with AD, ALS, anxiety disorders, insomnia, and depressive disorder. Bioinformatics analyses revealed the hub shared genes and the common pathways between GERD and 6 neurodegenerative and psychiatric disorders. Our findings demonstrated the complex nature of the genetic architecture across these diseases and clarified their causality, highlighting that treatments for the cure or remission of GERD may serve as potential strategies for preventing and managing neurodegenerative and psychiatric disorders.

Association between Atopic Dermatitis and Colorectal Cancer: TET2 as a Shared Gene Signature and Prognostic Biomarker.

Background: Recent studies have linked atopic dermatitis (AD) to colorectal cancer (CRC) risk. Their causality and potential molecular mechanisms remain unclear. Methods: We performed Mendelian randomization (MR) analysis to evaluate the causality between AD and CRC. Summary statistic data-based Mendelian randomization (SMR) analysis was used to identify CRC-related causal genes. Transcriptome analyses and immunohistochemical methods were applied to investigate the shared gene signature and potential mechanisms that contribute to the pathogenesis of both AD and CRC. A predictive analysis was performed to examine the shared gene signature associated with immunotherapy response in CRC. Results: MR analysis indicated a causal association between AD and a decreased risk of CRC. SMR analysis uncovered TET2 as a CRC-related causal gene, showing an inverse relationship with the risk of CRC. Transcriptome analyses identified TET2 as a shared gene signature between AD and CRC. Decreased TET2 expression is associated with impaired demethylation and worse prognosis in CRC patients. We observed ten pathways related to the inflammatory response and immune regulation that may be shared mechanisms underlying both AD and CRC. These findings were validated through single-cell analysis. TET2 shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Conclusion: There is a causal association between AD and a decreased risk of CRC. AD may influence the occurrence of CRC by modulating immune and inflammatory responses. TET2 could serve as a potential biomarker for prognosis and may be considered a novel therapeutic target for methylation and immune-related interventions.

Pyrene-Based Deep-Blue Fluorophores with Narrow-Band Emission.

High-efficiency narrow-band luminescent materials have attracted intense interest, resulting in their great colorimetric purity. This has led to a variety of high-tech applications in high-definition displays, spectral analysis, and biomedicine. In this study, a rigid pyrene core was employed as the molecular backbone, and four narrow-band pyrene-based blue emitters were synthesized using various synthetic methods (such as Lewis-acid catalyzed cyclization domino reactions, Pd-catalyzed coupling reactions like Suzuki-Miyaura and Sonogashira). Due to the steric effect of the hydroxy group at the 2-position, the target compounds exhibit deep blue emission (<429 nm, CIEy < 0.08) with full width at half-maximum (FWHM) less than 33 nm both in solution and when solidified. The experimental and theoretical results indicated that the substituents at the 1- and 3-positions afford a large dihedral angle with the pyrene core, and the molecular motion is almost fixed by multiple intra- and intermolecular hydrogen bonding interactions in the crystallized state, leading to a suppression of the vibrational relaxation of the molecular structure. Moreover, we observed that the suppression of the vibrational relaxation in the molecular structures and the construction of rigid conjugated structures can help develop narrow-band organic light-emitting materials.

Porcine Intestinal Mucosal Peptides Target Macrophage-Modulated Inflammation and Alleviate Intestinal Homeostasis in Dextrose Sodium Sulfate-Induced Colitis in Mice.

Porcine intestinal mucosal proteins are novel animal proteins that contain large amounts of free amino acids and peptides. Although porcine intestinal mucosal proteins are widely used in animal nutrition, the peptide bioactivities of their enzymatic products are not yet fully understood. In the present study, we investigated the effect of porcine intestinal mucosal peptides (PIMP) on the RAW264.7 cell model of LPS-induced inflammation. The mRNA expression of inflammatory factors (interleukin 6, tumor necrosis factor-α, and interleukin-1ß) and nitrous oxide levels were all measured by quantitative real-time PCR and cyclooxygenase-2 protein expression measured by Western blot. To investigate the modulating effect of PIMP and to establish a model of dextran sodium sulfate (DSS)-induced colitis in mice, we examined the effects of hematoxylin-eosin staining, myeloperoxidase levels, pro-inflammatory factor mRNA content, tight junction protein expression, and changes in intestinal flora. Nuclear factor κB pathway protein levels were also assessed by Western blot. PIMP has been shown in vitro to control inflammatory responses and prevent the activation of key associated signaling pathways. PIMP at doses of 100 and 400 mg/kg/day also alleviated intestinal inflammatory responses, reduced tissue damage caused by DSS, and improved intestinal barrier function. In addition, PIMP at 400 mg/kg/day successfully repaired the dysregulated gut microbiota and increased short-chain fatty acid levels. These findings suggest that PIMP may positively influence inflammatory responses and alleviate colitis. This study is the first to demonstrate the potential of PIMP as a functional food for the prevention and treatment of colitis.

Influence of Steric Effects on the Emission Behavior of Pyrene-Based Blue Luminogens.

Pyrene-based derivatives have been widely deployed in organic luminescent materials because of their bright fluorescence, high charge carrier mobility, and facile modification. Nevertheless, the fluorescence output of conventional pyrenes is prone to quenching upon aggregation due to extensive intermolecular π-π stacking interactions. To address this issue, a set of new Y-shaped pyrene-containing luminogens are synthesized from a new bromopyrene chemical precursor, 2-hydroxyl-7-tert-butyl-1,3-bromopyrene, where the bromo and hydroxyl groups at the pyrene core can be readily modified to obtain the target products and provide great flexibility in tuning the photophysical performances. When the hydroxy group at the 2-position of pyrene was replaced by a benzyl group, the steric hindrance of the benzyl group not only efficiently inhibits the detrimental intermolecular π-π stacking interactions but also rigidifies the molecular conformation, resulting in a narrow-band blue emission. Moreover, the TPE-containing compounds 2c and 3c possessed characteristic aggregation-induced emission (AIE) properties with fluorescence quantum yields of up to 66% and 38% in the solid state, respectively. Thus, this article has methodically investigated the factors influencing the optical behavior, such as intermolecular interactions, and the steric effects of the substituent group, thereby opening up the potential to develop narrow-band pyrene-based blue emitters for OLED device applications.

New pyrrolo[3,2-b]pyrroles with AIE characteristics for detection of dichloromethane and chloroform.

Three new pyrrolo[3,2-b]pyrrole derivatives containing methoxyphenyl, pyrene or tetraphenylethylene (TPE) units (compounds 1-3) have been designed, synthesized and fully characterized. The aggregation-induced emission (AIE) properties of compounds 1-3 were tested in different water fraction (fw ) of tetrahydrofuran (THF). The pyrrolo[3,2-b]pyrrole derivative 3 containing TPE units exhibited typical AIE features with an enhanced emission (∼32-fold) in the solid state versus in solution; compounds 1 and 2 exhibited an aggregation-caused quenching effect. In addition, the steric and electronic effects of the peripheral moieties on the emission behavior, both in solution and in the solid state, have been investigated. Moreover, pyrrolo[3,2-b]pyrrole 1 exhibits high sensitivity and selectivity for dichloromethane and chloroform solvents, with the system displaying a new emission peak and fast response time under ultraviolet irradiation.

Intrinsically Stretchable, Self-Healing, and Large-Scale Epidermal Bioelectrode Arrays for Electrophysiology and Gesture Recognition.

Electrophysiological (EP) signals, referred to as low-level biopotentials driven by active or passive human movements, are of great importance for kinesiology, rehabilitation, and human-machine interaction. To capture high-fidelity EP signals, bioelectrodes should possess high conductivity, high stretchability, and high conformability to skin. While traditional metal bioelectrodes are endowed with stretchability via complex structural designs, they are vulnerable to external or internal inference due to their low fracture strain and large modulus. Here, we report a self-healing elastic composite of silver nanowire (AgNW), graphite nanosheet, and styrene-block-poly(ethylene-ran-butylene)-block-polystyrene, which exhibits high stretchability of ε = 500%, high conductivity of σ = ∼1923 S·cm-1, and low resistance change (ΔR/R0) of 0.14 at ε = 40% while its resistance increases ∼0.8% after a 24 h stretching operation at ε = 50%. We employed the elastic composites for accurate and stable monitoring of electrocardiograph and surface electromyography (sEMG) signals. Further, we demonstrate an all-solution and printable process to obtain a large-scale sEMG bioelectrode array, enabling highly conformal adhesion on skin and high-fidelity gesture recognition.

Association between 23 drugs and Parkinson's disease: A two-sample Mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is a common degenerative nervous system disease. At present, there are certain limitations in various treatment options aimed at preventing or delaying the progression of PD. Therefore, the exploration of new drugs for PD is beneficial. Mendelian randomization (MR) analysis can be used to explore the association between drugs and diseases. In this study, MR analysis was adopted to investigate the causal relationship between 23 drugs and PD. These drugs have been approved for the treatment of different diseases, such as salicylic acid and derivatives (collectively called salicylates, e.g., aspirin, used for fever and pain relief), antithrombotic agents (e.g., warfarin, aspirin, used for preventing thrombotic events). METHODS: The GWAS data for the 23 drugs were obtained from the UK Biobank (UKB) project, while the GWAS data for PD were sourced from FinnGen. Single-Nucleotide Polymorphisms (SNPs) were selected as instrumental variables (IVs). We first performed a series of quality control steps (including MR-PRESSO) to select the appropriate SNPs. Two-sample MR analysis was performed using five different methods, including inverse variance weighting (IVW) with random-effects model, weighted median, MR-Egger, simple model, and weighted model. At the same time, sensitivity analysis was carried out using the MR-Egger and Cochran's Q test to ensure the authenticity and reliability of the results. RESULTS: In MR-PRESSO, salicylates and antithrombotic agents showed statistically significant associations with PD, respectively. In the main MR analysis (IVW), there was a negative causal relationship between salicylates and PD (OR = 0.73, 95% CI = 0.54-0.98, p = .039). Similarly, there was a negative causal relationship between antithrombotic agents and PD (OR = 0.70, 95%CI = 0.52-0.96, p = .027). No statistically significant association was found between the remaining 21 drugs and PD. CONCLUSION: This MR study demonstrated that salicylates and antithrombotic agents can reduce the risk of PD, thus providing a novel avenue for future drug exploration in PD.

Heat-Killed Lacticaseibacillus paracasei Repairs Lipopolysaccharide-Induced Intestinal Epithelial Barrier Damage via MLCK/MLC Pathway Activation.

Intestinal epithelial barrier function is closely associated with the development of many intestinal diseases. Heat-killed Lacticaseibacillus paracasei (HK-LP) has been shown to improve intestinal health and enhance immunity. However, the function of HK-LP in the intestinal barrier is still unclear. This study characterized the inflammatory effects of seven HK-LP (1 µg/mL) on the intestinal barrier using lipopolysaccharide (LPS) (100 µg/mL)-induced Caco-2 cells. In this study, HK-LP 6105, 6115, and 6235 were selected, and their effects on the modulation of inflammatory factors and tight junction protein expression (claudin-1, zona occludens-1, and occludin) were compared. The effect of different cultivation times (18 and 48 h) was investigated in response to LPS-induced intestinal epithelial barrier dysfunction. Our results showed that HK-LP 6105, 6115, and 6235 improved LPS-induced intestinal barrier permeability reduction and transepithelial resistance. Furthermore, HK-LP 6105, 6115, and 6235 inhibited the pro-inflammatory factors (TNF-α, IL-1ß, IL-6) and increased the expression of the anti-inflammatory factors (IL-4, IL-10, and TGF-ß). HK-LP 6105, 6115, and 6235 ameliorated the inflammatory response. It inhibited the nuclear factor kappa B (NF-κB) signaling pathway-mediated myosin light chain (MLC)/MLC kinase signaling pathway by downregulating the Toll-like receptor 4 (TLR4)/NF-κB pathway. Thus, the results suggest that HK-LP 6150, 6115, and 6235 may improve intestinal health by regulating inflammation and TJ proteins. Postbiotics produced by these strains exhibit anti-inflammatory properties that can protect the intestinal barrier.

Influence of Left Ventricular Diastolic Dysfunction on the Diagnostic Performance of Coronary Computed Tomography Angiography-Derived Fractional Flow Reserve.

OBJECTIVES: Our study aimed to demonstrate the influence of left ventricular (LV) diastolic dysfunction on the diagnostic performance of coronary computed tomography angiography-derived fractional flow reserve (CT-FFR). METHODS: One hundred vessels from 90 patients were retrospectively analyzed. All patients underwent echocardiography, coronary computed tomography angiography (CCTA), CT-FFR, invasive coronary angiography (ICA), and fractional flow reserve (FFR). The study population was divided into normal and dysfunction groups according to the LV diastolic function, and the diagnostic performance in both groups was assessed. RESULTS: There was a good correlation between CT-FFR and FFR (R = 0.768 p < 0.001) on a per-vessel basis. The sensitivity, specificity, and accuracy were 82.3%, 81.8%, and 82%, respectively. The sensitivity, specificity, and accuracy were 84.6%, 88.5%, and 87.2% in the normal group and 81%, 77.5%, and 78.7% in the dysfunction group, respectively. CT-FFR showed no statistically significant difference in the AUC in the normal group vs. the dysfunction group (AUC: 0.920 [95% CI 0.787-0.983] vs. 0.871 [95% CI 0.761-0.943], Z = 0.772 p = 0.440). However, there was still a good correlation between CT-FFR and FFR in the normal group (R = 0.767, p < 0.001) and dysfunction group (R = 0.767 p < 0.001). CONCLUSIONS: LV diastolic dysfunction had no effect on the diagnostic accuracy of CT-FFR. CT-FFR has good diagnostic performance in both LV diastolic dysfunction and the normal group and can be used as an effective tool for finding lesion-specific ischemia while screening for arterial disease in patients.

Characteristic Genes and Immune Infiltration Analysis for Acute Rejection after Kidney Transplantation.

Background: Renal transplantation can significantly improve the survival rate and quality of life of patients with end-stage renal disease, but the probability of acute rejection (AR) in adult renal transplant recipients is still approximately 12.2%. Machine learning (ML) is superior to traditional statistical methods in various clinical scenarios. However, the current AR model is constructed only through simple difference analysis or a single queue, which cannot guarantee the accuracy of prediction. Therefore, this study identified and validated new gene sets that contribute to the early prediction of AR and the prognosis prediction of patients after renal transplantation by constructing a more accurate AR gene signature through ML technology. Methods: Based on the Gene Expression Omnibus (GEO) database and multiple bioinformatic analyses, we identified differentially expressed genes (DEGs) and built a gene signature via LASSO regression and SVM analysis. Immune cell infiltration and immunocyte association analyses were also conducted. Furthermore, we investigated the relationship between AR genes and graft survival status. Results: Twenty-four DEGs were identified. A 5 gene signature (CPA6, EFNA1, HBM, THEM5, and ZNF683) were obtained by LASSO analysis and SVM analysis, which had a satisfied ability to differentiate AR and NAR in the training cohort, internal validation cohort and external validation cohort. Additionally, ZNF683 was associated with graft survival. Conclusion: A 5 gene signature, particularly ZNF683, provided insight into a precise therapeutic schedule and clinical applications for AR patients.

Taxifolin ameliorates lipopolysaccharide-induced intestinal epithelial barrier dysfunction via attenuating NF-kappa B/MLCK pathway in a Caco-2 cell monolayer model.

Intestinal epithelial barrier dysfunction can cause several intestinal diseases. Flavonoids have been shown to be beneficial to the intestinal epithelial barrier function. However, the effects of taxifolin (TAX), a naturally occurring flavonoid, on the intestinal epithelial barrier function are unclear. Thus, the aims of this study were to investigate the protective effect and potential mechanism of TAX against lipopolysaccharide (LPS)-induced intestinal epithelial barrier dysfunction in a Caco-2 cell monolayer model. Our results showed that TAX increased the transepithelial electrical resistance (TEER) and decreased the fluorescein isothiocyanate (FITC)-dextran (4 kDa) flux in the damaged intestinal epithelial barrier. Meanwhile, TAX inhibited an LPS-induced decrease in mRNA and protein expression of tight junction (TJ) proteins (claudin-1, zonula occludens [ZO]-1, and occludin), and ameliorating the continuous distribution pattern disrupted of TJs. These results suggested that TAX ameliorated intestinal epithelial barrier dysfunction. Regarding the underlying mechanism, TAX reduced the LPS-induced secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in Caco-2 cell monolayers. In addition, TAX suppressed the phosphorylation of nuclear factor kappa-B (NF-κB), inhibitor protein of NF-κBα (IκBα), and myosin light chain (MLC), and downregulated the expression of myosin light chain kinase (MLCK) in LPS-treated Caco-2 cells. In summary, TAX can maintain TJ proteins by inhibiting the NF-κB/MLCK pathway and pro-inflammatory factor secretion to ameliorate LPS-induced intestinal epithelial barrier dysfunction. Thus, TAX is a promising candidate agent for use in functional food to ameliorate intestinal barrier dysfunction.

Rapid sequence and functional diversification of a miRNA superfamily targeting calcium signaling components in seed plants.

MicroRNA (miRNA)-directed posttranscriptional gene silencing (miR-PTGS) is an integral component of gene regulatory networks governing plant development and responses to the environment. The sequence homology between Sly-miR4376, a miRNA common to Solanaceae and reported to target autoinhibited Ca2+ -ATPase 10 (ACA10) messenger RNA (mRNA) in tomato, and Arabidopsis miR391 (Ath-miR391), previously annotated as a nonconserved member of the deeply conserved miR390 family, has prompted us to revisit the function of Ath-miR391, as well as its regulatory conservation. A combination of genetic, molecular, and bioinformatic analyses revealed a hidden conservation for miR-PTGS of ACA10 homologs in spermatophytes. We found that the Arabidopsis ACA10 mRNA undergoes miR391-directed cleavage in vivo. Furthermore, transgenic overexpression of miR391 recapitulated the compact inflorescence (cif) phenotypes characteristic of ACA10 loss-of-function mutants, due to miR391-directed PTGS of ACA10. Significantly, comprehensive data mining revealed robust evidence for widespread PTGS of ACA10 homologs directed by a superfamily of related miRNAs sharing a conserved sequence core. Intriguingly, the ACA-targeting miRNAs in Poaceae also direct PTGS for calmodulin-like proteins which are putative Ca2+ sensors. The PTGS of ACA10 homologs is therefore directed by a miRNA superfamily that is of ancient origin and has undergone rapid sequence diversification associated with functional innovation.

A unimorph nanocomposite dielectric elastomer for large out-of-plane actuation.

Dielectric elastomer actuators (DEAs) feature large, reversible in-plane deformation, and stacked DEA layers are used to produce large strokes in the thickness dimension. We introduce an electrophoretic process to concentrate boron nitride nanosheet dispersion in a dielectric elastomer precursor solution onto a designated electrode surface. The resulting unimorph nanocomposite dielectric elastomer (UNDE) has a seamless bilayer structure with 13 times of modulus difference. The UNDE can be actuated to large bending curvatures, with enhanced breakdown field strength and durability as compared to conventional nanocomposite dielectric elastomer. Multiple UNDE units can be formed in a simple electrophoretic concentration process using patterned electrode areas. A disc-shaped actuator comprising six UNDE units outputs large bidirectional stroke up to 10 Hz. This actuator is used to demonstrate a high-speed lens motor capable of varying the focal length of a two-lens system by 40 times.

Exome-wide Analysis of De Novo and Rare Genetic Variants in Patients With Brain Arteriovenous Malformation.

BACKGROUND AND OBJECTIVES: Brain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of bAVM. However, the biological relevance of disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM. METHODS: Probands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4,609 individuals, including 251 individuals with parental samples sequenced. We first analyzed de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases. RESULTS: We collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By first focusing on de novo variants, we observed a significant mutational burden of likely gene-disrupting variants in cases vs controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4,394 in-house exome data as controls, we identified SLC19A3 as a disease-associated gene for bAVM. In addition, we found that the SLC19A3 variants in cases are preferably located at the N' side of the SLC19A3 protein. These findings implicate a phenotypic expansion of SLC19A3-related disorders with a domain-specific effect. DISCUSSION: This study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.

A population-based predictive model to identify patients with signet ring cell carcinoma of the stomach who are most suitable for primary tumor resection.

BACKGROUND: Though the survival benefit of primary tumor operation for patients with signet ring cell carcinoma of the stomach is known, the specific characteristics of those patients who would profit from the operation are yet to be determined. To this end, a predictive model was developed to identify the conjecture that the survival profit from primary tumor operation would only be obtained by patients. METHOD: The clinical data of the patients with signet ring cell carcinoma of the stomach were obtained from the Surveillance, Epidemiology, and End Results database, and then divided into operation and no-operation groups based on whether the patients underwent the primary tumor operation. To remove the confounding factors, propensity score matching was employed, and it was hypothesized that the patients who had been operated on and lived a longer life than the median cancer-specific survival time of those who hadn't must have profited from the surgery. To discuss the independent factors of cancer-specific survival time in the beneficial group and the non-beneficial group, the Cox model was used, and based on the various vital predictive factors, a nomogram was drawn using logistic regression. RESULT: The number of eligible patients was 12,484, with 43.9% (5483) of them having received surgery. After employing propensity score matching, the cancer-specific survival time of the operation group was found to be apparently longer (median: 21 vs. 5 months; p < 0.001) than the no-operation group. In the operation group, 4757 (86.7%) of the patients lived longer than five months (beneficial group). The six indexes (beneficial and non-beneficial group) included gender, age, Tumor Node Metastasis stage, histologic type, differentiation grade, and tumor position, and were used as predictors to draw the nomogram. The nomogram was used to divide the patients who had taken operations into two groups: the beneficial operation group and the non-beneficial operation group. The beneficial operation group, it was found, survived longer than the non-beneficial operation group (median cancer-specific survival time: 28 vs. 3 months, p < 0.001). Moreover, there was we could tell little difference in survival between the two groups (median cancer-specific survival time: 3 vs. 5 months). CONCLUSIONS: The predictive model created to select suitable candidates for surgical treatment from patients with signet ring carcinoma of the stomach could be adopted to identify certain patients benefiting from the primary tumor operation.

Mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation.

BACKGROUND: Brain arteriovenous malformations (BAVMs) are abnormal vessels that are apt to rupture, causing life-threatening intracranial hemorrhage (ICH). The estimated prevalence of BAVMs is 0.05% among otherwise healthy individuals. In this study, we aim to investigate the mutational spectrum of syndromic genes in sporadic BAVM. METHODS: We recruited a cohort of 150 patients with BAVM and performed whole-exome sequencing on their peripheral blood DNA. To explore the mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation, we selected six genes according to the Online Mendelian Inheritance in Man (OMIM) and literature. All variants in the six candidate genes were extracted and underwent filtering for qualifying variants. RESULTS: There are a total of four patients with rare variants in hereditary hemorrhagic telangiectasia-related genes. In addition, we identified two patients have the variant of RASA1 gene in our database, which are also rare mutations that are absent from population databases. However, we did not find any patients with GNAQ mutations in our database. CONCLUSIONS: In conclusion, we demonstrated that variants in syndromic vascular malformations play important roles in the etiology of sporadic BAVM.

Serum-Derived Exosomes from Patients with Coronary Artery Disease Induce Endothelial Injury and Inflammation in Human Umbilical Vein Endothelial Cells.

Endothelial injury and inflammation have been found to be essential in the pathogenesis of coronary artery disease (CAD). Circulating exosomes are of great value as novel biomarkers for CAD. However, the role of circulating exosomes in the pathogenesis of CAD remains unclear. Thus, in this study, we aimed to examine whether circulating exosomes from CAD are involved in the endothelial injury and inflammation. The serum-derived exosomes were isolated from CAD and controls using an ExoQuick reagent, and these were then quantified by measuring the protein levels using BCA methods. The uptake of exosomes by human umbilical vein endothelial cells (HUVECs) was observed by laser scanning microscope and analyzed via flow cytometry. Then, HUVECs were treated with vehicle, exosomes from CAD (CAD-exo), and controls (ctrl-exo) in the absence and presence of vascular endothelial growth factor (VEGF). Cell viability, migration, and angiogenesis were evaluated using CCK-8 assay, scratch assay, and tube formation assay. Inflammatory factors including IL-1ß, IL-6, TNF-α, ICAM-1, and VCAM-1 levels were detected via qPCR. As per our findings, no significant differences were noted in uptake of ctrl-exo and CAD-exo by HUVECs. CAD-exo suppressed cell viability in a dose-dependent manner. Compared with ctrl-exo, CAD-exo-treated HUVECs significantly suppressed migration and angiogenesis. However, CAD-exo had a stronger inhibitory effect on VEGF-induced migration and angiogenesis compared with ctrl-exo. Moreover, IL-1ß, TNF-α, and ICAM-1 were determined to be significantly upregulated in HUVECs treated with CAD-exo, but IL-6 and VCAM-1 expressions were not affected. Overall, our results suggest that CAD-exo are involved in endothelial injury and inflammation, which may, in turn, cause endothelial dysfunction and potentially promote the development of CAD.