Long noncoding RNA SPRY4-IT1 acts as a miR-101-5p sponge to promote gastrointestinal stromal tumor progression by inhibiting ZEB1.

OBJECTIVES: Research on long noncoding RNAs (lncRNAs) has been conducted in different areas of oncology. Currently, the biological significance of lncRNAs and their regulatory features in gastrointestinal stromal tumors (GIST) remain largely unknown. We have previously identified SPRY4-IT1 overexpression in GIST through lncRNA sequencing of GIST tissues. Coincidentally, SPRY4-IT1 is an intron of the SPRY4 gene, and SPRY4 is specifically highly expressed in GIST. Thus the aim of the present study was to investigate the role of lncRNA SPRY4-IT1 in GIST pathogenesis. METHODS: Herein, we screened for SPRY4-IT1 and analyzed its possible phenotypes using Gene set enrichment analysis (GSEA). The phenotypes of GIST were verified using CCK-8, colony formation, and wound-healing assays. The ceRNA mechanism was determined by the location of lncRNA SPRY4-IT1, and its relationship to the Ago2 protein. The SPRY4-IT1/miR-101-5p/ZEB1 axis was predicted using online software and sequencing. Luciferase and pull-down assays were performed for verification. Pathway-associated and phenotype-associated proteins were detected by western blotting. RESULTS: Sequencing analysis revealed 117 differentially expressed lncRNAs in GIST and normal gastric tissue samples. Accordingly, SPRY4-IT1 was screened out and its phenotype was predicted by GSEA. Mechanistically, SPRY4-IT1 was identified as a competing endogenous RNA (ceRNA) that downregulated miR-101-5p and upregulated ZEB1, which activated extracellular signal-regulated kinase (ERK) signaling to stimulate GIST proliferation, invasion, and epithelial-mesenchymal transition. Although this effect was regulated by a negative feedback loop through SPRY4, it was still controlled by SPRY4-IT1. CONCLUSIONS: In GIST, we revealed a ceRNA mechanism by which SPRY4-IT1 modulates ZEB1 by sponging miR-101-5p, eventually driving tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT).

Efficacy of a four-curvature auxiliary arch at preventing maxillary central incisor linguoclination during orthodontic treatment: a finite element analysis.

BACKGROUND: Correct torque of the incisors is beneficial in the assessment of the effects of orthodontic treatment. However, evaluating this process effectively remains a challenge. Improper anterior teeth torque angle can cause bone fenestrations and exposure of the root surface. METHODS: A three-dimensional finite element model of the maxillary incisor torque controlled by a homemade four-curvature auxiliary arch was established. The four-curvature auxiliary arch placed on the maxillary incisors was divided into four different state groups, among which 2 groups had tooth extraction space retracted traction force set to 1.15 N. Initial displacements and pressure stresses of the periodontal tissue in the maxillary incisors and molars were calculated after torque forces (0.5, 1, 1.5, and 2 N) were applied to the teeth at different stable states. RESULTS: The effect of using the four-curvature auxiliary arch on the incisors was significant but did not affect the position of the molars. Given the absence of tooth extraction space, when the four-curvature auxiliary arch was used in conjunction with absolute anchorage, the recommended force value was < 1.5 N. In the other 3 groups (i.e., molar ligation, molar retraction, and microimplant retraction groups), the recommended force value was < 1 N. The application of a four-curvature auxiliary arch did not influence the molar periodontal and displacement. CONCLUSION: A four-curvature auxiliary arch may treat severely upright anterior teeth and correct cortical fenestrations of the bone and root surface exposure.

Neuronal differentiation and functional maturation of neurons from neural stem cells induced by bFGF-chitosan controlled release system.

Available methods for differentiating stem cells into neurons require a large number of cytokines and neurotrophic factors, with complex steps and slow processes, and are inefficient to produce functional neurons and form synaptic contacts, which is expensive and impractical in clinical application. Here, we demonstrated a bioactive material, basic fibroblast growth factor (bFGF)-chitosan controlled release system, for facilitating neuronal differentiation from NSCs and the functional maturation of the induced neurons with high efficiency. We illustrated by immunostaining that the neurons derived from NSCs expressed mature immunomarkers of interneurons and excitatory neurons. And we found by patch-clamp that the induced neurons exhibited diverse electrophysiological properties as well as formed functional synapses. In vivo, we implanted bFGF-chitosan into lesion area in traumatic brain injury (TBI) mice and similarly observed abundance of neuroblasts in SVZ and the presence of newborn functional neurons in injury area, which integrated into synaptic networks. Taken together, our efficient and rapid tissue engineering approach may be a potential method for the generation of functional neuronal lineage cells from stem cells and a therapy of brain injury and disease.

Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics.

Eriocalyxin B (EB), 17-hydroxy-jolkinolide B (HJB), parthenolide (PN), xanthatin (XT) and andrographolide (AG) are terpenoid natural products with a variety of promising antitumor activities, which commonly bear electrophilic groups (α,ß-unsaturated carbonyl groups and/or epoxides) capable of covalently modifying protein cysteine residues. However, their direct targets and underlying molecular mechanisms are still largely unclear, which limits the development of these compounds. In this study, we integrated activity-based protein profiling (ABPP) and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways. We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231. Tandem mass tag (TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways. ABPP platform identified the preferentially modified targets of EB and PN, two natural products with high anti-proliferation activity. Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10 (USP10). Together, this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.

Characterization of procyanidin extracts from hawthorn (Crataegus pinnatifida) in human colorectal adenocarcinoma cell line Caco-2, simulated Digestion, and fermentation identified unique and novel prebiotic properties.

The health-promoting activities of procyanidin extracts from hawthorn (HPCs) are closely related to their digestive behaviors, absorption, and colonic metabolism, all of which remain unknown for now and thus hinder further exploration. This study aims to explore the dynamic changes of HPCs during in vitro digestion and fermentation, as well as their Caco-2 permeability, focusing mainly on the interaction between gut microbiota and HPCs. The results showed that the digested HPC samples had characteristic absorption peaks at 280 nm, and there were absorption peaks in the stretching vibration zone, including OH and CC on the benzene ring, which suggested that procyanidins were the main components in HPCs after in vitro digestion. Meanwhile, HPCs had the highest stability in the oral phase. However, the total procyanidin content of HPCs decreased during gastrointestinal digestion, and flavan-3-ol dimers and trimers in HPCs are partially degraded into epicatechin. Uptake of epicatechin (4.07 %), procyanidin B2 (2.15 %), and procyanidin B5 (39.44 %) through Caco-2 monolayer was also observed in HPC treatment, while there was still a large portion of procyanidins that was not absorbed. Subsequent fermentation resulted in a decrease in pH along with the production of short-chain fatty acids (SCFAs), mainly due to the degradation and utilization of HPC, as indicated by a reduction of total procyanidins. Furthermore, the HPCs modulated gut microbial populations: down-regulated the abundances of Bacteroides, Fusobacterium, Enterococcus, Parabacteroides, and Bilophila, and up-regulated Escherichia-Shigella, Klebsiella, Turicibacter, Actinobacillus, Roseburia, and Blautia. Ultimately, epicatechin and procyanidin B2, B5 and C1 were converted into phenolic acids through the metabolism of Bacteroides, Sutterella, Butyrobacter and Blautia. 4-ethylbenzoic acid, 4-hydroxyphenylpropionic acid, 3,4-dihydroxyphenyl acetic acid were confirmed as the significant metabolites in the fermentation. These results elucidated the potential mechanisms of HPCs metabolism and their beneficial effects on gut microbiota and colonic phenolic acids production.

Effect of different doses of Lacticaseibacillus paracasei K56 on body fat and metabolic parameters in adult individuals with obesity: a pilot study.

BACKGROUND: Studies have shown that probiotics have an effect on reducing body fat on a strain-specific and dose-response bases. The purpose of this study was to evaluate the effect of a novel probiotic strain Lacticaseibacillus paracasei K56 on body fat and metabolic biomarkers in adult individuals with obesity. METHODS: 74 adult subjects with obesity (body mass index ≥ 30 kg/m2, or percent body fat > 25% for men, percent body fat > 30% for women) were randomized into 5 groups and supplemented with different doses of K56 (groups VL_K56, L_K56, H_K56, and VH_K56: K56 capsules, 2 × 107 CFU/day, 2 × 109 CFU/day, 2 × 1010 CFU/day, 2 × 1011 CFU/day, respectively) or placebo (group Pla: placebo capsule) for 60 days. Subjects were advised to maintain their original dietary intake and physical activity. Anthropometric measurements, body composition assessment, and metabolic parameters were measured at baseline and after 60 days of intervention. RESULTS: The results showed that the L_K56 group had significant decreases in percent body fat (p = 0.004), visceral fat area (p = 0.0007), total body fat mass (p = 0.018), trunk body fat mass (p = 0.003), waist circumference (p = 0.003), glycosylated hemoglobin(p = 0.002) at the end of the study compared with baseline. There were non-significant reductions in Body weight and BMI in the L_K56, H_K56, VL_K56 groups, whereas increases were observed in the placebo and VH_K56 groups compared with baseline values. In addition, K56 supplementation modulated gut microbiota characteristics and diversity indices in the L-K56 group. However, mean changes in body fat mass, visceral fat area, weight, body mass index, waist circumference and hip circumference were not significantly different between groups. CONCLUSIONS: The results suggest that supplementation with different doses of Lacticaseibacillus paracasei K56 has certain effect on reducing body fat and glycosylated hemoglobin, especially at a dose of 109 CFU/day. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT04980599.

Association between thyroid hormones and diabetic kidney disease in Chinese adults.

OBJECTIVE: We aimed to explore the association between thyroid hormones and different stages of diabetic kidney disease (DKD) in Chinese adults. METHODS: This is a retrospective study involving 2,832 participants. DKD was diagnosed and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: After propensity score matching (PSM) on age, gender, hypertension, hemoglobin A1c(HbA1c), total cholesterol (TC), serum triglyceride (TG) and duration of diabetes, per 0.2 pg/mL increment in serum free triiodothyronine (FT3) was significantly associated with 13%, 22% and 37% reduced risk of moderate-risk (OR, 95% CI, P: 0.87, 0.70-0.87, < 0.001), high-risk (0.78, 0.70-0.87, < 0.001) and very-high-risk (0.63, 0.55-0.72, < 0.001) DKD stages relative to the low-risk DKD stage, respectively. After PSM analyses, serum FT4 and TSH showed no statistical significance in risk estimates for all DKD stages. To facilitate clinical application, a nomogram prediction model was established for the moderate-risk, high-risk and very-high-risk DKD stages, with decent accuracy. CONCLUSION: Our results indicate that high concentrations of serum FT3 were associated with the significantly reduced risk of having moderate-risk to very-high-risk DKD stages.

DNA barcoding of Chinese snakes reveals hidden diversity and conservation needs.

DNA barcoding has greatly facilitated studies of taxonomy, biodiversity, biological conservation, and ecology. Here, we establish a reliable DNA barcoding library for Chinese snakes, unveiling hidden diversity with implications for taxonomy, and provide a standardized tool for conservation management. Our comprehensive study includes 1,638 cytochrome c oxidase subunit I (COI) sequences from Chinese snakes that correspond to 17 families, 65 genera, 228 named species (80.6% of named species) and 36 candidate species. A barcode gap analysis reveals gaps, where all nearest neighbor distances exceed maximum intraspecific distances, in 217 named species and all candidate species. Three species-delimitation methods (ABGD, sGMYC, and sPTP) recover 320 Operational Taxonomic Units (OTUs), of which 192 OTUs correspond to named and candidate species. Twenty-eight other named species share OTUs, such as Azemiops feae and A. kharini, Gloydius halys, G. shedaoensis, and G. intermedius, and Bungarus multicinctus and B. candidus, representing inconsistencies most likely caused by imperfect taxonomy, recent and rapid speciation, weak taxonomic signal, introgressive hybridization, and/or inadequate phylogenetic signal. In contrast, 43 species and candidate species assign to two or more OTUs due to having large intraspecific distances. If most OTUs detected in this study reflect valid species, including the 36 candidate species, then 30% more species would exist than are currently recognized. Several OTU divergences associate with known biogeographic barriers, such as the Taiwan Strait. In addition to facilitating future studies, this reliable and relatively comprehensive reference database will play an important role in the future monitoring, conservation, and management of Chinese snakes.

Correlative increasing expressions of KIF5b and Nav1.7 in DRG neurons of rats under neuropathic pain conditions.

Nav1.7, one of tetrodotoxin-sensitive voltage-gated sodium channels, mainly expressed in the small diameter dorsal root ganglion (DRG) neurons. The expression and accumulation on neuronal membrane of Nav1.7 increased following peripheral tissue inflammation or nerve injury. However, the mechanisms for membrane accumulation of Nav1.7 remained unclear. We report that KIF5b, a highly expressed member of the kinesin-1 family in DRGs, promoted the translocation of Nav1.7 to the plasma membrane in DRG neurons of the rat. Following nociceptive behaviors in rats induced by peripheral spared nerve injury (SNI), synchronously increased KIF5b and Nav1.7 expressions were observed in DRGs. Immunohistochemistry staining demonstrated the co-expressions of KIF5b and Nav1.7 in the same DRG neurons. Immunoprecipitation experiments further confirmed the interactions between KIF5b and Nav1.7. Moreover, intrathecal injections of KIF5b shRNA moderated the SNI-induced both mechanical and thermal hyperalgesia. The rescued analgesic effects also alleviated SNI-induced anxiety-like behaviors. In sum, KIF5b was required for the membrane localizations of Nav1.7, which suggests a novel mechanism for the trafficking of Nav1.7 involved in neuropathic pain.

Combined analysis of PHOX2B at two time points and its value for further risk stratification in high-risk neuroblastoma.

BACKGROUND: Risk stratification of high-risk neuroblastoma (NB) is crucial for exploring treatments. This study aimed to explore the value of minimal residual disease (MRD) based on PHOX2B levels for further risk stratification in high-risk NB. METHODS: The expression of PHOX2B was monitored at two time points (after two and six cycles of induction chemotherapy, TP1 and TP2, respectively) by real-time polymerase chain reaction (RT-PCR). The clinical characteristics between groups and survival rates were analyzed. RESULTS: The study included 151 high-risk patients. Positive expression of PHOX2B at diagnosis was seen in 129 cases. PHOX2B was mainly expressed in patients with high lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) levels (p < .001), bone marrow metastasis (p < .001), more than three metastatic organs (p < .001), 11q23 loss of heterozygosity (LOH) (p = .007), and when more events occurred (p = .012). The 4-year EFS rate was significantly lower in patients with positive PHOX2B expression compared to the negative group at diagnosis (32.9% ± 6.2% vs. 74.5% ± 10.1%, p = .005). We stratified the 151 patients into three MRD risk groups: low high-risk (low-HR), with TP1 less than 10-4 and TP2 less than 10-4 ; ultra-HR, with TP1 greater than or equal to 10-2 or TP2 greater than or equal to 10-4 , and others classified as intermediate-HR. Patients in ultra-HR had the worst survival rate compared with other two groups (p = .02). In a multivariate model, MRD risk stratification based on PHOX2B levels at TP1 and TP2 was an independent prognostic factor for high-risk patients (p = .001). Patients in ultra-HR were associated with 11q23 LOH (p < .001), more than three organs of metastasis (p = .005), bone marrow metastasis (p < .001), and occurrence of more events (p = .009). CONCLUSIONS: MRD risk stratification based on PHOX2B levels at two time points (after two and six cycles of induction chemotherapy) provided a stratification system for high-risk NB, which successfully predicted treatment outcomes. Our results present an effective method for further stratification of high-risk NB.

Colorful Triplet Excitons in Carbon Nanodots for Time Delay Lighting.

Time delay lighting offers an added period of buffer illumination for human eyes upon switching off the light. Long-lifetime emission from triplet excitons has outstanding potential, but the forbidden transition property due to the Pauli exclusion principle makes them dark, and it stays challenging to develop full-color and bright triplet excitons. Herein, triplet excitons emission from ultraviolet (UV) to near infrared (NIR) in carbon nanodots (CNDs) is achieved by confining multicolor CNDs emitters in NaCNO crystal. NaCNO crystal can isolate the CNDs, triplet excitons quenching caused by the excited state electrons aggregation induced energy transfer is suppressed, and the confinement crystal can furthermore promote phosphorescence by inhibiting the dissipation of the triplet excitons due to non-radiative transition. The phosphorescence from radiative recombination triplet excitons in the CNDs covers the spectral region from 300 nm (UV) to 800 nm (NIR), and the corresponding lifetimes can reach 15.8, 818.0, 239.7, 168.4, 426.4, and 127.6 ms. Furthermore, the eco-friendly luminescent lampshade is designed based on the multicolor phosphorescent CNDs, time delay LEDs are thus demonstrated. The findings will motivate new opportunities for the development of UV to NIR phosphorescent CNDs and multicolor time delay lighting applications. This article is protected by copyright. All rights reserved.

CaV1 and CaV2 calcium channels mediate the release of distinct pools of synaptic vesicles.

Activation of voltage-gated calcium channels at presynaptic terminals leads to local increases in calcium and the fusion of synaptic vesicles containing neurotransmitter. Presynaptic output is a function of the density of calcium channels, the dynamic properties of the channel, the distance to docked vesicles, and the release probability at the docking site. We demonstrate that at Caenorhabditis elegans neuromuscular junctions two different classes of voltage-gated calcium channels, CaV2 and CaV1, mediate the release of distinct pools of synaptic vesicles. CaV2 channels are concentrated in densely packed clusters ~250 nm in diameter with the active zone proteins Neurexin, α-Liprin, SYDE, ELKS/CAST, RIM-BP, α-Catulin, and MAGI1. CaV2 channels are colocalized with the priming protein UNC-13L and mediate the fusion of vesicles docked within 33 nm of the dense projection. CaV2 activity is amplified by ryanodine receptor release of calcium from internal stores, triggering fusion up to 165 nm from the dense projection. By contrast, CaV1 channels are dispersed in the synaptic varicosity, and are colocalized with UNC-13S. CaV1 and ryanodine receptors are separated by just 40 nm, and vesicle fusion mediated by CaV1 is completely dependent on the ryanodine receptor. Distinct synaptic vesicle pools, released by different calcium channels, could be used to tune the speed, voltage-dependence, and quantal content of neurotransmitter release.

Postbiotics Derived from L. paracasei ET-22 Inhibit the Formation of S. mutans Biofilms and Bioactive Substances: An Analysis.

Globally, dental caries is one of the most common non-communicable diseases for patients of all ages; Streptococcus mutans (S. mutans) is its principal pathogen. Lactobacillus paracasei (L. paracasei) shows excellent anti-pathogens and immune-regulation functions in the host. The aim of this study is to evaluate the effects of L. paracasei ET-22 on the formation of S. mutans biofilms. The living bacteria, heat-killed bacteria, and secretions of L. paracasei ET-22 were prepared using the same number of bacteria. In vitro, they were added into artificial-saliva medium, and used to coculture with the S. mutans. Results showed that the living bacteria and secretions of L. paracasei ET-22 inhibited biofilm-growth, the synthesis of water-soluble polysaccharide and water-insoluble polysaccharide, and virulence-gene-expression levels related to the formation of S. mutans biofilms. Surprisingly, the heat-killed L. paracasei ET-22, which is a postbiotic, also showed a similar regulation function. Non-targeted metabonomics technology was used to identify multiple potential active-substances in the postbiotics of L. paracasei ET-22 that inhibit the formation of S. mutans biofilms, including phenyllactic acid, zidovudine monophosphate, and citrulline. In conclusion, live bacteria and its postbiotics of L. paracasei ET-22 all have inhibitory effects on the formation of S. mutans biofilm. The postbiotics of L. paracasei ET-22 may be a promising biological anticariogenic-agent.

Toxicity of herbicide glyphosate to planarian Dugesia japonica and its potential molecular mechanisms.

Glyphosate (GLY) is one of the most widely used agrochemicals in the world, and its exposure has become a public health concern. The freshwater planarian is an ideal test organism for detecting the toxicity of pollutants and has been an emerging animal model in toxicological studies. Nevertheless, the underlying toxicity mechanism of GLY to planarians has not been thoroughly explored. To elucidate the toxicity effects and molecular mechanism involved in GLY exposure of planarians, we studied the acute toxicity, histological change, and transcriptional response of Dugesia japonica subjected to GLY. Significant morphological malformations and histopathological changes were observed in planarians after GLY exposure for different times. Also, a number of differentially expressed genes (DEGs) were obtained at 1, 3 and 5 d after exposure; Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these DEGs were performed, and a global and dynamic view was obtained in planarians upon GLY exposure at the transcriptomic level. Furthermore, real-time quantitative PCR (qRT-PCR) was conducted on nine DEGs associated with detoxification, apoptosis, stress response, DNA repair, etc. The expression patterns were well consistent with the RNA sequencing (RNA-seq) results at different time points, which confirmed the reliability and accuracy of the transcriptome data. Collectively, our results established that GLY could pose adverse effects on the morphology and histo-architecture of D. japonica, and the planarians are capable of responding to the disadvantageous stress by dysregulating the related genes and pathways concerning immune response, detoxification, energy metabolism, DNA damage repair, etc. To the best of our knowledge, this is the first report of transcriptomic analyses of freshwater planarians exposed to environmental pollutants, and it provided detailed sequencing data deriving from transcriptome profiling to deepen our understanding the molecular toxicity mechanism of GLY to planarians.

Direct observation of cation diffusion driven surface reconstruction at van der Waals gaps.

Weak interlayer van der Waals (vdW) bonding has significant impact on the surface/interface structure, electronic properties, and transport properties of vdW layered materials. Unraveling the complex atomistic dynamics and structural evolution at vdW surfaces is therefore critical for the design and synthesis of the next-generation vdW layered materials. Here, we show that Ge/Bi cation diffusion along the vdW gap in layered GeBi2Te4 (GBT) can be directly observed using in situ heating scanning transmission electron microscopy (STEM). The cation concentration variation during diffusion was correlated with the local Te6 octahedron distortion based on a quantitative analysis of the atomic column intensity and position in time-elapsed STEM images. The in-plane cation diffusion leads to out-of-plane surface etching through complex structural evolutions involving the formation and propagation of a non-centrosymmetric GeTe2 triple layer surface reconstruction on fresh vdW surfaces, and GBT subsurface reconstruction from a septuple layer to a quintuple layer. Our results provide atomistic insight into the cation diffusion and surface reconstruction in vdW layered materials.

Drug repurposing strategy II: from approved drugs to agri-fungicide leads.

Epidemic diseases of crops caused by fungi deeply affected the course of human history and processed a major restriction on social and economic development. However, with the enormous misuse of existing antimicrobial drugs, an increasing number of fungi have developed serious resistance to them, making the diseases caused by pathogenic fungi even more challenging to control. Drug repurposing is an attractive alternative, it requires less time and investment in the drug development process than traditional R&D strategies. In this work, we screened 600 existing commercially available drugs, some of which had previously unknown activity against pathogenic fungi. From the primary screen at a fixed concentration of 100 µg/mL, 120, 162, 167, 85, 102, and 82 drugs were found to be effective against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, Phytophthora capsici, Fusarium graminearum and Fusarium oxysporum, respectively. They were divided into nine groups lead compounds, including quinoline alkaloids, benzimidazoles/carbamate esters, azoles, isothiazoles, pyrimidines, pyridines, piperidines/piperazines, ionic liquids and miscellaneous group, and simple structure-activity relationship analysis was carried out. Comparison with fungicides to identify the most promising drugs or lead structures for the development of new antifungal agents in agriculture.

Is serum hemoglobin level an independent prognostic factor for IgA nephropathy?: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Decreased serum hemoglobin (Hb) level is associated with Immunoglobulin A nephropathy (IgAN) progression. However, whether serum Hb level is an independent prognostic factor of IgAN remains controversial. Herein, we aimed to investigate the prognostic value of serum Hb level in IgAN. METHODS: The Cochrane Library, Embase, PubMed and Open Grey databases were systematically searched and reviewed. Kidney disease progression of IgAN was defined as a doubling of serum creatinine (SCr), a 30% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), or death. We evaluated the hazard ratio (HR) between serum Hb level and the incidence of kidney disease progression in IgAN before and after adjusting for relevant covariates. RESULTS: We included nine studies with 10006 patients in the meta-analysis. As a continuous variable, we found that serum Hb was an independent prognostic factor of IgAN [unadjusted HR = 0.89, 95% confidence interval (CI) = 0.84-0.95, I2 = 98%; adjusted HR = 0.85, 95% CI = 0.79-0.91, I2 = 0%]. The sensitivity analysis confirmed the stability of these results. Consistently, as a dichotomous variable defined as the below/above cutoff for anemia, we observed a positive correlation between serum Hb and kidney disease progression in IgAN (unadjusted HR = 2.12, 95% CI = 1.44-3.12, I2 = 79%; adjusted HR = 1.65, 95% CI = 1.20-2.27, I2 = 0%). CONCLUSION: Serum Hb level was independently correlated with the incidence of kidney disease progression in IgAN.

Comparison of Dynamic Contrast-Enhanced MRI and Non-Mono-Exponential Model-Based Diffusion-Weighted Imaging for the Prediction of Prognostic Biomarkers and Molecular Subtypes of Breast Cancer Based on Radiomics.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI and non-mono-exponential model-based diffusion-weighted imaging (NME-DWI) that does not require contrast agent can both characterize breast cancer. However, which technique is superior remains unclear. PURPOSE: To compare the performances of DCE-MRI, NME-DWI and their combination as multiparametric MRI (MP-MRI) in the prediction of breast cancer prognostic biomarkers and molecular subtypes based on radiomics. STUDY TYPE: Prospective. POPULATION: A total of 477 female patients with 483 breast cancers (5-fold cross-validation: training/validation, 80%/20%). FIELD STRENGTH/SEQUENCE: A 3.0 T/DCE-MRI (6 dynamic frames) and NME-DWI (13 b values). ASSESSMENT: After data preprocessing, high-throughput features were extracted from each tumor volume of interest, and optimal features were selected using recursive feature elimination method. To identify ER+ vs. ER-, PR+ vs. PR-, HER2+ vs. HER2-, Ki-67+ vs. Ki-67-, luminal A/B vs. nonluminal A/B, and triple negative (TN) vs. non-TN, the following models were implemented: random forest, adaptive boosting, support vector machine, linear discriminant analysis, and logistic regression. STATISTICAL TESTS: Student's t, chi-square, and Fisher's exact tests were applied on clinical characteristics to confirm whether significant differences exist between different statuses (±) of prognostic biomarkers or molecular subtypes. The model performances were compared between the DCE-MRI, NME-DWI, and MP-MRI datasets using the area under the receiver-operating characteristic curve (AUC) and the DeLong test. P < 0.05 was considered significant. RESULTS: With few exceptions, no significant differences (P = 0.062-0.984) were observed in the AUCs of models for six classification tasks between the DCE-MRI (AUC = 0.62-0.87) and NME-DWI (AUC = 0.62-0.91) datasets, while the model performances on the two imaging datasets were significantly poorer than on the MP-MRI dataset (AUC = 0.68-0.93). Additionally, the random forest and adaptive boosting models (AUC = 0.62-0.93) outperformed other three models (AUC = 0.62-0.90). DATA CONCLUSION: NME-DWI was comparable with DCE-MRI in predictive performance and could be used as an alternative technique. Besides, MP-MRI demonstrated significantly higher AUCs than either DCE-MRI or NME-DWI. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases.

The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis - traditionally thought of as uncontrolled cell death - in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.

Significant increase of serum extracellular vesicle-packaged growth differentiation factor 15 in type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-inducible factor involved in the inflammatory progression of many complications, including type 2 diabetes mellitus (T2DM). Growing evidence suggests that molecules in extracellular vesicles (EVs) are associated with diabetes or diabetes-related complications. However, the correlation between serum extracellular vesicle-derived growth differentiation factor15 (EV-GDF15) and T2DM is unknown. The aim of this cross-sectional study is to investigate whether serum EV-GDF15 is associated with T2DM incidence. METHODS: 116 individuals, including 78 T2DM and 38 non-T2DM, were recruited as participants. The concentrations of serum EV-GDF15 and serum GDF15 were determined by Luminex assay. Serum EVs were obtained by ultracentrifugation. Multivariate stepwise regression analysis was used to determine the association between serum GDF15 levels and fasting plasma glucose (FPG) as well as glycated hemoglobin (HbA1c). The association of serum EV-GDF15 levels with T2DM was determined by multivariate logistic regression analysis. RESULTS: Our data showed that the levels of serum EV-GDF15 and serum GDF15 were significantly increased in T2DM patients compared with non-T2DM subjects (EV-GDF15 levels, 13.68 (6.61-23.44) pg/mL vs. 5.56 (3.44-12.09) pg/mL, P < 0.001; and serum GDF15 levels, 1025.49 (677.87-1626.36) pg/mL vs. 675.46 (469.53-919.98) pg/mL, P < 0.001). There was a linear correlation between EV-GDF15 levels and fasting plasma glucose (FPG) and Hemoglobin A1C (HbA1c) levels (normalized ß = 0.357, P < 0.001; normalized ß = 0.409, P < 0.001, respectively). Elevated levels of EV-GDF15 were accompanied by an increase in the proportion of patients with T2DM (from 47.5 to 78.9%) and a progressive independent association with the incidence of T2DM (from OR = 3.06, 95% CI 1.02-9.19, P = 0.047 to OR = 3.75, 95% CI 1.14-12.26, P = 0.029). Notably, high levels of serum GDF15 plus high levels of serum EV-GDF15 were significantly associated with T2DM more than either alone. CONCLUSION: This study elucidated that increased levels of GDF15 in serum EVs were independently associated with T2DM.