Expression analysis of genes including Zfhx4 in mice and zebrafish reveals a temporospatial conserved molecular basis underlying craniofacial development.

BACKGROUND: Embryonic craniofacial development involves several cellular and molecular events that are evolutionarily conserved among vertebrates. Vertebrate models such as mice and zebrafish have been used to investigate the molecular and cellular etiologies underlying human craniofacial disorders, including orofacial clefts. However, the molecular mechanisms underlying embryonic development in these two species are unknown. Therefore, elucidating the shared mechanisms of craniofacial development between disease models is crucial to understanding the underlying mechanisms of phenotypes in individual species. RESULTS: We selected mice and zebrafish as model organisms to compare various events during embryonic craniofacial development. We identified genes (Sox9, Zfhx3 and 4, Cjun, and Six1) exhibiting similar temporal expression patterns between these species through comprehensive and stage-matched gene expression analyses. Expression analysis revealed similar gene expression in hypothetically corresponding tissues, such as the mice palate and zebrafish ethmoid plate. Furthermore, loss-of-function analysis of Zfhx4/zfhx4, a causative gene of human craniofacial anomalies including orofacial cleft, in both species resulted in deformed skeletal elements such as the palatine and ethmoid plate in mice and zebrafish, respectively. CONCLUSIONS: These results demonstrate that these disease models share common molecular mechanisms, highlighting their usefulness in modeling craniofacial defects in humans.

Effect of Different Insertion Methods on LMA Protector-Related Complications: A Prospective Randomized Double-Blind Clinical Trail.

OBJECTIVE: The authors compared the effect of 2 insertion methods, namely the conventional laryngeal mask airway (LMA) insertion and the index finger-assisted LMA insertion, on the incidence of complications associated with LMA Protector insertion. METHODS: The authors enrolled 300 patients, who underwent painless bronchoscopy. The patients ranged in age between 18 and 75 and were classified as American Society of Anesthesiologists grade I to III. They were randomly divided into 2 groups: a control group of 150 patients and an assisted group comprising 150 patients. LMA was inserted using the conventional and index finger-assisted insertion methods in both groups, respectively. The primary outcome was postoperative complications, such as oral mucosal injury and pharyngeal pain. Secondary outcomes included the success rate of first-time insertion, the incidence rate of inverse folding of LMA tips, oropharyngeal leak pressure (OLP), and other postoperative complications. RESULTS: Compared with the conventional LMA insertion method, index finger-assisted LMA insertion can significantly reduce the incidence rate of oral mucosal injury and pharyngeal pain, with fewer insertion failures. There was a statistically significant difference between the 2 groups in the visual field grading before adjustment for LMA alignment (P<0.0001). The conventional insertion method increased the likelihood of inverse folding of LMA tips. When the conventional insertion method was utilized, there was a significant difference in airway pressure and tidal volume before and after alignment under a fiberoptic bronchoscope (P<0.0001), but no significant difference in visual field grading and respiratory mechanics-related indicators. CONCLUSIONS: Index finger-assisted insertion can significantly reduce the incidence rate of LMA Protector-related complications and inverse folding of LMA tips.

New insights into the stromal interaction molecule 2 function and its impact on the immunomodulation of tumor microenvironment.

Immune cells-enhanced immunotherapy exhibits unprecedented overall survival-prolongation even curable in some cancer patients. Although so, most of the patients show no response. Tumor microenvironment (TME) where immune cells settle down has multi-faceted influences, but usually creates an immunosuppressive niche that facilitating tumor cells escape from immune attack. The metabolites and malnutrition of TME exert enormous effects on the resident immune cells, but the underlying mechanism is largely unknown. The stromal interaction molecules 2 (STIM2) is an endoplasmic reticulum (ER) calcium (Ca2+) sensor to maintain Ca2+ homeostasis. Notably, the cytosol STIM2 C-terminus is long with various domains that are available for the combination or/and molecular modification. This distinct structure endows STIM2 with a high susceptibility to numerous permeable physico-chemical molecules or protein interactions. STIM2 and its variants are extensively expressed in various immune cells, especially in T immune cells. STIM2 was reported closely correlated with the function of immune cells via regulating Ca2+ signaling, energy metabolism and cell fitness. Herein, we sum the latest findings on the STIM2 structure, focusing on its distinct characteristics and profound effect on the regulation of Ca2+ homeostasis and multi-talented functionality. We also outline the advancements on the underlying mechanism how STIM2 anomalies influence the function of immune cells and on the turbulent expression or/and amenably modification of STIM2 within the tumor niches. Then we discuss the translation of these researches into antitumor approaches, emphasizing the potential of STIM2 as a therapeutic target for direct inhibition of tumor cells or more activation towards immune cells driving to flare TME. This review is an update on STIM2, aiming to rationalize the potential of STIM2 as a therapeutic target for immunomodulation, engaging immune cells to exert the utmost anti-tumor effect.

An Electron-Coupled Co-ZrO2 Nanodot Heterojunction Electrocatalyst with Lewis Acid-Base Site Pairs Enables High Redox Reaction Kinetics of Li-S Batteries.

Using electrocatalysts is effective in solving the slow reaction kinetics of polysulfides in Li-S batteries, but designing stable electrocatalysts with an integrated adsorption-catalysis-desorption system is challenging. Here, we report a stable metal-semiconductor (Co-ZrO2) heterojunction electrocatalyst fabricated by assembling electron-coupled Co-ZrO2 nanodots into macroporous carbon nanofibers. The Co-ZrO2 contact causes interfacial electron enrichment and electron transfer from Co to ZrO2, which creates abundant Lewis-acid sites on Co that can adsorb polysulfides. Simultaneously, the enriched interfacial electrons can activate the S-S bond and boost the catalytic conversion of long-chain polysulfides, while the ZrO2 with Lewis-base sites facilitate the desorption of short-chain polysulfides from the electrocatalyst. Moreover, the nanodot heterojunctions show great chemical stability and high redox reaction kinetics of polysulfides. Li-S batteries show high discharge capacities of 954.5 mA h·g-1 at 0.5 C with a retention of 84.9% over 200 cycles, and 710.2 mA hg-1 at 1 C with a retention of 98.6% over 200 cycles. This study provides an effective strategy for developing active and durable electrocatalysts for Li-S batteries.

The performance of a combination of heparin-binding protein with other biomarkers for sepsis diagnosis: an observational cohort study.

BACKGROUND: HBP, a novel biomarker released from neutrophils, may induce inflammatory responses and exacerbate vascular permeability, representing the pathophysiological characteristics of sepsis and septic shock. However, it remains uncertain whether the combination of HBP with other biomarkers yields enhanced diagnostic capacity for sepsis. We hypothesized that measurements included IL-6·IL-8·HBP, IL-6·IL-8·HBP/ALB and HBP/ALB which based on HBP will improve its diagnostic efficacy and even better than the traditional infection biomarkers. METHODS: Between July 2021 and June 2022, we carried out a comprehensive, multi-center, observational cohort study spanning six leading tertiary hospitals located in Heilongjiang Province, China. Patients were stratified into three categories based on the severity of infection: non-sepsis, sepsis, and septic shock. We collected clinical and laboratory data, along with infection and inflammation biomarkers, for analysis. RESULTS: A total of 195 patients were enrolled. Among the three groups, patients with septic shock (n = 75, 38.5%) had significantly higher baseline levels of HBP, WBC, Lac, CRP, PCT, IL-6, IL-8, and IL-10 compared to non-sepsis patients (n = 43, 22.0%) and sepsis patients (n = 77, 39.5%), with statistically significant differences (p < 0.05) observed for all parameters. When compared to SOFA score and traditional markers of CRP, PCT, IL-6 and IL-8, the combined indexes of IL-6·IL-8·HBP and IL-6·IL-8·HBP/ALB demonstrated significantly improved diagnostic performance for sepsis and septic shock (AUC 0.911 and 0.902 respectively, p < 0.001). CONCLUSIONS: The combined measurements of IL-6·IL-8·HBP and IL-6·IL-8·HBP/ALB can augment the diagnostic capacity of HBP for sepsis, and offer reliable early supplementary indicators to traditional biomarkers for assessing disease severity in patients with infection.

Experimental Study on the Effect of Polycarboxylate Superplasticizer on the Performance of Cement-Based Grouting Materials.

Polycarboxylate superplasticizers BMC-L and BMC-S were utilized as modifiers in the formulation of novel cement-based grouting materials. Indoor tests were conducted on 32 groups of cement slurries, varying by water-cement ratio (0.5:1 and 0.6:1) and modifier content (0, 2‱, 4‱, 6‱, 8‱, 10‱, 12‱, and 14‱), to test their density, funnel viscosity, water separation rate, and stone rate. Four groups of slurry modified with BMC-L were selected as the preferred slurry, and the apparent viscosity test, uniaxial, and triaxial compression test of the slurry stone body were conducted. The study investigated the influence of BMC-L on various properties of the slurry, including its apparent viscosity, uniaxial compressive strength, stress-strain relationships, shear strength parameters, and elastic modulus. Ultimately, the pore structure and phase composition of the slurry stone body were detected by Nuclear Magnetic Resonance (NMR) and X-ray Diffraction (XRD), and the impact of BMC-L on slurry performance was examined from a microstructural perspective. Results indicate that the two polycarboxylate superplasticizers exert minimal influence on the density and water separation rate of the slurry. Within the effective incorporation range of the polycarboxylate superplasticizer, increasing the dosage correlates with a decrease in both the stone rate and viscosity of the slurry. BMC-L significantly enhances the mechanical properties of the slurry stone body by promoting more complete cement hydration and reducing porosity. The uniaxial compressive strength of slurry stone body with a 6 ‱ BMC-L dosage reached 29.7 MPa after 7 days and 38.5 MPa after 28 days of curing, representing increases of 118.4% and 64%, respectively, compared to masonry with 0 BMC-L dosage. The shear strength parameters and elastic modulus of the slurry stone body also showed corresponding increases.

Current Status and Development Trend of Research on Polymer-Based Kinetic Inhibitors for Natural Gas Hydrates.

As the understanding of natural gas hydrates as a vast potential resource deepens, their importance as a future clean energy source becomes increasingly evident. However, natural gas hydrates trend towards secondary generation during extraction and transportation, leading to safety issues such as pipeline blockages. Consequently, developing new and efficient natural gas hydrate inhibitors has become a focal point in hydrate research. Kinetic hydrate inhibitors (KHIs) offer an effective solution by disrupting the nucleation and growth processes of hydrates without altering their thermodynamic equilibrium conditions. This paper systematically reviews the latest research progress and development trends in KHIs for natural gas hydrates, covering their development history, classification, and inhibition mechanisms. It particularly focuses on the chemical properties, inhibition effects, and mechanisms of polymer inhibitors such as polyvinylpyrrolidone (PVP) and polyvinylcaprolactam (PVCap). Studies indicate that these polymer inhibitors provide an economical and efficient solution due to their low dosage and environmental friendliness. Additionally, this paper explores the environmental impact and biodegradability of these inhibitors, offering guidance for future research, including the development, optimization, and environmental assessment of new inhibitors. Through a comprehensive analysis of existing research, this work aims to provide a theoretical foundation and technical reference for the commercial development of natural gas hydrates, promoting their safe and efficient use as a clean energy resource.

ZFHX3 methylation in peripheral blood monocytes as a potential biomarker for pancreatic cancer detection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the digestive malignancy with poor prognosis, and there is still a lack of effective diagnostic biomarkers. OBJECTIVE: We aimed to explore the diagnostic efficiency of DNA methylation in peripheral blood monocytes (PBMCs) in PDAC. METHODS: 850K BeadChips were used to detect genome-wide methylation of PBMCs. For the selected sites, MethylTarget assays was used for further verification. The support vector machine was used to establish the combined panel. RESULTS: A total of 167 PDAC patients and 113 healthy controls were included in this study and were divided into three sets. In the discovery set, we found 4625 differentially methylated positions (DMPs) between cancer group and healthy controls. ZFHX3 (0.16 ± 0.04 vs. 0.18 ± 0.04, P = 0.001), cg01904886 (0.84 ± 0.05 vs. 0.81 ± 0.04, P = 0.02) and NUMBL (0.96 ± 0.005 vs. 0.957 ± 0.005, P = 0.04) were found to be significantly different in training set. The locus with more significant differences, namely ZFHX3, was used for further validation and to establish a combined diagnostic panel with CA19-9. In the validation set, the ROC curve indicated that the AUC value of ZFHX3 was 0.75. The AUC value of the combined model (AUC = 0.92) was higher than that of CA19-9 alone (AUC = 0.88). In patients with normal CA19-9 levels, the ZFHX3 methylation biomarker still maintained good diagnostic efficacy (AUC = 0.71). CONCLUSION: Our study preliminarily suggests that ZFHX3 methylation combined with CA19-9 can improve the detection rate of PDAC. Especially in patients with normal CA19-9, ZFHX3 methylation can maintain stable diagnostic efficacy. The diagnostic value of ZFHX3 methylation still needs to be prospectively validated.

Tailoring Practical Solid Electrolyte Composites Containing Ferroelectric Ceramic Nanofibers and All-Trans Block Copolymers for All-Solid-State Lithium Metal Batteries.

Ion transport efficiency, the key to determining the cycling stability and rate capability of all-solid-state lithium metal batteries (ASSLMBs), is constrained by ionic conductivity and Li+-migration ability across the multicomponent phases and interfaces in ASSLMBs. Here, we report a robust strategy for the large-scale fabrication of a practical solid electrolyte composite with high-throughput linear Li+-transport channels by compositing an all-trans block copolymer PVDF-b-PTFE matrix with ferroelectric BaTiO3-TiO2 nanofiber films. The electrolyte shows a sustainable electromechanical-coupled deformability that enables the rapid dissociation of anions with Li+ to create more movable Li+ ions and spontaneously transform the battery internal strain into Li+-ion migration kinetic energy. The ceramic framework homogenizes the interfacial potential with electrodes, endowing the electrolyte with a high conductivity of 0.782 mS·cm-1 and stable ion transport ability in ASSLMBs at room temperature. The batteries of LiFePO4/Li can stably cycle 1000 times at 0.5 C with a high capacity retention of 96.1%, and Ah-grade pouch or high-voltage Li(Ni0.8Mn0.1Co0.1)O2/Li batteries also exhibit excellent rate capability and cycling performance.

The footprint of gut microbiota in gallbladder cancer: a mechanistic review.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.

Efficient nitrogen removal from municipal wastewater using an integrated fixed-film activated sludge process in a novel air-lifting loop reactor: A pilot-scale demonstration.

A novel air-lifting loop reactor combines anoxic, oxic, and settling zones to achieve organic and nutrient removal, as well as solid-liquid separation. To address sludge settling ability and operation stability issues caused by low dissolved oxygen in aerobic zones, this study proposes using modified polypropylene carriers to establish a fixed-film activated sludge (IFAS) system. A pilot-scale demonstration of the IFAS-based air-lifting loop reactor is conducted, and the results show successful operation for approximately 300 days. The pilot-scale reactor achieves a maximum aerobic granulation ratio of 16% in the bulk liquid. The IFAS system contributes to efficient removal of organic matter (96%) and nitrogen (94%) by facilitating simultaneous nitrification and denitrification, as well as fast solid-liquid separation with a low sludge volume index of 34 mL/g. Microbial analysis reveals enrichment of functional bacteria involved in nitrification, denitrification, and flocculation throughout the operation process.

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms.

Background: CXC chemokine receptor 4 (CXCR4) is associated with the progression and metastasis of numerous malignant tumors. However, its relationship with Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3 (GEP-NENs G3) is unclear. The aim of this study was to characterize the expression of CXCR4 in GEP-NENS and to explore the clinical and prognostic value of CXCR4. Methods: This study retrospectively collected clinical and pathological data from patients with GEP-NENs who receiving surgery in Qilu Hospital of Shandong University from January 2013 to April 2021, and obtained the overall survival of the patients based on follow-up. Immunohistochemistry (IHC) was performed on pathological paraffin sections to observe CXCR4 staining. Groups were made according to pathological findings. Kaplan-Meier (K-M) curve was used to evaluate prognosis. SPSS 26.0 was used for statistical analysis. Results: 100 GEP-NENs G3 patients were enrolled in this study. There was a significant difference in primary sites (P=0.002), Ki-67 index (P<0.001), and Carcinoembryonic Antigen (CEA) elevation (P=0.008) between neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC). CXCR4 was highly expressed only in tumors, low or no expressed in adjacent tissues (P<0.001). The expression level of CXCR4 in NEC was significantly higher than that in NET G3 (P=0.038). The K-M curves showed that there was no significant difference in overall survival between patients with high CXCR4 expression and patients with low CXCR4 expression, either in GEP-NEN G3 or NEC (P=0.920, P=0.842. respectively). Conclusion: Differential expression of CXCR4 was found between tumor and adjacent tissues and between NET G3 and NEC. Our results demonstrated that CXCR4 can be served as a new IHC diagnostic indicator in the diagnosis and differential diagnosis of GEP-NENs G3. Further studies with multi-center, large sample size and longer follow-up are needed to confirm the correlation between CXCR4 expression level and prognosis.

Ruminal microbiota and muscle metabolome characteristics of Tibetan plateau yaks fed different dietary protein levels.

Introduction: The dietary protein level plays a crucial role in maintaining the equilibrium of rumen microbiota in yaks. To explore the association between dietary protein levels, rumen microbiota, and muscle metabolites, we examined the rumen microbiome and muscle metabolome characteristics in yaks subjected to varying dietary protein levels. Methods: In this study, 36 yaks were randomly assigned to three groups (n = 12 per group): low dietary protein group (LP, 12% protein concentration), medium dietary protein group (MP, 14% protein concentration), and high dietary protein group (HP, 16% protein concentration). Results: 16S rDNA sequencing revealed that the HP group exhibited the highest Chao1 and Observed_species indices, while the LP group demonstrated the lowest. Shannon and Simpson indices were significantly elevated in the MP group relative to the LP group (P < 0.05). At the genus level, the relative abundance of Christensenellaceae_R-7_group in the HP group was notably greater than that in the LP and MP groups (P < 0.05). Conversely, the relative abundance of Rikenellaceae_RC9_gut_group displayed an increasing tendency with escalating feed protein levels. Muscle metabolism analysis revealed that the content of the metabolite Uric acid was significantly higher in the LP group compared to the MP group (P < 0.05). The content of the metabolite L-(+)-Arabinose was significantly increased in the MP group compared to the HP group (P < 0.05), while the content of D-(-)-Glutamine and L-arginine was significantly reduced in the LP group (P < 0.05). The levels of metabolites 13-HPODE, Decanoylcarnitine, Lauric acid, L-(+)-Arabinose, and Uric acid were significantly elevated in the LP group relative to the HP group (P < 0.05). Furthermore, our observations disclosed correlations between rumen microbes and muscle metabolites. The relative abundance of NK4A214_group was negatively correlated with Orlistat concentration; the relative abundance of Christensenellaceae_R-7_group was positively correlated with D-(-)-Glutamine and L-arginine concentrations. Discussion: Our findings offer a foundation for comprehending the rumen microbiome of yaks subjected to different dietary protein levels and the intimately associated metabolic pathways of the yak muscle metabolome. Elucidating the rumen microbiome and muscle metabolome of yaks may facilitate the determination of dietary protein levels.

miR-451a suppresses the proliferation and migration of high-grade serous ovarian cancer by targeting RAB5A through the Ras/Raf/MEK/ERK pathway.

BACKGROUND: Ovarian cancer is one of the most common cancers in women. Profiles changes of microRNAs (miRNAs) are closely linked to malignant tumors. In the present study, we investigated expression of miR-451a in high-grade serous ovarian cancer (HGSOC). We also investigated the potential pathological roles and the likely mechanism of miR-451a in the development of HGSOC using animal models and cell lines. METHODS: Using bioinformatics techniques and a real-time PCR, we analyzed differently expressed miRNAs in HGSOC compared to normal tissue. MTT (i.e. 3-[4, 5-dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), EDU (i.e. 5-ethynyl-2'-deoxyuridine) and transwell assays were performed to investigate the effect of miR-451a on the proliferation and migration of HGSOC SKOV-3 cells. A dual luciferase reporter assay was performed to verify the targeting relationship of miR-451 and RAB5A (one of the Rab GTPase proteins that regulates endocytosis and vesicle transport). Also, we analyzed levels of the RAB5A mRNA and protein by real-time PCR, western blotting and immunohistochemistry assays in HGSOC cells and tissues. Finally, we performed in vivo experiments using HGSOC mice. RESULTS: miR-451a was substantially upregulated in HGSOC and associated with favorable clinical characteristics. miR-451a knockdown significantly increased growth and metastasis of HGSOC cell line SKOV-3 through Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. In addition, RAB5A, an early endosome marker, was shown to be a direct target of miR-451a. Moreover, RAB5A is correlated with unfavorable clinical features and shows independent prognostic significance in HGSOC. CONCLUSIONS: We found that the miR-451a/RAB5A axis is associated with tumorigenesis and progression through the Ras/Raf/MEK/ERK pathway, providing prognostic indicators and therapeutic targets for patients with HGSOC.

Simplification of the pretreatment method for phosphate oxygen isotope measurement in phosphogypsum leachate.

The stacking of phosphogypsum has caused considerable phosphorus pollution in water bodies near phosphogypsum yards through surface runoff and underground infiltration. The phosphate oxygen isotope (δ18Op) tracing method has served as a valuable tool for tracing phosphorus pollution in water. However, the existing δ18Op enrichment and purification methods are complex, costly, and inefficient for phosphate recovery, particularly for phosphogypsum leachate with complex compositions. Herein, a simplified and optimized pretreatment method for δ18Op measurement in phosphogypsum leachate was developed. Zirconium/polyvinyl alcohol (Zr/PVA) gel beads showed good selectivity for phosphate enrichment from water at different initial phosphate concentrations with appropriate Zr/PVA dosage. The optimal enrichment pH value was <7, and the concentrated phosphate on the Zr/PVA gel beads could be effectively eluted in an alkaline environment. Compared with the traditional Fe or Mg coprecipitation enrichment methods, impurities in the solution showed no obvious adverse effects on the phosphate enrichment process. Further, the phosphate solution eluted from the Zr/PVA gel beads was purified by a simple adjustment of the pH instead of cation exchange in the traditional purification process. Magnesium ions in the solution could be completely removed when the pH ranged from 3.17 to 6.15, and the phosphate recovery rate could reach 98.66% when the eluent pH was 5.02. Fourier-transform infrared spectroscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy revealed that similar to traditional pretreatment method, the proposed method can obtain high-purity Ag3PO4 solids for δ18OP measurement and no isotope fractionation of δ18OP was observed. Therefore, this study provides a promising and reliable pretreatment method for δ18OP measurement, especially in complex phosphogypsum leachate.

Safety evaluation of PEGylated MNPs and p-PEGylated MNPs in SD rats.

Polyethylene glycol-coated magnetic nanoparticles (PEGylated MNPs) have demonstrated prominent advantages in cancer diagnosis and hyperthermia therapy. However, there is currently lack of standard mode and sufficient toxicity data for determining the delayed risk of PEGylated MNPs. Nevertheless, the toxicity potentials, especially those associated with the oxidative stress, were ubiquitously reported. In this study, PEGylated MNPs and p-PEGylated MNPs were administrated to SD (Sprague Dawley) rats by single intravenously injection, and various toxicity indicators were monitored till 56 days post-administration for a comprehensive toxicity evaluation. We revealed that both nanoparticles could be rapidly cleared from plasma and enter tissues, such as, liver, kidneys and spleen, and p-PEGylated MNP is less prone to be accumulated in the tissues, indicating a lower toxicity risk. PEGylated MNPs were more likely to up-regulate the expression levels of Th2 type cytokines and trigger inflammatory pathways, but no related pathological change was found. Both MNPs are not mutagenic, while recoverable mild DNA damage associated with the presence of nanoparticles might also be observed. This study demonstrated a research approach for the non-clinical safety evaluation of nanoparticles. It also provided comprehensive valuable safety data for PEGylated and p-PEGylated MNPs, for promoting the clinical application and bio-medical translation of such MNPs with PEG modifications in the cancer diagnosis and therapy.

Prognostic value of serum ammonia in critical patients with non-hepatic disease: A prospective, observational, multicenter study.

Background and Objectives: Non-hepatic hyperammonemia can damage the central nervous system (CNS), and possible prognostic factors are lacking. This study aimed to investigate the prognostic and risk factors for patients admitted to the intensive care unit (ICU). Materials and Methods: This prospective, observational, multicenter study was conducted between November and December 2019 at 11 ICUs in the Chinese Heilongjiang province. Changes in blood ammonia level during and after ICU admission were continuously monitored and expressed as the high level (H-), mean level (M-), and initial level (I-) of ammonia. The risk factors of poor prognosis were investigated by conducting univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive ability of Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE-II) score, lactic acid, total bilirubin (TBil), and M-ammonia. Results: A total of 1060 patients were included in this study, of which 707 (67%) had a favorable prognosis and 353 (33%) had a poor prognosis. As shown by univariate models, a poor prognosis was associated with elevated serum levels of lactic acid, TBil, and ammonia (P < 0.05) and pathologic scores from three assessments: APACHE-II, Glasgow Coma Scale (GCS), and Sequential Organ Failure Assessment (SOFA). Multivariate analysis revealed that circulating mean ammonia levels in ICU patients were independently associated with a poor prognosis (odds ratio [OR] = 1.73, 95% confidence interval [CI]: 1.07-2.80, P = 0.02). However, the APACHE-II score (area under the curve [AUC]: 0.714, sensitivity: 0.86, specificity: 0.68, P < 0.001) remained the most predictive factor for patient prognosis by ROC analysis. Conclusion: Elevated serum levels of ammonia in the blood were independently prognostic for ICU patients without liver disease.