Low-grade wind-driven directional flow in anchored droplets.

Low-grade wind with airspeed Vwind < 5 m/s, while distributed far more abundantly, is still challenging to extract because current turbine-based technologies require particular geography (e.g., wide-open land or off-shore regions) with year-round Vwind > 5 m/s to effectively rotate the blades. Here, we report that low-speed airflow can sensitively enable directional flow within nanowire-anchored ionic liquid (IL) drops. Specifically, wind-induced air/liquid friction continuously raises directional leeward fluid transport in the upper portion, whereas three-phase contact line (TCL) pinning blocks further movement of IL. To remove excessive accumulation of IL near TCL, fluid dives, and headwind flow forms in the lower portion, as confirmed by microscope observation. Such stratified circulating flow within single drop can generate voltage output up to ~0.84 V, which we further scale up to ~60 V using drop "wind farms". Our results demonstrate a technology to tap the widespread low-grade wind as a reliable energy resource.

Endoplasmic reticulum stress: The underlying mechanism of chronic pain.

Chronic pain (CP) affects over 30 % of the global population, imposing significant financial burdens on individuals and society. However, existing treatments for CP offer limited efficacy and troublesome side effects, primarily owing to a lack of knowledge of its precise underlying mechanism. Pathological stimuli disrupt the intricate process of protein folding and endoplasmic reticulum (ER) homeostasis. This disruption leads to the accumulation of misfolded or unfolded proteins in the ER, generating a condition termed ER stress. Emerging data have indicated that ER stress, occurring in the peripheral and central nervous systems, contributes to the development and maintenance of CP. This review aimed to comprehensively explore the intersection of ER stress and CP within the lower and upper nervous systems and highlight the cell-specific contributions of the unfolded protein response in different CP types. We provide a comprehensive synthesis of evidence from animal models, examining neuronal and non-neuronal mechanisms and discuss the damaging ER stress-linked inflammation, autophagy, oxidative stress, and apoptosis, which collectively drive disease progression and contribute to a neurotoxic environment. However, the mechanisms through which ER stress influences the most advanced centre-of-pain projections in the brain remain unclear. Further investigation in this area is crucial to elucidate the relationship between ER stress and CP and facilitate the development of novel therapeutic drugs for this intractable dilemma.

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

Quercetin regulates dendritic cell activation by targeting STAT4 in the treatment of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a class of autoimmune diseases mainly caused by the immune system attacking the myelin sheath of the axons in the nervous system. Although the pathogenesis of MS is complex, studies have shown that dendritic cells (DCs) play a vital role in the pathogenesis of MS. Quercetin (QU) has a unique advantage in clinical application, especially for treating autoimmune diseases. However, the mechanism of QU in the treatment of experimental autoimmune encephalomyelitis (EAE) remains unclear. In this study, we explore the potential role of QU in EAE. Finally, we find that QU has anti-inflammatory activities and neural protective effects in EAE. The experimental results suggest that the cellular basis for QU's function is to inhibit the activation of DCs while modulating the Th17 cell differentiation in the co-culture system. Further, QU may target STAT4 to inhibit its activation in DCs. This work will be of great significance for the future development and utilization of QU.

Fabrication of Highly Dispersed Ru Catalysts on CeO2 for Efficient C3H6 Oxidation.

Emissions of volatile organic compounds (VOCs) threaten both the environment and human health. To realize the elimination of VOCs, Ru/CeO2 catalysts have been intensively investigated and applied. Although it has been widely acknowledged that the catalytic performance of platinum group metal catalysts was highly determined by their dispersion and coordination environment, the most reactive structures on Ru/CeO2 catalysts for VOCs oxidation are still ambiguous. In this work, starting from Ce-BTC (BTC = 1,3,5-benzenetricarboxylic acid) materials, atomically dispersed Ru catalysts and agglomerated Ru catalysts were successfully created via one-step hydrothermal method (Ru-CeO2-BTC) and conventional incipient wetness impregnation method (Ru/CeO2-BTC), respectively. In a typical model reaction of C3H6 oxidation, atomically dispersed Ruδ+ species with the formation of abundant Ru-O-Ce linkages on Ru-CeO2-BTC were found to perform much better than agglomerated RuOx species on Ru/CeO2-BTC. Further characterizations and mechanism study disclosed that Ru-CeO2-BTC catalyst with atomically dispersed Ru ions and more superior low temperature redox performance compared to Ru/CeO2-BTC could better facilitate the adsorption/activation of C3H6 and the decomposition/desorption of intermediates, thus exhibiting superior C3H6 oxidation activity. This work elucidated the reactive sites on Ru/CeO2 catalysts in the C3H6 oxidation reaction and provided insightful guidance for designing efficient Ru/CeO2 catalysts to eliminate VOCs.

Constructing green superhydrophilic and superoleophobic COFs-MOFs hybrid-based membrane for efficiently emulsion separation and synchronous removal of microplastics, dyes, and pesticides.

Oil spills and micropollutants have become thorny environmental issues, posing serious threat to ecosystem and human health. To settle such dilemma, this study successfully constructed a robust and environmentally-friendly MOFs-COFs hybrid-based membrane (FS-50/COF(MATPA)-MOF(Zr)/PDA@PVDF) for the first time through solution synthesis and solvothermal method, combined with surface modification of FS-50 molecule. Importantly, we employed a simple two-step strategy to obtain the high-aspect-ratio MOFs fibers: (1) solvent regulation to generate smaller needle-like whiskers during the in-situ growth of MOFs on COFs; (2) high pressure induced directional crystallization in filtration process. The introduction of polydopamine (PDA) greatly improved the adhesion between coating and PVDF membrane. The in-situ growth of high length-diameter ratio MOFs fibers on blocky COFs greatly enhanced the specific surface area of MOFs-COFs hybrid, thus provided sufficient absorption sites. The functional groups of FS-50 endowed the hybrid membrane with superhydrophilicity and superoleophobicity, which facilitated to selectively penetrate water molecules and repel non-polar pollutants. The separation efficiency and decontamination mechanism of hybrid membrane to the simulated oily wastewater (containing various MPs, dyes, and pesticides) were investigated through experiments and theoretical calculations. The hybrid membrane could selectively and synchronously adsorb various dyes (20 mg/L-120 mg/L, almost 100% removal) and pesticides (10 mg/L for DIF and TET, adsorption rates 93.2% and 90.9%, respectively) from oil-water emulsion (50 mL). The large-scale coated sponge (6 cm × 4.5 cm × 3 cm) could quickly achieve separation of oil-water mixture (almost 100%) with a water permeability of more than 162 L m-2·h-1·bar-1, and simultaneously remove various MPs (PP-2000, PP-100, PE-2000, PS-100, 0.2 g/300 mL for each), Sudan Ⅲ (C0 = 200 mg/L), and DIF (C0 = 10 mg/L) from a simulant oily wastewater (300 mL), with the removal rates of almost 100% for MPs, 99.7% for Sudan Ⅲ, and 95.8% for DIF. Furthermore, we elucidated the removal mechanism of pesticide and dyes through simulating the theoretical adsorption energy and potential adsorption sites. The hybrid membrane not only provides a promising candidate for the removal of multiple pollutants from oil-water emulsion, but also opens a new strategy for achieving efficient and clean aquatic environment restoration.

Application of a dual-modality colorimetric analysis method to inkjet printing lateral flow detection of Salmonella typhimurium.

Lateral flow assay (LFA) color signal quantification methods were developed by utilizing both International Commission on Illumination (CIE) LAB (CIELAB) color space and grayscale intensity differences. The CIELAB image processing procedure included calibration, test, control band detection, and color difference calculation, which can minimize the noise from the background. The LFA platform showcases its ability to accurately discern relevant colorimetric signals. The rising occurrence of infectious outbreaks from foodborne pathogens like Salmonella typhimurium presents significant economic, healthcare, and public health risks. The study introduces an aptamer-based lateral flow (ABLF) platform by using inkjet printing for specially detecting S. typhimurium. The ABLF utilized gold-decorated polystyrene microparticles, functionalized with specific S. typhimurium aptamers (Ps-AuNPs-ssDNA). The platform demonstrates a detection limit of 102 CFU mL-1 in buffer solutions and 103 CFU mL-1 in romaine lettuce tests. Furthermore, it sustained performance for over 8 weeks at room temperature. The ABLF platform and analysis methods are expected to effectively resolve the low-sensitivity problems of the former LFA systems and to bridge the gap between lab-scale platforms to market-ready solutions by offering a simple, cost-effective, and consistent approach to detecting foodborne pathogens in real samples.

APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease.

INTRODUCTION: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs). RESULTS: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. DISCUSSION: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. HIGHLIGHTS: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.

Formamidinium Lead Iodide-Based Inverted Perovskite Solar Cells with Efficiency over 25 % Enabled by An Amphiphilic Molecular Hole-Transporter.

Formamidinium lead iodide (FAPbI3) represents an optimal absorber material in perovskite solar cells (PSCs), while the application of FAPbI3 in inverted-structured PSCs has yet to be successful, mainly owing to its inferior film-forming on hydrophobic or defective hole-transporting substrates. Herein, we report a substantial improvement of FAPbI3-based inverted PSCs, which is realized by a multifunctional amphiphilic molecular hole-transporter, (2-(4-(10H-phenothiazin-10-yl)phenyl)-1-cyanovinyl)phosphonic acid (PTZ-CPA). The phenothiazine (PTZ) based PTZ-CPA, carrying a cyanovinyl phosphonic acid (CPA) group, forms a superwetting hole-selective underlayer that enables facile deposition of high-quality FAPbI3 thin films. Compared to a previously established carbazole-based hole-selective material (2-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)phosphonic acid (MeO-2PACz), the crystallinity of FAPbI3 is enhanced and the electronic defects are passivated by the PTZ-CPA more effectively, resulting in remarkable increases in photoluminescence quantum yield (four-fold) and Shockley-Read-Hall lifetime (eight-fold). Moreover, the PTZ-CPA shows a larger molecular dipole moment and improved energy level alignment with FAPbI3, benefiting the interfacial hole-collection. Consequently, FAPbI3-based inverted PSCs achieve an unprecedented efficiency of 25.35 % under simulated air mass 1.5 (AM1.5) sunlight. The PTZ-CPA based device shows commendable long-term stability, maintaining over 90 % of its initial efficiency after continuous operation at 40 °C for 2000 hours.

ALKBH5-induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2.

Although circular RNAs (circRNAs) are involved in cell proliferation, differentiation, apoptosis, and invasion, the underlying regulatory mechanisms of circRNAs in thyroid cancer have not been fully elucidated. This article aimed to study the role of circRNA regulated by N6-methyladenosine modification in papillary thyroid cancer (PTC). Quantitative real-time PCR, western blotting, and immunohistochemistry were used to investigate the expressions of circRNA nuclear receptor-interacting protein 1 (circNRIP1) in PTC tissues and adjacent noncancerous thyroid tissues. In vitro and in vivo assays were carried out to assess the effects of circNRIP1 on PTC glycolysis and growth. The N6-methyladenosine mechanisms of circNRIP1 were evaluated by methylated RNA immunoprecipitation sequencing, luciferase reporter gene, and RNA stability assays. Results showed that circNRIP1 levels were significantly upregulated in PTC tissues. Furthermore, elevated circNRIP1 levels in PTC patients were correlated with high tumor lymph node metastasis stage and larger tumor sizes. Functionally, circNRIP1 significantly promoted glycolysis, PTC cell proliferation in vitro, and tumorigenesis in vivo. Mechanistically, circNRIP1 acted as a sponge for microRNA (miR)-541-5p and miR-3064-5p and jointly upregulated pyruvate kinase M2 (PKM2) expression. Knockdown of m6 A demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) significantly enhanced circNRIP1 m6 A modification and upregulated its expression. These results show that ALKBH5 knockdown upregulates circNRIP1, thus promoting glycolysis in PTC cells. Therefore, circNRIP1 can be a prognostic biomarker and therapeutic target for PTC by acting as a sponge for oncogenic miR-541-5p and miR-3064-5p to upregulate PKM2 expression.

FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2.

BACKGROUND & AIMS: Metastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis. METHODS: PLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment. RESULTS: ETV4 expression was positively related to higher tumour-node-metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8+ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19-ETV4-FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19-ETV4 signalling-induced HCC metastasis. CONCLUSIONS: ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis. IMPACT AND IMPLICATIONS: Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAM and MDSC accumulation and CD8+ T-cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19-ETV4 signalling-mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for patients with HCC.

Unfolded protein response pathways in stroke patients: a comprehensive landscape assessed through machine learning algorithms and experimental verification.

BACKGROUND: The unfolding protein response is a critical biological process implicated in a variety of physiological functions and disease states across eukaryotes. Despite its significance, the role and underlying mechanisms of the response in the context of ischemic stroke remain elusive. Hence, this study endeavors to shed light on the mechanisms and role of the unfolding protein response in the context of ischemic stroke. METHODS: In this study, mRNA expression patterns were extracted from the GSE58294 and GSE16561 datasets in the GEO database. The screening and validation of protein response-related biomarkers in stroke patients, as well as the analysis of the immune effects of the pathway, were carried out. To identify the key genes in the unfolded protein response, we constructed diagnostic models using both random forest and support vector machine-recursive feature elimination methods. The internal validation was performed using a bootstrapping approach based on a random sample of 1,000 iterations. Lastly, the target gene was validated by RT-PCR using clinical samples. We utilized two algorithms, CIBERSORT and MCPcounter, to investigate the relationship between the model genes and immune cells. Additionally, we performed uniform clustering of ischemic stroke samples based on expression of genes related to the UPR pathway and analyzed the relationship between different clusters and clinical traits. The weighted gene co-expression network analysis was conducted to identify the core genes in various clusters, followed by enrichment analysis and protein profiling for the hub genes from different clusters. RESULTS: Our differential analysis revealed 44 genes related to the UPR pathway to be statistically significant. The integration of both machine learning algorithms resulted in the identification of 7 key genes, namely ATF6, EXOSC5, EEF2, LSM4, NOLC1, BANF1, and DNAJC3. These genes served as the foundation for a diagnostic model, with an area under the curve of 0.972. Following 1000 rounds of internal validation via randomized sampling, the model was confirmed to exhibit high levels of both specificity and sensitivity. Furthermore, the expression of these genes was found to be linked with the infiltration of immune cells such as neutrophils and CD8 T cells. The cluster analysis of ischemic stroke samples revealed three distinct groups, each with differential expression of most genes related to the UPR pathway, immune cell infiltration, and inflammatory factor secretion. The weighted gene co-expression network analysis showed that all three clusters were associated with the unfolded protein response, as evidenced by gene enrichment analysis and the protein landscape of each cluster. The results showed that the expression of the target gene in blood was consistent with the previous analysis. CONCLUSION: The study of the relationship between UPR and ischemic stroke can help to better understand the underlying mechanisms of the disease and provide new targets for therapeutic intervention. For example, targeting the UPR pathway by blocking excessive autophagy or inducing moderate UPR could potentially reduce tissue injury and promote cell survival after ischemic stroke. In addition, the results of this study suggest that the use of UPR gene expression levels as biomarkers could improve the accuracy of early diagnosis and prognosis of ischemic stroke, leading to more personalized treatment strategies. Overall, this study highlights the importance of the UPR pathway in the pathology of ischemic stroke and provides a foundation for future studies in this field.

UNFERTILIZED EMBRYO SAC 12 phosphorylation plays a crucial role in conferring salt tolerance.

Arabidopsis (Arabidopsis thaliana) UNFERTILIZED EMBRYO SAC 12 (AtUNE12) belongs to the basic helix-loop-helix DNA-binding superfamily of proteins. However, its function is not well known. Here, we found that AtUNE12 plays an important role in mediating salt tolerance. AtUNE12 is a transcriptional activator located in the nucleus whose expression is induced by NaCl, mannitol, and abscisic acid. In addition to binding to the G-box "CACGTG", AtUNE12 also binds to the low temperature responsive element 15 (LTRE15) "CCGAC". Furthermore, the serine residue at position 108 of AtUNE12 is phosphorylated during the salt stress response, enabling AtUNE12 to trigger gene expression by binding to G-box and/or LTRE15 motifs. Phosphorylated AtUNE12 regulates the expression of the genes involved in ion transport leading to reduced Na+ accumulation and K+ loss. At the same time, phosphorylation of AtUNE12 also induces the expression of AtMYB61 to decrease stomatal aperture, leading to a reduced transpiration rate. Overall, AtUNE12 serves as a transcriptional activator that is induced and phosphorylated upon salt stress, and the induction and phosphorylation of AtUNE12 in turn activate the salt-overly-sensitive pathway and decrease the stomatal aperture, enabling improved salt tolerance.

Clinical and ultrasonic risk factors for high-volume central lymph node metastasis in cN0 papillary thyroid microcarcinoma: A retrospective study and meta-analysis.

OBJECTIVE: Papillary thyroid microcarcinoma (PTMC) comprises more than 50% of all newly detected cases of papillary thyroid carcinoma (PTC). High-volume lymph node metastasis (involving >5 lymph nodes) (hv-LNM) is associated with PTMC recurrence. In half of the clinically node-negative (cN0) PTMC patients, central lymph node metastasis (CLNM) is pathologically present. However, clinical risk factors for high-volume CLNM (hv-CLNM) in cN0 PTMC have not been defined well. Therefore, we aimed to obtain evidence for hv-CLNM risk factors in cN0 PTMC. DESIGN: Data on patients who visited our hospital between January 2020 and December 2021 were collected; a preoperative diagnosis of cN0 and a postoperative pathological confirmation of PTMC were obtained. After filtering by inclusion versus exclusion criteria, the obtained data (N = 2268) were included in the meta-analysis. Relevant studies published as of 10 April 2022, were identified from the Web of Science, PubMed, WANFANG, and CNKI databases. These eligible studies were included in the meta-analysis and the association between clinicopathological factors and hv-CLNM in cN0 PTMC was assessed. SPSS and MetaXL were used for statistical analyses. RESULTS: The meta-analysis included 10 previous studies (11,734 patients) and 2268 patients enroled in our hospital for a total of 14,002 subjects. The results of which suggested that younger age (<40, odds ratio [OR] = 3.28, 95% confidence interval [CI] = 2.75-3.92, p < .001 or <45 odds ratio [OR] = 2.93, 95% CI = 2.31-3.72, p < .001), male sex (OR = 2.81, 95% CI = 2.25-3.52, p < .001), tumour size >5 mm (OR = 1.85, 95% CI = 1.39-2.47, p < .001), multifocality (OR = 1.88, 95% CI = 1.56-2.26, p < .001), extrathyroidal extension (OR = 2.58, 95% CI = 2.02-3.30, p < .001), capsule invasion (OR = 2.02, 95% CI = 1.46-2.78, p < .001), microcalcification (OR = 3.25, 95% CI = 2.42-4.36, p < .001) and rich blood flow (OR = 1.65, 95% CI = 1.21-2.25, p = .002) were the significant factors related to an elevated hv-CLNM risk in cN0 PTMC patients. Hashimoto thyroiditis (OR = 0.76, 95% CI = 0.55-1.07, p = .114), irregular margin (versus regular margin, OR = 0.96, 95% CI = 0.68-1.33, p = .787) and hypoechoic (versus nonhypoechoic, OR = 1.27, 95% CI = 0.84-1.92, p = .261) showed no significant association with hv-CLNM. CONCLUSIONS: Younger age, tumour size >5 mm, males, extrathyroidal extension, multifocality, microcalcification, capsular invasion, and rich blood flow were the significant clinicopathological risk factors for hv-CLNM risk in cN0 PTMC patients. These predictors may compensate for the sensitivity of imaging diagnosis in the preoperative period, thus helping in the effective identification of PTMCs with an invasive phenotype.

Elucidation of Carboxylesterase Mediated Pharmacokinetic Interactions between Irinotecan and Oroxylin A in Rats via Physiologically Based Pharmacokinetic Modeling.

PURPOSE: Our previous screening studies identified Oroxylin A (OXA) as a strong inhibitor on the carboxyolesterase mediated hydrolysis of irinotecan to SN-38. The current study employed a whole-body physiologically based pharmacokinetic (PBPK) modeling approach to investigate the underlying mechanisms of the carboxylesterase-mediated pharmacokinetics interactions between irinotecan and OXA in rats. METHODS: Firstly, rats received irinotecan intravenous treatment at 35 µmol/kg without or with oral OXA pretreatment (2800 µmol/kg) daily for 5 days. On day 5, blood and tissues were collected for analyses of irinotecan/SN-38 concentrations and carboxylesterase expression. In addition, effects of OXA on the enzyme kinetics of irinotecan hydrolysis and unbound fractions of irinotecan and SN-38 in rat plasma, liver and intestine were also determined. Finally, a PBPK model that integrated the physiological parameters, enzyme kinetics, and physicochemical properties of irinotecan and OXA was developed. RESULTS: Our PBPK model could accurately predict the pharmacokinetic profiles of irinotecan/SN-38, with AUC0-6h and Cmax values within ±27% of observed values. When OXA was included as a carboxylesterase inhibitor, the model could also predict the irinotecan/SN-38 plasma concentrations within twofold of those observed. In addition, the PBPK model indicated inhibition of carboxylesterase-mediated hydrolysis of irinotecan in the intestinal mucosa as the major underlying mechanism for the pharmacokinetics interactions between irinotecan and OXA. CONCLUSION: A whole-body PBPK model was successfully developed to not only predict the impact of oral OXA pretreatment on the pharmacokinetics profiles of irinotecan but also reveal its inhibition on the intestinal carboxylesterase as the major underlying mechanism.

Serum biomarkers of colonic polyps in patients with acromegaly: a meta-analysis and systematic review.

PURPOSE: In the past few decades, acromegaly and colonic polyps have been associated with an increased risk of colorectal cancer. Previous studies highlighted the importance of serum biomarkers of colonic polyps in patients with acromegaly. METHODS: We reviewed studies on serum biomarkers of colonic polyps in patients with acromegaly, published on PubMed, Embase, Cochrane Library, Medline, and Chinese databases from January 1, 1966, to May 8, 2022. Meta-analysis and systematic review were conducted using Stata MP 14.0. RESULTS: Eight articles were included in this study. The mean (standard deviation) concentrations of serum biomarkers for acromegaly with and without colorectal polyps were extracted from these studies. Meta-analysis results showed that, compared to patients without colonic polyps, the levels of insulin-like growth factor-1 × upper limit of normal range (IGF-1 × ULN) and fasting insulin were significantly increased; while the levels of growth hormone (GH) were significantly decreased in patients with acromegaly and colonic polyps (IGF-1 × ULN: SMD 0.23; 95% CI 0.03-0.42, p < 0.05) (fasting insulin: SMD 0.95; 9 5% CI 0.11-1.8, p < 0.05) (GH: SMD - 0.25; 95% CI - 0.41 to - 0.08, p < 0.05). IGF-1 and FPG levels did not differ significantly (IGF-1: SMD -0.03; 95% CI - 0.22 to 0.17, p > 0.05) (FPG: SMD 0.14; 95% CI - 0.23 to 0.52, p > 0.05). The systematic review results suggest no significant differences in hemoglobin A1C, TSH, free thyroxine, FT4, T3, PRL, total cholesterol, HDL, LDL, fibrinogen, clathrate antigen, serum antigen 19-9, and α-fetoprotein levels, but serum Klotho levels. CONCLUSION: We present the first meta-analysis and systematic review of serum biomarkers in patients with acromegaly or colonic polyps. The prevalence of colonic lesion polyps, is associated with higher IGF-1 × ULN levels, higher insulin levels in acromegaly. Further research is required to confirm GH and serum soluble Klotho levels as biomarkers of colonic polyps. When IGF-1 × ULN, fasting insulin levels change in patients with acromegaly, the occurrence of colonic polyps should be monitored. Early detection may reduce the possibility of developing malignant colon neoplasms.

Comprehensive analysis of novel prognosis-related proteomic signature effectively improve risk stratification and precision treatment for patients with cervical cancer.

OBJECTIVE: Cervical cancer (CC) is one of the most common types of malignant female cancer, and its incidence and mortality are not optimistic. Protein panels can be a powerful prognostic factor for many types of cancer. The purpose of our study was to investigate a proteomic panel to predict the survival of patients with common CC. METHODS AND RESULTS: The protein expression and clinicopathological data of CC were downloaded from The Cancer Proteome Atlas and The Cancer Genome Atlas database, respectively. We selected the prognosis-related proteins (PRPs) by univariate Cox regression analysis and found that the results of functional enrichment analysis were mainly related to apoptosis. We used Kaplan-Meier analysis and multivariable Cox regression analysis further to screen PRPs to establish a prognostic model, including BCL2, SMAD3, and 4EBP1-pT70. The signature was verified to be independent predictors of OS by Cox regression analysis and the area under curves. Nomogram and subgroup classification were established based on the signature to verify its clinical application. Furthermore, we looked for the co-expressed proteins of three-protein panel as potential prognostic proteins. CONCLUSION: A proteomic signature independently predicted OS of CC patients, and the predictive ability was better than the clinicopathological characteristics. This signature can help improve prediction for clinical outcome and provides new targets for CC treatment.

HNRNPC downregulation inhibits IL-6/STAT3-mediated HCC metastasis by decreasing HIF1A expression.

RNA-binding protein (RBP) dysregulation is functionally linked to several human diseases, including neurological disorders, cardiovascular disease, and cancer. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RBPs involved in nucleic acid metabolism. A growing body of studies has shown that the dysregulated hnRNPs play important roles in tumorigenesis. Here, we found that heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) had good performance in distinguishing between hepatocellular carcinoma (HCC) and normal liver tissues through bioinformatics analysis. Further investigation revealed that HNRNPC was significantly correlated with multiple malignant characteristics of HCC, including tumor size, microvascular invasion, tumor differentiation, and TNM stage. Patients with HCC with positive HNRNPC expression exhibited decreased overall survival and increased recurrence rate. HNRNPC downregulation inhibited HCC invasion and metastasis. The decreased expression of hypoxia inducible factor 1 subunit alpha (HIF1A) was identified as the molecular mechanism underlying HNRNPC downregulation-inhibited HCC metastasis by RNA sequencing. Mechanistically, HNRNPC downregulation decreased HIF1A expression by destabilizing HIF1A mRNA. HIF1A overexpression rescued the decrease in invasiveness and metastasis of HCC induced by HNRNPC downregulation. Additionally, interleukin (IL)-6/STAT3 signaling upregulated HNRNPC expression in HCC cells, and knockdown of HNRNPC significantly inhibited IL-6/STAT3-enhanced HCC metastasis. Furthermore, anti-IL-6 antibody siltuximab significantly inhibited IL-6-mediated HCC metastasis. In summary, our research revealed the clinical value, functional role, and molecular mechanism of HNRNPC in HCC and showed the potential of HNRNPC as a biomarker for diagnosis, prognosis, and further therapeutic targets for HCC.

IL-1ß-Induced Elevation of Solute Carrier Family 7 Member 11 Promotes Hepatocellular Carcinoma Metastasis Through Up-regulating Programmed Death Ligand 1 and Colony-Stimulating Factor 1.

BACKGROUND AND AIMS: Because of a paucity of effective treatment options, metastasis is still a major cause for HCC-associated mortality. The molecular mechanism of inflammation-induced HCC metastasis is open for study. Here, we characterized the function of solute carrier family 7 member 11 (SLC7A11) in inflammation-related HCC metastasis and probed therapy strategies for this subpopulation of patients. APPROACH AND RESULTS: Elevated expression of SLC7A11 was positively correlated with poor tumor differentiation, and higher tumor-nodule-metastasis stage, and indicated poor prognosis in human HCC. SLC7A11 increased HIF1α expression through reducing α-ketoglutarate (αKG) level by exporting glutamate. SLC7A11 up-regulated programmed death ligand 1 (PD-L1) and colony-stimulating factor 1 (CSF1) expression through αKG-HIF1α cascade. SLC7A11 overexpression in HCC cells promoted intratumoral tumor-associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration through the CSF1/colony-stimulating factor 1 receptor (CSF1R) axis, whereas knockdown of CSF1 attenuated SLC7A11-mediated intratumoral TAM and MDSC infiltration and HCC metastasis. Depletion of either TAMs or MDSCs decreased SLC7A11-mediated HCC metastasis. Furthermore, the combination of CSF1R inhibitor BZL945 and anti-PD-L1 antibody blocked SLC7A11-induced HCC metastasis. In addition, IL-1ß up-regulated SLC7A11 expression through the interleukin-1 receptor type 1 (IL-1R1)/extracellular signal-regulated kinase/specificity protein 1 pathway. SLC7A11 knockdown impaired IL-1ß-promoted HCC metastasis. Anakinra, an IL-1R1 antagonist, reversed IL-1ß-promoted HCC metastasis. In human HCC tissues, SLC7A11 expression was positively associated with HIF1α, PD-L1, and CSF1 expression and intratumoral TAM and MDSC infiltration. CONCLUSIONS: IL-1ß-induced SLC7A11 overexpression up-regulated PD-L1 and CSF1 through the αKG/HIF1α axis, which promoted TAM and MDSC infiltration. Interruption of this oncogenic loop may provide a promising therapy strategy for the inhibition of SLC7A11-mediated HCC metastasis.

Meta-analysis of the efficacy and safety of thermal ablation for treating large benign thyroid nodules.

OBJECTIVE: Many large benign thyroid nodules have symptoms and cosmetic problems. This study consisted of a meta-analysis to accurately assess the effect of thermal ablation on these nodules. METHODS: The PubMed, Embase, Web of Science, and Scopus databases were systematically searched for retrospective or prospective studies of thermal ablation since June 1, 2021. The weighted mean differences of the measures were analysed before and after treatment. RESULTS: A total of 10 eligible studies were included. By comparing the initial nodule volume with the nodular volume after thermal ablation, we found that the volume reduction rate was increased significantly after 1 month (SMD = 0.453, 95% CI: 0.323-0.583, p < .001), 3 months (SMD = 0.655, 95% CI: 0.563-0.747, p < .001), 6 months (SMD = 0.691, 95% CI: 0.607-0.774, p < .001), and 12 months (SMD = 0.694, 95% CI: 0.583-0.803), p < .001). The nodular volume was also found to decrease significantly, after 1 month (SMD = 2.381, 95% CI: 1.278-3.485, p < .001), 3 months (SMD = 5.071, 95% CI: 2.386-7.756, p < .001), 6 months (SMD = 5.363, 95% CI: 2.765-7.962, p < .001), and 12 months (SMD = 8.194, 95% CI: 2.113-14.274), p < .001). Symptom score (SMD = 4.419, 95% CI: 2.573-6.265, p < .001)and cosmetic score (SMD = 4.245, 95% CI: 2.566-5.359, p < .001) were reduced after thermal ablation. CONCLUSIONS: Thermal ablation could become an alternative to manage large benign thyroid nodules.