Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification.

BACKGROUND: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. METHODS: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis. RESULTS: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively. CONCLUSION: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Identification and validation of serum metabolite biomarkers for endometrial cancer diagnosis.

Endometrial cancer (EC) stands as the most prevalent gynecological tumor in women worldwide. Notably, differentiation diagnosis of abnormity detected by ultrasound findings (e.g., thickened endometrium or mass in the uterine cavity) is essential and remains challenging in clinical practice. Herein, we identified a metabolic biomarker panel for differentiation diagnosis of EC using machine learning of high-performance serum metabolic fingerprints (SMFs) and validated the biological function. We first recorded the high-performance SMFs of 191 EC and 204 Non-EC subjects via particle-enhanced laser desorption/ionization mass spectrometry (PELDI-MS). Then, we achieved an area-under-the-curve (AUC) of 0.957-0.968 for EC diagnosis through machine learning of high-performance SMFs, outperforming the clinical biomarker of cancer antigen 125 (CA-125, AUC of 0.610-0.684, p < 0.05). Finally, we identified a metabolic biomarker panel of glutamine, glucose, and cholesterol linoleate with an AUC of 0.901-0.902 and validated the biological function in vitro. Therefore, our work would facilitate the development of novel diagnostic biomarkers for EC in clinics.

Neoadjuvant chemotherapy-induced remodeling of human hormonal receptor-positive breast cancer revealed by single-cell RNA sequencing.

Hormone receptor-positive breast cancer (HR+ BC) is known to be relatively insensitive to chemotherapy, and since chemotherapy has remained the major neoadjuvant therapy for HR+ BC, the undetermined mechanism of chemoresistance and how chemotherapy reshapes the immune microenvironment need to be explored by high-throughput technology. By using single-cell RNA sequencing and multiplexed immunofluorescence staining analysis of HR+ BC samples (paired pre- and post-neoadjuvant chemotherapy (NAC)), the levels of previously unrecognized immune cell subsets, including CD8+ T cells with pronounced expression of T-cell development (LMNA) and cytotoxicity (FGFBP2) markers, CD4+ T cells characterized by proliferation marker (ATP1B3) expression and macrophages characterized by CD52 expression, were found to be increased post-NAC, which were predictive of chemosensitivity and their antitumor function was also validated with in vitro experiments. In terms of immune checkpoint expression of CD8+ T cells, we found their changes were inconsistent post-NAC, that LAG3, VSIR were decreased, and PDCD1, HAVCR2, CTLA4, KLRC1 and BTLA were increased. In addition, we have identified novel genomic and transcriptional patterns of chemoresistant cancer cells, both innate and acquired, and have confirmed their prognostic value with TCGA cohorts. By shedding light on the ecosystem of HR+ BC reshaped by chemotherapy, our results uncover valuable candidates for predicting chemosensitivity and overcoming chemoresistance in HR+ BC.

Downregulated BMP-Smad1/5/8 signaling causes emphysema via dysfunction of alveolar type II epithelial cells.

Bone morphogenetic protein (BMP)-Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP-Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP-Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP-Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP-Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP-Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP-Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.

Rac2 mediate foam cell formation and associated immune responses in THP-1 to promote the process of atherosclerotic plaques.

Macrophages play an important role in the pathogenesis of atherosclerosis (AS) by mediating oxidative stress, inflammation and lipid metabolism, which can lead to the formation of vascular plaque. The Rac family isoforms of small molecules GTPase are active by binding to GTPase, but are inactivated by binding to GDP, and play a role in the switch of cell information conduction. This experiment adopts shRNA interference THP-1 cells respectively each subtype expression and inhibiting Rac1, Rac2, Rac3 activity, each subtype of Rac family on lipid metabolism, inflammatory reaction and oxidative stress. THP-1 cells were stimulated with Ox-LDL to establish AS cell models including lipid loading, adhesion, migration and chemotaxis. Oil Red O staining, cell immunofluorescence, scratching test, transwell, Western blot and other experiments were performed. To observe the different effects of three subtypes of Rac family on multiple links in the foaming process of THP-1 cells. ApoE-/- mice on a high-fat diet were used as animal models to examine the effects of Rac subtypes in vivo. The results showed that the activation of immune cells induced by ox-LDL was inhibited when Rac1, Rac2 and Rac3 in THP-1 were decreased, respectively. Thus, Rac1 and Rac3 act in combination with ox-LDL and are associated with cellular oxidative stress and inflammation. This study provides new means and ideas for finding potential intervention targets that have important regulatory effects on atherosclerosis, and provides a new direction for the development of clinical drugs.

Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis.

BACKGROUND: Chronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer. METHODS: Breast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry. RESULTS: Breast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases. CONCLUSIONS: Chronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

MnO2 nanoparticles decorated with Ag/Au nanotags for label-based SERS determination of cellular glutathione.

A novel stimulus-responsive surface-enhanced Raman scattering (SERS) nanoprobe has been developed for sensitive glutathione (GSH) detection based on manganese dioxide (MnO2) core and silver/gold nanoparticles (Ag/Au NPs). The MnO2 core is not only capable to act as a scaffold to amplify the SERS signal via producing "hot spots", but also can be degraded in the presence of the target and thus greatly enhance the nanoprobe sensitivity for sensing of GSH. This approach enables a wide linear range from 1 to 100 µM with a 2.95 µM (3σ/m) detection limit. Moreover, the developed SERS nanoprobe represents great possibility in both sensitive detection of intracellular GSH and even can monitor the change of intracellular GSH level when the stimulant occurs. This sensing system not merely offers a novel strategy for sensitive sensing of GSH, but also provides a new avenue for other biomolecules detection.

Identification of new aptamer BC-3 targeting RPS7 from rapid screening for bladder carcinoma.

Aptamers, short single DNA or RNA oligonucleotides, have shown immense application potential as molecular probes for the early diagnosis and therapy of cancer. However, conventional cell-SELEX technologies for aptamer discovery are time-consuming and laborious. Here we discovered a new aptamer BC-3 by using an improved rapid X-Aptamer selection process for human bladder carcinoma, for which there is no specific molecular probe yet. We show that BC-3 exhibited excellent affinity in bladder cancer cells but not normal cells. We demonstrate that BC-3 displayed high selectivity for tumor cells over their normal counterparts in vitro, in mice, and in patient tumor tissue specimens. Further endocytosis pathway analysis revealed that BC-3 internalized into bladder cancer cells via clathrin-mediated endocytosis. Importantly, we identified ribosomal protein S7 (RPS7) as the binding target of BC-3 via an integrated methodology (mass spectrometry, colocalization assay, and immunoblotting). Together, we report that a novel aptamer BC-3 is discovered for bladder cancer and its properties in the disease are unearthed. Our findings will facilitate the discovery of novel diagnostic and therapeutic strategies for bladder cancer.

A Non-G-Quadruplex DNA Aptamer Targeting NCL for Diagnosis and Therapy in Bladder Cancer.

Bladder cancer (BC) is a highly aggressive malignant tumor affecting the urinary system, characterized by metastasis and a poor prognosis that often leads to limited therapeutic success. This study aims to develop a novel DNA aptamer for the diagnosis and treatment of BC using a tissue-based systematic evolution of ligands by an exponential enrichment (SELEX) process. By using SELEX, this work successfully generates a new aptamer named TB-5, which demonstrates a remarkable and specific affinity for nucleolin (NCL) in BC tissues and displays marked biocompatibility both in vitro and in vivo. Additionally, this work shows that NCL is a reliable tissue-specific biomarker in BC. Moreover, according to circular dichroism spectroscopy, TB-5 forms a non-G-quadruplex structure, distinguishing it from the current NCL-targeting aptamer AS1411, and exhibits a distinct binding region on NCL compared to AS1411. Notably, this study further reveals that TB-5 activates NCL function by promoting autophagy and suppressing the migration and invasion of BC cells, which occurs by disrupting mRNA transcription processes. These findings highlight the critical role of NCL in the pathological examination of BC and warrant more comprehensive investigations on anti-NCL aptamers in BC imaging and treatment.

Targeting tumor endothelial cells with methyltransferase inhibitors: Mechanisms of action and the potential of combination therapy.

Tumor endothelial cells (TECs) reside in the inner lining of blood vessels and represent a promising target for targeted cancer therapy. DNA methylation is a chemical process that involves the transfer of a methyl group to a specific base in the DNA strand, catalyzed by a DNA methyltransferase (DNMT). DNMT inhibitors (DNMTis) can inhibit the activity of DNMTs, thereby preventing the transfer of methyl groups from s-adenosyl methionine (SAM) to cytosine. Currently, the most viable therapy for TECs is the development of DNMTis to release cancer suppressor genes from their repressed state. In this review, we first outline the characteristics of TECs and describe the development of tumor blood vessels and TECs. Abnormal DNA methylation is closely linked to tumor initiation, progression, and cell carcinogenesis, as evidenced by numerous studies. Therefore, we summarize the role of DNA methylation and DNA methyltransferase and the therapeutic potential of four types of DNMTi in targeting TECs. Finally, we discuss the accomplishments, challenges, and opportunities associated with combination therapy with DNMTis for TECs.

ChillsDB: A Gold Standard for Aesthetic Chills Stimuli.

We introduce ChillsDB the first validated database of audiovisual stimuli eliciting aesthetic chills (goosebumps, psychogenic shivers) in a US population. To discover chills stimuli "in the wild", we devised a bottom-up, ecologically-valid method consisting in searching for mentions of the emotion' somatic markers in user comments throughout social media platforms (YouTube and Reddit). We successfully captured 204 chills-eliciting videos of three categories: music, film, and speech. We then tested the top 50 videos in the database on 600+ participants and validated a gold standard of 10 stimuli with a 0.9 probability of generating chills. All ChillsDB tools and data are fully available on GitHub for researchers to be able to contribute and perform further analysis.

DH5α Outer Membrane-Coated Biomimetic Nanocapsules Deliver Drugs to Brain Metastases but not Normal Brain Cells via Targeting GRP94.

Receptor-mediated vesicular transport has been extensively developed to penetrate the blood-brain barrier (BBB) and has emerged as a class of powerful brain-targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low-density lipoprotein receptor-related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein-coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)-loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti-angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94-positive brain diseases.

Cocrystallization of 5-fluorouracil with gallic acid: A novel 5-fluorouracil cocrystal displaying synergistic anti-tumor activity both in oral and intraperitoneal injection administration.

Gallic acid (GA) is a naturally occurring polyphenolic compound exhibiting anti-tumor activity. To clarify the capability of GA in optimizing the in vitro/in vivo properties of the first line anti-tumor drug 5-fluorouracil (5-FU) and achieve synergistically enhanced anti-tumor activity, a novel cocrystal hydrate of 5-FU-GA-H2O was successfully screened and characterized based on various spectroscopic and experimental analysis including Fourier transform infrared spectroscopy (FT-IR), Raman spectra (Raman), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric (TG) and scanning electric microscope (SEM) techniques. The results suggested the existence of hydrogen bonding interactions between C=O group of 5-FU and O-H group of GA. Although the dissolution rate and solubility of 5-FU-GA-H2O cocrystal were slowed and lowered compared with that of 5-FU, respectively, the membrane permeability was enhanced for cocrystal compared with that of intact 5-FU and physical mixture (PM) of 5-FU and GA. For the cocrystal, the cumulative amount per unit area of permeated 5-FU in the first 10 h was 2.56 and 9.97 times of that of pure 5-FU and PM, respectively, in the case that transmembrane behavior of 5-FU depended on the type of solution from which the powder was dissolved. Meanwhile, improvement on oral bioavailability by co-crystallization was observed; AUC0-t of cocrystal was 2.78-fold higher than that of 5-FU. Furthermore, the cocrystal displayed a superior cytotoxic activity on 4T1 mouse breast cancer cells compared with pure 5-FU and even the PM. It was confirmed that the cocrystal solution induced higher autophagic flux than those of 5-FU and PM in 4T1 cell, suggesting that autophagy rather than apoptosis mainly mediated cell death. The obvious difference of tumor inhibition activity between PM and cocrystal in intraperitoneal injection administration indicated that some of the interactions formed in the solid cocrystal could retain in solution in some way. Benefiting from synergistic cytotoxicity, drug efficacy in vivo was enhanced through injection administration of solution from which cocrystal was dissolved.

CASP8 Is a Potential Therapeutic Target and Is Correlated with Pyroptosis in Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of neurological and psychological problems, especially long-term disability. The purpose of this article is to explore molecular mechanisms linking TBI and pyroptosis with the aim of providing a promising target for future therapeutic interventions. METHODS: GSE104687 microarray dataset was downloaded from the Gene Expression Omnibus database to obtain differential expressed genes. Meanwhile, pyroptosis-related genes were screened from GeneCards database, and the overlapped genes were considered as the pyroptosis-related genes in TBI. The immune infiltration analysis was conducted to quantify lymphocyte infiltration levels. Moreover, we researched the relevant microRNAs (miRNAs) and transcription factors and investigated the interactions and functions of miRNAs. In addition, the validation set and in vivo experiment further verified the expression of hub gene. RESULTS: Altogether, we found 240 differential expressed genes in GSE104687 and 254 pyroptosis-related genes in the GeneCards database, and the overlapped gene was caspase 8 (CASP8). Immune Infiltration Analysis suggested the abundance of Tregs cells was significantly higher in TBI group. The NKT and CD8+ Tem were positively correlated with the expression levels of CASP8. The most significant term regarding CASP8 in Reactome pathways analysis was related to NF-kappaB. A total of 20 miRNAs and 25 transcription factors associated with CASP8 were obtained. After investigating the interactions and functions of miRNAs, the NF-kappaB-related signaling pathway was still enriched with a relatively low P-value. The validation set and in vivo experiment further verified the expression of CASP8. CONCLUSIONS: Our study showed the potential role of CASP8 in pathogenesis of TBI, which may provide a new target for individualized therapy and drug development.

Does China's Pilot Carbon Market Cause Carbon Leakage? New Evidence from the Chemical, Building Material, and Metal Industries.

The carbon market is an effective market for reducing greenhouse gas emissions; however, the existence of carbon leakage affects the emissions reduction effect of the carbon market. Using the multiregional input-output (MRIO) model and the difference-in-differences (DID) methodology, this study examined whether the chemical, building materials, or metals industries in China's pilot carbon market have caused carbon leakage, the extent of the carbon leakage, and the areas to which the industries with carbon leakage have transferred their carbon emissions. The results showed that the pilot carbon market caused carbon leakage in the chemical, building materials, and metal industries. The building materials industry had the most serious carbon leakage, followed by the chemical industry, and the metal industry was the weakest. In addition, regardless of the industry, most of the areas affected by carbon leakage were concentrated in regions with relatively backward economic development and weak in-place environmental regulations, such as in the central and western regions. Compared with the other pilot areas, Guangdong was the area most likely to be affected by carbon leakage from other pilot areas. This study provides new evidence for the existence of carbon leakage in China's pilot carbon market from an industrial perspective.

Lipid-functionalized gold nanorods with plug-to-direct mitochondria targeting ligand for synergetic photothermal-chemotherapy of tumor therapy.

Mitochondria targeting therapeutic strategies are promising for more effective and precise cancer therapy. Photothermal therapy are extensively studied as noninvasive cancer treatment. With regards to all-in-one nanocarrier-mediated drug delivery platform, it is still a challenge to enhance one of the features but not compromise other merits. Herein, we present a mitochondrial targeting photothermal-chemotherapy all-in-one nanoplatform involving lipid-functionalized gold nanorods (AuNR) with plug-to-direct mitochondria targeting ligand for synergetic enhanced tumor therapy. Firstly, AuNR were modified by DSPE-PEG-SH owing to the special affinity of sulfhydryl group and gold. And then, DSPE-PEG-DOX with mitochondrial targeting character was directly inserted into DSPE-PEG-SH layer. Meanwhile, paclitaxel (PTX) was loaded in hydrophobic region of the lipid layer. Quite different from introducing additional mitochondrial targeting molecules, we incorporated amphiphilic DSPE-PEG-DOX into a DSPE-PEG-SH layer modified around AuNR to achieve both mitochondrial targeting, photothermal and dual drug loading in a simple AuNR-lipid-DOX/PTX platform, in the case that efficiently enhanced production of reactive oxygen species (ROS) in mitochondria and excellent anti-tumor efficacy were achieved. With good biocompatibility, the constructed nanoplatform based on lipid-functionalized AuNR synergistically combined mitochondrial targeted DSPE-PEG-DOX with mitochondrial-acted PTX and photothermal therapy (PTT), which provided a feasible strategy for organelle-targeted combination PTT-chemotherapy to improve therapeutic effects.

Quantitative MRI in distinguishing bladder paraganglioma from bladder leiomyoma.

PURPOSE: To investigate the feasibility of quantitative MRI in the differentiation of bladder paraganglioma from bladder leiomyoma. METHODS: From 2014 to 2021, 11 patients with bladder paraganglioma and 14 patients with bladder leiomyoma confirmed by surgical pathology were retrospectively collected. All patients underwent multiparametric scanning with a 3.0 T MR system. Quantitative parameters including the SI-ratio on T1WI between the solid component of tumours and piriformis, ADC value and E-rate of the solid component of tumours were assessed. Independent sample t test or Mann-Whitney U test was used to compare these parameters between the two groups. The diagnostic efficiency of the parameters was examined using ROC curve analysis and the DeLong test. RESULTS: There were significant differences in SI-ratio on T1WI (P < 0.001), ADC value (P = 0.002) and the E-rate (P = 0.040) between the paraganglioma group and the leiomyoma group. The cutoff value of SI-ratio on 3 leiomyoma was 1.241, and the AUC was 1.000 (0.858-1.000). The cutoff value of the ADC value was 0.979 × 10-3mm2/s, and the AUC was 0.907 (0.717-0.987). The cutoff value of E-rate was 98.7%, and the AUC was 0.714 (0.495-0.878). The AUCs of the SI-ratio on T1WI and ADC value were significantly higher than the E-rate AUC (P = 0.015 and 0.034, respectively). CONCLUSION: Quantitative MRI can effectively distinguish bladder paraganglioma from bladder leiomyoma with the SI-ratio on T1WI or ADC value.

In vivo hypoglycemic effects of bisphenol F exposure in high-fat diet mice.

Bisphenol F (BPF) is a widely used bisphenol A (BPA) substitute plastic additive that has attracted increasing public concerns due to its potential toxic effects on animal and human health. Although previous studies have indicated that BPF might have harmful effects on metabolic homeostasis, the systematic effects of BPF on glucose disorders remain controversial. In this study, mice fed a normal chow diet (ND) and high-fat diet (HFD) were administered BPF at a dose of 100 µg/kg of body weight, and glucose metabolism was monitored after both short- and long-term treatment. Little change in glucose metabolism was observed in BPF-treated ND mice, but improved glucose metabolism was observed in BPF-treated HFD mice. Consistently, BPF treatment led to increased insulin signalling in the skeletal muscle of HFD mice. Additionally, liver metabolite levels also revealed increased carbohydrate digestion and improved TCA cycle progression in BPF-treated HFD mice. Our results demonstrate that sustained BPF exposure at an environmentally relevant dosage may substantially improve glucose metabolism and enhance insulin sensitivity in mice fed a high-fat diet.

Dynamic Humoral Immune Response to Primary and Booster Inactivated SARS-CoV-2 Vaccination in Patients with Cirrhosis.

Background and Aims: Our aim was to determine the immune efficacy of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) booster vaccination in cirrhotic patients who had received the primary series. Methods: We performed a longitudinal assessment in 48 patients with cirrhosis, 57 patients with chronic hepatitis B (CHB) and 68 healthy controls (HCs) to continuously track the dynamics of SARS-CoV-2 specific antibodies and memory B cells after receiving the primary series and booster dose at different times. A pseudovirus neutralization assay was used to determine neutralization against Omicron subvariants BA.2.12.1, BA.4 and BA.5 from serum samples collected from three cohorts. Results: Serum anti-receptor-binding domain (RBD) immunoglobulin (Ig)G and neutralizing antibody (NAb) levels in cirrhotic patients were elevated within 15-45 days after completing the primary series before rapidly declining and reaching a valley at around 165-195 days. After receiving the booster dose, both antibody levels were significantly increased to levels comparable to patients with CHB and HCs. Subgroup analysis showed that booster vaccination induced weaker antibody responses in patients with decompensated cirrhosis than in those with compensated cirrhosis. The SARS-CoV-2 memory B-cell response in cirrhotic patients was durable during follow-up regardless of the hepatic fibro-cirrhosis grade. However, compared with the primary series, the booster dose did not result in an evident improvement of neutralization activity against the Omicron subvariants BA.2.12.1 and BA.4, and was followed by a significant decrease in the titer against BA.5. Conclusions: A booster dose elicited a robust and durable humoral response to the wild-type strain in cirrhotic patients but not the Omicron subvariants. Repeated vaccination of inactivated SARS-CoV-2 vaccine may not benefit cirrhotic patients in neutralization against newly circulating strains.