Polyhedral magnetic nanoparticles induce apoptosis in gastric cancer stem cells and suppressing tumor growth through magnetic force generation.

Gastric cancer is a prevalent malignant tumor worldwide, posing challenges due to its poor prognosis and limited treatment options. Cancer stem cells (CSCs) were demonstrated as a subset of cancer cells responsible for tumor initiation and progression, and their inherent resistance to conventional chemotherapy and radiotherapy critically contributes to tumor recurrence and metastasis. Promoting the eradication of cancer stem cells is crucial for enhancing the efficacy of cancer treatments. This study introduces a novel therapeutic strategy utilizing polyhedral magnetic nanoparticles (PMNPs) functionalized with CD44 antibodies and cell-penetrating peptides (CPPs) to improve uptake by gastric cancer stem cells (MCSCs). PMNPs, synthesized via thermal decomposition, exhibited a diameter of 90 nm ± 9 nm and a saturation magnetization of 79.9 emu/g. Functionalization enhanced their uptake capabilities. Under a rotating magnetic field (RMF) of 15 Hz, PMNPs disrupted cellular structure, leading to apoptosis and ferroptosis in MCSCs. The in vitro studies showed significant reduction in MCSCs viability, while in vivo studies demonstrated tumor growth suppression with minimal side effects and high biocompatibility. This work presents a novel strategy for designing magnetic nanoparticles to mechanically destroy cancer stem cells, offering a more efficient and safety treatment option for gastric cancer.

Erythrocyte membrane biomimetic EGCG nanoparticles attenuate renal injury induced by diquat through the NF-κB/NLRP3 inflammasome pathway.

Diquat (DQ) poisoning can cause multiple organ damage, and the kidney is considered to be the main target organ. Increasing evidence shows that alleviating oxidative stress and inflammatory response has promising application prospects. Epigallocatechin gallate (EGCG) has potent antioxidant and anti-inflammatory effects. In this study, red blood cell membrane (RBCm)-camouflaged polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were synthesized to deliver EGCG (EGCG-RBCm/NPs) for renal injury induced by DQ. Human renal tubular epithelial cells (HK-2 cells) were stimulated with 600 µM DQ for 12 h and mice were intraperitoneally injected with 50 mg/kg b.w. DQ, followed by 20 mg/kg b.w./day EGCG or EGCG-RBCM/NPs for 3 days. The assessment of cellular vitality was carried out using the CCK-8 assay, while the quantification of reactive oxygen species (ROS) was performed through ROS specific probes. Apoptosis analysis was conducted by both flow cytometry and TUNEL staining methods. Pathological changes in renal tissue were observed. The expressions of NLRP3, IL-1ß, IL-18, NFκB and Caspase1 were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, immunofluorescence, and Western blot. The results showed that the DQ group had increased ROS expression, increased the level of oxidative stress, and increased apoptosis rate compared with the control group. Histopathological analysis of mice in the DQ group showed renal tubular injury and elevated levels of blood urea nitrogen (BUN), serum creatinine (SCr), kidney injury molecule-1 (KIM-1), and cystatin C (Cys C). Furthermore, the DQ group exhibited heightened expression of NLRP3, p-NFκB p65, Caspase1 p20, IL-1ß, and IL-18. However, EGCG-RBCm/NPs treatment mitigated DQ-induced increases in ROS, apoptosis, and oxidative stress, as well as renal toxicity and decreases in renal biomarker levels. Meanwhile, the expression of the above proteins were significantly decreased, and the survival rate of mice was ultimately improved, with an effect better than that of the EGCG treatment group. In conclusion, EGCG-RBCm/NPs can improve oxidative stress, inflammation, and apoptosis induced by DQ. This effect is related to the NF-κB/NLRP3 inflammasome pathway. Overall, this study provides a new approach for treating renal injury induced by DQ.

Influence of Ocular Biometric Parameters on Intraocular Lens Position: A Prospective Cohort Study.

PURPOSE: To assess the influence of ocular biometric parameters on intraocular lens (IOL) tilt and decentration after cataract surgery. METHODS: Patients scheduled for cataract surgery were screened for inclusion in this prospective cohort study. Tilt and decentration of the crystalline lens and IOL were measured using the CASIA2 (Tomey). Anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were preoperatively measured by the IOLMaster 700 (Carl Zeiss Meditec AG). Multivariate regression analysis was performed to assess the influence of ocular biometric parameters on IOL tilt and decentration after cataract surgery. RESULTS: In total, 191 eyes of 120 patients were included. Age was positively correlated with IOL tilt, whereas ACD and AL were negatively correlated with IOL tilt. A strong positive correlation was found between preoperative crystalline lenses and postoperative IOLs in tilt magnitude (r = 0.769, P < .001) and tilt direction (r = 0.688, P < .001). A positive correlation was found between preoperative and postoperative lens decentration magnitude and decentration direction. Greater postoperative IOL tilt and decentration were significantly associated with greater preoperative crystalline lens tilt (P < .001) and decentration (P = .027). CONCLUSIONS: IOL tilt was greater in older patients. Shorter AL and shallower ACD contributed to greater IOL tilt. The tilt and decentration of the IOL will be greater in patients with greater tilt and decentration of the crystalline lens. [J Refract Surg. 2024;40(7):e438-e444.].

Strategies for the Isolation and Identification of Gastric Cancer Stem Cells.

Gastric cancer stem cells (GCSCs) originate from both gastric adult stem cells and bone marrow cells and are conspicuously present within the histological milieu of gastric cancer tissue. GCSCs play pivotal and multifaceted roles in the initiation, progression, and recurrence of gastric cancer. Hence, the characterization of GCSCs not only facilitates precise target identification for prospective therapeutic interventions in gastric cancer but also has significant implications for targeted therapy and the prognosis of gastric cancer. The prevailing techniques for GCSC purification involve their isolation using surface-specific cell markers, such as those identified by flow cytometry and immunomagnetic bead sorting techniques. In addition, in vitro culture and side-population cell sorting are integral methods in this context. This review discusses the surface biomarkers, isolation techniques, and identification methods of GCSCs, as well as their role in the treatment of gastric cancer.

Mild endoplasmic reticulum stress alleviates FB1-triggered intestinal pyroptosis via the Sec62-PERK pathway.

Fumonisin B1 (FB1), a water-soluble mycotoxin released by Fusarium moniliforme Sheld, is widely present in corn and its derivative products, and seriously endangers human life and health. Recent studies have reported that FB1 can lead to pyroptosis, however, the mechanisms by which FB1-induced pyroptosis remain indistinct. In the present study, we aim to investigate the mechanisms of pyroptosis in intestinal porcine epithelial cells (IPEC-J2) and the relationship between FB1-induced endoplasmic reticulum stress (ERS) and pyroptosis. Our experimental results showed that the pyroptosis protein indicators in IPEC-J2 were significantly increased after exposure to FB1. The ERS markers, including glucose-regulated Protein 78 (GRP78), PKR-like ER kinase protein (PERK), and preprotein translocation factor (Sec62) were also significantly increased. Using small interfering RNA silencing of PERK or Sec62, the results demonstrated that upregulation of Sec62 activates the PERK pathway, and activation of the PERK signaling pathway is upstream of FB1-induced pyroptosis. After using the ERS inhibitor 4-PBA reduced the FB1-triggered intestinal injury by the Sec62-PERK pathway. In conclusion, we found that FB1 induced pyroptosis by upregulating Sec62 to activate the PERK pathway, and mild ERS alleviates FB1-triggered damage. It all boils down to one fact, the study provides a new perspective for further, and improving the toxicological mechanism of FB1.

DDX39B protects against sorafenib-induced ferroptosis by facilitating the splicing and cytoplasmic export of GPX4 pre-mRNA in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main histological subtype of primary liver cancer and remains one of the most common solid malignancies globally. Ferroptosis was recently defined as an iron-catalyzed form of regulated necrosis. Because cancer cells exhibit higher iron requirements than noncancer cells, treatment with ferroptosis-inducing compounds may be a feasible strategy for cancer therapy. However, cancer cells develop acquired resistance to evade ferroptosis, and the mechanisms responsible for ferroptosis resistance are not fully clarified. In the current study, we reported that DDX39B was downregulated during sorafenib-induced ferroptosis in a dose- and time-dependent manner. Exogenous introduction of DDX39B ensured the survival of HCC cells upon exposure to sorafenib, while the opposite phenomenon was observed in DDX39B-silenced HCC cells. Mechanistically, we demonstrated that DDX39B increased GPX4 levels by promoting the splicing and cytoplasmic translocation of GPX4 pre-mRNA, which was sufficient to detoxify sorafenib-triggered excess lipid ROS production, lipid peroxidation accumulation, ferrous iron levels, and mitochondrial damage. Inhibition of DDX39B ATPase activity by CCT018159 repressed the splicing and cytoplasmic export of GPX4 pre-mRNA and synergistically assisted sorafenib-induced ferroptotic cell death in HCC cells. Taken together, our data uncover a novel role for DDX39B in ferroptosis resistance by modulating the maturation of GPX4 mRNA via a posttranscriptional approach and suggest that DDX39B inhibition may be a promising therapeutic strategy to enhance the sensitivity and vulnerability of HCC cells to sorafenib.

Quality-of-Life Bronchiectasis Respiratory Symptom Scale Predicts the Risk of Exacerbations in Adults with Bronchiectasis: A Prospective Observational Study.

Rationale: The relationship between symptoms, measured using a validated disease-specific questionnaire, and longitudinal exacerbation risk has not been demonstrated in bronchiectasis. Objectives: The aim of this study is to investigate whether baseline symptoms, assessed using the Quality-of-Life Bronchiectasis Respiratory Symptom Scale (QoL-B-RSS) and its individual component scores, could predict future exacerbation risk in patients with bronchiectasis. Methods: The study included 436 adults with bronchiectasis from three tertiary hospitals. Symptoms were measured using the QoL-B-RSS, with scores ranging from 0 to 100, where lower scores indicated more severe symptoms. We examined whether symptoms as continuous measures were associated with the risk of exacerbation over 12 months. The analysis was also repeated for individual components of the QoL-B-RSS score. Results: The baseline QoL-B-RSS score was associated with an increased risk of exacerbations (rate ratio, 1.25 for each 10-point decrease; 95% confidence interval [CI], 1.15-1.35; P < 0.001), hospitalizations (rate ratio, 1.24; 95% CI, 1.05-1.43; P = 0.02), and reduced time to the first exacerbation (hazard ratio, 1.12; 95% CI, 1.03-1.21; P = 0.01) over 12 months, even after adjusting for relevant confounders, including exacerbation history. The QoL-B-RSS score was comparable to exacerbation history in its association with future frequent exacerbations (defined as three or more exacerbations per year) and hospitalization (area under the curve, 0.86 vs. 0.84; P = 0.46; and area under the curve, 0.81 vs. 0.83; P = 0.41, respectively). Moreover, patients with more severe symptoms in the majority of individual components of the QoL-B-RSS were more likely to experience exacerbations. Conclusions: Symptoms can serve as useful indicators for identifying patients at increased risk of exacerbation in bronchiectasis. Beyond relying solely on exacerbation history, a comprehensive assessment of symptoms could facilitate timely and cost-effective implementation of interventions for exacerbation prevention.

Hybrid Organic-Inorganic Additive for Robust Al Anode in Alkaline Aluminum-Air Battery.

Aluminum-air batteries (AABs), known for their high energy density, environmental friendliness, and cost-effectiveness, show immense promise in the realm of energy conversion applications. Nonetheless, their commercialization has encountered inherent challenges of Al anode corrosion and material degradation. In this study, economical hybrid electrolyte additives to inhibit the Al corrosion are developed, safeguarding the integrity of the Al anode. Due to the synergistic interplay between the organic compound dithiothreitol, and inorganic compounds zinc chloride, a robust zinc film is formed on the Al surface This Zn film plays a pivotal role in quelling parasitic hydrogen evolution reactions that typically can plague the Al electrode. Consequently, the as-prepared hybrid additive culminates in a remarkable enhancement to AABs, delivering exceptional discharge capacity of 1793.37 mAh g-1 , high energy density of 2047 Wh kg-1 , and excellent battery longevity (over 20 h in on/off cycling tests). This study, therefore, introduces a novel approach in utilizing hybrid electrolyte additives to effectively counteract corrosion-related challenges and boost the stability and performance of AABs.

Deficiency of apoA-IV in Female 129X1/SvJ Mice Leads to Diet-Induced Obesity, Insulin Resistance, and Decreased Energy Expenditure.

Obesity is one of the main risk factors for cardiovascular diseases, type II diabetes, hypertension, and certain cancers. Obesity in women at the reproductive stage adversely affects contraception, fertility, maternal well-being, and the health of their offspring. Being a major protein component in chylomicrons and high-density lipoproteins, apolipoprotein A-IV (apoA-IV) is involved in lipid metabolism, food intake, glucose homeostasis, prevention against atherosclerosis, and platelet aggregation. The goal of the present study is to determine the impact of apoA-IV deficiency on metabolic functions in 129X1/SvJ female mouse strain. After chronic high-fat diet feeding, apoA-IV-/- mice gained more weight with a higher fat percentage than wild-type (WT) mice, as determined by measuring their body composition. Increased adiposity and adipose cell size were also observed with a microscope, particularly in periovarian fat pads. Based on plasma lipid and adipokine assays, we found that obesity in apoA-IV-/- mice was not associated with hyperlipidemia but with higher leptin levels. Compared to WT mice, apoA-IV deficiency displayed glucose intolerance and elevated insulin levels, according to the data of the glucose tolerance test, and increased HOMA-IR values at fasting, suggesting possible insulin resistance. Lastly, we found obesity in apoA-IV-/- mice resulting from reduced energy expenditure but not food intake. Together, we established a novel and excellent female mouse model for future mechanistic study of obesity and its associated comorbidities.

A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection.

BACKGROUND: Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection. RESEARCH QUESTION: Can TIS effectively reduce sputum P aeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with P aeruginosa infection? STUDY DESIGN AND METHODS: This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300 mg/5 mL twice daily) or normal saline (5 mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28 days on-treatment and 28 days off-treatment. The coprimary end points included changes from baseline in P aeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day 29. RESULTS: The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P aeruginosa density (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; P < .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95% CI, 5.72-10.11; P < .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for P aeruginosa in the tobramycin group than in the placebo group on day 29 (29.3% vs 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups. INTERPRETATION: TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with P aeruginosa infection. TRIAL REGISTRATION: ClinicalTrials.gov; No. NCT03715322; URL: www. CLINICALTRIALS: gov.

The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China): Protocol of a prospective multicenter observational study.

BACKGROUND: Bronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China. METHODS: The BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at - 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation. CONCLUSIONS: Findings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China. Trial registration Registration Number in ClinicalTrials.gov: NCT03643653.

The lncRNA TERC promotes gastric cancer cell proliferation, migration, and invasion by sponging miR-423-5p to regulate SOX12 expression.

Background: Long non-coding RNAs (lncRNAs) play critical roles in gastric cancer (GC) initiation progression. However, the biological function of the lncRNA telomerase RNA component (TERC) remains unknown in human GC. The present study sought to determine the biological function and underlying molecular mechanism of the lncRNA TERC in GC progression. Methods: The expression levels of the lncRNA TERC in GC tissues and cell lines were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of the lncRNA TERC on the proliferation, migration, and invasion of GC cells were determined using Cell Counting Kit-8 (CCK-8) and Transwell assays. Dual luciferase reporter and argonaute 2 (AGO2)-RNA immunoprecipitation (RIP) assays were used to detect the binding between the lncRNA TERC and microRNA-423-5p (miR-423-5p). Western blotting was performed to measure the expression levels of sex determining region Y-box 12 (SOX12), N-cadherin, E-cadherin, matrix metallopeptidase 9 (MMP9), and proliferating cell nuclear antigen (PCNA). Results: The results demonstrated that the lncRNA TERC expression levels were upregulated in GC cells and tissues, while miR-423-5p expression levels were downregulated. The upregulation of the lncRNA TERC was associated with a shorter overall survival in patients with GC. The knockdown of the lncRNA TERC significantly reduced the proliferation, migration, and invasion of human GC cell lines HGC-27 and SNU-1 cells. Further, the lncRNA TERC knockdown in the HGC-27 and SNU-1 cells significantly downregulated the expression levels of SOX12, N-cadherin, MMP9, and PCNA, and upregulated the expression levels of miR-423-5p and E-cadherin. MiR-423-5p was also identified as a target of the lncRNA TERC and was found to directly bind to the lncRNA TERC. Additionally, miR-423-5p was found to directly target SOX12 to inhibit the proliferation, migration, and invasion of the HGC-27 and SNU-1 cells. Conclusions: In conclusion, the findings of this study suggested that the lncRNA TERC may regulate the miR-423-5p/SOX12 signaling axis by directly sponging miR-423-5p and inhibiting SOX12 expression, thereby leading to the progression of GC. These findings may reveal novel targets for future GC therapy.

Anterior segment pars plana vitrectomy combined with posterior capsulorhexis, phacoemulsification and trabeculectomy in treatment of medically uncontrolled acute primary angle-closure glaucoma: A retrospective study.

To explore the clinical efficacy of quadruple surgery (anterior segment pars plana vitrectomy + phacoemulsification + posterior capsulorhexis + intraocular lens (IOL) implantation + trabeculectomy) and dual surgery (phacoemulsification + IOL implantation + trabeculectomy) to treat medically uncontrolled acute primary angle-closure glaucoma (APACG). The clinical data of 44 patients (45 eyes) with APACG treated in the Department of Ophthalmology of Taihe Hospital were retrospectively analyzed. They were divided into 2 groups based on quadruple surgery and dual surgery. There were 20 patients (20 eyes) underwent quadruple surgery in group A. And there were 24 patients (25 eyes) dual surgery in group B. The changes in intraocular pressure (IOP), visual improvement, and complications were observed between the 2 groups preoperatively and 1 month, 3 months, and 6 months postoperatively. Preoperative best corrected visual acuity (BCVA) was the influencing factor of postoperative BCVA at 1 month, 3 months and 6 months. Before surgery, the mean IOP of group A was significantly higher than that of group B (P < .001), and no significant difference was found in the BCVA, age, gender, eyes, axial length (AL), anterior chamber depth (ACD) (PBCVA = 0.12, Page = 0.76, Peyes = 0.20, Pgender = 0.37, PAL = 0.94, PACD = 0.08). On comparison at postoperative 1week, there was no significant difference in the IOP and BCVA between the 2 groups (PIOP = 0.64, PBCVA = 0.66). The mean IOP of group A was significantly lower than that of group B 1 month, 3 months, and 6 months postoperatively (P1month = 0.002, P3months < 0.001, P6months < 0.001). The degree of visual acuity recovery was significantly higher in group A at 1 month, 3 months, and 6 months postoperatively (P1month = 0.03, P3months = 0.02, P6months = 0.02). During treatment, the incidence of complications in group B was significantly higher than that in group A (P < .01). The clinical efficacy of anterior segment pars plana vitrectomy combined with posterior capsulorhexis, phacoemulsification, and trabeculectomy elicits clinical safety in treating medically uncontrolled APACG. It has remarkable effects and leads to a significant decrease in the occurrence of complications.

Crucial Function of Caveolin-1 in Deoxynivalenol-Induced Enterotoxicity by Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis.

Deoxynivalenol (DON) is one of the most pervasive contaminating mycotoxins in grain, and exposure to DON is known to cause acute and chronic intestinal damage. As the gut is the most important target organ of DON, it is essential to identify the pivotal molecules involved in DON-induced enterotoxicity as well as the potential regulatory mechanisms. In the present study, we found that DON treatment dramatically decreased the jejunal villus height and increased the crypt depth in mice. DON exposure induced oxidative stress and NLRP3 inflammasome activation while increasing the levels of pyroptosis-related factors GSDMD, ASC, Caspase-1 P20, and IL-1ß and inflammatory cytokines IL-18, TNF-α, and IL-6. In vitro, 0.5-2 µM DON caused cytotoxicity and oxidative stress, as well as NLRP3-mediated pyroptosis in IPEC-J2 cells. Furthermore, DON treatment substantially improved the expression of Caveolin-1 (Cav-1) in vitro and in vivo. Interestingly, Cav-1 knockdown effectively attenuated DON-induced oxidative stress and NLRP3-mediated pyroptosis in IPEC-J2 cells. Meanwhile, treatment with the antioxidant NAC significantly alleviated DON-induced cytotoxicity and pyroptosis in IPEC-J2 cells. Likewise, after inhibiting NLRP3 inflammasome activation with the inhibitor MCC950, DON-induced cytotoxicity, pyroptosis, and inflammatory response were attenuated. However, NLRP3 inhibition did not affect Cav-1 expression. In conclusion, our study demonstrated that pyroptosis may be an underlying mechanism in DON-induced intestinal injury, and Cav-1 plays a pivotal role in DON-induced pyroptosis via regulating oxidative stress, which suggests a novel strategy to overcome DON-induced enterotoxicity.

Airway acidification impaired host defense against Pseudomonas aeruginosa infection by promoting type 1 interferon ß response.

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonß (IFN-ß) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-ß signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.

Lipocalin-2-Mediated Insufficient Oligodendrocyte Progenitor Cell Remyelination for White Matter Injury After Subarachnoid Hemorrhage via SCL22A17 Receptor/Early Growth Response Protein 1 Signaling.

Insufficient remyelination due to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation is strongly associated with irreversible white matter injury (WMI) and neurological deficits. We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2 (LCN2) in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1 (EGR1) as the key signals contributing to LCN2-mediated insufficient OPC remyelination. In LCN-knockdown and OPC EGR1 conditional-knockout mice, we discovered enhanced OPC differentiation in developing and injured white matter (WM); consistent with this, the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical, acute WMI due to subarachnoid hemorrhage and typical, chronic WMI due to multiple sclerosis. This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.

Soft Movable Polymer Gel for Controlling Water Coning of Horizontal Well in Offshore Heavy Oil Cold Production.

Horizontal well water coning in offshore fields is one of the most common causes of rapid declines in crude oil production and, even more critical, can lead to oil well shut down. The offshore Y oil field with a water cut of 94.7% urgently needs horizontal well water control. However, it is a challenge for polymer gels to meet the requirements of low-temperature (55 °C) gelation and mobility to control water in a wider range. This paper introduced a novel polymer gel cross-linked by hydrolyzed polyacrylamide and chromium acetate and phenolic resin for water coning control of a horizontal well. The detailed gelant formula and treatment method of water coning control for a horizontal well in an offshore field was established. The optimized gelant formula was 0.30~0.45% HPAM + 0.30~0.5% phenolic resin + 0.10~0.15% chromium acetate, with corresponding gelation time of 26~34 h at 55 °C. The results showed that this gel has a compact network structure and excellent creep property, and it can play an efficient water control role in the microscopic model. The thus-optimized gelants were successively injected with injection volumes of 500.0 m3. The displacement fluid was used to displace gelants into the lost zone away from the oil zone. Then, the formed gel can be worked as the chemical packer in the oil-water interface to control water coning after shutting in for 4 days of gelation. The oil-field monitoring data indicated that the oil rate increased from 9.2 m3/d to 20.0 m3/d, the average water cut decreased to 60~70% after treatment, and the cumulative oil production could obtain 1.035 × 104 t instead of 3.9 × 103 t.

Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study.

BACKGROUND: Existing clinical studies supported the potential efficacy of mesenchymal stromal cells as well as derived exosomes in the treatment of COVID-19. We aimed to explore the safety and efficiency of aerosol inhalation of the exosomes derived from human adipose-derived MSCs (haMSC-Exos) in patients with COVID-19. METHODS: The MEXCOVID trial is a phase 2a single-arm, open-labelled, interventional trial and patients were enrolled in Jinyintan Hospital, Wuhan, China. Eligible 7 patients were assigned to receive the daily dose of haMSCs-Exos (2.0 × 108 nano vesicles) for consecutively 5 days. The primary outcomes included the incidence of prespecified inhalation-associated events and serious adverse events. We also observed the demographic data, clinical characteristics, laboratory results including lymphocyte count, levels of D-dimer and IL-6 as well as chest imaging. RESULTS: Seven severe COVID-19 related pneumonia patients (4 males and 3 females) were enrolled and received nebulized haMSC-Exos. The median age was 57 year (interquartile range (IQR), 43 year to 70 year). The median time from onset of symptoms to hospital admission and administration of nebulized haMSC-Exos was 30 days (IQR, 15 days to 40 days) and 54 d (IQR, 34 d to 69 d), respectively. All COVID-19 patients tolerated the haMSC-Exos nebulization well, with no evidence of prespecified adverse events or clinical instability during the nebulization or during the immediate post-nebulization period. All patients presented a slight increase of serum lymphocyte counts (median as 1.61 × 109/L vs. 1.78 × 109/L). Different degrees of resolution of pulmonary lesions after aerosol inhalation of haMSC-Exos were observed among all patients, more obviously in 4 of 7 patients. CONCLUSIONS: Our trial shows that a consecutive 5 days inhalation dose of clinical grade haMSC-Exos up to a total amount of 2.0 × 109 nano vesicles was feasible and well tolerated in seven COVID-19 patients, with no evidence of prespecified adverse events, immediate clinical instability, or dose-relevant toxicity at any of the doses tested. This safety profile is seemingly followed by CT imaging improvement within 7 days. Further trials will have to confirm the long-term safety or efficacy in larger population. TRIAL REGISTRATION: MEXCOVID, NCT04276987.