Fluorescence Sensors for the Detection of L-Histidine Based on Silver Nanoclusters Modulated by Copper Ions.

In this study, Cu2+ modulated silver nanoclusters were constructed for the turn-on, label-free detection of L-histidine. Six Ag NCs protected by oligonucleotides (DNA-Ag NCs) were tested in a series of experiments. Finally, A-DAN-Ag NCs were chosen as the best candidate due to their excellent fluorescent properties. The fluorescence of A-DAN-Ag NCs was quenched using Cu2+ through energy or electron transfer. However, quenched fluorescence could be restored dramatically in the presence of L-histidine due to Cu2+ liberation from A-DAN-Ag NCs and because of the chelation between the imidazole group of L-histidine and Cu2+. The proposed sensor exhibited high selectivity towards L-histidine over other amino acids, with a limit of detection (LOD) of 0.096 µM ranging from 0 to 8 µM. The proposed sensor succeeded in detecting L-histidine in diluted human urine. Therefore, the sensor has promising practical applications in biological systems.

Turn-on fluorescent nanoprobe for ATP detection based on DNA-templated silver nanoclusters.

A turn-on fluorescence nanoprobe was constructed for the determination of adenosine 5'-triphosphate (ATP) based on DNA-templated silver nanoclusters (DNA-AgNCs). The significant enhancement fluorescence intensity of DNA-AgNCs in the presence of ATP is due to the high special binding affinity between ATP and the aptamer, resulting in the environment of DNA-AgNCs with darkish fluorescence lying at one terminus of DNA slightly altering owing to the change of ATP aptamer conformation. A good linear range runs from 9 to 24 mM with a satisfactory detection limit of 3 µM. Furthermore, the proposed nanoprobe exhibited good performance for ATP detection in diluted fetal bovine serum.

A multi-functional fluorescent probe for visualization of H2S and viscosity/polarity and its application in cancer imaging.

As an important endogenous gasotransmitter, hydrogen sulfide (H2S) plays a critical role in various physiological functions and has been regarded as a biomarker of cancer due to its overexpression in cancer cells. In addition, the early stages of cancer are often accompanied by abnormalities in the intracellular microenvironments, and distinguishing between cancer cell/tissues and normal cell/tissues is of great significance to the accuracy of cancer diagnosis. However, deep insights into the simultaneous detection of H2S and viscosity/polarity variations in cancer cells/tissues are rarely reported. In this work, we designed and synthesized a mitochondria-targeting fluorescent probe PDQHS, which exhibits high selectivity for H2S with an emission peak around 632 nm and excellent response (17-fold) to viscosity/polarity beyond 706 nm. Meanwhile, PDQHS shows good biocompatibility and can specifically accumulate into mitochondria. Using PDQHS, the visual distinguishing of cancer cells from normal cells was achieved via dual-channel detection of H2S and viscosity/polarity. More importantly, PDQHS has been successfully applied to visualize endogenous and exogenous H2S in living cells and tumor tissue. Obviously, compared to the detection of a single biomarker, monitoring multiple biomarkers simultaneously through dual-channel response is conducive to amplifying the detection signal, providing a more sensitive and reliable imaging tool in the tumor region, which is beneficial for cancer prediction.

Three E2F target-related genes signature for predicting prognosis, immune features, and drug sensitivity in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is extremely malignant and difficult to treat. The adenoviral early region 2 binding factors (E2Fs) target pathway is thought to have a major role in tumor growth. This study aimed to identify a predictive E2F target signature and facilitate individualized treatment for HCC patients. Methods: We constructed an E2F target-related gene profile using univariate COX and LASSO regression models and proved its predictive efficacy in external cohorts. Furthermore, we characterized the role of the E2F target pathway in pathway enrichment, immune cell infiltration, and drug sensitivity of HCC. Results: Lasso Cox regression created an E2F target-related gene signature of GHR, TRIP13, and CDCA8. HCC patients with high risk were correlated with shorter survival time, immune evasion, tumor stem cell characteristics and high sensitivity to Tipifarnib and Camptothecin drugs. Conclusion: Hepatocellular carcinoma prognosis was predicted by an E2F target signature. This finding establishes the theoretical usefulness of the E2F target route in customized identification and treatment for future research.

Emerging extracellular vesicle-based carriers for glioblastoma diagnosis and therapy.

Glioblastoma (GBM) treatment is still a big clinical challenge because of its highly malignant, invasive, and lethal characteristics. After treatment with the conventional therapeutic paradigm of surgery combined with radio- and chemotherapy, patients bearing GBMs generally exhibit a poor prognosis, with high mortality and a high disability rate. The main reason is the existence of the formidable blood-brain barrier (BBB), aggressive growth, and the infiltration nature of GBMs. Especially, the BBB suppresses the delivery of imaging and therapeutic agents to lesion sites, and thus this leads to difficulties in achieving a timely diagnosis and treatment. Recent studies have demonstrated that extracellular vesicles (EVs) exhibit favorable merits including good biocompatibility, a strong drug loading capacity, long circulation time, good BBB crossing efficiency, specific targeting to lesion sites, and high efficiency in the delivery of a variety of cargos for GBM therapy. Importantly, EVs inherit physiological and pathological molecules from the source cells, which are ideal biomarkers for molecularly tracking the malignant progression of GBMs. Herein, we start by introducing the pathophysiology and physiology of GBMs, followed by presenting the biological functions of EVs in GBMs with a special focus on their role as biomarkers for GBM diagnosis and as messengers in the modulation of the GBM microenvironment. Furthermore, we provide an update on the recent progress of using EVs in biology, functionality, and isolation applications. More importantly, we systematically summarize the most recent advances of EV-based carriers for GBM therapy by delivering different drugs including gene/RNA-based drugs, chemotherapy drugs, imaging agents, and combinatory drugs. Lastly, we point out the challenges and prospects of future research on EVs for diagnosing and treating GBMs. We hope this review will stimulate interest from researchers with different backgrounds and expedite the progress of GBM treatment paradigms.

NIR-IIb fluorescence-image guided synergistic surgery/starvation/chemodynamic therapy: an innovative treatment paradigm for malignant non-small cell lung cancers.

Background: Currently, the prognosis and survival rate for patients bearing non-small cell lung cancer (NSCLC) is still quite poor, mainly due to lack of efficient theranostic paradigms to exert in time diagnostics and therapeutics. Methods: Herein, for NSCLC treatment, we offer a customized theranostic paradigm, termed NIR-IIb fluorescence diagnosis and synergistic surgery/starvation/chemodynamic therapeutics, with a newly designed theranostic nanoplatform PEG/MnCuDCNPs@GOx. The nanoplatform is composed of brightly NIR-II emissive downconversion nanoparticles (DCNPs)-core and Mn/Cu-silica shell loaded with glucose oxidase (GOx) to achieve synergistic starvation and chemodynamic therapy (CDT). Results: It is found that 10% Ce3+ doped in the core and 100% Yb3+ doped in the middle shell greatly improves the NIR-IIb emission up to even 20.3 times as compared to the core-shell DCNPs without Ce3+ doping and middle shell. The bright NIR-IIb emission of the nanoplatform contributes to sensitive margin delineation of early-stage NSCLC (diameter < 1 mm) with a signal-to-background ratio (SBR) of 2.18, and further assists in visualizing drug distribution and guiding surgery/starvation/chemodynamic therapy. Notably, the starvation therapy mediated by GOx-driven oxidation reaction efficiently depletes intratumoral glucose, and supplies H2O2 to boost the CDT mediated by the Mn2+ and Cu2+, which consequently realized a highly effective synergistic treatment for NSCLC. Conclusion: This research demonstrates an efficient treatment paradigm for NSCLC with NIR-IIb fluorescence diganosis and image-guided synergistic surgery/starvation/chemodynamic therapeutics.

An investigation on the respiratory mechanics of mechanically ventilated patients during spontaneous breathing trials with enhanced low-level pressure support ventilation.

INTRODUCTION: Low-level pressure support ventilation (PSV) is most commonly adopted in spontaneous breathing trials (SBTs), and some have proposed setting the positive end-expiratory pressure (PEEP) to 0 cmH2 O in order to shorten the observation time of SBTs. This study aims to investigate the effects of two PSV protocols on the patients' respiratory mechanics. MATERIAL AND METHOD: A prospective randomized self-controlled crossover design was adopted in this study, which involved enrolling 30 difficult-to-wean patients who were admitted to the intensive care unit of the First Affiliated Hospital of Guangzhou Medical University between July 2019 and September 2021. Patients were subjected to the S group (pressure support: 8 cmH2 O, PEEP: 5 cmH2 O) and S1 group (PS: 8 cmH2 O, PEEP: 0 cmH2 O) for 30 min in a random order, and respiratory mechanics indices were dynamically monitored via a four-lumen multi-functional catheter with an integrated gastric tube. Among the 30 enrolled patients, 27 were successfully weaned. RESULT: The S group showed higher airway pressure (Paw), intragastric pressure (Pga) and airway pressure-time product (PTP) than the S1 group. The S group also showed a shorter inspiratory trigger delay, (93.80 ± 47.85) versus (137.33 ± 85.66) ms (P = 0.004); and fewer abnormal triggers, (0.97 ± 2.65) versus (2.67 ± 4.48) (P = 0.042) compared with the S1 group. Stratification based on the causes of mechanical ventilation revealed that under the S1 protocol, patients with chronic obstructive pulmonary disease (COPD) had a longer inspiratory trigger delay compared to both post-thoracic surgery (PTS) patients and patients with acute respiratory distress syndrome. Despite providing greater respiratory support, S group led to significant reductions in inspiratory trigger delay and less abnormal triggers compared to S1 group, especially among patients with chronic obstructive pulmonary disease. CONCLUSION: These findings suggest that the zero PEEP group was more likely to induce a higher number of patient-ventilator asynchronies in difficult-to-wean patients.

Comprehensive Transcriptome Analysis of Responses during Cold Stress in Wheat (Triticum aestivum L.).

Wheat production is often impacted by pre-winter freezing damage and cold spells in later spring. To study the influences of cold stress on wheat seedlings, unstressed Jing 841 was sampled once at the seedling stage, followed by 4 °C stress treatment for 30 days and once every 10 days. A total of 12,926 differentially expressed genes (DEGs) were identified from the transcriptome. K-means cluster analysis found a group of genes related to the glutamate metabolism pathway, and many genes belonging to the bHLH, MYB, NAC, WRKY, and ERF transcription factor families were highly expressed. Starch and sucrose metabolism, glutathione metabolism, and plant hormone signal transduction pathways were found. Weighted Gene Co-Expression Network Analysis (WGCNA) identified several key genes involved in the development of seedlings under cold stress. The cluster tree diagram showed seven different modules marked with different colors. The blue module had the highest correlation coefficient for the samples treated with cold stress for 30 days, and most genes in this module were rich in glutathione metabolism (ko00480). A total of eight DEGs were validated using quantitative real-time PCR. Overall, this study provides new insights into the physiological metabolic pathways and gene changes in a cold stress transcriptome, and it has a potential significance for improving freezing tolerance in wheat.

Occurrence of Nigrospora osmanthi Causing Leaf Blight on Water Lettuce in China.

Water lettuce (Pistia stratiotes L.), is one of the emerging invasive weeds for inland water bodies in Asia and become a major problem for local water ecosystem. Biocontrol of water lettuce by mycobiota is being considered as a promising and sustainable method (Kongjornrak et al. 2019). During July 2021, a leaf blight of water lettuce was observed within about 1.5 ha in Shenxi stream (N25°66', E119°05') in Putian, Fujian, China. The disease severity was about 100% with 80% incidence, early symptoms appeared as small irregularly yellow or brown blight, severely infected leaves turned to be rot, then death and sink. Small pieces (5 × 5 mm) of symptomatic leaves were excised and surface disinfected with 75% ethanol and 0.1% HgCl2 solution, air dried and plated on potato dextrose agar (PDA). 3~5 days after incubation at 28°C, six fungal pure cultures showing similar morphology were obtained from the infected leaves. On PDA, colonies were flat, aerial mycelium grew sparsely, most of it grew inside the agar medium, it reverses white to grey to black with age. Hyphae were branched, septate, smooth and hyaline. Conidiophores mostly reduced to conidiogenous cells and setae were not observed. Conidiogenous cells were monoblastic, discrete and solitary, at first hyaline, subspherical, then turning to pale brown, ampulliform, 4.5-10 × 3.5-6 µm in size. Conidia were solitary, globose or ellipsoidal, black, smooth, some of it formed directly from the mycelia, aseptate, 8-12 µm diam (n=10). Genomic DNA was extracted from one of the representative isolate Z1. ITS1/ITS4 (Mills et al. 1992), Bt-2a/Bt-2b (Glass and Donaldson 1995) and EF1-728F/EF-2 (O'Donnell et al. 1998) primer pairs were used to amplify the isolate's internal transcribed spacer (ITS), the Beta-tubulin fragment (TUB) and the partial translation elongation factor (TEF1), respectively. The isolate's sequences were deposited in the GenBank with accession numbers of OM279539 (ITS), OM296034 (TUB) and OM296035 (TEF1). Phylogenetic analysis using maximum likelihood based on the ITS-TUB-TEF1 concatenated sequences from Nigrospora species revealed that isolate Z1 is closely clustered with N. osmanthi strain LC4487. The fungus was identified as N. osmanthi based on the morphological characteristics and molecular analyses (Hao et al. 2020; Wang et al. 2017). Pathogenicity test were performed using twenty inoculated and control plants, respectively. Conidial suspensions (107 CFU/ml) of Z1 isolate were spray-inoculated on the leaves of healthy water lettuce seedlings, while sterile distilled water was used as control. Inoculated and control plants were kept in the differential 50-liter plastic tanks and maintained in a greenhouse at room temperature (19 to 24°C) for one month. Symptoms appeared 7 days post inoculation, which was similar to what occurs in the field. No symptoms occurred on controls. Pathogen was reisolated and confirmed by morphology and molecular analysis. Koch's postulates were conducted twice. N. osmanthi is a pathogenic fungus of many crop plants, such as buckwheat (Shen et al 2021), Java tea (Ismail et al. 2022) or buffalograss (Mei et al. 2019) in Asia and particularly in China. However, to our knowledge, this is the first report of N. osmanthi causing leaf blight on water lettuce. Further studies on how to apply formulated N. osmanthi will be required so that the strain could be effectively used to control water lettuce, moreover, its environmental safety also need a rigorous experimental evaluation.

Changes of blood gas analysis in moderate-to-severe acute respiratory distress syndrome patients during long-term prone position ventilation: a retrospective cohort study.

Background: Prone position ventilation (PPV) has been recommended for patients with acute respiratory distress syndrome (ARDS) to improve oxygenation. However, whether prolonged prone ventilation will aggravate hyperoxia and whether abdominal compression will aggravate permissive hypercapnia acidosis are topics of concern. We carried out a retrospective analysis to investigate the issues above. Methods: Clinical data were collected from 97 moderate-to-severe ARDS patients who received PPV as part of their treatment in the intensive care unit (ICU) of the First Affiliated Hospital of Guangzhou Medical University from November 2015 to May 2021. We collected arterial blood gas of patients according to the 3 periods: supine position ventilation (SPV), PPV early stage (within 4 hours), and PPV middle and late stage (6 hours or later). We established a linear mixed-effects models with "body position changes, times of PPV, gender, age, baseline SOFA, and baseline APACHE II" as fixed effects, and individual and the number of prone positions as random intercept and random slope to investigate the effect of body position changes on blood gas analysis. Results: Among the 97 patients received PPV included, 51 were ICU survivors. Arterial partial pressure of oxygen (PaO2) and PaO2/fraction of inspired oxygen (FiO2) ratio were significantly higher at the early, middle and late stages of PPV than those in SPV [PFR (mmHg): 158 (118.00, 203.00) vs. 161 (129.00, 202.75) vs. 123 (91.75, 163.00), P<0.05]. Despite the synchronized reduction of FiO2, the incidence of hyperoxia in the prone position was still significantly higher than that in the supine position [hyperoxia (%):33.33 vs. 33.56 vs. 12.42, P<0.05]; there was no significant change in arterial carbon dioxide partial pressure (PaCO2) at each stage of PPV, but there was a significant increase in PH at PPV middle and late stages than those at early stage [PH: 7.39 (7.34, 7.42) vs. 7.37 (7.31, 7.41), P<0.05]. Conclusions: Although PPV improves the patients' oxygenation, the associated incidence of hyperoxia exceeds 33%. Down-regulate FiO2 more sharply after PPV is necessary, if oxygenation conditions permit. PPV may alleviate the acidosis associated with permissive hypercapnia in ARDS patients treated with lung protective ventilation strategy (LPVS).

Bioinformatics identification and validation of biomarkers and infiltrating immune cells in endometriosis.

Background: Endometriosis (EM) is a common gynecological disorder that often leads to irregular menstruation and infertility. The pathogenesis of EM remains unclear and delays in diagnosis are common. Thus, it is urgent to explore potential biomarkers and underlying molecular mechanisms for EM diagnosis and therapies. Methods: Three EM-related datasets (GSE11691, GSE25628, and GSE86534) were downloaded from the Gene Expression Omnibus (GEO) which were integrated into a combined dataset after removing batch effect. Differentially expressed immune cell-related genes were obtained by CIBERSORT, WGCNA, and the identification of differentially expressed genes. Random forest model (RF), support vector machine model (SVM), and generalized linear model (GLM) were then constructed and the biomarkers for EM were determined. A nomogram evaluating the risk of disease was constructed and the validity was assessed by the calibration curve, DCA curve, and clinical impact curve. Single-gene Gene Set Enrichment Analysis (GSEA)was performed to explore the molecular mechanisms of biomarkers. The ceRNA regulatory network of biomarkers was created by Cytoscape and potential target drugs were obtained in the DGIdb database (Drug-Gene Interaction database).The expression levels of biomarkers from clinical samples was quantified by RT-qPCR. Results: The ratio of eight immune cells was significantly different between the eutopic and ectopic endometrium samples. A total of eight differentially expressed immune cell-related genes were investigated. The SVM model was a relatively suitable model for the prediction of EM and five genes (CXCL12, PDGFRL, AGTR1, PTGER3, and S1PR1) were selected from the model as biomarkers. The calibration curve, DCA curve, and clinical impact curve indicated that the nomogram based on the five biomarkers had a robust ability to predict disease. Single gene GSEA result suggested that all five biomarkers were involved in labyrinthine layer morphogenesis and transmembrane transport-related biological processes in EM. A ceRNA regulatory network containing 184 nodes and 251 edges was constructed. Seven drugs targeting CXCL12, 49 drugs targeting AGTR1, 16 drugs targeting PTGER3, and 21 drugs targeting S1PR1 were extracted as potential drugs for EM therapy. Finally, the expression of PDGFRL and S1PR1 in clinical samples was validated by RT-qPCR, which was consistent with the result of public database. Conclusions: In summary, we identified five biomarkers (CXCL12, PDGFRL, AGTR1, PTGER3, and S1PR1) and constructed diagnostic model, furthermore predicted the potential therapeutic drugs for EM. Collectively, these findings provide new insights into EM diagnosis and treatment.

Application and Development of Minimally Invasive Techniques in the Treatment of Spinal Metastases.

With the improvement of medical technology, the quality of life and prognosis of patients with malignant tumors have been greatly improved, and surgical treatment strategies for patients with spinal metastatic tumors have received extensive attention. Traditional open surgery for spinal metastases has problems such as large trauma, slow recovery, and influence on subsequent systemic treatment. Minimally invasive spine surgery has similar clinical outcomes to traditional open surgery, but minimally invasive spine surgery is less invasive and has a shorter recovery time. Minimally invasive spine surgery was initially applied to non-neoplastic diseases such as spinal degeneration and trauma, and was gradually applied to the treatment of spinal metastatic tumors and spinal deformities. For patients with spinal metastases, a shorter recovery time is helpful for early postoperative radiotherapy, thereby achieving a more satisfactory tumor control effect. This review discusses the application of minimally invasive spine surgery in the treatment of spinal metastatic tumors from the concept, surgical purpose, indications, and surgical selection, so as to provide reference for clinical practice.

A label-free aptasensor for the detection of ATP based on turn-on fluorescence DNA-templated silver nanoclusters.

A label-free aptasensor has been fabricated in order to detect adenosine triphosphate (ATP) using turn-on fluorescence DNA-Ag NCs. The fluorescence of the DNA-Ag NCs could increase remarkably with the addition of ATP mainly because ATP specifically interacts with its aptamer to change the microenvironment of the darkish DNA-Ag NCs located at one terminus or two termini due to the conformational alteration of the aptamer structure. The proposed sensor can detect ATP in a linear range of 6-27 mM with a good detection limit of 5.0 µM. Additionally, the proposed method succeeded in detecting ATP in fetal bovine serum.

A novel pyroptosis-regulated gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma.

Background: Pyroptosis, a newly discovered type of programmed cell death, has both anti-tumor and tumor-promoting effects on carcinogenesis. In hepatocellular carcinoma (HCC), however, the associations between pyroptosis-regulated genes and prognosis, immune microenvironment, and immunotherapy response remain unclear. Samples and methods: Sequencing data were collected from The Cancer Genome Atlas database, The International Cancer Genome Consortium (ICGC), and The Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). First, we investigated the expression levels and copy number variations (CNVs) of 56 pyroptosis genes in HCC and pan-cancer. Next, we identified 614 genes related to 56 pyroptosis-associated genes at the expression, mutation, and CNVs levels. Pathway enrichment analysis of 614 genes in the Hallmark, KEGG, and Reactome databases yielded a total of 253 significant signaling pathways. The pyroptosis-regulated genes (PRGs) comprised 108 genes that were derived from the top 20 signaling pathways, of which 57 genes had prognostic value in HCC. The least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for PRGs with prognostic values. Ultimately, we constructed a risk score model with seven PRGs to predict HCC prognosis and validated its predictive value in three independent HCC cohorts. Risk scores were used to illustrate receiver operating characteristic (ROC) curves predicting 1, 3, and 5-years overall survival (OS). Single-sample gene set enrichment analysis (ssGSEA), was performed to study 28 types of immune cells infiltrated in HCC. The relationship between the risk signature and six immune checkpoint genes and immunotherapy was analyzed. Results: A total of seven PRGs were obtained following multiple screening steps. The risk score model containing seven PRGs was found to correlate significantly with the HCC prognosis of the training group. In addition, we validated the risk score model in two additional HCC cohorts. The risk score significantly correlated with infiltrating immune cells (i. e. CD4+ T cells, etc.), ICB key molecules (i. e. HAVCR2, etc.), and ICB response. Conclusions: This study demonstrated a vital role of PRGs in predicting the prognosis and immunotherapy response of HCC patients. The risk model could pave the way for drugs targeting pyroptosis and immune checkpoints in HCC.

Multifunctional nanotheranostics for near infrared optical imaging-guided treatment of brain tumors.

Malignant brain tumors, a heterogeneous group of primary and metastatic neoplasms in the central nervous system (CNS), are notorious for their highly invasive and devastating characteristics, dismal prognosis and low survival rate. Recently, near-infrared (NIR) optical imaging modalities including fluorescence imaging (FLI) and photoacoustic imaging (PAI) have displayed bright prospect in innovation of brain tumor diagnoses, due to their merits, like noninvasiveness, high spatiotemporal resolution, good sensitivity and large penetration depth. Importantly, these imaging techniques have been widely used to vividly guide diverse brain tumor therapies in a real-time manner with high accuracy and efficiency. Herein, we provide a systematic summary of the state-of-the-art NIR contrast agents (CAs) for brain tumors single-modal imaging (e.g., FLI and PAI), dual-modal imaging (e.g., FLI/PAI, FLI/magnetic resonance imaging (MRI) and PAI/MRI) and triple-modal imaging (e.g., MRI/FLI/PAI and MRI/PAI/computed tomography (CT) imaging). In addition, we update the most recent progress on the NIR optical imaging-guided therapies, like single-modal (e.g., photothermal therapy (PTT), chemotherapy, surgery, photodynamic therapy (PDT), gene therapy and gas therapy), dual-modal (e.g., PTT/chemotherapy, PTT/surgery, PTT/PDT, PDT/chemotherapy, PTT/chemodynamic therapy (CDT) and PTT/gene therapy) and triple-modal (e.g., PTT/PDT/chemotherapy, PTT/PDT/surgery, PTT/PDT/gene therapy and PTT/gene/chemotherapy). Finally, we discuss the opportunities and challenges of the CAs and nanotheranostics for future clinic translation.

Dynamic evaluation of the pulmonary protective effects of prone position ventilation via respiratory mechanics for patients with moderate to severe acute respiratory distress syndrome.

Background: Patients with moderate to severe acute respiratory distress syndrome (ARDS) have been recommended to receive prone position ventilation (PPV). However, the dynamic changes in respiratory mechanics during PPV and their relationship with the prognosis have not been sufficiently evaluated. In addition, the impact of using neuromuscular blocking agents (NMBAs) during PPV on respiratory mechanics is not clear enough. Thus, the study aims to investigate the above-mentioned issues. Methods: A prospective cohort study was conducted on 22 patients with moderate to severe ARDS who received PPV in the intensive care unit (ICU) of the First Affiliated Hospital of Guangzhou Medical University. A multifunctional gastric tube was used to measure the patients' respiratory mechanics during supine position ventilation (SPV), early PPV (PPV within 4 h of initiation), and middle/late PPV (more than 6 h after the initiation of PPV). Longitudinal data were analyzed with generalized estimating equations (GEE). Results: Compared with SPV, the esophageal pressure swings (ΔPes) measured during the PPV was significantly higher (SPV 7.46 vs. early PPV 8.00 vs. middle/late PPV 8.30 cmH2O respectively; PSPV vs. middle/late PPV =0.025<0.05). A stratified analysis by patients' outcome showed that the peak airway pressure (Ppeak), ΔPes and respiration rate (RR) in the death group were significantly higher than survival group. On the contrary, the tidal volume (Vt), diaphragmatic electromyogram (EMGdi) and PaO2/FiO2 ratio (PFR) in the death group were significantly lower than survival group. Notably, the ΔPes and transpulmonary driving pressure (DPL) were significantly lower in the patients treated with NMBAs (7.08 vs. 8.76 cmH2O ΔPes; P<0.01), (14.82 vs. 18.08 cmH2O DPL; P<0.001). Conclusions: During the transition from SPV to early PPV and then to middle/late PPV, the ΔPes in the PPV were greater than SPV and it fluctuated within a normal range while oxygenation improved significantly in all patients. The Ppeak, ΔPes and RR in the death group were significantly higher than survival group. When NMBAs were used, the ΔPes, inspiratory transpulmonary pressure (PLei), driving pressure (DP) and DPL were significantly decreased, suggesting that the rational combination of NMBAs and PPV may exert a synergistic protective effect on the lungs.

Bone mesenchymal stem cell-derived exosomes prevent hyperoxia-induced apoptosis of primary type II alveolar epithelial cells in vitro.

Background: The presence of alveolar epithelial type II cells (AECIIs) is one of the most important causes of bronchopulmonary dysplasia (BPD). Exosomes from bone mesenchymal stem cells (BMSCs) can reduce hyperoxia-induced damage and provide better results in terms of alveolar and pulmonary vascularization parameters than BMSCs. Currently, intervention studies using BMSC-derived exosomes on the signaling pathways regulating proliferation and apoptosis of alveolar epithelial cells under the condition of BPD have not been reported. This study investigated the effects of rat BMSC-derived exosomes on the proliferation and apoptosis of hyperoxia-induced primary AECIIs in vitro. Methods: The isolated AECIIs were grouped as follows: normal control (21% oxygen), hyperoxia (85% oxygen), hyperoxia+exosome (20 µg/mL), hyperoxia+exosome+LY294002 (PI3K/Akt inhibitor, 20 µM), and hyperoxia+exosome+rapamycin (mTOR inhibitor, 5 nM). We used the PI3K/Akt inhibitor LY294002 and the mTOR inhibitor rapamycin to determine the roles of the PI3K/Akt and mTOR signaling pathways. The effects of BMSC-derived exosomes on AECII proliferation and apoptosis were assessed, respectively. Results: Decreased levels of the antiapoptotic protein Bcl-2, the cell proliferation protein Ki67, p-PI3K, p-Akt, and p-mTOR, as well as increased levels of AECII apoptosis and the proapoptotic protein Bax in the hyperoxia group were observed. Notably, Sprague Dawley rat BMSC-derived exosomes could reverse the effect of hyperoxia on AECII proliferation. However, the application of LY294002 and rapamycin inhibited the protective effects of BMSC-derived exosomes. Conclusion: Our findings revealed that BMSC-derived exosomes could regulate the expression of apoptosis-related proteins likely via the PI3K/Akt/mTOR signaling pathway, thereby preventing hyperoxia-induced AECII apoptosis.

Effect of IFN-α and other commonly used nebulization drugs in different nebulization methods on the resistance of breathing circuit filters under invasive mechanical ventilation.

Background: Interferon (IFN) is widely used in clinical practice and nebulization inhalation is one of the commonly used routes of administration. However, nebulization drugs such as interferon-α (IFN-α) with large molecular weights may deposit in the membrane of the breathing filters, causing its resistance to gradually increase. Thus, our study explores the effect of IFN-α and other nebulization drugs on the resistance of breathing circuit filters under invasive mechanical ventilation. Methods: We divided 96 breathing filters into eight groups. The baseline group was not treated while the blank group was installed but were not nebulized. The remaining groups received jet nebulized or vibrating nebulized with either normal saline, Combivent, Amphotericin B, or IFN-α at a frequency of once every 12 hours separately and were removed from the breathing circuit after 24 hours. The resistance of the filter of each group was then measured and statistical comparisons were made. Results: Filter resistance of the IFN-α jet nebulization group was greater than that of the other groups, and there were statistical differences except for the Amphotericin B jet nebulization group. Comparison of the resistance [cmH2O/(L·s)] of the IFN-α jet nebulization group vs. the baseline group showed 2.56 (2.40, 2.68) vs. 2.26 (2.03, 2.40), P=0.037; of the IFN-α jet nebulization group vs. the blank group showed 2.56 (2.40, 2.68) vs. 2.11 (1.98, 2.27), P=0.003; of the IFN-α jet nebulization group vs. the normal saline group: 2.56 (2.40, 2.68) vs. 2.16 (2.08, 2.32), P=0.023; of the IFN-α jet nebulization group vs. the Combivent jet nebulization group: 2.56 (2.40, 2.68) vs. 2.18 (2.14, 2.27), P=0.018; and of the IFN-α jet nebulization group vs. the Amphotericin B jet nebulization group: 2.56 (2.40, 2.68) vs. 2.33 (2.05, 2.45), P=0.221. The effect of jet nebulization and vibrating mesh nebulization on the resistance of breathing filters showed no significant statistical difference. Conclusions: Jet nebulization with IFN-α significantly increased the resistance of the breathing filter within 24 hours and there was no significant difference in filter resistance between jet nebulization and vibrating mesh nebulization of IFN-α or Amphotericin B.

Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila.

Hyccin/FAM126A mutations are linked to hypomyelination and congenital cataract disease (HCC), but whether and how Hyccin/FAM126A deficiency causes hypomyelination remains undetermined. This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila. Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma membrane-targeting recombinant mouse PI4KIIIα. Additionally, PI4KIIIα knockdown in glia phenocopied Hyccin/FAM126A knockdown, and this was partially rescued by overexpressing the recombinant PI4KIIIα, but not human FAM126A or FAM126B. This study establishes an animal model of HCC and indicates that Hyccin/FAM126A plays an essential role in glial enrichment and axonal sheath in a cell-autonomous manner in the visual system via controlling the expression and stabilization of the PI4KIIIα complex at the plasma membrane.

Effect of sequential high-flow nasal cannula oxygen therapy and non-invasive positive-pressure ventilation in patients with difficult weaning from mechanical ventilation after extubation on respiratory mechanics.

BACKGROUND: Patients with difficult weaning who undergo mechanical ventilation are more likely to be at risk of reintubation and the sequential use of oxygen therapy after extubation is a concern for clinicians. Therefore, the aim of the present study was to compare the effects of transnasal high-flow nasal cannula (HFNC) oxygen therapy and non-invasive positive-pressure ventilation (NIV) on respiratory mechanics in patients with difficult weaning. METHODS: The present study was a single-center, retrospective, observational study. Twenty-nine patients with difficult weaning off invasive mechanical ventilation from the Department of Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, from December 2018 to April 2021, were included. Within 48 h after extubation, alternate respiratory support with HFNC and NIV was provided. Relevant indicators were recorded after each support mode had been maintained for at least 60 min. These included esophageal pressure (Pes), gastric pressure (Pga), transdiaphragmatic pressure (Pdi), pressure-time product of Pes (PTPes), pressure-time product of Pga (PTPga), pressure-time product of Pdi (PTPdi), ratio of the PTPdi to the PTPes (PTPdi/PTPes), and ratio of the Pes to the Pdi (Pes/Pdi), diaphragmatic electromyogram (EMGdi), percentage of esophageal pressure coefficient of variation (CVes%),diaphragmatic electromyogram coefficient of variation (CVEMG),inspiratory time (Ti), expiratory time (Te) and respiratory cycle time (Ttot). RESULTS: Of the 29 patients included, 22 were males and 7 were females [age: 63.97±15.34 years, Acute Physiological and Chronic Health Estimation II (APACHE II) score: 18.00±5.63]. The CVes% and the Pes/Pdi were significantly higher in patients with NIV than HFNC using 40 L/min, CVes%: 9 (-6, 20) vs. -7 (-23, 6) and Pes/Pdi: 0.17 (-0.1, 0.53), vs. -0.12 (-0.43, 0.08) (P<0.05). The remaining indicators were not statistically different. CONCLUSIONS: The sequential NIV and HFNC can be tolerated in patients with such difficult weaning off mechanical ventilation after extubation, and more patients tend to choose HFNC subjectively. Compared with HFNC, NIV reduces the work of adjunctive respiratory muscle, but the patient's Pes dispersion is high when NIV is used, and it is necessary to pay attention to patient-ventilator coordination in clinical practice. We recommend alternating HFNC and NIV during the sequential respiratory therapy after extubation.