Short-Term Effects of Ambient Air Pollution on Chronic Obstructive Pulmonary Disease Admissions in Jiuquan, China.

Recent findings indicate that air pollution contributes to the onset and advancement of chronic obstructive pulmonary disease (COPD). Nevertheless, there is insufficient research indicating that air pollution is linked to COPD in the region of inland northwest China. Daily hospital admission records for COPD, air pollutant levels, and meteorological factor information were collected in Jiuquan for this study between 1 January 2018 and 31 December 2019. We employed a distributed lag non-linear model (DLNM) integrated with the generalized additive model (GAM) to assess the association between air pollution and hospital admissions for COPD with single lag days from lag0 to lag7 and multiday moving average lag days from lag01 to lag07. For example, the pollutant concentration on the current day was lag0, and on the prior 7th day was lag7. The present and previous 7-day moving average pollutant concentration was lag07. Gender, age, and season-specific stratified analyses were also carried out. It is noteworthy that the delayed days exhibited a different pattern, and the magnitude of associations varied. For NO2 and CO, obvious associations with hospitalizations for COPD were found at lag1, lag01-lag07, and lag03-lag07, with the biggest associations at lag05 and lag06 [RR = 1.015 (95%CI: 1.008, 1.023) for NO2, RR = 2.049 (95%CI: 1.416, 2.966) for CO], while only SO2 at lag02 was appreciably linked to hospitalizations for COPD [1.167 (95%CI: 1.009, 1.348)]. In contrast, short-term encounters with PM2.5, PM10, and O3 were found to have no significant effects on COPD morbidity. The lag effects of NO2 and CO were stronger than those of PM2.5 and PM10. Males and those aged 65 years or older were more vulnerable to air pollution. When it came to the seasons, the impacts appeared to be more pronounced in the cold season. In conclusion, short-term encounters with NO2 and CO were significantly correlated with COPD hospitalization in males and the elderly (≥65).

Preparation and Characterization of a Hypoglycemic Complex of Gallic Acid-Antarctic Krill Polypeptide Based on Polylactic Acid-Hydroxyacetic Acid (PLGA) and High-Pressure Microjet Microencapsulation.

Gallic acid-Antarctic krill peptides (GA-AKP) nanocapsules (GA-AKP-Ns) were prepared using a dual delivery system with complex emulsion as the technical method, a high-pressure microjet as the technical means, polylactic acid-hydroxyacetic acid (PLGA) as the drug delivery vehicle, and GA-AKP as the raw material for delivery. This study aimed to investigate the effects of microjet treatment and the concentration of PLGA on the physicochemical properties and stability of the emulsion. Under optimal conditions, the physicochemical properties and hypoglycemic function of nano-microcapsules prepared after lyophilization by the solvent evaporation method were analyzed. Through the microjet treatment, the particle size of the emulsion was reduced, the stability of the emulsion was improved, and the encapsulation rate of GA-AKP was increased. The PLGA at low concentrations decreased the particle size of the emulsion, while PLGA at high concentrations enhanced the encapsulation efficiency of the emulsion. Additionally, favorable results were obtained for emulsion preparation through high-pressure microjet treatment. After three treatment cycles with a PLGA concentration of 20 mg/mL and a microjet pressure of 150 MPa (manometric pressure), the emulsion displayed the smallest particle size (285.1 ± 3.0 nm), the highest encapsulation rates of GA (71.5%) and AKP (85.2%), and optimal physical stability. GA-AKP was uniformly embedded in capsules, which can be slowly released in in vitro environments, and effectively inhibited α-amylase, α-glucosidase, and DPP-IV at different storage temperatures. This study demonstrated that PLGA as a carrier combined with microjet technology can produce excellent microcapsules, especially nano-microcapsules, and these microcapsules effectively improve the bioavailability and effectiveness of bioactive ingredients.

Changes in the Quality and Microbial Communities of Precooked Seasoned Crayfish Tail Treated with Microwave and Biological Preservatives during Room Temperature Storage.

The qualities of precooked foods can be significantly changed by the microorganisms produced during room temperature storage. This work assessed the effects of different antibacterial treatments (CK, without any treatment; microwave treatment, MS; microwave treatment and biological preservatives, MSBP) on the physicochemical properties and microbial communities of precooked crayfish tails during room temperature storage. Only the combination of microwave sterilization and biological preservatives significantly inhibited spoilage, as evidenced by the total viable count (4.15 log CFU/g) after 3 days of room temperature storage, which satisfied the transit time of most logistics companies in China. Changes in pH and TVB-N were also significantly inhibited in the MSBP group compared with those in the CK and MS groups. More than 30 new volatile compounds were produced in the CK groups during room temperature storage. However, in the MSBP groups, the volatile compounds were almost unchanged. The correlations between the microbial composition and volatile compounds suggested that specific bacterial species with metabolic activities related to amino acid, energy, cofactor, and vitamin metabolism, as well as xenobiotics biodegradation and metabolism, were responsible for the changes in volatile compounds. These bacteria included Psychrobacter, Arthrobacter, Facklamia, Leucobacter, Corynebacterium, Erysipelothrix, Devosia, Dietzia, and Acidovorax. Overall, our findings provide a foundation for the development of strategies to inhibit spoilage in precooked crayfish tails stored at room temperature.

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer.

BACKGROUND: ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. METHODS: 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs. RESULTS: In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib. CONCLUSIONS: This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

Cfp1 Controls Cardiomyocyte Maturation by Modifying Histone H3K4me3 of Structural, Metabolic, and Contractile Related Genes.

Cardiomyocyte maturation is the final stage of heart development, and abnormal cardiomyocyte maturation will lead to serious heart diseases. CXXC zinc finger protein 1 (Cfp1), a key epigenetic factor in multi-lineage cell development, remains underexplored in its influence on cardiomyocyte maturation. This study investigates the role and mechanisms of Cfp1 in this context. Cardiomyocyte-specific Cfp1 knockout (Cfp1-cKO) mice died within 4 weeks of birth. Cardiomyocytes derived from Cfp1-cKO mice showed an inhibited maturation phenotype, characterized by structural, metabolic, contractile, and cell cycle abnormalities. In contrast, cardiomyocyte-specific Cfp1 transgenic (Cfp1-TG) mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) overexpressing Cfp1 displayed a more mature phenotype. Mechanistically, deficiency of Cfp1 led to a reduction in trimethylation on lysine 4 of histone H3 (H3K4me3) modification, accompanied by the formation of ectopic H3K4me3. Furthermore, Cfp1 deletion decreased the level of H3K4me3 modification in adult genes and increased the level of H3K4me3 modification in fetal genes. Collectively, Cfp1 modulates the expression of genes crucial to cardiomyocyte maturation by regulating histone H3K4me3 modification, thereby intricately influencing the maturation process. This study implicates Cfp1 as an important molecule regulating cardiomyocyte maturation, with its dysfunction strongly linked to cardiac disease.

Lineage tracing for multiple lung cancer by spatiotemporal heterogeneity using a multi-omics analysis method integrating genomic, transcriptomic, and immune-related features.

Introduction: The distinction between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) holds clinical significance in staging, therapeutic intervention, and prognosis assessment for multiple lung cancer. Lineage tracing by clinicopathologic features alone remains a clinical challenge; thus, we aimed to develop a multi-omics analysis method delineating spatiotemporal heterogeneity based on tumor genomic profiling. Methods: Between 2012 and 2022, 11 specimens were collected from two patients diagnosed with multiple lung cancer (LU1 and LU2) with synchronous/metachronous tumors. A novel multi-omics analysis method based on whole-exome sequencing, transcriptome sequencing (RNA-Seq), and tumor neoantigen prediction was developed to define the lineage. Traditional clinicopathologic reviews and an imaging-based algorithm were performed to verify the results. Results: Seven tissue biopsies were collected from LU1. The multi-omics analysis method demonstrated that three synchronous tumors observed in 2018 (LU1B/C/D) had strong molecular heterogeneity, various RNA expression and immune microenvironment characteristics, and unique neoantigens. These results suggested that LU1B, LU1C, and LU1D were MPLC, consistent with traditional lineage tracing approaches. The high mutational landscape similarity score (75.1%), similar RNA expression features, and considerable shared neoantigens (n = 241) revealed the IPM relationship between LU1F and LU1G which were two samples detected simultaneously in 2021. Although the multi-omics analysis method aligned with the imaging-based algorithm, pathology and clinicopathologic approaches suggested MPLC owing to different histological types of LU1F/G. Moreover, controversial lineage or misclassification of LU2's synchronous/metachronous samples (LU2B/D and LU2C/E) traced by traditional approaches might be corrected by the multi-omics analysis method. Spatiotemporal heterogeneity profiled by the multi-omics analysis method suggested that LU2D possibly had the same lineage as LU2B (similarity score, 12.9%; shared neoantigens, n = 71); gefitinib treatment and EGFR, TP53, and RB1 mutations suggested the possibility that LU2E might result from histology transformation of LU2C despite the lack of LU2C biopsy and its histology. By contrast, histological interpretation was indeterminate for LU2D, and LU2E was defined as a primary or progression lesion of LU2C by histological, clinicopathologic, or imaging-based approaches. Conclusion: This novel multi-omics analysis method improves the accuracy of lineage tracing by tracking the spatiotemporal heterogeneity of serial samples. Further validation is required for its clinical application in accurate diagnosis, disease management, and improving prognosis.

Study on the mechanism of PM2.5 affecting Th1/Th2 immune imbalance through the notch signaling pathway in asthmatic mice.

Some research has shown that PM2.5 causes Th1/Th2 immune imbalance and aggravates asthma. However, the exact mechanism of PM2.5 causing aggravation of asthma remains unclear. The purpose of this study was to investigate whether exposure to PM2.5 exacerbates Th1/Th2 immune imbalance through the Notch signaling pathway. Eight-week-old SPF female BALF/c mice were sensitized by ovalbumin to establish an asthma mouse model. PM2.5 exposure was carried out by aerosol inhalation of PM2.5 (510 µg/m3) after each provocation. The lung function of mice was measured and Splenic T lymphocyte subsets were detected. Notch signaling pathway was tested. The levels of interferon (IFN)-γ and interleukin (IL)-4 in serum and bronchoalveolar lavage fluid were determined. The results showed that the expression of the mRNA and protein of Notch1 and Hes1 in the asthma group were significantly higher than those in healthy controls. The levels of IL-4 were also remarkably high; while the levels of IFN-γ were remarkably low in serum and BALF, the Th1% and Th1/Th2 ratios were significantly lower, and Th2% was significantly higher in the asthma group than in the healthy controls. PM2.5 promoted further activation of the Notch signaling pathway and aggravated Th1/Th2 immune imbalance in asthmatic mice. γ-secretase inhibitor can partially inhibit the activation of the Notch signaling pathway and alleviate aggravation of immune imbalance. In conclusion, the asthmatic mice had a Th1/Th2 immune imbalance and an overactivated Notch signaling pathway. PM2.5 further aggravated Th1/Th2 immune imbalance by activating the Notch signaling pathway.

Ambient carbon monoxide and relative risk of daily hospital outpatient visits for respiratory diseases in Lanzhou, China.

At present, evidence of the associations between carbon monoxide (CO) and respiratory diseases (RD) in Northwest China is limited and controversial. The aim of this study is to evaluate the impact of ambient CO on outpatient visits for RD in Lanzhou, China. The daily amount of outpatient visits for total and cause-specific RD, air pollutant, and weather variables were collected in Lanzhou, China from 1st January 2013 to 31st December 2019. A generalized additive model and distributed lag nonlinear model were used to assess associations between CO and outpatient visits for RD. During the study period, a total of 1,623,361 RD outpatient visits were recorded. For each interquartile range (IQR) (0.77 mg/m3) increase in CO, the relative risk (RR) was 1.163 (95% CI: 1.138, 1.188) for total RD at lag07, 1.153 (95% CI: 1.128,1.179) for upper respiratory tract infection (URTI) at lag07, 1.379 (95% CI: 1.338,1.422) for pneumonia at lag07, 1.029 (95% CI: 0.997,1.062) for chronic obstructive pulmonary disease (COPD) lag04, 1.068 (95% CI: 1.028,1.110) for asthma lag03, and 1.212 (95% CI: 1.178,1.247) for bronchitis lag07, respectively. In the subgroup analyses, the impacts of CO were more pronounced on total RD, pneumonia, COPD, and bronchitis in males than females, while the opposite was true in URTI and asthma. The impact of CO on RD was the strongest for children under 15 years-of-age. We also found significantly stronger effects during cold seasons compared to warm seasons. In addition, we observed a roughly linear exposure-response curve between CO and RD with no threshold effect. This study in Lanzhou revealed a remarkable association between CO level and an elevated risk of total and cause-specific RD outpatient visits, especially for pneumonia.

MiR-155 enhances phagocytosis of alveolar macrophages through the mTORC2/RhoA pathway.

Alveolar macrophage phagocytosis is significantly reduced in Chronic obstructive pulmonary disease, and cigarette smoke extract is one of the chief reasons for this decrease. Nevertheless, the specific underlying mechanism remains elusive. In this study, the role and possible mechanism of miR-155-5p/mTORC2/RhoA in the phagocytosis of mouse alveolar macrophages (MH-S) were explored. Our results revealed that cigarette smoke extract intervention reduced MH-S cell phagocytosis and miR-155-5p expression. Meanwhile, the dual-luciferase reporter assay validated that Rictor is a target of miR-155-5p. On the one hand, transfecting miR-155-5p mimic, mimic NC, miR-155-5p inhibitor, or inhibitor NC in MH-S cells overexpressing miR-155-5p increased the Alveolar macrophage phagocytotic rate, up-regulated the expression level of RhoA and p-RhoA, and down-regulated that of mTOR and Rictor mRNA and protein. On the other hand, inhibiting the expression of miR-155-5p lowered the phagocytotic rate, up-regulated the expression of mTOR, Rictor mRNA, and protein, and down-regulated the expression of RhoA and p-RhoA, which taken together, authenticated that miR-155-5p participates in macrophage phagocytosis via the mTORC2/RhoA pathway. Finally, confocal microscopy demonstrated that cells overexpressing miR-155-5p underwent cytoskeletal rearrangement during phagocytosis, and the phagocytic function of cells was enhanced, signaling that miR-155-5p participated in macrophage skeletal rearrangement and enhanced alveolar macrophage phagocytosis by targeting the expression of Rictor in the mTORC2/RhoA pathway.

Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the -187 to -2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation.

Clonal dynamics and Stereo-seq resolve origin and phenotypic plasticity of adenosquamous carcinoma.

The genomic origin and development of the biphasic lung adenosquamous carcinoma (ASC) remain inconclusive. Here, we derived potential evolutionary trajectory of ASC through whole-exome sequencing, Stereo-seq, and patient-derived xenografts. We showed that EGFR and MET activating mutations were the main drivers in ASCs. Phylogenetically, these drivers and passenger mutations found in both components were trunk clonal events, confirming monoclonal origination. Comparison of multiple lesions also revealed closer genomic distance between lymph node metastases and the ASC component with the same phenotype. However, as mutational signatures of EGFR-positive lung squamous carcinomas (LUSCs) were more comparable to EGFR-positive ASCs than to wild-type LUSCs, we postulated different origination of these LUSCs, with ASC being the potential intermediate state of driver-positive LUSCs. Spatial transcriptomic profiling inferred transformation from adenocarcinoma to squamous cell carcinoma, which was then histologically captured in vivo. Together, our results explained the development of ASC and provided insights into future clinical decisions.

Ambient carbon monoxide and the risk of cardiovascular disease emergency room visits: a time-series study in Lanzhou, China.

Until now, the epidemiological evidence on the association between short-term exposure to ambient carbon monoxide (CO) and cardiovascular diseases (CVDs) is relatively lacking and controversial. This study aims to examine the relationship between ambient CO and daily emergency room visits (ERVs) for total and cause-specific CVD in Lanzhou, China. A distributed lag nonlinear model was used to examine the association. For every 1 mg/m3 increase in the CO concentration, the relative risks of daily ERVs were 1.041 (95% CI: 1.017, 1.065) for total CVD, 1.065 (95% CI: 1.018, 1.114) for ischemic heart disease (IHD), 1.083 (95% CI: 1.020, 1.149) for heart rhythm disturbances (HRD), 1.062 (95% CI: 1.011, 1.115) for heart failure (HF), and 1.057 (95% CI: 1.017, 1.098) for cerebrovascular diseases (CD). For the two different gender subgroups, the short-term impact of CO on total CVD, IHD, and CD was relatively stronger for the females than for the males, while the opposite was true for HRD and HF. In the age subgroup analyses, the effect of ambient CO on total CVD and IHD appeared to be greater for the age ≥ 65 years group, while the opposite was true for HRD, HF, and CD. The associations for all disease categories were stronger in cold seasons than in warm seasons. We also observed a nearly linear correlation between CO and CVD ERVs. In conclusion, the study showed that exposure to ambient CO may increase the risks of ERVs for total and cause-specific CVD. Besides, CO-ERVs associations may vary by gender and age.

The long noncoding RNA CIRBIL is a regulator of steroidogenesis in mice.

Infertility affects roughly 8-12 % of couples worldwide, and in above 50 % of couples, male factors are the primary or contributing cause. Many long noncoding RNAs (lncRNAs) are detected in the testis, but their functions are not well understood. CIRBIL was 862 nucleotides in length and was found to be localized mostly in the cytosol of Leydig cell, a small portion was positioned inside the seminiferous tubules. Loss of CIRBIL in mice resulted in male subfertility, characterized by smaller testis and increased germ cell apoptosis. Deletion of CIRBIL significant decreased the number of sperm and impaired the integrity of sperm head and tail. In CIRBIL KO mice, testosterone levels in serum and expression of testosterone biosynthesis genes (STAR and 3ß-HSD) were both reduced. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were primarily enriched in steroid synthesis process in CIRBIL-binding proteins. Protein-protein (PPI) interaction networks revealed that both cis- and trans-regulated target genes of CIRBIL were associated with testosterone synthesis. Collectively, our results strongly suggest that CIRBIL is a regulator of steroid hormone synthesis.

Analysis of Communal Molecular Mechanism Between Chronic Obstructive Pulmonary Disease and Osteoporosis.

Background: Chronic obstructive pulmonary disease (COPD) patients with osteoporosis (OP) usually experience more frequent exacerbations, worse quality of life, and heavier economic burden, however, few studies have investigated common molecular mechanisms of COPD and OP. Objective: To explore the relationship between COPD and OP through bioinformatics analysis. Methods: The miRNA microarray data of COPD and OP were retrieved from the Gene Expression Database (GEO), and the differentially expressed microRNAs (DEmiRNAs) were screened and the intersection was obtained. The Targetscan, miRDB, and miRWalk databases were used to predict the target genes of DEmiRNA, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the R package clusterProfiler, the STRING database was used to analyze the target protein-protein interaction network (PPI) and screens to determine the core modules and core genes. Results: Two DEmiRNAs (miR-23a-5p, miR-194-3p) have been found in COPD and OP, which have predicted 76 and 114 target genes, respectively. GO functional annotations of miR-23a-5p were significantly enriched in CD40 signaling pathway, ubiquitin-conjugating enzyme activity, etc; KEGG pathways of miR-23a-5p were significantly enriched in ubiquitin-mediated proteolysis, folate biosynthesis, and regulation of actin cytoskeleton. GO function annotations of miR-194-3p were significantly enriched in T cell activation regulation, ubiquitin protein ligase activity, and DNA transcription factor binding; KEGG pathways of miR-194-3p were significantly enriched in cell adhesion molecules, intercellular tight junctions, and lysosomal pathway. PPI analysis found target coding proteins formed complex regulatory networks. Ten core genes (TP53, SRC, PXN, CHD4, SYK, TNRC6B, PML, KAT5, BRD1 and IGF2) were picked out among them, then we used the MCODE plugin found three core subnetworks. Conclusion: Two identical DEmiRNAs (miR-23a-5p, miR-194-3p) exist in the peripheral blood of COPD and OP patients, which are important biomarkers for COPD patients with OP and may represent novel targets for diagnosis and treatment of COPD patients with OP.

Recent Progress in Microencapsulation of Active Peptides-Wall Material, Preparation, and Application: A Review.

Being a natural active substance with a wide variety of sources, easy access, significant curative effect, and high safety, active peptides have gradually become one of the new research directions in food, medicine, agriculture, and other fields in recent years. The technology associated with active peptides is constantly evolving. There are obvious difficulties in the preservation, delivery, and slow release of exposed peptides. Microencapsulation technology can effectively solve these difficulties and improve the utilization rate of active peptides. In this paper, the commonly used materials for embedding active peptides (natural polymer materials, modified polymer materials, and synthetic polymer materials) and embedding technologies are reviewed, with emphasis on four new technologies (microfluidics, microjets, layer-by-layer self-assembly, and yeast cells). Compared with natural materials, modified materials and synthetic polymer materials show higher embedding rates and mechanical strength. The new technology improves the preparation efficiency and embedding rate of microencapsulated peptides and makes the microencapsulated particle size tend to be controllable. In addition, the current application of peptide microcapsules in different fields was also introduced. Selecting active peptides with different functions, using appropriate materials and efficient preparation technology to achieve targeted delivery and slow release of active peptides in the application system, will become the focus of future research.

Interdependent Nuclear Co-Trafficking of ASPP1 and p53 Aggravates Cardiac Ischemia/Reperfusion Injury.

OBJECTIVE: ASPP1 (apoptosis stimulating of p53 protein 1) is critical in regulating cell apoptosis as a cofactor of p53 to promote its transcriptional activity in the nucleus. However, whether cytoplasmic ASPP1 affects p53 nuclear trafficking and its role in cardiac diseases remains unknown. This study aims to explore the mechanism by which ASPP1 modulates p53 nuclear trafficking and the subsequent contribution to cardiac ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: The immunofluorescent staining showed that under normal condition ASPP1 and p53 colocalized in the cytoplasm of neonatal mouse ventricular cardiomyocytes, while they were both upregulated and translocated to the nuclei upon hypoxia/reoxygenation treatment. The nuclear translocation of ASPP1 and p53 was interdependent, as knockdown of either ASPP1 or p53 attenuated nuclear translocation of the other one. Inhibition of importin-ß1 resulted in the cytoplasmic sequestration of both p53 and ASPP1 in neonatal mouse ventricular cardiomyocytes with hypoxia/reoxygenation stimulation. Overexpression of ASPP1 potentiated, whereas knockdown of ASPP1 inhibited the expression of Bax (Bcl2-associated X), PUMA (p53 upregulated modulator of apoptosis), and Noxa, direct apoptosis-associated targets of p53. ASPP1 was also increased in the I/R myocardium. Cardiomyocyte-specific transgenic overexpression of ASPP1 aggravated I/R injury as indicated by increased infarct size and impaired cardiac function. Conversely, knockout of ASPP1 mitigated cardiac I/R injury. The same qualitative data were observed in neonatal mouse ventricular cardiomyocytes exposed to hypoxia/reoxygenation injury. Furthermore, inhibition of p53 significantly blunted the proapoptotic activity and detrimental effects of ASPP1 both in vitro and in vivo. CONCLUSIONS: Binding of ASPP1 to p53 triggers their nuclear cotranslocation via importin-ß1 that eventually exacerbates cardiac I/R injury. The findings imply that interfering the expression of ASPP1 or the interaction between ASPP1 and p53 to block their nuclear trafficking represents an important therapeutic strategy for cardiac I/R injury.

Association between short-term ambient air pollution and outpatient visits for acute exacerbation of chronic obstructive pulmonary disease in Lanzhou, 2013-19.

Evidence between air pollution and hospital visits for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is inconsistent and limited in China. In this study, we constructed a time-series study to evaluate the association between air pollution and AECOPD outpatient visits. Daily hospital outpatient visits for AECOPD in three top level hospitals in Lanzhou from January 2013 to December 2019, as well as the air pollutants and meteorological data in the same period, were collected. Then, generalized additive models with quasi-Poisson regression were utilized to estimate the associations with single-day lags from lag0 to lag7 and cumulative-day lag from lag01 to lag07. For example, lag0 referred to the concentration of air pollutants at the current day and lag1 referred to the previous-day air pollutant concentration and so on. Lag01 meant the average concentration of air pollutants at the current and previous day, and lag07 corresponded to the eight-day moving average value of the current and previous 7 days. In addition, stratified analyses were performed by gender, age, and season. The risk estimates were expressed in terms of the percentage changes (PC) in AECOPD outpatient visits per 10 µg/m3 increment of air pollutants (except that CO was per 1 mg/m3) and their respective 95% confidence intervals (CIs). The strongest effect on AECOPD morbidity was found lag07 for PM2.5 (PC = 1.96, 95% CI 1.07, 2.86 per 10 µg/m3), lag03 for PM10 (PC = 0.25, 95% CI 0.01, 0.49 per 10 µg/m3), lag05 for SO2 (PC = 1.67, 95% CI 0.54, 3.93 per 10 µg/m3), and lag03 for NO2 (PC = 1.37, 95% CI 0.25, 2.51 per 10 µg/m3). No significant association of O3 and CO with AECOPD onset was found. In the subgroup analyses, the associations of PM2.5 and SO2 were more pronounced on males than female, the patients aged < 65 years were more vulnerable to PM2.5 and NO2, but 65-74 years old were more vulnerable to PM2.5, SO2, and NO2. Patients aged ≥ 75 years suffered more from PM2.5, PM10, and SO2. The associations between PM2.5, PM10, SO2, NO2, and AECOPD outpatients were stronger in the cold season than those in the hot season. From exposure-response curves, we observe linear relationships of PM2.5, SO2, NO2, O38h, and CO with hospital outpatient visits for AECOPD. The increase in PM2.5, PM10, SO2, and NO2 concentration will lead to an increase in the number of outpatient visits for AECOPD and have different influence patterns in different genders, ages, and seasons.

Tumor mutational burden and efficacy of chemotherapy in lung cancer.

PURPOSE: TMB is one of the potent biomarkers of response to immune checkpoint blockade. The association between TMB and efficacy of chemotherapy in advanced lung cancer has not been comprehensively explored. METHODS: Ninety lung cancer patients receiving first-line chemotherapy with large panel next-generation sequencing data of pre-treatment tumor tissue were identified. The effect of TMB on PFS of chemotherapy were evaluated in univariate and multivariate analyses. RESULTS: The median TMB level of lung cancer patients enrolled in this study was 9.4 mutations/Mb, with TMB levels in smokers significantly higher than those in non-smokers. All patients were divided into high TMB and low TMB groups with the cutoff of the median TMB. The patients with low TMB had longer PFS of first-line chemotherapy (median PFS 9.77 vs 6.33 months, HR = 0.523, 95% CI 0.32-0.852, log-rank P = 0.009). Subgroup analysis showed that PFS of chemotherapy favored low TMB than high TMB among subgroups of male, age < 60, NSCLC, adenocarcinoma, stage IV, ECOG PS 0, driver mutation positive, TP53 wild type and patients not receiving bevacizumab. In multivariate analysis, PFS of chemotherapy remained significantly longer in low TMB group (HR = 0.554, p = 0.036). In those patients received immunotherapy upon unsatisfactory chemotherapy, PFS of immunotherapy was much longer in high TMB group (median PFS 32.88 vs 6.62 months, HR = 0.2426, 95% CI 0.06-0.977, log-rank P = 0.04). CONCLUSIONS: TMB level of tumor tissue is a potent biomarker for efficacy of chemotherapy and immunotherapy in lung cancer. It may provide some clues for the decision of treatment strategy.

Corticosteroids showed more efficacy in treating hospitalized patients with COVID-19 than standard care but the effect is minimal: A systematic review and meta-analysis.

Background: During the ongoing coronavirus disease 2019 (COVID-19) pandemic, the use of corticosteroids for COVID-19 has ignited worldwide debate. Previous systematic reviews, including randomized controlled trials (RCTs) and retrospective observational studies, found that corticosteroids have beneficial effects in treating COVID-19. Aim: This systematic review and meta-analysis only included RCTs to assess the effectiveness and safety of corticosteroids in hospitalized patients with COVID-19. Methods: Comprehensive research strategies (PubMed, Embase, MEDLINE, and Coherence Library) were used to search for RCTs from December 2019 to January 2021. Results: Five RCTs were included with 7,235 patients, of which 2,508 patients were receiving corticosteroid treatments (dexamethasone or methylprednisolone), and 4,727 received standard care. The primary outcome was mortality within 28 days. The use of corticosteroids decreased the 28-day mortality of patients with COVID-19, but the findings were not statistically significant (RR, 0.91; 95% CI, 0.78-1.06, p = 0.24). The secondary outcome was the duration of hospitalization; no differences were found between the corticosteroid and standard care groups. However, corticosteroids were associated with a higher hospital discharge rate than standard treatment, but the result was not statistically significant (RR, 1.36; 95% CI, 0.95-1.96, p = 0.09). Conclusions: The results suggest that corticosteroids are comparable to standard care in terms of safety in treating COVID-19. Corticosteroids showed greater efficacy than standard care; however, the effect was minimal.

Letter to the Editor: An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection.

Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.