Association of telomere length with risk of lung cancer: A large prospective cohort study from the UK Biobank.

OBJECTIVES: Leukocyte telomere length (LTL) is associated with a wide variety of diseases, including cancer. However, findings regarding the association between LTL and the risk for lung cancer have been inconclusive and inconsistent across previous observational studies. METHODS: This prospective cohort study included data from 425,146 participants 37-73 years of age housed in the UK Biobank. Quantitative polymerase chain reaction (qPCR) was used to measure LTL in baseline DNA samples. A multivariate Cox proportional hazards model was used to evaluate the relationship between LTL and the risk for lung cancer. RESULTS: An increase in LTL per interquartile range (IQR) was associated with a 9% increase in the risk for lung cancer (hazard ratio [HR] 1.09 [95% confidence interval (CI) 1.03-1.16]). Participants in the highest LTL quintile exhibited an approximately 25% elevated risk for developing lung cancer (HR 1.25 [95% CI 1.09-1.45]) compared with those in the lowest quintile. The relationship between per IQR increase in LTL and elevated risk for lung cancer was greater in the histological subtype of adenocarcinoma (HR 1.30 [95% CI 1.18-1.43]), female sex (HR 1.16 [95% CI 1.06-1.26]), non-smokers (HR 1.45 [95% CI 1.23-1.71]), and individuals with high genetic risk for lung cancer (HR 1.18 [95% CI 1.03-1.34]), respectively. Surprisingly, a per IQR increase in LTL was associated with increased risks for both lung adenocarcinoma (HR 1.56 [95% CI 1.24-1.96]) and squamous cell carcinoma (HR 2.01 [95% CI 1.13-3.56]) in never smokers. CONCLUSIONS: Longer LTL was associated with an elevated risk for lung cancer, particularly for adenocarcinoma and squamous cell carcinoma in never smokers. The results suggest the potential of telomeres as non-invasive biomarkers for the early screening of lung cancer, particularly in non-smokers, who are typically overlooked.

Quercetin protects against LPS-induced lung injury in mice via SIRT1-mediated suppression of PKM2 nuclear accumulation.

The role of NOD-like receptor protein 3 (NLRP3)-mediated macrophages pyroptosis in acute lung injury (ALI) is well-established. Quercetin (Que) is a natural bioflavonoid compound with anti-inflammatory and antioxidative properties that reportedly inhibits the NLRP3 inflammasome in sepsis-induced organ dysfunctions such as ALI. However, the mechanism underlying the inhibitory effect of quercetin on NLRP3 activation remains unclear. In this study, we established an endotoxin-induced ALI mouse model with an in vitro LPS challenge. We demonstrated that the administration of quercetin could significantly reduce pulmonary injury and decrease the production of pro-inflammatory cytokines. Moreover, we found that quercetin could inhibit the activation of the NLRP3 inflammasome by suppressing the nuclear accumulation of PKM2 and increasing SIRT1 levels. Importantly, treatment with SRT1720 (a specific SIRT1 activator) could inhibit the nuclear accumulation of PKM2 and the activation of NLRP3. Besides, preventing PKM2 dimerization with ML265 yielded an anti-inflammatory effect, similar to findings observed for SRT1720. In addition, we found that SIRT1 silencing or inhibition by EX527 could increase NLRP3 activation and nuclear accumulation of PKM2 and override quercetin-mediated anti-inflammatory activity. These findings indicated that quercetin could downregulate NLRP3 inflammasome activation by inhibiting the nuclear accumulation of PKM2 and upregulating SIRT1 expression, expanding the treatment landscape for ARDS.

A prediction model for acute respiratory distress syndrome among patients with severe acute pancreatitis: a retrospective analysis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication among patients with severe acute pancreatitis (SAP), which may be associated with increased mortality in hospitalized patients. Thus, an effective model to predict ARDS in patients with SAP is urgently required. METHODS: We retrospectively analyzed the data from the patients with SAP who recruited in Xiangya Hospital between April 2017 and May 2021. Patients meeting the Berlin definition of ARDS were categorized into the ARDS group. Logistic regression models and a nomogram were utilized in the study. Descriptive statistics, logistic regression models, and a nomogram were used in the current study. RESULTS: Comorbidity of ARDS occurred in 109 (46.58%) of 234 patients with SAP. The SAP patients with ARDS group had a higher 60-day mortality rate, an increased demand for invasive mechanical ventilation, and a longer intensive care unit (ICU) stay than those without ARDS (p < .001 for all). Partial pressure of oxygen (PaO2): fraction of inspired oxygen (FiO2) < 200, platelets <125 × 109/L, lactate dehydrogenase >250 U/L, creatinine >111 mg/dL, and procalcitonin >0.5 ng/mL were independent risk variables for development of ARDS in SAP patients. The area under the curve for the model was 0.814, and the model fit was acceptable [p = .355 (Hosmer-Lemeshow)]. Incorporating these 5 factors, a nomogram was established with sufficient discriminatory power (C-index 0.814). Calibration curve indicated the proper discrimination and good calibration in the predicting nomogram model. CONCLUSION: The prediction nomogram for ARDS in patients with SAP can be applied using clinical common variables after the diagnosis of SAP. Future studies would be warranted to verify the potential clinical benefits of this model.

MiR-29a-3p Improves Acute Lung Injury by Reducing Alveolar Epithelial Cell PANoptosis.

Alveolar epithelial cell damage is an important determinant of the severity of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the molecular mechanisms of alveolar epithelial death during the development of ALI/ARDS remain unclear. In this study, we explore the role of miR-29a-3p in ALI/ARDS and its molecular mechanism. Plasma samples were collected from healthy controls and ARDS patients. Mice were intratracheally instilled with lipopolysaccharide (LPS) to establish acute lung injury. N6-adenosine (m6A) quantification, RNA-binding protein immunoprecipitation, cell viability assay, quantitative real-time polymerase chain reaction, and western blotting were performed. We found that miR-29a-3p was down-regulated in plasma of ARDS patients and lung tissue of ALI model mice, and miR-29a-3p agomir injection down-regulated the levels of the inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in the lungs, reducing alveolar epithelial cell PANoptosis as evaluated by the downregulation of Z-DNA binding protein 1 (ZBP1), gasdermin D (GSDMD), caspase-3, caspase-8, and mixed lineage kinase domain-like protein (MLKL), ultimately improving lung injury in the ALI model mice. Mechanism studies demonstrated that the knockout of methyltransferase 3 (N6-adenosine-methyltransferase complex catalytic subunit) removed the m6A modification of miR-29a-3p and reduced miR-29a-3p expression. Our findings suggest that miR-29a-3p is a potential target that can be manipulated for ALI/ARDS.

Delayed neutrophil apoptosis may enhance NET formation in ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a neutrophil-associated disease. Delayed neutrophil apoptosis and increased levels of neutrophil extracellular traps (NETs) have been described in ARDS. We aimed to investigate the relationship between these phenomena and their potential as inflammation drivers. We hypothesized that delayed neutrophil apoptosis might enhance NET formation in ARDS. METHOD: Our research was carried out in three aspects: clinical research, animal experiments, and in vitro experiments. First, we compared the difference between neutrophil apoptosis and NET levels in healthy controls and patients with ARDS and analyzed the correlation between neutrophil apoptosis and NET levels in ARDS. Then, we conducted animal experiments to verify the effect of neutrophil apoptosis on NET formation in Lipopolysaccharide-induced acute lung injury (LPS-ALI) mice. Furthermore, this study explored the relationship between neutrophil apoptosis and NETs at the cellular level. Apoptosis was assessed using morphological analysis, flow cytometry, and western blotting. NET formation was determined using immunofluorescence, PicoGreen assay, SYTOX Green staining, and western blotting. RESULTS: ARDS neutrophils lived longer because of delayed apoptosis, and the cyclin-dependent kinase inhibitor, AT7519, reversed this phenomenon both in ARDS neutrophils and neutrophils in bronchoalveolar lavage fluid (BALF) of LPS-ALI mice. Neutrophils in a medium containing pro-survival factors (LPS or GM-CSF) form more NETs, which can also be reversed by AT7519. Tissue damage can be reduced by promoting neutrophil apoptosis. CONCLUSIONS: Neutrophils with extended lifespan in ARDS usually enhance NET formation, which aggravates inflammation. Enhancing neutrophil apoptosis in ARDS can reduce the formation of NETs, inhibit inflammation, and consequently alleviate ARDS.

Exploring the Mechanisms of Arsenic Trioxide (Pishuang) in Hepatocellular Carcinoma Based on Network Pharmacology.

OBJECTIVE: Arsenic trioxide (Pishuang, Pishi, arsenolite, As2O3, and CAS 1327-53-3), a naturally occurring and toxic mineral as a drug for more than 2000 years in China, has been found to have a valuable function in hepatocellular carcinoma (HCC) in recent years. However, its exact mechanism remains to be elucidated. Therefore, this study was intended to explore the potential anti-HCC mechanism of arsenic trioxide through network pharmacology. METHODS: The potential targets of arsenic trioxide were collected from PubChem and TargetNet. HCC targets were obtained from the GeneCards database. Then, a protein-protein interaction (PPI) network of arsenic trioxide and HCC common targets was established using STRING. GO and KEGG pathway enrichment analyses were performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Finally, an arsenic trioxide-target-pathway-HCC network was built by Cytoscape 3.2.1, and network topological analysis was carried out to screen the key candidate targets. RESULTS: A total of 346 corresponding targets of arsenic trioxide and 521 HCC-related targets were collected. After target mapping, a total of 52 common targets were obtained. GO analysis showed that the biological process was mainly involved in the negative regulation of cellular senescence, response to tumor necrosis factor, and cellular response to hypoxia. Molecular functions included NF-kappa B binding, enzyme binding, p53 binding, and transcription factor binding. Cellular components mainly were replication fork, ESC/E(Z) complex, RNA polymerase II transcription factor complex, and organelle membrane. KEGG pathways were mainly enriched in the PI3K-Akt signaling pathway, VEGF signaling pathway, p53 signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, AMPK signaling pathway, NF-kappa B signaling pathway, FoxO signaling pathway, ErbB signaling pathway, and MAPK signaling pathway. In the arsenic trioxide-target-pathway-HCC network, targets such as AKT1, RAF1, RELA, TP53, and PTEN had a higher degree. Conclusions. Our study showed that key targets of arsenic trioxide were mainly involved in multiple biological processes and pathways. It provided a theoretical basis for the screening of drug targets.

Early Prediction of Disease Progression in Patients with Severe COVID-19 Using C-Reactive Protein to Albumin Ratio.

BACKGROUND: Early identification of patients with severe coronavirus disease (COVID-19) at an increased risk of progression may promote more individualized treatment schemes and optimize the use of medical resources. This study is aimed at investigating the utility of the C-reactive protein to albumin (CRP/Alb) ratio for early risk stratification of patients. METHODS: We retrospectively reviewed 557 patients with COVID-19 with confirmed outcomes (discharged or deceased) admitted to the West Court of Union Hospital, Wuhan, China, between January 29, 2020 and April 8, 2020. Patients with severe COVID-19 (n = 465) were divided into stable (n = 409) and progressive (n = 56) groups according to whether they progressed to critical illness or death during hospitalization. To predict disease progression, the CRP/Alb ratio was evaluated on admission. RESULTS: The levels of new biomarkers, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, CRP/Alb ratio, and systemic immune-inflammation index, were higher in patients with progressive disease than in those with stable disease. Correlation analysis showed that the CRP/Alb ratio had the strongest positive correlation with the sequential organ failure assessment score and length of hospital stay in survivors. Multivariate logistic regression analysis showed that percutaneous oxygen saturation (SpO2), D-dimer levels, and the CRP/Alb ratio were risk factors for disease progression. To predict clinical progression, the areas under the receiver operating characteristic curves of Alb, CRP, CRP/Alb ratio, SpO2, and D-dimer were 0.769, 0.838, 0.866, 0.107, and 0.748, respectively. Moreover, patients with a high CRP/Alb ratio (≥1.843) had a markedly higher rate of clinical deterioration (log - rank p < 0.001). A higher CRP/Alb ratio (≥1.843) was also closely associated with higher rates of hospital mortality, ICU admission, invasive mechanical ventilation, and a longer hospital stay. CONCLUSION: The CRP/Alb ratio can predict the risk of progression to critical disease or death early, providing a promising prognostic biomarker for risk stratification and clinical management of patients with severe COVID-19.

Lipid metabolism changes in patients with severe COVID-19.

BACKGROUND: We investigated the dynamic changes in lipid profiles and their correlations with disease severity and clinical outcome in patients with severe COVID-19. METHODS: We retrospectively reviewed 519 severe COVID-19 patients with confirmed outcomes (discharged or deceased), admitted to the West Court of Union Hospital in Wuhan, China, between 29 January and 8 April 2020. RESULTS: Altogether, 424 severe COVID-19 patients, including 34 non-survivors and 390 survivors, were included in the final analyses. During hospitalization, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) showed an increasing trend in survivors, but showed a downward trend in non-survivors. The serum concentrations of HDL-C and apoA-I were inversely correlated with C-reactive protein (CRP), length of hospital stay of survivors, and disease severity scores. For in-hospital deaths, the areas under the receiver operating characteristic curves (AUCs) of the ratios of CRP/HDL-C and CRP/apoA-I at admission were 0.84 and 0.83, respectively. Moreover, patients with high ratios of CRP/HDL-C (＞77.39) or CRP/apoA-I (＞72.37) had higher mortality rates during hospitalization (log-rank p < 0.001). Logistic regression analysis demonstrated that hypertension, lactate dehydrogenase, SOFA score, and High CRP/HDL-C ratio were independent predictors of in-hospital mortality. CONCLUSIONS: During severe COVID-19, HDL-C and apoA-I concentrations are dramatically decreased in non-survivors. Moreover, High CRP/HDL-C ratio is significantly associated with an increase in mortality and a poor prognosis.

Thyroid dysfunction may be associated with poor outcomes in patients with COVID-19.

BACKGROUND: Coronavirus disease (COVID-19) has resulted in considerable morbidity and mortality worldwide. Thyroid hormones play a key role in modulating metabolism and the immune system. However, the prevalence of thyroid dysfunction (TD) and its association with the prognosis of COVID-19 have not yet been elucidated. In this study, we seek to address this gap and understand the link between TD and COVID-19. METHODS: Herein, we enrolled patients who were hospitalized with COVID-19 and had normal or abnormal thyroid function test results at the West Court of Union Hospital in Wuhan, China, between 29 January and February 26, 2020. We carried out follow up examinations until April 26, 2020. Data on clinical features, treatment strategies, and prognosis were collected and analyzed. TD was defined as an abnormal thyroid function test result, including overt thyrotoxicosis, overt hypothyroidism, subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid sick syndrome. RESULTS: A total of 25 and 46 COVID-19 patients with and without TD, respectively, were included in the study. COVID-19 patients with TD had significantly higher neutrophil counts and higher levels of C-reactive protein, procalcitonin, lactate dehydrogenase, serum creatine kinase, aspartate transaminase, and high-sensitive troponin I and a longer activated partial thromboplastin time but lower lymphocyte, platelet, and eosinophil counts. A longitudinal analysis of serum biomarkers showed that patients with TD presented persistently high levels of biomarkers for inflammatory response and cardiac injury. COVID-19 patients with TD were more likely to develop a critical subtype of the disease. Patients with TD had a significantly higher fatality rate than did those without TD during hospitalization (20% vs 0%, P = 0.002). Patients with TD were more likely to stay in the hospital for more than 28 days than were those without TD (80% vs 56.52%, P = 0.048). CONCLUSIONS: Our preliminary findings suggest that TD is associated with poor outcomes in patients with COVID-19.

A predictive model for the severity of COVID-19 in elderly patients.

Elderly patients with coronavirus disease 2019 (COVID-19) are more likely to develop severe or critical pneumonia, with a high fatality rate. To date, there is no model to predict the severity of COVID-19 in elderly patients. In this study, patients who maintained a non-severe condition and patients who progressed to severe or critical COVID-19 during hospitalization were assigned to the non-severe and severe groups, respectively. Based on the admission data of these two groups in the training cohort, albumin (odds ratio [OR] = 0.871, 95% confidence interval [CI]: 0.809 - 0.937, P < 0.001), d-dimer (OR = 1.289, 95% CI: 1.042 - 1.594, P = 0.019) and onset to hospitalization time (OR = 0.935, 95% CI: 0.895 - 0.977, P = 0.003) were identified as significant predictors for the severity of COVID-19 in elderly patients. By combining these predictors, an effective risk nomogram was established for accurate individualized assessment of the severity of COVID-19 in elderly patients. The concordance index of the nomogram was 0.800 in the training cohort and 0.774 in the validation cohort. The calibration curve demonstrated excellent consistency between the prediction of our nomogram and the observed curve. Decision curve analysis further showed that our nomogram conferred significantly high clinical net benefit. Collectively, our nomogram will facilitate early appropriate supportive care and better use of medical resources and finally reduce the poor outcomes of elderly COVID-19 patients.

Early predictors for mechanical ventilation in COVID-19 patients.

OBJECTIVE: To identify potential predictors for invasive and non-invasive mechanical ventilation in coronavirus disease 2019 (COVID-19) patients. METHODS: This study retrospectively analyzes data of 516 patients with confirmed COVID-19, who were categorized into three groups based on which mechanical ventilation method was used during the hospitalization period. RESULTS: Among 516 confirmed cases with COVID-19, 446 patients did not receive mechanical ventilation, 38 patients received invasive mechanical ventilation (IMV) and 32 received non-invasive mechanical ventilation (NIMV). The median age of the included patients was 61 years old (interquartile range, 52-69). A total of 432 patients had one or more coexisting illnesses. The main clinical symptoms included fever (79.46%), dry cough (66.47%) and shortness of breath (46.90%). IMV and NIMV patients included more men, more coexisting illnesses and received more medication. Patients in the IMV group and NIMV had higher leukocyte and neutrophil count, lower lymphocyte count, higher aspartate aminotransferase (AST), lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin (PCT) and D-dimer levels and lower albumin (ALB) level. The univariate and multiple logistic regression analysis showed that the use of glucocorticoid, increased neutrophil count and LDH had a predictive role as indicators for IMV, and the use of glucocorticoid, increased neutrophil count and PCT had a predictive role as indicators for NIMV. The area under the curve (AUC) of use of glucocorticoid, increased neutrophil count and LDH was 0.885 (95% confidence interval (CI) 0.838-0.933, p < 0.0001), which provided the specificity and sensitivity 77.7% and 90.9%, respectively. AUC of the use of glucocorticoid, increased neutrophil count and PCT for NIMV was 0.888 (95% CI 0.825-0.952, p < 0.0001), which provided the specificity and sensitivity 70.3% and 96.4%, respectively. CONCLUSION: Glucocorticoid, increased neutrophil and LDH were predictive indicators for IMV, whereas glucocorticoid, increased neutrophil and PCT were predictive indicators for NIMV. In addition, the above-mentioned mediators had the most predictive meaning for mechanical ventilation when combined.The reviews of this paper are available via the supplemental material section.

Association of diabetes mellitus with disease severity and prognosis in COVID-19: A retrospective cohort study.

AIMS: The 2019 novel coronavirus disease (COVID-19) emerged in Wuhan, China, and was characterized as a pandemic by the World Health Organization. Diabetes is an established risk associated with poor clinical outcomes, but the association of diabetes with COVID-19 has not been reported yet. METHODS: In this cohort study, we retrospectively reviewed 258 consecutive hospitalized COVID-19 patients with or without diabetes at the West Court of Union Hospital in Wuhan, China, recruited from January 29 to February 12, 2020. The clinical features, treatment strategies and prognosis data were collected and analyzed. Prognosis was followed up until March 12, 2020. RESULTS: Of the 258 hospitalized patients (63 with diabetes) with COVID-19, the median age was 64 years (range 23-91), and 138 (53.5%) were male. Common symptoms included fever (82.2%), dry cough (67.1%), polypnea (48.1%), and fatigue (38%). Patients with diabetes had significantly higher leucocyte and neutrophil counts, and higher levels of fasting blood glucose, serum creatinine, urea nitrogen and creatine kinase isoenzyme MB at admission compared with those without diabetes. COVID-19 patients with diabetes were more likely to develop severe or critical disease conditions with more complications, and had higher incidence rates of antibiotic therapy, non-invasive and invasive mechanical ventilation, and death (11.1% vs. 4.1%). Cox proportional hazard model showed that diabetes (adjusted hazard ratio [aHR] = 3.64; 95% confidence interval [CI]: 1.09, 12.21) and fasting blood glucose (aHR = 1.19; 95% CI: 1.08, 1.31) were associated with the fatality due to COVID-19, adjusting for potential confounders. CONCLUSIONS: Diabetes mellitus is associated with increased disease severity and a higher risk of mortality in patients with COVID-19.

Delivery and Biosafety of Oncolytic Virotherapy.

In recent years, oncolytic virotherapy has emerged as a promising anticancer therapy. Oncolytic viruses destroy cancer cells, without damaging normal tissues, through virus self-replication and antitumor immunity responses, showing great potential for cancer treatment. However, the clinical guidelines for administering oncolytic virotherapy remain unclear. Delivery routes for oncolytic virotherapy to patients vary in existing studies, depending on the tumor sites and the objective of studies. Moreover, the biosafety of oncolytic virotherapy, including mainly uncontrolled adverse events and long-term complications, remains a serious concern that needs to be accurately measured. This review provides a comprehensive and detailed overview of the delivery and biosafety of oncolytic virotherapy.

Environmental evaluation of a distributed-centralized biomass pyrolysis system: A case study in Shandong, China.

The limited quality of liquid product from the fast pyrolysis of biomass resources is a great obstacle to its large-scale application. Herein, a distributed-centralized agricultural straw pyrolysis (DCP) system with products of high market acceptance was implemented based on the design of a pilot plant and previous research. The system consisted of distributed pyrolysis workshops and a centralized upgrading factory that involved crude oil separation, hydrogen production, and hydrorefining. The crude fuel was separated by distillation before hydrotreatment, which avoids external hydrogen and energy consumption compared with direct hydrotreatment, and the hydrotreatment unit is independent of external hydrogen supply. The environmental impacts of a specific case designed for the northern region of Shandong province in China were evaluated using a life cycle assessment (LCA) method. LCA results indicated that abiotic depletion potential, acidification potential, global warming potential, ozone layer depletion potential, and human toxicity potential were primarily from fuel combustion, electricity, and N fertilizer. Eutrophication potential was primarily from the biomass production stage. Results demonstrated that the GWP of the system was -0.62 kg CO2,eq per kg crop straw. Comparison with the conventional straw incorporation method indicated the economic and social benefits of the DCP system, which is thus expected to be a promising option for crop residue disposal.

Maize bran feruloylated oligosaccharides inhibited AGEs formation in glucose/amino acids and glucose/BSA models.

Various Maillard reaction systems were established to investigate the effect of maize bran feruloylated oligosaccharides (FOs) on the formation of both endogenous and exogenous advanced glycation end-products (AGEs) under different pH values. The formation of AGEs and four kinds of dicarbonyl compounds (glyoxal, methylglyoxal, 3-deoxyglucosulose, 2,3-butanedione) were determined by fluorescence spectrophotometry and HPLC, respectively. Results showed that maize bran FOs effectively inhibited the production of fluorescent AGEs. Moreover, increase in pH, temperature and concentration of FOs in reaction systems elevated the inhibition effects of feruloylated oligosaccharides, fluorescent AGEs and dicarbonyl compounds. Mainly because of the ester bond of FOs at high pH and/or temperature systems are readily to be hydrolyzed, resulting in the release of ferulic acid.