The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy.

BACKGROUND: Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. RESULTS: In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. CONCLUSION: In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment.

Effect of abutment type and creep behavior on the mechanical properties of implant restorations in the anterior region: A finite element analysis.

PURPOSE: This study aimed to assess the effect of abutment variation and creep on dental implant restorations. MATERIALS AND METHODS: Three finite element analysis (FEA) models of implant restorations were created, which were restored by conventional one-piece abutment (CA), hybrid abutment crown (HAC), and multi-unit abutment (MUA). The contacts were considered intimate (no friction), except for implant/abutment, abutment/screw, and abutment/screw/crown (HAC) attachments. The related mechanical parameters were used to improve the authenticity of the study. Instantaneous loads and constant loads (100 s) of 130 N were applied at a 30° angle to the palatal portion of the crown. Results were qualitatively and quantitatively evaluated using the equivalent von Mises stress, micro-gap distance of the implant-abutment interface (IAI), preload changes, and safety index. RESULTS: The stress state of each component differed depending on the restoration type, from CA and HAC to MUA. Implants and screws were the structures that suffered the most stress under instantaneous loads. Each metal structure exhibited a substantial decrease in stress during a constant loading period. The screws of the MUA abutment showed more preload loss (62.1 N) after constant loads for 100 s. MUA base produced less micro-gap (0.72 µm) at the IAI when it was compared with the CA group (0.93 µm) and HAC group (3.29 µm). CONCLUSIONS: The abutment type influences the mechanical properties and performance of implant restorations. The creep effect decreases the maximum stress level and increases the safety factors of each structure, indicating that stress-related mechanical complications may not occur more easily.

Rational Designs of Biomaterials for Combating Oral Biofilm Infections.

Oral biofilms, which are also known as dental plaque, are the culprit of a wide range of oral diseases and systemic diseases, thus contributing to serious health risks. The manner of how to achieve good control of oral biofilms has been an increasing public concern. Novel antimicrobial biomaterials with highly controllable fabrication and functionalization have been proven to be promising candidates. However, previous reviews have generally emphasized the physicochemical properties, action mode, and application effectiveness of those biomaterials, whereas insufficient attention has been given to the design rationales tailored to different infection types and application scenarios. To offer guidance for better diversification and functionalization of anti-oral-biofilm biomaterials, this review details the up-to-date design rationales in three aspects: the core strategies in combating oral biofilm, as well as the biomaterials with advanced antibiofilm capacity and multiple functions based on the improvement or combination of the abovementioned antimicrobial strategies. Thereafter, insights on the existing challenges and future improvement of biomaterial-assisted oral biofilm treatments are proposed, hoping to provide a theoretical basis and reference for the subsequent design and application of antibiofilm biomaterials.

Construction and validation of a nomogram based on N6-Methylandenosine-related lncRNAs for predicting the prognosis of non-small cell lung cancer patients.

BACKGROUND: The N6-methyladenosine (m6 A) can modify long non-coding RNAs (lncRNAs), thereby influencing a wide array of biological functions. However, the prognosis of m6 A-related lncRNAs (m6 ARLncRNAs) in non-small cell lung cancer (NSCLC) remains largely unknown. METHODS: Pearson correlation analysis was used to identify m6 ARLncRNAs in 1835 NSCLC patients and with the condition (|Pearson R| > 0.4 and p < 0.001). Univariant Cox regression analysis was conducted to explore the prognostic m6 ARLncRNAs. We filtered prognostic m6 ARLncRNAs by LASSO regression and multivariate Cox proportional hazard regression to construct and validate an m6 ARLncRNAs signature (m6 ARLncSig). We analyzed the correlation between the m6 ARLncSig score and clinical features, immune microenvironment, tumor mutation burden, and therapeutic sensitivity and conducted independence and clinical stratification analysis. Finally, we established and validated a nomogram for prognosis prediction in NSCLC patients. RESULTS: Forty-one m6 ARLncRNAs were identified as prognostic lncRNAs, and 12 m6 ARLncRNAs were selected to construct m6 ARLncSig in the TCGA training dataset. The m6 ARLncSig was further validated in the testing dataset, GSE31210, GSE37745, GSE30219, and our NSCLC samples. In terms of m6 ARLncSig, NSCLC patients were divided into high- and low-risk groups, with significantly different overall survival (OS), clinical features (age, sex, and tumor stage), tumor-infiltrating immune cells, chemotherapeutic sensitivity, radiotherapeutic response, and biological pathways. Moreover, m6 ARLncSig independently predicted the OS of NSCLC patients. Finally, the robustness and clinical practicability for predicting NSCLC patient prognosis was improved by constructing a nomogram containing the m6 ARLncSig, age, gender, and tumor stage. CONCLUSIONS: Our study demonstrated that m6 ARLncSig could act as a potential biomarker for evaluating the prognosis and therapeutic efficacy in NSCLC patients.

Identification of a novel gene signature of lung adenocarcinoma based on epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Introduction: Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) mutations are commonly administered to EGFR-positive lung cancer patients. However, resistance to EGFR-TKIs (mostly gefitinib and erlotinib) is presently a significant problem. Limited studies have focused on an EGFR-TKI resistance-related gene signature (ERS) in lung adenocarcinoma (LUAD). Methods: Gefitinib and erlotinib resistance-related genes were obtained through the differential analyses of three Gene Expression Omnibus datasets. These genes were investigated further in LUAD patients from The Cancer Genome Atlas (TCGA). Patients in the TCGA-LUAD cohort were split into two groups: one for training and one for testing. The training cohort was used to build the ERS, and the testing cohort was used to test it. GO and KEGG analyses were explored for the enriched pathways between the high-risk and low-risk groups. Various software, mainly CIBERSORT and ssGSEA, were used for immune infiltration profiles. Somatic mutation and drug sensitivity analyses were also explored. Results: An ERS based on five genes (FGD3, PCDH7, DEPDC1B, SATB2, and S100P) was constructed and validated using the TCGA-LUAD cohort, resulting in the significant stratification of LUAD patients into high-risk and low-risk groups. Multivariable Cox analyses confirmed that ERS had an independent prognostic value in LUAD. The pathway enrichment analyses showed that most of the genes that were different between the two risk groups were related to the immune system. Further immune infiltration results revealed that a lower immune infiltration score was observed in high-risk patients, and that various leukocytes were significantly related to the ERS. Importantly, samples from the high-risk group showed lower levels of PD-1, PD-L1, and CTLA-4, which are important biomarkers for immunotherapy responses. Patients in the high-risk group also had more gene mutation changes and were more sensitive to chemotherapy drugs like docetaxel and sorafenib. The ERS was also validated in the GSE30219, GSE11969 and GSE72094, and showed a favorable prognostic value for LUAD patients. Discussion: The ERS established during this study was able to predict a poor prognosis for LUAD patients and had great potential for predicting drug responses.

Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation.

Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells.

Exploration of a Novel Circadian miRNA Pair Signature for Predicting Prognosis of Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the primary histological subtype of lung cancer with a markedly heterogeneous prognosis. Therefore, there is an urgent need to identify optimal prognostic biomarkers. We aimed to explore the value of the circadian miRNA (cmiRNA) pair in predicting prognosis and guiding the treatment of LUAD. We first retrieved circadian genes (Cgenes) from the CGDB database, based on which cmiRNAs were predicted using the miRDB and mirDIP databases. The sequencing data of Cgenes and cmiRNAs were retrieved from TCGA and GEO databases. Two random cmiRNAs were matched to a single cmiRNA pair. Finally, univariate Cox proportional hazard analysis, LASSO regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature consisting of seven cmiRNA pairs. The signature exhibited good performance in predicting the overall and progression-free survival. Patients in the high-risk group also showed lower IC50 values for several common chemotherapy and targeted medicines. In addition, we constructed a cmiRNA-Cgenes network and performed a corresponding Gene Ontology and Gene Set enrichment analysis. In conclusion, the novel circadian-related miRNA pair signature could provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for LUAD.

Identification of Ubiquitin-Related Gene-Pair Signatures for Predicting Tumor Microenvironment Infiltration and Drug Sensitivity of Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common pathological type of lung cancer worldwide, and new biomarkers are urgently required to guide more effective individualized therapy for patients. Ubiquitin-related genes (UbRGs) partially participate in the initiation and progression of lung cancer. In this study, we used ubiquitin-related gene pairs (UbRGPs) in tumor tissues to access the function of UbRGs in overall survival, immunocyte infiltration, and tumor mutation burden (TMB) of patients with LUAD from The Cancer Genome Atlas (TCGA) database. In addition, we constructed a prognostic signature based on six UbRGPs and evaluated its performance in an internal (TCGA testing set) and an external validation set (GSE13213). The prognostic signature revealed that risk scores were negatively correlated with the overall survival, immunocyte infiltration, and expression of immune checkpoint inhibitor-related genes and positively correlated with the TMB. Patients in the high-risk group showed higher sensitivity to partially targeted and chemotherapeutic drugs than those in the low-risk group. This study contributes to the understanding of the characteristics of UbRGPs in LUAD and provides guidance for effective immuno-, chemo-, and targeted therapy.

Predictive Risk Factors at Admission and a "Burning Point" During Hospitalization Serve as Sequential Alerts for Critical Illness in Patients With COVID-19.

Background: We intended to establish a novel critical illness prediction system combining baseline risk factors with dynamic laboratory tests for patients with coronavirus disease 2019 (COVID-19). Methods: We evaluated patients with COVID-19 admitted to Wuhan West Union Hospital between 12 January and 25 February 2020. The data of patients were collected, and the illness severity was assessed. Results: Among 1,150 enrolled patients, 296 (25.7%) patients developed into critical illness. A baseline nomogram model consists of seven variables including age [odds ratio (OR), 1.028; 95% confidence interval (CI), 1.004-1.052], sequential organ failure assessment (SOFA) score (OR, 4.367; 95% CI, 3.230-5.903), neutrophil-to-lymphocyte ratio (NLR; OR, 1.094; 95% CI, 1.024-1.168), D-dimer (OR, 1.476; 95% CI, 1.107-1.968), lactate dehydrogenase (LDH; OR, 1.004; 95% CI, 1.001-1.006), international normalised ratio (INR; OR, 1.027; 95% CI, 0.999-1.055), and pneumonia area interpreted from computed tomography (CT) images (medium vs. small [OR, 4.358; 95% CI, 2.188-8.678], and large vs. small [OR, 9.567; 95% CI, 3.982-22.986]) were established to predict the risk for critical illness at admission. The differentiating power of this nomogram scoring system was perfect with an area under the curve (AUC) of 0.960 (95% CI, 0.941-0.972) in the training set and an AUC of 0.958 (95% CI, 0.936-0.980) in the testing set. In addition, a linear mixed model (LMM) based on dynamic change of seven variables consisting of SOFA score (value, 2; increase per day [I/d], +0.49), NLR (value, 10.61; I/d, +2.07), C-reactive protein (CRP; value, 46.9 mg/L; I/d, +4.95), glucose (value, 7.83 mmol/L; I/d, +0.2), D-dimer (value, 6.08 µg/L; I/d, +0.28), LDH (value, 461 U/L; I/d, +13.95), and blood urea nitrogen (BUN value, 6.51 mmol/L; I/d, +0.55) were established to assist in predicting occurrence time of critical illness onset during hospitalization. Conclusion: The two-checkpoint system could assist in accurately and dynamically predicting critical illness and timely adjusting the treatment regimen for patients with COVID-19.

Targeting Cancer Cell Ferroptosis to Reverse Immune Checkpoint Inhibitor Therapy Resistance.

In recent years, cancer therapies using immune checkpoint inhibitors (ICIs) have achieved meaningful success, with patients with advanced tumors presenting longer survival times and better quality of life. However, several patients still do not exhibit good clinical outcomes for ICI therapy due to low sensitivity. To solve this, researchers have focused on identifying the cellular and molecular mechanisms underlying resistance to ICI therapy. ICI therapy induces apoptosis, which is the most frequent regulated cell death (RCD) but lacks immunogenicity and is regarded as an "immune silent" cell death. Ferroptosis, a unique type of non-apoptotic-RCD, has been preliminarily identified as an immunogenic cell death (ICD), stimulating tumor-antigen-specific immune responses and augmenting anti-tumor immune effects. However, ferroptosis has rarely been used in clinical practice. Present evidence strongly supports that the interferon-γ signaling pathway is at the crossroads of ICI therapy and ferroptosis. TYRO3, a receptor tyrosine kinase, is highly expressed in tumors and can induce anti-programmed cell death (PD)-ligand 1/PD-1 therapy resistance by limiting tumoral ferroptosis. Therefore, in this review, we summarize the clinical practice and effects of ICI therapy in various cancers. We also provide an overview of ferroptosis and report the molecular connections between cancer cell ferroptosis and ICI therapy, and discuss the possibility to reverse ICI therapy resistance by inducing cancer cell ferroptosis.

Changes in glomerular filtration rate and metabolomic differences in severely ill coronavirus disease survivors 3 months after discharge.

To explore the recovery of renal function in severely ill coronavirus disease (COVID-19) survivors and determine the plasma metabolomic profile of patients with different renal outcomes 3 months after discharge, we included 89 severe COVID-19 survivors who had been discharged from Wuhan Union Hospital for 3 months. All patients had no underlying kidney disease before admission. At patient recruitment, renal function assessment, laboratory examination, chest computed tomography (CT) were performed. Liquid chromatography-mass spectrometry was used to detect metabolites in the plasma. We analyzed the longitudinally change in the estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin-c levels using the CKD-EPI equation and explored the metabolomic differences in patients with different eGFR change patterns from hospitalization to 3 months after discharge. Lung CT showed good recovery; however, the median eGFR significantly decreased at the 3-month follow-up. Among the 89 severely ill COVID-19 patients, 69 (77.5%) showed abnormal eGFR (<90 mL/min per 1.73 m2) at 3 months after discharge. Age (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.08-1.47, p = 0.003), body mass index (OR = 1.97, 95% CI = 1.20-3.22, p = 0.007), and cystatin-c level (OR = 1.22, 95% CI = 1.07-1.39, p = 0.003) at discharge were independent risk factors for post-discharge abnormal eGFR. Plasma metabolomics at the 3-months follow-up revealed that ß-pseudouridine, uridine, and 2-(dimethylamino) guanosine levels gradually increased with an abnormal degree of eGFR. Moreover, the kynurenine pathway in tryptophan metabolism, vitamin B6 metabolism, cysteine and methionine metabolism, and arginine biosynthesis were also perturbed in survivors with abnormal eGFR.

Near-Infrared Light-Triggered Unfolding Microneedle Patch for Minimally Invasive Treatment of Myocardial Ischemia.

It is hard to achieve safe, effective, and minimally invasive therapies on myocardial infarction (MI) via conventional treatments. To address this challenge, a vascular endothelial growth factor (VEGF)-loaded and near-infrared (NIR)-triggered self-unfolding graphene oxide (GO)-poly(vinyl alcohol) (PVA) microneedle (MN) patch was designed and fabricated to treat MI through a minimally invasive surgery (MIS). The folded MN patch can be easily placed into the chest cavity through a small cut (4 mm) and quickly recover to its original shape with 10 s of irradiation of NIR light (1.5 W/cm2, beam diameter = 0.5 cm), thanks to its excellent shape memory effect and fast shape recovery ability. Meanwhile, the unfolded MN patch can be readily punctured into the heart and wrap the heart tightly, thanks to its sufficient mechanical strength and adjustable morphological structure, thus ensuring a high fixation strength to withstand the high-frequency pulsation of the heart. In addition, the prepared MN patch has low cytotoxicity and controllable and sustainable release of VEGF. More importantly, the MN patch can effectively promote neovascularization, reduce myocardial fibrosis, and restore cardiac function, which indicates its promising application prospects in MIS.

Comparison of Residual Pulmonary Abnormalities 3 Months After Discharge in Patients Who Recovered From COVID-19 of Different Severity.

Background and Objectives: To investigate whether coronavirus disease 2019 (COVID-19) survivors who had different disease severities have different levels of pulmonary sequelae at 3 months post-discharge. Methods: COVID-19 patients discharged from four hospitals 3 months previously, recovered asymptomatic patients from an isolation hotel, and uninfected healthy controls (HCs) from the community were prospectively recruited. Participants were recruited at Wuhan Union Hospital and underwent examinations, including quality-of-life evaluation (St. George Respiratory Questionnaire [SGRQ]), laboratory examination, chest computed tomography (CT) imaging, and pulmonary function tests. Results: A total of 216 participants were recruited, including 95 patients who had recovered from severe/critical COVID-19 (SPs), 51 who had recovered from mild/moderate disease (MPs), 28 who had recovered from asymptomatic disease (APs), and 42 HCs. In total, 154 out of 174 (88.5%) recovered COVID-19 patients tested positive for serum SARS-COV-2 IgG, but only 19 (10.9%) were still positive for IgM. The SGRQ scores were highest in the SPs, while APs had slightly higher SGRQ scores than those of HCs; 85.1% of SPs and 68.0% of MPs still had residual CT abnormalities, mainly ground-glass opacity (GGO) followed by strip-like fibrosis at 3 months after discharge, but the pneumonic lesions were largely absorbed in the recovered SPs or MPs relative to findings in the acute phase. Pulmonary function showed that the frequency of lung diffusion capacity for carbon monoxide abnormalities were comparable in SPs and MPs (47.1 vs. 41.7%), while abnormal total lung capacity (TLC) and residual volume (RV) were more frequent in SPs than in MPs (TLC, 18.8 vs. 8.3%; RV, 11.8 vs. 0%). Conclusions: Pulmonary abnormalities remained after recovery from COVID-19 and were more frequent and conspicuous in SPs at 3 months after discharge.

Identification of the Prognostic Significance of Somatic Mutation-Derived LncRNA Signatures of Genomic Instability in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a highly heterogeneous tumor with substantial somatic mutations and genome instability, which are emerging hallmarks of cancer. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in genomic instability. However, the identification of genome instability-related lncRNAs (GInLncRNAs) and their clinical significance has not been investigated in LUAD. Methods: We determined GInLncRNAs by combining somatic mutation and transcriptome data of 457 patients with LUAD and probed their potential function using co-expression network and Gene Ontology (GO) enrichment analyses. We then filtered GInLncRNAs by Cox regression and LASSO regression to construct a genome instability-related lncRNA signature (GInLncSig). We subsequently evaluated GInLncSig using correlation analyses with mutations, external validation, model comparisons, independent prognostic significance analyses, and clinical stratification analyses. Finally, we established a nomogram for prognosis prediction in patients with LUAD and validated it in the testing set and the entire TCGA dataset. Results: We identified 161 GInLncRNAs, of which seven were screened to develop a prognostic GInLncSig model (LINC01133, LINC01116, LINC01671, FAM83A-AS1, PLAC4, MIR223HG, and AL590226.1). GInLncSig independently predicted the overall survival of patients with LUAD and displayed an improved performance compared to other similar signatures. Furthermore, GInLncSig was related to somatic mutation patterns, suggesting its ability to reflect genome instability in LUAD. Finally, a nomogram comprising the GInLncSig and tumor stage exhibited improved robustness and clinical practicability for predicting patient prognosis. Conclusion: Our study identified a signature for prognostic prediction in LUAD comprising seven lncRNAs associated with genome instability, which may provide a useful indicator for clinical stratification management and treatment decisions for patients with LUAD.

Inflammatory Profiles and Clinical Features of Coronavirus 2019 Survivors 3 Months After Discharge in Wuhan, China.

BACKGROUND: Postdischarge immunity and its correlation with clinical features among patients recovered from coronavirus disease 2019(COVID-19) are poorly described. This prospective cross-sectional study explored the inflammatory profiles and clinical recovery of patients with COVID-19 at 3 months after hospital discharge. METHODS: Patients with COVID-19 discharged from 4 hospitals in Wuhan, recovered asymptomatic patients (APs) from an isolation hotel, and uninfected healthy controls (HCs) were recruited. Viral nucleic acid and antibody detection, laboratory examination, computed tomography, pulmonary function assessment, multiplex cytokine assay, and flow cytometry were performed. RESULTS: The72 age-, sex- and body mass index-matched participants included 19 patients with severe/critical COVID-19 (SPs), 20 patients with mild/moderate COVID-19 (MPs), 16 APs, and 17 HCs. At 3 months after discharge, levels of proinflammatory cytokines and factors related to vascular injury/repair in patients recovered from COVID-19 had not returned to those of the HCs, especially among recovered SPs compared with recovered MPs and APs. These cytokines were significantly correlated with impaired pulmonary function and chest computed tomographic abnormalities. However, levels of immune cells had returned to nearly normal levels and were not significantly correlated with abnormal clinical features. CONCLUSION: Vascular injury, inflammation, and chemotaxis persisted in patients with COVID-19 and were correlated with abnormal clinical features 3 months after discharge, especially in recovered SPs.

Plasma Metabolomic Profiling of Patients Recovered From Coronavirus Disease 2019 (COVID-19) With Pulmonary Sequelae 3 Months After Discharge.

BACKGROUND: Elucidation of the molecular mechanisms involved in the pathogenesis of coronavirus disease 2019 (COVID-19) may help to discover therapeutic targets. METHODS: To determine the metabolomic profile of circulating plasma from COVID-19 survivors with pulmonary sequelae 3 months after discharge, a random, outcome-stratified case-control sample was analyzed. We enrolled 103 recovered COVID-19 patients as well as 27 healthy donors, and performed pulmonary function tests, computerized tomography (CT) scans, laboratory examinations, and liquid chromatography-mass spectrometry. RESULTS: Plasma metabolite profiles of COVID-19 survivors with abnormal pulmonary function were different from those of healthy donors or subjects with normal pulmonary function. These alterations were associated with disease severity and mainly involved amino acid and glycerophospholipid metabolic pathways. Furthermore, increased levels of triacylglycerols, phosphatidylcholines, prostaglandin E2, arginine, and decreased levels of betain and adenosine were associated with pulmonary CO diffusing capacity and total lung capacity. The global plasma metabolomic profile differed between subjects with abnormal and normal pulmonary function. CONCLUSIONS: Further metabolite-based analysis may help to identify the mechanisms underlying pulmonary dysfunction in COVID-19 survivors, and provide potential therapeutic targets in the future.

Immune-Related lncRNA Pairs as Prognostic Signature and Immune-Landscape Predictor in Lung Adenocarcinoma.

BACKGROUND: Suppressive tumor microenvironment is closely related to the progression and poor prognosis of lung adenocarcinoma (LUAD). Novel individual and universal immune-related biomarkers to predict the prognosis and immune landscape of LUAD patients are urgently needed. Two-gene pairing patterns could integrate and utilize various gene expression data. METHODS: The RNA-seq and relevant clinicopathological data of the LUAD project from the TCGA and well-known immune-related genes list from the ImmPort database were obtained. Co-expression analysis followed by an analysis of variance was performed to identify differentially expressed immune-related lncRNA (irlncRNA) (DEirlncRNA) between tumor and normal tissues. Two arbitrary DEirlncRNAs (DEirlncRNAs pair) in a tumor sample underwent pairwise comparison to generate a score (0 or 1). Next, Univariate analysis, Lasso regression and Multivariate analysis were used to screen survival-related DEirlncRNAs pairs and construct a prognostic model. The Acak information standard (AIC) values of the receiver operating characteristic (ROC) curve for 3 years are calculated to determine the cut-off point for high- or low-risk score. Finally, we evaluated the relationship between the risk score and overall survival, clinicopathological features, immune landscape, and chemotherapy efficacy. RESULTS: Data of 54 normal and 497 tumor samples of LUAD were enrolled. After a strict screening process, 15 survival-independent-related DEirlncRNA pairs were integrated to construct a prognostic model. The AUC value of the 3-year ROC curve was 0.828. Kaplan-Meier analysis showed that patients with low risk lived longer than patients with high risk (p <0.001). Univariate and Multivariate Cox analysis suggested that the risk score was an independent factor of survival. The risk score was negatively associated with most tumor-infiltrating immune cells, immune score, and microenvironment scores. The low-risk group was correlated with increased expression of ICOS. The high-risk group had a connection with lower half inhibitory centration (IC50) of most chemotherapy drugs (e.g., etoposide, paclitaxel, vinorelbine, gemcitabine, and docetaxel) and targeted medicine-erlotinib, but with higher IC50 of methotrexate. CONCLUSION: The established irlncRNA pairs-based model is a promising prognostic signature for LUAD patients. Furthermore, the prognostic signature has great potential in the evaluation of tumor immune landscape and guiding individualized treatment regimens.

Clinical Characteristics and Outcomes of Severe or Critical COVID-19 Patients Presenting No Respiratory Symptoms or Fever at Onset.

It is difficult to identify suspected cases of atypical patients with coronavirus disease 2019 (COVID-19), and data on severe or critical patients are scanty. This retrospective study presents the clinical, laboratory, and radiological profiles, treatments, and outcomes of atypical COVID-19 patients without respiratory symptoms or fever at onset. The study examined ten atypical patients out of 909 severe or critical patients diagnosed with COVID-19 in Wuhan Union Hospital West Campus between 25 January 2020 and 10 February 2020. Data were obtained from the electronic medical records of severe or critical patients without respiratory symptoms or fever at onset. Outcomes were followed up to discharge or death. Among 943 COVID-19 patients, 909 (96.4%) were severe or critical type. Of the severe or critical patients, ten (1.1%) presented without respiratory symptoms or fever at admission. The median age of the ten participants was 63 years (interquartile range (IQR): 57-72), and seven participants were men. The median time from symptom onset to admission was 14 d (IQR: 7-20). Eight of the ten patients had chronic diseases. The patients had fatigue (n = 5), headache or dizziness (n = 4), diarrhea (n = 5), anorexia (n = 3), nausea or vomiting (n = 3), and eye discomfort (n = 1). Four patients were found to have lymphopenia. Imaging examination revealed that nine patients had bilateral pneumonia and one had unilateral pneumonia. Eventually, two patients died and eight were discharged. In the discharged patients, the median time from admission to discharge lasted 24 d (IQR: 13-43). In summary, some severe or critical COVID-19 patients were found to have no respiratory symptoms or fever at onset. All such atypical cases should be identified and quarantined as early as possible, since they tend to have a prolonged hospital stay or fatal outcomes. Chest computed tomography (CT) scan and nucleic acid detection should be performed immediately on close contacts of COVID-19 patients to screen out those with atypical infections, even if the contacts present without respiratory symptoms or fever at onset.

Novel pre-vascularized tissue-engineered dermis based on stem cell sheet technique used for dermis-defect healing.

Insufficient donor dermis and the shortage of three-dimensional vascular networks are the main limitations in the tissue-engineered dermis (TED). To solve these problems, we initially constructed pre-vascularized bone marrow mesenchymal stem cell sheet (PBMCS) and pre-vascularized fibroblasts cell sheet (PFCS) by cell sheet technology, and then superimposed or folded them together to construct a pre-vascularized TED (PTED), aiming to mimic the real dermis structure. The constructed PTED was implanted in nude mice dorsal dermis-defect wound and the wound-healing effect was quantified at Days 1, 7 and 14 via the methods of histochemistry and immunohistochemistry. The results showed that PTED could rapidly promote the wound closure, especially at Day 14, and the wound-healing rate of three-layer PTED could reach 97.2% (P < 0.01), which was faster than the blank control group (89.1%), PBMCS (92.4%), PFCS (93.8%) and six-layer PTED (92.3%). In addition, the vessel density in the PTED group was higher than the other groups on the 14th day. Taken together, it is proved that the PTED, especially three-layer PTED, is more conducive to the full-thickness dermis-defect repair and the construction of the three-dimensional vascular networks, indicating its potential application in dermis-defect repair.

Comparison of clinical characteristics among younger and elderly deceased patients with COVID-19: a retrospective study.

We aimed to compare the age-related clinical characteristics between younger and elderly deceased COVID-19 patients. This single-center retrospective study included 163 adult deceased COVID-19 patients who were admitted to Wuhan Union Hospital West Campus from January 12, 2020, to March 30, 2020. Demographic and clinical features were collected by reviewing the medical records. The median age of the 163 deceased patients was 69 (interquartile range [IQR], 62-78) years. They were classified as younger (age 18-69 years; 86/163, 52.8%) and elderly (≥70 years; 77/163, 47.2%) subjects. Younger deceased patients were more likely to develop fever (72/86 vs 54/77, P=0.039) than elderly deceased patients were while anorexia was (29/77 vs 19/86, P=0.029) more common in elderly deceased patients than in younger deceased patients. In multivariate analyses, age was a protective factor for acute cardiac injury of deceased COVID-19 patients (odds ratio [OR] 0.968, [95% confidence interval (CI), 0.940-0.997]; P=0.033) while chronic cardiac disease was a risk factor for acute cardiac injury of deceased COVID-19 patients (OR 2.660 [95%CI, 1.034-6.843]; P=0.042). Our study described the clinical characteristics of younger and elderly deceased COVID-19 patients and demonstrated that younger deceased patients were more likely to develop an acute cardiac injury.