Novel Three-Dimensional Hierarchical Porous Carbon Probe for the Discovery of N-Glycan Biomarkers and Early Hepatocellular Carcinoma Detection.

Due to the highly heterogeneous nature of hepatocellular carcinoma (HCC), the accurate diagnosis of HCC during the early phase of development is still a challenging task. Therefore, the further development of novel diagnostic methods by discovering new biomarkers is required to improve the rate of HCC diagnosis in the early phase. In this work, an oxygen-modified three-dimensional interconnected porous carbon probe is designed and fabricated to profile the differences of N-glycans in human serum from health controls (H) and patients with hepatic dysfunction (HD) and HCC for the discovery of new biomarkers with HCC development. Excitingly, we discovered that the expression levels of 12 serum N-glycans were gradually increased from H to patients with HD and eventually to patients with HCC. Moreover, two machine learning models established based on these 12 serum N-glycans reached a satisfactory accuracy for predicting HCC development where the receiver operating characteristic curve arrived above 0.95 for distinguishing healthy controls and patients with liver diseases (HD or HCC) and the ROC curve arrived at 0.85 for distinguishing HD and HCC. Our work not only developed a new method for the large-scale characterization of serum N-glycans but also provided valuable guidance for accurate and highly sensitive diagnosis of early liver cancer development in a non-invasive manner.

Naked-Eye Readout Distance Quantitative Lateral Flow Assay Based on the Permeability Changes of Enzyme-Catalyzed Hydrogelation.

Traditional lateral flow assay (LFA) is restricted to providing qualitative or semi-quantitative results and often requires special equipment for obtaining quantitative results. Herein, we proposed a naked-eye readout distance quantitative lateral flow assay based on the permeability changes in enzyme-catalyzed hydrogelation, which not only has the advantages of being simple, immediate, of high efficiency and low cost, and accurate in quantification but also avoids the use of special equipment. The developed LFA method includes three principal components of a nitrocellulose (NC) membrane containing a control line (C line) loading goat anti-rabbit (GAR) antibodies and a test line (T line) loading specific antibodies, alginate-tyramine conjugates forming a hydrogel in the presence of hydrogen peroxide (H2O2) and horseradish peroxidase (HRP), and the HRP-AuNPs-Ab probe only labeling targets captured on the T line. Hemoglobin A1c (HbA1c) was chosen as a representative example to demonstrate the feasibility of our method. Under the optimal conditions, the developed LFA method shows excellent performance in standard samples and real human blood samples where the results of real human blood samples show a high linear correlation with the clinical data obtained by ion exchange chromatography (R2 = 0.9929) and the margin of recovery is only 3.8%. All results demonstrated that our developed LFA method not only has enormous potential in the quantitative detection of HbA1c in clinical complex samples but also can serve as a versatile method for highly efficient detection of other target biomolecules due to the fungibility of antibodies.

SARS-CoV-2 Omicron XBB subvariants exhibit enhanced fusogenicity and substantial immune evasion in elderly population, but high sensitivity to pan-coronavirus fusion inhibitors.

Numerous emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have shown significant immune evasion capacity and caused a large number of infections, as well as vaccine-breakthrough infections, especially in elderly populations. Recently emerged Omicron XBB was derived from the BA.2 lineage, but bears a distinct mutant profile in its spike (S) protein. In this study, we found that Omicron XBB S protein drove more efficient membrane-fusion kinetics on human lung-derived cells (Calu-3). Considering the high susceptibility of the elderly to the current Omicron pandemic, we performed a comprehensive neutralization assessment of elderly convalescent or vaccine sera against XBB infection. We found that the sera from elderly convalescent patients who experienced with BA.2 infection or breakthrough infection potently inhibited BA.2 infection, but showed significantly reduced efficacy against XBB. Moreover, recently emerged XBB.1.5 subvariant also showed more significant resistance to the convalescent sera of BA.2- or BA.5-infected elderly. On the other hand, we found that the pan-CoV fusion inhibitors EK1 and EK1C4 can potently block either XBB-S- or XBB.1.5-S-mediated fusion process and viral entry. Moreover, EK1 fusion inhibitor showed potent synergism when combined with convalescent sera of BA.2- or BA.5-infected patients against XBB and XBB.1.5 infection, further indicating that EK1-based pan-CoV fusion inhibitors are promising candidates for development as clinical antiviral agents to combat the Omicron XBB subvariants.

Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells.

Perfluorooctanoic acid (PFOA) is a highly persistent and widespread chemical in the environment with endocrine disruption effects. Although it has been reported that PFOA can affect multiple aspects of thyroid function, the exact mechanism by which it reduces thyroxine levels has not yet been elucidated. In this study, FRTL-5 rat thyroid follicular cells were used as a model to study the toxicity of PFOA to the genes related to thyroid hormone synthesis and their regulatory network. Our results reveal that PFOA interfered with the phosphorylation of the cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) induced by thyroid-stimulating hormone (TSH), as well as the transcription levels of paired box 8 (PAX8), thyroid transcription factor 1 (TTF1), sodium/iodide cotransporter (NIS), thyroglobulin (TG), and thyroid peroxidase (TPO). However, the above outcomes can be alleviated by enhancing cAMP production with forskolin treatment. Further investigations showed that PFOA reduced the mRNA level of TSH receptor (TSHR) and impaired its N-glycosylation, suggesting that PFOA has disrupting effects on both transcriptional regulation and post-translational regulation. In addition, PFOA increased endoplasmic reticulum (ER) stress and decreased ER mass in FRTL-5 cells. Based on these findings, it can be inferred that PFOA disrupts the TSH-activated cAMP signaling pathway by inhibiting TSHR expression and its N-glycosylation. We propose that this mechanism may contribute to the decrease in thyroid hormone levels caused by PFOA. Our study sheds light on the molecular mechanism by which PFOA can disrupt thyroid function and provides new insights and potential targets for interventions to counteract the disruptive effects of PFOA.

Serum Ferritin in Geriatric Individuals in the Shanghai Region: Distribution, Correlations, and Reference Intervals.

BACKGROUND: Serum ferritin levels have a clinical application in diagnosing diseases. However, the clinical standard levels and distribution characteristics of serum ferritin based on reference intervals (RIs) in the geriatric Han Chinese population in the East China region have not previously been well reported. This work aimed to investigate the correlation between serum ferritin levels and 14 metabolic markers, analyse the distribution of serum ferritin, and establish serum ferritin RIs for geriatric (> 60 years) individuals in Shanghai. METHODS: Four hundred and sixty-nine healthy Chinese Han subjects (age, 61 - 95 years; median, 71 years) were recruited from the Health Examination Center of Shanghai Fourth People's Hospital in 2021. Serum ferritin was measured on a Roche Cobas 8000 e602, and 14 biochemical parameters were measured on a Siemens Atellica CH-930 to analyse distributions and correlations and to establish serum ferritin RIs for the elderly population in Shanghai. RESULTS: Serum ferritin levels were significantly different between genders (p = 0.06). The established RIs for serum ferritin were 24.44 - 627.09 ng/mL and 48.18 - 554.88 ng/mL in males and females, respectively. Correlation analyses revealed that ferritin levels were correlated with 7 parameters, including body mass index (BMI, p = 0.02), gamma-glutamyl transferase (GGT, p < 0.01), alanine aminotransferase (ALT, p < 0.01), triglycerides (TGs, p < 0.01), high-density lipoprotein (HDL, p < 0.01), total protein (TP, p < 0.01) and prealbumin (PAB, p < 0.01). When the participants were further divided by BMI, aspartate aminotransferase (AST) was an additional variable that was positively correlated only in the overweight/obese group (p = 0.04), while globulin (GLO) was an additional variable that was positively correlated only in the other group (p < 0.01). CONCLUSIONS: Nutrition and metabolism may play a great role in the regulation of serum ferritin levels in geriatric individuals in vivo. The RIs established for serum ferritin may provide precise references for further studies on ferritin-related disease in geriatric individuals.

Water-stable hydrophilic metal organic framework composite for the recognition of N-glycopeptides during diabetes progression by mass spectrometry.

A hydrophilic Al-MOFs composite was prepared using cheap and available reagents in water via a suitable large-scale production, an economical and environment-friendly method for capturing N-glycopeptides. The prepared Al-MOFs composite with high hydrolytically stable and hydrophilic 1D channels exhibits an ultralow detection limit (0.5 fmol/µL), and excellent reusability (at least 10 cycles) in the capture of N-glycopeptides from standard bio-samples. Interestingly, the Al-MOFs composite also shows remarkable performance in practical applications, where 300 N-glycopeptides ascribed to 124 glycoproteins were identified in 1 µL human serum and were successfully applied in profiling the differences of N-glycopeptides during diabetes progression. Moreover, 12 specific glycoproteins used as biomarkers to accurately distinguish the progression of diabetes are identified. The present work provides a potential commercial method for large-scale glycoproteomics research in complex clinical samples while offering new guidance for the precise diagnosis of diabetes progression.

Perfluorooctanoic acid exposure increases both proliferation and apoptosis of human placental trophoblast cells mediated by ER stress-induced ROS or UPR pathways.

Perfluorooctanoate acid (PFOA) is a highly persistent and widespread chemical in the environment. PFOA serum levels in pregnant women are positively associated with an increased risk of placenta-related disorders. However, the mechanism of PFOA cytotoxicity involved in placental cells and cellular responses such as ER stress remains poorly understood. In this study, we studied the cellular toxicity of PFOA with a focus on proliferation and apoptosis in a human placental trophoblast cell line. Cell viability, number, apoptosis, stress response, activation of the involved signaling pathways were assessed. Our results showed PFOA affected cell viability, proliferation and also resulted in apoptosis. Besides, both pro-proliferation and pro-apoptosis effects were attenuated by endoplasmic reticulum (ER) stress inhibitors. Further experiments demonstrated that two different signaling pathways were activated by PFOA-induced ER stress and involved in PFOA toxicity: the reactive oxygen species (ROS)-dependent ERK signaling triggered trophoblast proliferation, while the ATF4-dependent C/EBP homologous protein (CHOP) signaling was the trigger of apoptosis. We conclude that PFOA-induced ER stress is the trigger of proliferation and apoptosis of trophoblast via ROS or UPR signaling pathway, which leads to the altered balance critical to the normal development and function of the placenta.

Temporal trends in the mortality rate of Alzheimer's disease and other dementias attributable to smoking, 1990-2017.

BACKGROUND: Smoking is a well-defined modifiable risk factor for dementia. Understanding national temporal trends of dementia deaths due to smoking is critical for prioritizing action for the global prevention of dementia, as well as smoking prevention. We aimed to estimate the patterns and temporal trends of smoking-attributable dementia-related deaths for 195 countries from 1990 to 2017. METHODS: Detailed data on dementia deaths attributable to smoking were obtained from the Global Burden of Disease Study 2017. The estimated annual percentage change (EAPC) was used to quantify the temporal trends in the age-standardized mortality rate (ASMR) of dementia attributable to smoking by age, sex, region, and country. RESULTS: In 2017, approximately 2.51 million deaths attributable to dementia occurred globally; among them, 317,747 dementia-related deaths were attributable to smoking. The corresponding ASMR decreased by 31.1% from 6.33 per 100,000 population in 1990 to 4.36 per 100,000 population in 2017, with an EAPC of -1.43 (95% CI -1.48, -1.37). The reduction in the ASMR in women (EAPC = -2.13; 95% CI -2.18, -2.08) was more pronounced than that in men (EAPC = -1.26; 95% CI -1.32, -1.20). Most geographic region have achieved significant declines in ASMRs since 1990; however, Central Asia and 24 countries and territories showed increased trends in ASMRs over the same period. CONCLUSIONS: Despite large reductions in the ASMRs of dementia attributable to smoking over the past three decades, the corresponding number of deaths has steadily increased due to population growth and aging. The ASMR trend patterns were heterogeneous across countries, and there were undesirable increases in the dementia ASMR in some countries. Strengthened efforts for tobacco prevention are still needed to reduce the disease burden due to smoking, particularly in countries where the dementia ASMR is increasing.

Stroke burden and mortality attributable to ambient fine particulate matter pollution in 195 countries and territories and trend analysis from 1990 to 2017.

BACKGROUND: Fine particulate matter (PM2.5) exposure is associated with stroke incidence and mortality. However, the global distribution and trends of stroke burden and mortality attributable to PM2.5 are rarely studied. We estimated the spatial patterns and temporal trends of PM2.5-attributable stroke burden in 195 countries and territories from 1990 to 2017. METHODS: Detailed data on stroke burden attributable to PM2.5 were extracted from the Global Burden of Disease Study (GBD) 2017. The numbers and age-standardized rates of stroke disability-adjusted life years (DALYs) and mortality (ASDR and ASMR) were estimated by age, sex, subtype, region, and country. Temporal trends in ASDR and ASMR were analyzed using estimated annual percentage change (EAPC). RESULTS: Globally, in 2017, 10.5 million DALYs and 0.4 million deaths related to stroke were attributable to PM2.5. The corresponding ASDR and ASMR increased with age, were highest in males and for intracerebral hemorrhage, and varied greatly across countries, with the largest burden in high-middle sociodemographic index (SDI) regions and East Asia. The global ASDR and ASMR decreased by 7.2% and 12.2% from 1990 to 2017, with EAPCs of -0.42 (95% confidence interval [CI]: -0.55, -0.28) and -0.57 (95% CI: -0.72, -0.42), respectively. Age-specific stroke burden rates declined significantly, except in the middle-aged population. The decrease was more pronounced in women and for subarachnoid hemorrhage, while proportions of ischemic stroke burden increased globally and in all SDI regions. Most geographic regions achieved significant declines in ASDR and ASMR since 1990; however, Asia and approximately 30% of countries and territories, especially in low-income countries, showed undesirable increasing trends. CONCLUSIONS: The patterns and trends were heterogeneous across countries. Strengthened and tailored approaches for stroke prevention and air pollution management are still needed to reduce the disease burden associated with PM2.5, particularly in males, middle-age populations, and low-income countries and for ischemic stroke.

Peripheral blood leukocyte Telomere length and endometriosis: A Mendelian randomization study.

Background: The link between peripheral blood leukocyte telomere length (LTL) and endometriosis has remained uncertain. In order to investigate this association, a two-sample Mendelian randomization(MR) analysis was performed. Methods: We extracted Single-nucleotide polymorphisms (SNPs) associated with LTL from a published genome-wide association study (GWAS) comprising 472,174 individuals. Data on endometriosis, including its seven subtypes, were sourced from the iue open gwas project. Four methods were employed for MR: Inverse-variance weighted analysis (IVW), Mendelian randomization-Egger regression (MR Egger), weighted-median analysis, and Weighted Mode. Results: Genetically determined LTL was identified as a factor that can promote the occurrence of endometriosis. With every 1-SD increase in LTL, the risk of endometriosis increased by 26 % (OR = 1.260, 95 % CI = 1.073 to 1.479; P = 0.005). Genetically determined LTL also contributed to endometriosis subtypes: intestine (OR = 3.584, 95 % CI = 1.597 to 8.041; P = 0.002), ovary (OR = 1.308, 95 % CI = 1.033 to 1.655; P = 0.026), rectovaginal septum and vagina (OR = 1.360, 95 % CI = 1.000 to 1.851; P = 0.049). There was no observed causal relationship between LTL and the other four subtypes. Conclusion: This study, utilizing genetic data, offers evidence that longer LTL may cause increased risks of endometriosis, specifically endometriosis of the intestine, ovary, rectovaginal septum and vagina. These findings not only suggest that LTL may serve as a predictive factor for assessing the prevalence of three endometriosis subtypes but also provide new insights into the study of endometriosis pathogenesis.

Bidirectional Mendelian Randomization Reveals Causal Effects of Immune Cell Traits on Endometriosis Risk.

PURPOSE: Previous studies have identified associations between immune cell traits and endometriosis, but the causality of these relationships remains uncertain. In this study, we utilized Mendelian randomization (MR) to investigate the causal relationship between immune cell traits and endometriosis for the first time. METHODS: Seven hundred and thirty-one immune cell signatures associated with single-nucleotide polymorphisms (SNPs) were extracted from a published genome-wide association study (GWAS) involving 472 174 individuals, while endometriosis data, including four stages and seven subtypes, were obtained from the FinnGen consortium. Four methods were used for MR. The causal effect of immune cell traits on endometriosis was explored after Bonferroni correction. RESULTS: Significant causal relationship included 92 immune cell traits distributed among B cell (28 cells), cDC (2 cells), maturation stages of T cell (10 cells), monocyte (12 cells), Myeloid cell (5 cells), TBNK (13 cells), and Treg panels (22 cells). One of the most significant findings is that for every 1-standard deviation (SD) increase in CD8 on Central Memory CD8+ T cell, the risks of developing endometriosis of the fallopian tube increased by 72%. In the reverse MR analysis, a one-unit increase in the log odds of endometriosis of the ovary risk corresponded to a decrease in the absolute count of CD4+ CD8dim T cell by 0.10. CONCLUSION: This study represents the first comprehensive evaluation of the causal effects of immune cell traits on the risk/protection of different stages/subtypes of endometriosis. The findings highlight the complex and significant role of immune-derived factors in the pathogenesis of the disease.

Early-life perfluorooctanoic acid exposure disrupts the function of dopamine transporter protein with glycosylation changes implicating the links between decreased dopamine levels and disruptive behaviors in larval zebrafish.

Exposure to perfluorooctanoic acid (PFOA) during early embryonic development is associated with the increased risk of developmental neurotoxicity and neurobehavioral disorders in children. In our previous study, we demonstrated that exposure to PFOA affected locomotor activity and disrupted dopamine-related gene expression in zebrafish larvae. Consequently, we continue to study the dopaminergic system with a focus on dopamine levels and dopamine's effect on behaviors in relation to PFOA exposure. In the present study, we found a decrease in dopamine levels in larval zebrafish. We studied the dopamine transporter (DAT) protein, which is responsible for regulating dopamine levels through the reuptake of dopamine in neuronal cells. We demonstrated that exposure to PFOA disrupted the glycosylation process of DAT, inhibited its uptake function, and induced endoplasmic reticulum (ER) stress in dopaminergic cells. Besides, we conducted a light-dark preference test on larval zebrafish and observed anxiety/depressive-like behavioral changes following exposure to PFOA. Dopamine is one of the most prominent neurotransmitters that significantly influences human behavior, with low dopamine levels being associated with impairments such as anxiety and depression. The anxiety-like response in zebrafish larvae exposure to PFOA implies the link with the reduced dopamine levels. Taken together, we can deduce that glycosylation changes in DAT lead to dysfunction of DAT to regulate dopamine levels, which in turn alters behavior in larval zebrafish. Therefore, alternation in dopamine levels may play a pivotal role in the development of anxiety/depressive-like behavioral changes induced by PFOA.

Development and validation of a prognostic model based on clinical laboratory biomarkers to predict admission to ICU in Omicron variant-infected hospitalized patients complicated with myocardial injury.

Aims: The aim of this study was to develop and validate a prognostic model based on clinical laboratory biomarkers for the early identification of high-risk patients who require intensive care unit (ICU) admission among those hospitalized with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complicated with myocardial injury (MI). Methods: This single-center study enrolled 263 hospitalized patients with confirmed Omicron variant infection and concurrent MI. The patients were randomly divided into training and validation cohorts. Relevant variables were collected upon admission, and the least absolute shrinkage and selection operator (LASSO) was used to select candidate variables for constructing a Cox regression prognostic model. The model's performance was evaluated in both training and validating cohorts based on discrimination, calibration, and net benefit. Results: Of the 263 eligible patients, 210 were non-ICU patients and 53 were ICU patients. The prognostic model was built using four selected predictors: white blood cell (WBC) count, procalcitonin (PCT) level, C-reactive protein (CRP) level, and blood urea nitrogen (BUN) level. The model showed good discriminative ability in both the training cohort (concordance index: 0.802, 95% CI: 0.716-0.888) and the validation cohort (concordance index: 0.799, 95% CI: 0.681-0.917). For calibration, the predicted probabilities and observed proportions were highly consistent, indicating the model's reliability in predicting outcomes. In the 21-day decision curve analysis, the model had a positive net benefit for threshold probability ranges of 0.2 to 0.8 in the training cohort and nearly 0.2 to 1 in the validation cohort. Conclusion: In this study, we developed a clinically practical model with high discrimination, calibration, and net benefit. It may help to early identify severe and critical cases among Omicron variant-infected hospitalized patients with MI.

Sleep Pattern, Genetic Susceptibility, and Abdominal Aortic Aneurysm in UK Biobank Participants: Large-Scale Cohort Study.

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality. Objectives: The authors aimed to explore the associations between sleep patterns and genetic susceptibility to AAA. Methods: We included 344,855 UK Biobank study participants free of AAA at baseline. A sleep pattern was defined by chronotype, sleep duration, insomnia, snoring, and daytime sleepiness, and an overall sleep score was constructed with a range from 0 to 5, where a high score denotes a healthy sleep pattern. Polygenic risk score based on 22 single nucleotide polymorphisms was categorized into tertiles and used to evaluate the genetic risk for AAA. Cox proportional hazards regression models were used to assess the association between sleep, genetic factors, and the incidence of AAA. Results: During a median of 12.59 years of follow-up, 1,622 incident AAA cases were identified. The HR per 1-point increase in the sleep score was 0.91 (95% CI: 0.86-0.96) for AAA. Unhealthy sleep patterns, defined as a sleep score ranging from 0 to 3, were found to be associated with a higher risk of AAA for the intermediate (HR: 1.18, 95% CI: 1.06-1.31) and poor sleep patterns (HR: 1.40, 95% CI: 1.13-1.73), respectively, compared to the healthy pattern. Participants with poor sleep patterns and high genetic risks had a 2.5-fold higher risk of AAA than those with healthy sleep patterns and low genetic risk. Conclusions: In this large prospective study, healthy sleep patterns were associated with a lower risk of AAA among participants with low, intermediate, or high genetic risk.

Risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly patients infected with the Omicron variant of SARS-CoV-2: a retrospective study at Shanghai Fourth People's Hospital, School of Medicine, Tongji University.

Introduction: In elderly patients infected with the Omicron variant, disease progression to severe infection can result in poor outcomes. This study aimed to identify risk and protective factors associated with disease progression to severe infection and viral clearance time in elderly Omicron-infected patients. Methods: Shanghai Fourth People's Hospital, School of Medicine, Tongji University, was officially designated to provide treatment to patients with COVID-19. This study was conducted on confirmed Omicron cases admitted to the hospital between 10 April 2022 and 21 June 2022. In total, 1,568 patients aged 65 years or older were included. We conducted a retrospective, observational study using logistic regression to analyze risk and protective factors for the development of severe disease and Cox proportional hazards regression models to analyze factors influencing viral clearance time. Results: Aged over 80 years, having 2 or more comorbidities, combined cerebrovascular disease, chronic neurological disease, and mental disorders were associated with the development of severe disease, and full vaccination was a protective factor. Furthermore, aged over 80 years, combined chronic respiratory disease, chronic renal disease, cerebrovascular disease, mental disorders, and high viral load were associated with prolonged viral clearance time, and full vaccination was a protective factor. Discussion: This study analyzed risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly Omicron-infected patients. Aged patients with comorbidities had a higher risk of developing severe infection and had longer viral clearance, while vaccination protected them against the Omicron infection.

A study of clinical and serological correlation of early myocardial injury in elderly patients infected with the Omicron variant.

Introduction: Myocardial injury in elderly Omicron variant patients is a leading cause of severe disease and death. This study focuses on elucidating the clinical characteristics and potential risk factors associated with myocardial injury in elderly patients infected with the Omicron variant. Methods: Myocardial injury was defined based on elevated cardiac troponin concentrations exceeding the 99th percentile upper reference limit. Among 772 elderly Omicron-infected patients, categorized into myocardial injury (n = 263) and non-myocardial injury (n = 509) groups. The stratified log-rank statistic was used to compare the probability of patients developing intensive care. Receiver operating characteristic curves were used to determine the best cut-off values of clinical and laboratory data for predicting myocardial injury. Univariate and multivariate logistic regression was adopted to analyze the risk factors for myocardial injury. Results: The occurrence of myocardial injury in Omicron variant-infected geriatric patients was up to 34.07% and these patients may have a higher rate of requiring intensive care (P < 0.05). By comparing myocardial injury patients with non-myocardial injury patients, notable differences were observed in age, pre-existing medical conditions (e.g., hypertension, coronary heart disease, cerebrovascular disease, arrhythmia, chronic kidney disease, and heart failure), and various laboratory biomarkers, including cycle threshold-ORF1ab gene (Ct-ORF1ab), cycle threshold-N gene (Ct-N), white blood cell count, neutrophil (NEUT) count, NEUT%, lymphocyte (LYM) count, LYM%, and D-dimer, interleukin-6, procalcitonin, C-reactive protein, serum amyloid A, total protein, lactate dehydrogenase, aspartate aminotransferase, glomerular filtration rate, blood urea nitrogen, and serum creatinine (sCr) levels (P < 0.05). Furthermore, in the multivariable logistic regression, we identified potential risk factors for myocardial injury in Omicron variant-infected elderly patients, including advanced age, pre-existing coronary artery disease, interleukin-6 > 22.69 pg/ml, procalcitonin > 0.0435 ng/ml, D-dimer > 0.615 mg/L, and sCr > 81.30 µmol/L. Conclusion: This study revealed the clinical characteristics and potential risk factors associated with myocardial injury that enable early diagnosis of myocardial injury in Omicron variant-infected elderly patients, providing important reference indicators for early diagnosis and timely clinical intervention.

Neutralization of SARS-CoV-2 BA.2.86 and JN.1 by CF501 adjuvant-enhanced immune responses targeting the conserved epitopes in ancestral RBD.

The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2.86 and JN.1 raise concerns regarding their potential to evade immune surveillance and spread globally. Here, we test sera from rhesus macaques immunized with 3 doses of wild-type SARS-CoV-2 receptor-binding domain (RBD)-Fc adjuvanted with the STING agonist CF501. We find that the sera can potently neutralize pseudotyped XBB.1.5, XBB.1.16, CH.1.1, EG.5, BA.2.86, and JN.1, with 50% neutralization titers ranging from 3,494 to 7,424. We also demonstrate that CF501, but not Alum, can enhance immunogenicity of the RBD from wild-type SARS-CoV-2 to improve induction of broadly neutralizing antibodies (bnAbs) with binding specificity and activity similar to those of SA55, BN03, and S309, thus exhibiting extraordinary broad-spectrum neutralizing activity. Overall, the RBD from wild-type SARS-CoV-2 also contains conservative epitopes. The RBD-Fc adjuvanted by CF501 can elicit potent bnAbs against JN.1, BA.2.86, and other XBB subvariants. This strategy can be adopted to develop broad-spectrum vaccines to combat future emerging and reemerging viral infectious diseases.

Estimation of the biological dose received by five victims of a radiation accident using three different cytogenetic tools.

The present study aims to estimate the biological doses received by five victims (A, B, C, D and E) of the Shanxi Taiyuan radiation accident in China of 2008 and to investigate the value of the cytokinesis-block micronuclei (CBMN) and premature chromosome condensation (PCC) assays in the estimation of biological doses received by the victims of a radiation accident. Conventional chromosome aberration analysis and the CBMN assay, as well as a drug-induced PCC assay recently established by our group, were performed on peripheral blood and bone marrow samples from five victims after the accident. The biological doses were estimated by scoring dicentrics plus centric rings, micronuclei and PCC rings. A high dose-effect curve and the nuclear division index (NDI) we previously established were used to estimate the dose received by victim A, the most highly affected victim of the five. The doses for the five victims (A, B, C, D and E) were 12.4, 3.4, 2.5, 2.1 and 2.2Gy, respectively, estimated by scoring dicentrics plus rings in peripheral blood lymphocytes. Similar results were obtained by combining the CBMN and NDI (CBMN+NDI) assays and the PCC assay. The doses estimated by the three methods were in accordance with the clinical symptoms observed. The specific dicentric assay with a low background level may be a better indicator for biological dose evaluation than the CBMN and PCC assays. The high dose curve we established is reliable and could become a suitable supplement to traditional biodosimetry for dose estimation. The CBMN and drug-induced PCC assays are simple, rapid and accurate. The two methods reinforce and verify the results observed with chromosome aberration analysis.

Development and validation of a prognostic model based on immune variables to early predict severe cases of SARS-CoV-2 Omicron variant infection.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has prevailed globally since November 2021. The extremely high transmissibility and occult manifestations were notable, but the severity and mortality associated with the Omicron variant and subvariants cannot be ignored, especially for immunocompromised populations. However, no prognostic model for specially predicting the severity of the Omicron variant infection is available yet. In this study, we aim to develop and validate a prognostic model based on immune variables to early recognize potentially severe cases of Omicron variant-infected patients. Methods: This was a single-center prognostic study involving patients with SARS-CoV-2 Omicron variant infection. Eligible patients were randomly divided into the training and validation cohorts. Variables were collected immediately after admission. Candidate variables were selected by three variable-selecting methods and were used to construct Cox regression as the prognostic model. Discrimination, calibration, and net benefit of the model were evaluated in both training and validation cohorts. Results: Six hundred eighty-nine of the involved 2,645 patients were eligible, consisting of 630 non-ICU cases and 59 ICU cases. Six predictors were finally selected to establish the prognostic model: age, neutrophils, lymphocytes, procalcitonin, IL-2, and IL-10. For discrimination, concordance indexes in the training and validation cohorts were 0.822 (95% CI: 0.748-0.896) and 0.853 (95% CI: 0.769-0.942). For calibration, predicted probabilities and observed proportions displayed high agreements. In the 21-day decision curve analysis, the threshold probability ranges with positive net benefit were 0~1 and nearly 0~0.75 in the training and validation cohorts, correspondingly. Conclusions: This model had satisfactory high discrimination, calibration, and net benefit. It can be used to early recognize potentially severe cases of Omicron variant-infected patients so that they can be treated timely and rationally to reduce the severity and mortality of Omicron variant infection.

Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is often associated with poor outcomes due to lung metastasis. ICAM-1+ circulating tumor cells, termed circulating cancer stem cells (CCSCs), possess stem cell-like characteristics. However, it is still unexplored how their presence indicates lung metastasis tendency, and particularly, what mechanism drives their lung metastasis. Here, we demonstrated that a preoperative CCSC count in 5 mL of blood (CCSC5) of >3 was a risk factor for lung metastasis in clinical HCC patients. The CSCs overexpressed with circ-CDYL entered the bloodstream and developed lung metastases in mice. Mechanistically, circ-CDYL promoted COL14A1 expression and thus ERK signaling to facilitate epithelial-mesenchymal transition. Furthermore, we uncovered that an RNA-binding protein, EEF1A2, acted as a novel transcriptional (co-) factor to cooperate with circ-CDYL and initiate COL14A1 transcription. A high circ-CDYL level is caused by HIF-1⍺-mediated transcriptional upregulation of its parental gene CDYL and splicing factor EIF4A3 under a hypoxia microenvironment. Hence, the hypoxia microenvironment enables the high-tendency lung metastasis of ICAM-1+ CCSCs through the HIF-1⍺/circ-CDYL-EEF1A2/COL14A1 axis, potentially allowing clinicians to preoperatively detect ICAM-1+ CCSCs as a real-time biomarker for precisely deciding HCC treatment strategies.