A case of Aspergillus quadrilineatus pulmonary infection in China.

A 91-year-old Chinese male was hospitalized on June 28, 2021, due to a sudden fever. The patient had a long history of smoking, a 10-year history of type 2 diabetes, a family history of hypertension, and a history of coronary heart disease and lower extremity arterial occlusive disease. He presented with cough, sputum, and dry and wet rales in both lungs. A computed tomography scan revealed multiple infectious lesions in both lungs and a small pleural effusion. His procalcitonin level was 1.75 ng/mL. Microscopic examination of the sputum revealed abundant fungal spores and hyphae. Sputum culture results revealed Aspergillus quadrilineatus, which was confirmed by matrix-assisted laser desorption/ionization time-of-flight and internal transcribed spacer gene sequencing. Fungal drug sensitivity testing revealed that azoles (excluding fluconazole) and echinocandins exhibited high activity against Aspergillus quadrilineatus. The patient's condition improved following intravenous voriconazole treatment for 2 weeks, after which he was discharged. Subsequently, the patient was hospitalized six times for pulmonary infections, with the most recent hospitalization being on March 8, 2024. The symptoms improved, and the patient was discharged on March 15, 2024.

How close are the classical two-body potentials to ab initio calculations? Insights from linear machine learning based force matching.

In this work, we propose a linear machine learning force matching approach that can directly extract pair atomic interactions from ab initio calculations in amorphous structures. The local feature representation is specifically chosen to make the linear weights a force field as a force/potential function of the atom pair distance. Consequently, this set of functions is the closest representation of the ab initio forces, given the two-body approximation and finite scanning in the configurational space. We validate this approach in amorphous silica. Potentials in the new force field (consisting of tabulated Si-Si, Si-O, and O-O potentials) are significantly different than existing potentials that are commonly used for silica, even though all of them produce the tetrahedral network structure and roughly similar glass properties. This suggests that the commonly used classical force fields do not offer fundamentally accurate representations of the atomic interaction in silica. The new force field furthermore produces a lower glass transition temperature (Tg ∼ 1800 K) and a positive liquid thermal expansion coefficient, suggesting the extraordinarily high Tg and negative liquid thermal expansion of simulated silica could be artifacts of previously developed classical potentials. Overall, the proposed approach provides a fundamental yet intuitive way to evaluate two-body potentials against ab initio calculations, thereby offering an efficient way to guide the development of classical force fields.

Silica Polymerization Driving Opposite Effects of pH on Aqueous Carbonation Using Crystalline and Amorphous Calcium Silicates.

The aqueous carbonation of calcium silicate (CS), a representative alkaline-earth silicate, has been widely explored in studies of carbon dioxide (CO2) mineralization. In this context, we conducted a specific comparison of the carbonation behaviors between the crystalline calcium silicate (CCS) and amorphous calcium silicate (ACS) across a pH range from 9.0 to 12.0. Interestingly, we observed opposite pH dependencies in the carbonation efficiencies (i.e., CaO conversion into CaCO3 in 1 M Na2CO3/NaHCO3 solution under ambient conditions) of CCS and ACS─the carbonation efficiency of CCS decreased with increasing the solution basicity, while that of ACS showed an inverse trend. In-depth insights were gained through in situ Raman characterizations, indicating that these differing trends appeared to originate from the polymerization/depolymerization behaviors of silicates released from minerals. More specifically, higher pH conditions seemed to favor the carbonation of minerals containing polymerized silica networks. These findings may contribute to a better understanding of the fundamental factors influencing the carbonation behaviors of alkaline earth silicates through interfacial coupled dissolution and precipitation processes. Moreover, they offer valuable insights for selecting optimal carbonation conditions for alkaline-earth silicate minerals.

Ceftriaxone Modulates Ubiquitination of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptors to Improve Long-Term Potentiation Impairment Induced by Exogenous ß-Amyloid in a Glutamate Transporter-1 Dependent Manner.

Α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are crucial for properties of synaptic plasticity, such as long-term potentiation (LTP). LTP impairment can occur early in the onset of Alzheimer's disease (AD). The downregulation or decreased abundance of AMPAR expression in the postsynaptic membrane is closely associated with LTP impairment. Ceftriaxone (Cef) can improve LTP impairment in the early stages of AD in a mouse model. The purpose of this study was to explore the mechanism underlying this process from the aspects of AMPAR expression and ubiquitination degree. In this study, we found that ß-amyloid (Aß) treatment induced hippocampal LTP impairment and AMPAR downregulation and ubiquitination. Cef pretreatment ameliorated Aß-induced hippocampal LTP impairment, reduced AMPAR ubiquitination, and increased AMPAR expression, especially in the plasma membrane, in Aß-treated mice. Administration of USP46 siRNA and DHK (a specific blocker of glutamate transporter-1) significantly inhibited the above effects of Cef, suggesting a role for anti-AMPAR ubiquitination and upregulation of glutamate transporter-1 (GLT-1) in the Cef-induced improvements mentioned above. The above findings demonstrate that pretreatment with Cef effectively mitigated Aß-induced impairment of hippocampal LTP by suppressing the ubiquitination process of AMPARs in a GLT-1-dependent manner. These results provide novel insights into the underlying mechanisms elucidating the anti-AD by Cef.

Visualization-enhanced under-oil open microfluidic system for in situ characterization of multi-phase chemical reactions.

Under-oil open microfluidic system, utilizing liquid-liquid boundaries for confinements, offers inherent advantages including clogging-free flow channels, flexible access to samples, and adjustable gas permeation, making it well-suited for studying multi-phase chemical reactions that are challenging for closed microfluidics. However, reports on the novel system have primarily focused on device fabrication and functionality demonstrations within biology, leaving their application in broader chemical analysis underexplored. Here, we present a visualization-enhanced under-oil open microfluidic system for in situ characterization of multi-phase chemical reactions with Raman spectroscopy. The enhanced system utilizes a semi-transparent silicon (Si) nanolayer over the substrate to enhance visualization in both inverted and upright microscope setups while reducing Raman noise from the substrate. We validated the system's chemical stability and capability to monitor gas evolution and gas-liquid reactions in situ. The enhanced under-oil open microfluidic system, integrating Raman spectroscopy, offers a robust open-microfluidic platform for label-free molecular sensing and real-time chemical/biochemical process monitoring in multi-phase systems.

STS â ¡A inhibited angiogenesis of lung adenocarcinoma by activating FOXO3 to inhibit CXCL1/STAT3/VEGF pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most popular type of lung cancer. Sulfotanshinone IIA sodium (STS IIA) has been proven to have an anticancer effect. However, its role in LUAD and its underlying mechanism remain unclear. OBJECTIVE: To investigate the role and mechanism of STS IIA in LUAD angiogenesis. METHODS: The mRNA levels of genes, including forkhead box O3 (FOXO3) and chemokine C-X-C motif ligand 1 (CXCL1), were detected by qRT-PCR. The levels of proteins, including FOXO3, CXCL1, and vascular endothelial growth factor (VEGF), were measured by Western blot. The proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) were detected by the EdU assay and the tubule formation assay, respectively. The binding relationship between FOXO3 and CXCL1 was detected by dual-luciferase reporter assay. RESULTS: Our results illustrated that different concentrations of STS IIA inhibited the proliferation and angiogenesis of HUVECs. FOXO3 regulated the proliferation and angiogenesis of HUVECs inhibited by STS ⅡA via targeting CXCL1. Subsequently, we proved that exogenous CXCL1 alleviated the inhibition of proliferation and angiogenesis of HUVECs regulated by STS IIA via activating the STAT3/VEGF pathway. Finally, we found that STS IIA inhibited the angiogenesis of lung adenocarcinoma though FOXO3 to inhibit the CXCL1/STAT3/VEGF pathway. CONCLUSION: Our study finally elucidated the underlying molecular mechanism by which STS ⅡA inhibits LUAD angiogenesis.

Safety and immunogenicity of heterologous boosting with orally administered aerosolized bivalent adenovirus type-5 vectored COVID-19 vaccine and B.1.1.529 variant adenovirus type-5 vectored COVID-19 vaccine in adults 18 years and older: a randomized, double blinded, parallel controlled trial.

Vaccination strategies that can induce a broad spectrum immune response are important to enhance protection against SARS-CoV-2 variants. We conducted a randomized, double-blind and parallel controlled trial to evaluate the safety and immunogenicity of the bivalent (5×1010viral particles) and B.1.1.529 variant (5×1010viral particles) adenovirus type-5 (Ad5) vectored COVID-19 vaccines administrated via inhalation. 451 eligible subjects aged 18 years and older who had been vaccinated with three doses inactivated COVID-19 vaccines were randomly assigned to inhale one dose of either B.1.1.529 variant Ad5 vectored COVID-19 vaccine (Ad5-nCoVO-IH group, N=150), bivalent Ad5 vectored COVID-19 vaccine (Ad5-nCoV/O-IH group, N=151), or Ad5 vectored COVID-19 vaccine (5×1010viral particles; Ad5-nCoV-IH group, N=150). Adverse reactions reported by 37 (24.67%) participants in the Ad5-nCoVO-IH group, 28 (18.54%) in the Ad5-nCoV/O-IH group, and 26 (17.33%) in the Ad5-nCoV-IH group with mainly mild to moderate dry mouth, oropharyngeal pain, headache, myalgia, cough, fever and fatigue. No serious adverse events related to the vaccine were reported. Investigational vaccines were immunogenic, with significant difference in the GMTs of neutralizing antibodies against Omicron BA.1 between Ad5-nCoV/O-IH (43.70) and Ad5-nCoV-IH (29.25) at 28 days after vaccination (P=0.0238). The seroconversion rates of neutralizing antibodies against BA.1 in Ad5-nCoVO-IH, Ad5-nCoV/O-IH, and Ad5-nCoV-IH groups were 56.00%, 59.60% and 48.67% with no significant difference among the groups. Overall, the investigational vaccines were demonstrated to be safe and well tolerated in adults, and was highly effective in inducing mucosal immunities in addition to humoral and cellular immune responses defending against SARS-CoV-2 variants.Trial registration: Chictr.org identifier: ChiCTR2200063996.

LncRNA MIR210HG promotes the proliferation, migration, and invasion of lung cancer cells by inhibiting the transcription of SH3GL3.

Lung cancer (LCa), the most frequent malignancy worldwide, causes millions of mortalities each year. Overexpression of the long noncoding RNA MIR210HG in LCa has been established; however, a more comprehensive investigation into its biological role within LCa is imperative. This study aimed to validate the MIR210H levels in LCa tissues and cells. The expression of indicated genes was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and/or Western blotting. The viability, proliferation, migration, and invasion of LCa cells were measured using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), colony formation, wound healing, and transwell assays, respectively. The methylation levels of LCa cells were determined via methylation-specific PCR; additionally, chromatin immunoprecipitation or RNA immunoprecipitation assays were performed to determine the targeting relationship between DNA methyltransferase 1 (DNMT1) and the SH3-domain containing CRB2 like 3 (SH3GL3) promoters and the interaction between DNMT1 and MIR210HG, respectively. Our findings revealed the upregulation of MIR210HG, coupled with a diminished expression of SH3GL3 in LCa tissues and cells. Knockdown of MIR210HG or overexpression of SH3GL3 suppressed the proliferative, migratory, and invasive capacities of the cells. DNMT1 bound to the SH3GL3 promoter region, and MIR210HG inhibited the transcription of SH3GL3 by recruiting DNMT1. These findings indicate that MIR210HG facilitates LCa cell growth and metastasis by repressing SH3GL3 transcription via the recruitment of DNMT1 to the SH3GL3 promoter region.

Enhancing Aqueous Carbonation of Calcium Silicate through Acid and Base Pretreatments with Implications for Efficient Carbon Mineralization.

Carbon dioxide (CO2) mineralization based on aqueous carbonation of alkaline earth silicate minerals is a promising route toward large-scale carbon removal. Traditional aqueous carbonation methods largely adopt acidification-based approaches, e.g., using concentrated/pressurized CO2 or acidic media, to accelerate mineral dissolution and carbonation. In this study, we designed and tested three distinctive routes to evaluate the effect of pretreatments under different pH conditions on aqueous carbonation, using amorphous calcium silicate (CS) as an example system. Pretreating CS with high concentrations (100 mM) of HCl (Route I) or NaOH (Route II and III) enhanced their carbonation degrees. However, NaOH pretreatment overall yielded higher carbonation degrees than the HCl pretreatment, with the highest carbonation degree achieved through Route III, where an extra step is taken after the NaOH pretreatment to remove the solution containing dissolved silica prior to carbonation. The HCl and NaOH pretreatments formed different intermediate silica products on the CS surface. Silica precipitated from the HCl pretreatment had a minimal effect on the carbonation degree. The high Ca/Si ratio intermediate phases formed from the NaOH, on the other hand, can be readily carbonated. In contrast to commonly utilized acidification-based approaches, basification offers a more promising route to accelerate aqueous carbonation as it can mitigate the need for costly pH swing and high-concentration/pressurized CO2. The key to aqueous carbonation under basic conditions, as suggested by this study, is the control of aqueous silica species that have a suppressing effect on carbonation. Overall, this study highlights the critical needs for investigations of aqueous mineral carbonation in a broader pH region.

Immune checkpoint inhibitor-related chronic pneumonitis: a case report and literature review.

Immune checkpoint inhibitor (ICI)-related chronic pneumonitis is rare. Limited information is available on the characteristics of this condition. Herein, we present the case of a 54-year-old man with recurrent severe ICI-related pneumonitis. The patient developed fever and dyspnea during both episodes of pneumonitis. He had been previously diagnosed with gastric signet ring cell carcinoma and was undergoing treatment with an anti-PD-1 combination chemotherapy regimen. We reviewed previous case reports of ICI-related pneumonitis according to the primary cancer, time of onset in relation to ICI therapy and chest imaging findings. ICI-related pneumonitis can progress to chronic pneumonitis. Repeated computed tomography imaging showing lung changes in the same location may help to make the diagnosis.

Immune checkpoint inhibitors (ICIs) are a type of medicine that helps fight stomach cancer but sometimes they can cause problems with the lungs. This case report is about a man who had two bad lung incidents after taking ICI medicine. He had trouble breathing and fever both times. Other people have had similar problems with their lungs after being given ICI treatment. We compared chest pictures of the patient receiving ICI treatment over time and saw changes in the same spot meaning there might be a long-term problem with the lungs. We need to do more research to figure out how to treat this problem better.

First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial.

To explore targeted treatment options in patients with non-small-cell lung cancer (NSCLC) with rare genetic mutations in the context of a patient-centric clinical trial, we initiated, in parallel, a phase 2 adaptive umbrella trial consisting of a criteria-fulfilled (CF) cohort and a compassionate use (CU) cohort under expanded eligibility criteria, and a prospective real-world study (RWS). Here, we present efficacy and safety data from 48 patients with treatment-naive, advanced HER2-mutant NSCLC treated with the pan-HER receptor tyrosine kinase inhibitor pyrotinib (CF and CU cohorts) or physician's therapy of choice (RWS cohort). In the phase 2 trial CF cohort (n = 28), the primary endpoint was reached with an objective response rate of 35.7% after pyrotinib treatment. Secondary endpoints included disease control rate (89.3%), median progression-free survival (PFS) (7.3 months), median overall survival (OS) (14.3 months) and toxicity, which was acceptable, with grade 3 or 4 treatment-related adverse events occurring in three patients (10.7%). The phase 2 trial CU cohort (n = 12) showed an objective response rate of 16.7%, disease control rate of 83.4%, median PFS of 4.7 months and median OS of 14.2 months after pyrotinib treatment. The RWS cohort (n = 8) had no responses to physician's therapy of choice, while median PFS and OS were 3.0 and 12.2 months, respectively. Phase 2 umbrella trial, clinicaltrials.gov identifier: NCT03574402 . RWS, clinicaltrials.gov identifier: NCT03605602 .

Sodium tanshinone IIA sulphate inhibits angiogenesis in lung adenocarcinoma via mediation of miR-874/eEF-2K/TG2 axis.

CONTEXT: Sodium tanshinone IIA sulphate (STS) is a product originated from Salvia miltiorrhiza Bunge [Lamiaceae], which exerts an antitumour effect. However, the role of STS on lung adenocarcinoma (LUAD) remains unexplored. OBJECTIVE: Our study explores the effect and mechanism of STS against LUAD. MATERIALS AND METHODS: LUAD cells were treated with 100 µM STS for 24 h and control group cells were cultured under normal medium conditions. Functionally, the viability, migration, invasion and angiogenesis of LUAD cells were examined by MTT, wound healing, transwell and tube formation assay, respectively. Moreover, cells were transvected with different transfection plasmids. Dual luciferase reporter and RNA immunoprecipitation (RIP) assays were used to verify the relationship between miR-874 and eEF-2K. RESULTS: STS significantly decreased the viability (40-50% reduction), migration (migration rate of A549 cells from 0.67 to 0.28, H1299 cells from 0.71 to 0.41), invasion (invasion numbers of A549 cells from 172 to 55, H1299 cells from 188 to 35) and angiogenesis (80-90% reduction) of LUAD cells. Downregulation of miR-874 partially abolished the antitumour effect of STS. EEF-2K was identified to be the target of miR-874, and its downregulation markedly abolished the effects of miR-874 downregulation on tumourigenesis of LUAD. Moreover, silencing of TG2 abrogated eEF-2K-induced progression of LUAD. DISCUSSION AND CONCLUSIONS: STS attenuated the tumourigenesis of LUAD through the mediation of the miR-874/eEF-2K/TG2 axis. STS is a promising drug to fight against lung cancer, which might effectively reverse drug resistance when combined with classical anticancer drugs.

Safety and immunogenicity of heterologous boosting with orally aerosolised or intramuscular Ad5-nCoV vaccine and homologous boosting with inactivated vaccines (BBIBP-CorV or CoronaVac) in children and adolescents: a randomised, open-label, parallel-controlled, non-inferiority, single-centre study.

BACKGROUND: Heterologous booster immunisation with orally administered aerosolised Ad5-nCoV vaccine (AAd5) has been shown to be safe and highly immunogenic in adults. Here, we aimed to assess the safety and immunogenicity of heterologous booster immunisation with orally administered AAd5 in children and adolescents aged 6-17 years who had received two doses of inactivated vaccine (BBIBP-CorV or CoronaVac). METHODS: We did a randomised, open-label, parallel-controlled, non-inferiority study to assess the safety and immunogenicity of heterologous booster immunisation with AAd5 (0·1 mL) or intramuscular Ad5-nCoV vaccine (IMAd5; 0·3 mL) and homologous booster immunisation with inactivated vaccine (BBIBP-CorV or CoronaVac; 0·5 mL) in children (aged 6-12 years) and adolescents (aged 13-17 years) who had received two doses of inactivated vaccine at least 3 months earlier in Hunan, China. Children and adolescents who were previously immunised with two-dose BBIBP-CorV or CoronaVac were recruited for eligibility screening at least 3 months after the second dose. A stratified block method was used for randomisation, and participants were stratified by age and randomly assigned (3:1:1) to receive AAd5, IMAd5, or inactivated vaccine. The study staff and participants were not masked to treatment allocation. Laboratory and statistical staff were masked during the study. In this interim analysis, adverse events within 14 days and geometric mean titre (GMT) of serum neutralising antibodies on day 28 after the booster vaccination, based on the per-protocol population, were used as the primary outcomes. The analysis of non-inferiority was based on comparison using a one-sided 97·5% CI with a non-inferiority margin of 0·67. This study was registered at ClinicalTrials.gov, NCT05330871, and is ongoing. FINDINGS: Between April 17 and May 28, 2022, 436 participants were screened and 360 were enrolled: 220 received AAd5, 70 received IMAd5, and 70 received inactivated vaccine. Within 14 days after booster vaccination, vaccine-related adverse reactions were reported: 35 adverse events (in 13 [12%] of 110 children and 22 [20%] of 110 adolescents) in 220 individuals in the AAd5 group, 35 (in 18 [51%] of 35 children and 17 [49%] of 35 adolescents) in 70 individuals in the IMAd5 group, and 13 (in five [14%] of 35 children and eight [23%] of 35 adolescents) in 70 individuals in the inactivated vaccine group. Solicited adverse reactions were also reported: 34 (13 [12%] of 110 children and 21 [10%] of 110 adolescents) in 220 individuals in the AAd5 group, 34 (17 [49%] of 35 children and 17 [49%] of 35 adolescents) in 70 individuals in the IMAd5 group, and 12 (five [14%] of 35 children and seven [20%] of 35 adolescents) in 70 individuals in the inactivated vaccine group. The GMTs of neutralising antibodies against ancestral SARS-CoV-2 Wuhan-Hu-1 (Pango lineage B) in the AAd5 group were significantly higher than the GMTs in the inactivated vaccine group (adjusted GMT ratio 10·2 [95% CI 8·0-13·1]; p<0·0001). INTERPRETATION: Our study shows that a heterologous booster with AAd5 is safe and highly immunogenic against ancestral SARS-CoV-2 Wuhan-Hu-1 in children and adolescents. FUNDING: National Key R&D Program of China.

Comparison of Over-the-Scope Clips to Standard Endoscopic Treatment as the Initial Treatment in Patients With Bleeding From a Nonvariceal Upper Gastrointestinal Cause : A Randomized Controlled Trial.

BACKGROUND: Current endoscopic methods in the control of acute nonvariceal bleeding have a small but clinically significant failure rate. The role of over-the-scope clips (OTSCs) as the first treatment has not been defined. OBJECTIVE: To compare OTSCs with standard endoscopic hemostatic treatments in the control of bleeding from nonvariceal upper gastrointestinal causes. DESIGN: A multicenter, randomized controlled trial. (ClinicalTrials.gov: NCT03216395). SETTING: University teaching hospitals in Hong Kong, China, and Australia. PATIENTS: 190 adult patients with active bleeding or a nonbleeding visible vessel from a nonvariceal cause on upper gastrointestinal endoscopy. INTERVENTION: Standard hemostatic treatment (n = 97) or OTSC (n = 93). MEASUREMENTS: The primary outcome was 30-day probability of further bleeds. Other outcomes included failure to control bleeding after assigned endoscopic treatment, recurrent bleeding after initial hemostasis, further intervention, blood transfusion, and hospitalization. RESULTS: The 30-day probability of further bleeding in the standard treatment and OTSC groups was 14.6% (14 of 97) and 3.2% (3 of 93), respectively (risk difference, 11.4 percentage points [95% CI, 3.3 to 20.0 percentage points]; P = 0.006). Failure to control bleeding after assigned endoscopic treatment in the standard treatment and OTSC groups was 6 versus 1 (risk difference, 5.1 percentage points [CI, 0.7 to 11.8 percentage points]), respectively, and 30-day recurrent bleeding was 8 versus 2 (risk difference, 6.6 percentage points [CI, -0.3 to 14.4 percentage points]), respectively. The need for further interventions was 8 versus 2, respectively. Thirty-day mortality was 4 versus 2, respectively. In a post hoc analysis with a composite end point of failure to successfully apply assigned treatment and further bleeds, the event rate was 15 of 97 (15.6%) and 6 of 93 (6.5%) in the standard and OTSC groups, respectively (risk difference, 9.1 percentage points [CI, 0.004 to 18.3 percentage points]). LIMITATION: Clinicians were not blinded to treatment and the option of crossover treatment. CONCLUSION: Over-the-scope clips, as an initial treatment, may be better than standard treatment in reducing the risk for further bleeding from nonvariceal upper gastrointestinal causes that are amenable to OTSC placement. PRIMARY FUNDING SOURCE: General Research Fund to the University Grant Committee, Hong Kong SAR Government.

Clinical Characterization of the Expression of Insulin-Like Growth Factor Binding Protein 1 and Tumor Immunosuppression Caused by Ferroptosis of Neutrophils in Non-Small Cell Lung Cancer.

Purpose: The efficacy of immunotherapy for non-small cell lung cancer (NSCLC) is limited owing to cold tumors and drug resistance. Therefore, it is important to identify the molecular mechanisms underlying immune evasion in NSCLC. Spontaneous ferroptosis of neutrophils has been suggested as a key mechanism of immunosuppression in cancer. Insulin-like growth factor binding protein 1 (IGFBP1) plays an important role in immune infiltration in several cancers. However, the role of IGFBP1 in NSCLC is unknown. Therefore, in this study, we aimed to investigate the association of IGFBP1 mRNA expression with infiltration of myeloid-derived suppressor cells and prognosis in NSCLC. Patients and Methods: Retrospective RNA-seq data from 990 patients in the Cancer Genome Atlas (TCGA) database were analyzed in relation to patient clinical characteristics. The Timer2 database was used to assess immune infiltration, and the FerrDb V2 database was used to obtain ferroptosis-related genes. Finally, the results were validated by the proteomic analysis of serum samples collected from six patients with NSCLC and six healthy individuals. Results: IGFBP1 expression was enriched in lung adenocarcinoma samples and positively correlated with the pathological grade of NSCLC. IGFBP1 expression was an independent prognostic factor for the overall survival of patients with NSCLC. In addition, IGFBP1 expression correlated with myeloid-derived suppressor cell infiltration. Notably, Gene Ontology analysis of IGFBP1-related genes revealed that the major molecular functions of their protein products were related to NADP+ 1-oxidoreductase activity. Furthermore, expression levels of multiple ferroptosis suppressor genes positively correlated with IGFBP1 expression. Conclusion: High IGFBP1 expression indicates a poor prognosis in patients with NSCLC, which may be related to tumor immunosuppression caused by neutrophil ferroptosis.

Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial.

BACKGROUND: Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. METHODS: This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. FINDINGS: Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively; p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7-837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0-672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0-71·4]; p<0·0001). INTERPRETATION: A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. FUNDING: National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.

Active Ingredients of Reduning Injection Maintain High Potency against SARS-CoV-2 Variants.

OBJECTIVE: To investigate the anti-coronavirus potential and the corresponding mechanisms of the two ingredients of Reduning Injection: quercetin and luteolin. METHODS: A pseudovirus system was designed to test the efficacy of quercetin and luteolin to inhibit SARS-CoV-2 infection and the corresponding cellular toxicity. Luteolin was tested for its activities against the pseudoviruses of SARS-CoV-2 and its variants. Virtual screening was performed to predict the binding sites by Autodock Vina 1.1.230 and PyMol. To validate docking results, surface plasmon resonance (SPR) was used to measure the binding affinity of the compounds with various proteins of the coronaviruses. Quercetin and luteolin were further tested for their inhibitory effects on other coronaviruses by indirect immunofluorescence assay on rhabdomyosarcoma cells infected with HCoV-OC43. RESULTS: The inhibition of SARS-CoV-2 pseudovirus by luteolin and quercetin were strongly dose-dependent, with concentration for 50% of maximal effect (EC50) of 8.817 and 52.98 µmol/L, respectively. Their cytotoxicity to BHK21-hACE2 were 177.6 and 405.1 µmol/L, respectively. In addition, luetolin significantly blocked the entry of 4 pseudoviruses of SARS-CoV-2 variants, with EC50 lower than 7 µmol/L. Virtual screening and SPR confirmed that luteolin binds to the S-proteins and quercetin binds to the active center of the 3CLpro, PLpro, and helicase proteins. Quercetin and luteolin showed over 99% inhibition against HCoV-OC43. CONCLUSIONS: The mechanisms were revealed of quercetin and luteolin inhibiting the infection of SARS-CoV-2 and its variants. Reduning Injection is a promising drug for COVID-19.

Comparative analysis of antigen coding genes in 15 red cell blood group systems of Yunnan Yi nationality in China: A cross-sectional study.

Introduction: There are few analyses of the 15 red blood group system antigen coding genes found in the Yunnan Yi nationality. This has caused many poteintial dangers relating to clinical blood transfusion. In this report, the coding genes and distribution of 15 blood group antigens system in the Yi nationality were tested and compared with those of Han nationality and other ethnic minorities. Methods: The samples came from the healthy subjects in the first people's Hospital of Qujing, Yunnan Province. Two hundred and three Yunnan Yi and 197 Han nationality individuals were included. Thirty-three blood group antigens with a low frequency from the 15 blood group systems of Yunnan Yi blood donors were genotyped and analyzed by PCR-SSP. Sanger sequencing was used to detect A4GALT from the Yunnan Yi nationality. The χ 2 test was used to analyze observed and expected values of gene distribution to verify conformation to the Hardy-Weinberg equilibrium law. Fisher's exact test was used to analyze gene frequency distribution, and the statistical significance was set at p < 0.05. Results: The ABO blood group examination results for the Yi nationality and the local Han nationality in Qujing City, Yunnan Province, showed the majority were type A and type O, while the least prevalent was type AB. RhD+ accounts for more than 98% of the Yi and Han populations. There was a significant difference in ABO blood group antigen distribution between these two nationalities (p < 0.05), but there was no significant difference in the composition ratio of D antigen in the Rh blood group system (p > 0.05). Compared with Tibetan (Tibet), Zhuang (Nanning), and Dong (Guangxi), the gene distribution frequencies of Rh blood group system phenotype CC were significantly lower in the Yunnan Yi nationality (p < 0.05). There were significant differences in six erythrocyte phenotypic antigens in the Yi nationality in Yunnan compared with Han nationality, such as LW(a-b-), JK(a-b+), MMSs, Di(a-b+), Wr(a-b-), and Kp(a-b+) (p < 0.05). There were gene phenotypes with a low frequency in the four rare blood group systems: LW, MNS, Wright, and Colton. Several different mutation types occurred in the P1PK blood group system's A4GALT gene. Conclusion: Yunnan Yi nationality has a unique genetic background. There are some significantly different distributions of blood group system genes with a low frequency in different regions and groups in China. Multiple mutations in the A4GALT gene of the P1PK blood group system may be related to their environment and ethnic evolution.

Re-positioning pretarsal tissue layers for double-eyelid surgery: 6-year experience.

Double-eyelid surgery is a very common practice in East Asian patients. The differential distribution of pretarsal tissue layers is considered to be the anatomical mechanism of natural Asiatic single eyelid, it is possible to form double-eyelid crease by re-positioning the pretarsal structure layers. The author presents a new double-eyelid surgery based on re-positioning of the pretarsal structure layers without tissue removal. Over a 6-year period, 1440 patients underwent new double-eyelid surgeries. With the pretarsal orbicularis oculi muscle incised, the pre-pretarsal levator aponeurosis fascia fibroadipose was first dissected to form a fibroadipose flap, and then repositioned with the eyelid lower lip orbicularis oculi muscle flap. The new composite structure was anchored at 3 points on the pretarsal levator aponeurosis fascia; the skin was sutured to form a smooth crease. Post-operative outcome and follow-up data were analyzed. Patients were followed up for an average of 2 years. esthetic outcomes were satisfactory for 97.91% of patients, who enjoyed new double upper eyelids with smooth creases and invisible incision lines. Outcomes were unsatisfactory for 2.08% of patients (double-eyelid regression, 0.76%; asymmetric creases, 1.32%). All patients who were not satisfied with their esthetic outcomes underwent second correction surgery. This new Pan-flap technique focuses on the correct dissection and repositioning of differentially thickened pre-pretarsal levator aponeurosis fascia fibroadipose tissue in East Asian patients. This new technique can generate broader and tighter attachment between pretarsal orbicularis oculi muscle and levator aponeurosis fascia, and form smooth double-eyelid crease without pretarsal soft tissue removal.

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer.

ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor-positive (ER+) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.