Real-world application of nirmatrelvir/ritonavir in hospitalized COVID-19 patients with onset of symptoms beyond 5 days: a comparative study.

PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.

CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth.

BACKGROUND: B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent 'death domain' while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined. METHODS: CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo. RESULTS: We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells. CONCLUSIONS: This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.

Phenotypic Analysis and Molecular Characterization of Enlarged Cell Size Mutant in Nannochloropsis oceanica.

The cell cycle is the fundamental cellular process of eukaryotes. Although cell-cycle-related genes have been identified in microalgae, their cell cycle progression differs from species to species. Cell enlargement in microalgae is an essential biological trait. At the same time, there are various causes of cell enlargement, such as environmental factors, especially gene mutations. In this study, we first determined the phenotypic and biochemical characteristics of a previously obtained enlarged-cell-size mutant of Nannochloropsis oceanica, which was designated ECS. Whole-genome sequencing analysis of the insertion sites of ECS indicated that the insertion fragment is integrated inside the 5'-UTR of U/P-type cyclin CYCU;1 and significantly decreases the gene expression of this cyclin. In addition, the transcriptome showed that CYCU;1 is a highly expressed cyclin. Furthermore, cell cycle analysis and RT-qPCR of cell-cycle-related genes showed that ECS maintains a high proportion of 4C cells and a low proportion of 1C cells, and the expression level of CYCU;1 in wild-type (WT) cells is significantly increased at the end of the light phase and the beginning of the dark phase. This means that CYCU;1 is involved in cell division in the dark phase. Our results explain the reason for the larger ECS size. Mutation of CYCU;1 leads to the failure of ECS to fully complete cell division in the dark phase, resulting in an enlargement of the cell size and a decrease in cell density, which is helpful to understand the function of CYCU;1 in the Nannochloropsis cell cycle.

Soil phosphorus drives plant trait variations in a mature subtropical forest.

Earth system models are implementing soil phosphorus dynamic and plant functional traits to predict functional changes in global forests. However, the linkage between soil phosphorus and plant traits lacks empirical evidence, especially in mature forests. Here, we examined the soil phosphorus constraint on plant functional traits in a mature subtropical forest based on observations of 9943 individuals from 90 species in a 5-ha forest dynamic plot and 405 individuals from 15 species in an adjacent 10-year nutrient-addition experiment. We first confirmed a pervasive phosphorus limitation on subtropical tree growth based on leaf N:P ratios. Then, we found that soil phosphorus dominated multidimensional trait variations in the 5-ha forest dynamic plot. Soil phosphorus content explained 44% and 53% of the variance in the traits defining the main functional space across species and communities, respectively. Lastly, we found much stronger phosphorus effects on most plant functional traits than nitrogen at both species and community levels in the 10-year nutrient-addition experiment. This study provides evidence for the consistent pattern of soil phosphorus constraint on plant trait variations between the species and community levels in a mature evergreen broadleaf forest in the East Asian monsoon region. These findings shed light on the predominant role of soil phosphorus on plant functional trait variations in mature subtropical forests, providing new insights for models to incorporate soil phosphorus constraint in predicting future vegetation dynamics.

The Growth, Lipid Accumulation and Fatty Acid Profile Analysis by Abscisic Acid and Indol-3-Acetic Acid Induced in Chlorella sp. FACHB-8.

Microalgae are considered a promising source for biodiesel. The addition of plant hormone can exert a significant impact on the production of microalgae biomass and lipid accumulation. Nevertheless, the response of microalgae cells to hormones is species- or strain-dependent. It remains controversial which genes involved in strong increase of fatty acids production in response to abscisic acid (ABA) in Chlorella sp. FACHB-8 strain. We investigated cell growth, lipid accumulation, and fatty acid composition when ABA and indol-3-acetic acid (IAA) were used in the growth medium of Chlorella sp. FACHB-8. The four treatments, including 5 mg/L IAA (E1), 10 mg/L IAA (E2), 10 mg/L ABA (E3), the combination of 5 mg/L IAA and 5 mg/L ABA (E4), were found to increase cell growth, but only 10 mg/L ABA treatment could enhance the lipid accumulation. The fatty acid profile was changed by the addition of ABA, making fatty acids afflux from polyunsaturated fatty acids to monounsaturated and saturated fatty acids, which were suitable for diesel application. Furthermore, a transcriptome analysis was conducted, unraveling the differentially expressed genes enriched in fatty acid biosynthesis, fatty acid metabolism, and biosynthesis of the unsaturated fatty acid pathway in response to ABA. Our results clarified the correlation of fatty acid synthesis-related genes and fatty acid profiles, helping understand the potential response mechanism of Chlorella sp. FACHB-8 strain respond to ABA treatment.

Association between uterine volume and pregnancy outcomes in adenomyosis patients undergoing frozen-thawed embryo transfer.

RESEARCH QUESTION: What is the relationship between uterine volume before frozen-thawed embryo transfer (FET) and reproductive outcomes among adenomyosis patients? DESIGN: Clinical characteristics and outcomes of adenomyosis patients undergoing IVF and FET in a tertiary academic hospital were retrospectively analysed. Only first blastocyst transfer cycles were included. The main outcome measures included clinical pregnancy rate (CPR), miscarriage rate and live birth rate (LBR). RESULTS: A total of 158 adenomyosis patients were enrolled. Receiver operating characteristic (ROC) curve analysis indicated that uterine volume before FET was negatively related to LBR, with area under the curve of 0.622 (95% confidence interval [CI] = 0.531-0.712, P = 0.012). The cut-off value for the curve was 98.81 cm3. Grouped by the cut-off of uterine volume, 83 women were included in group A (≤98.81 cm3) and 75 in group B (>98.81 cm3). No significant difference was found in CPR between two groups. Compared with group A, the incidence of miscarriage in group B was significantly increased (51.28% versus 16.28%, P = 0.001). LBR in group B was markedly lower than in group A (25.33% versus 43.37%, P = 0.020). Logistic regression analysis revealed that, after adjusting for potential confounders, uterine volume before FET was not associated with CPR (odds ratio [OR] 1.149, 95% CI 0.577-2.286, P = 0.693) but was positively related to miscarriage rate (OR 8.509, 95% CI 2.290-2.575, P = 0.001). CONCLUSIONS: Adenomyosis patients with larger uterine volume (>98.81 cm3) before FET might have a lower LBR due to higher incidence of miscarriage. Reduction of uterine volume before embarking on FET procedures should be recommended.

Outcomes of in vitro fertilization-embryo transfer in women with diminished ovarian reserve after growth hormone pretreatment.

The study was to evaluate the in vitro fertilization-embryo transfer (IVF-ET) outcomes in women with diminished ovarian reserve (DOR) after pretreatment with growth hormone (GH). Retrospective propensity score matching study, which included 92 women received GH over 4 weeks pretreatment before their subsequent IVF cycles and 92 matched controls who underwent IVF cycles between July 2017 and August 2018. The evaluation parameters included ovarian response, embryological parameters, and pregnancy outcomes after embryo transfer (ET). The mean number of retrieved oocytes and transferable day-3 embryos were significantly higher after GH pretreatment. The implantation rate, clinical pregnancy rate, and ongoing pregnancy rate per fresh ET cycle were similar between the GH group and control group. In women who either achieved pregnancy or utilized all the embryos resulting from the index stimulation cycle, the cumulative clinical pregnancy rate was significantly higher in women with GH compared to the control group. 4 weeks pretreatment with GH could increase ovarian response to stimulation and then improved IVF-ET outcomes in women with DOR.

Comparison of sputum induction and bronchoscopy in diagnosis of sputum smear-negative pulmonary tuberculosis: a systemic review and meta-analysis.

BACKGROUND: Pulmonary tuberculosis is one of the most common infectious diseases worldwide. Patients with suspected pulmonary tuberculosis with negative smear are recommended to undergo further tests including sputum induction and bronchoscopy. Our study is aimed to compare sputum induction and bronchoscopic specimens in the diagnosis of sputum smear-negative pulmonary tuberculosis. METHOD: PubMed, Web of Science, Cochrane Library and Embase were searched for eligible studies. The pooled sensitivities (SEN), specificities (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and 95% confidence intervals (CI) were constructed, and the areas under the curves (AUCs) were calculated. RESULTS: Five studies with a total number of 586 cases were included. For mycobacterial culture, the SEN and SPE of sputum induction were 0.72(95% CI, 0.66-0.77) and 1.00(95%CI, 0.99-1.000) respectively, whereas the SEN and SPE of bronchoscopy were 0.70(95%CI, 0.64-0.75) and 1.00(95%CI, 0.99-1.00) respectively. Sputum induction had a similar AUC (0.9564, SE = 0.0749) with bronchoscopy (0.8618, SE = 0.1652) (P = 0.602). For specimen of acid-fast bacilli smear, the SEN and SPE of sputum induction were 0.35(95% CI, 0.29-0.42) and 0.99(95% CI, 0.96-1.00) respectively, whereas the SEN and SPE of bronchoscopy were 0.38(95% CI, 0.32-0.45) and 0.99(95% CI, 0.96-1.00) respectively. There is no statistically significant difference in the AUC for sputum induction (0.6016) compared with bronchoscopy (0.8163) (P = 0.792). CONCLUSIONS: For the diagnosis of sputum smear-negative pulmonary tuberculosis, the diagnosis yield of sputum induction and bronchoscopy is similar.

Mediterranean diet improves embryo yield in IVF: a prospective cohort study.

BACKGROUND: Mediterranean diet (MediDiet) had been reported to be beneficial to human health. However the relationship between diet pattern and outcomes of in vitro fertilization (IVF) treatment was scarcely researched. This study was aimed to explore the correlation between MediDiet pattern of infertile women and their clinical outcomes of IVF cycles. METHODS: An observational prospective cohort study was conducted in the reproductive center from September 2016 to December 2017. Seven hundred infertile women about to undergo IVF treatment were asked to conduct a questionnaire survey. Patients were assigned to higher MediDiet adherence group or lower MediDiet adherence group according to their Mediterranean diet scores. Laboratory parameters and clinical outcomes were compared and those were different between groups were further analyzed for their relationship with MediDiet adherence. RESULTS: A total of 590 women were finally included in the study. According to MediDiet scores, 228 participants were categorized as higher MediDiet adherence group and 362 others as lower MediDiet adherence group. No significant differences were found in baseline characteristics between groups. Higher MediDiet adherence group showed larger number of embryos available (8.40 ± 5.26 vs 7.40 ± 4.71, P = 0.028). Clinical pregnancy rate and implantation rate were similar between the two groups. In further correlation tests and multivariate linear regression analysis, number of fertilized oocytes and embryo yield were positively correlated to MediDiet adherence of participants. CONCLUSION: Infertile women with greater adherence to Mediterranean diet pattern were likely to obtain more embryos available in IVF cycle.

Factors inducing decreased oocyte maturation rate: a retrospective analysis of 20,939 ICSI cycles.

PURPOSE: Decreased oocyte maturation rate (OMR) is associated with worse clinical outcomes in IVF/ICSI cycles. The clinical features inducing decreased OMR remain unknown. The study is designed to explore the factors influencing the incidence of decreased OMR and its effects on clinical outcomes. METHODS: This is a retrospective case-control study analyzing data from 20,939 ICSI cycles in a reproductive center of university affiliated hospital from January 2015 to December 2017. Patients with a decreased OMR (< 30%) were characterized as Group A and those with an OMR ≥ 30% constituted Group B. Candidate factors of decreased OMR and clinical outcomes were compared between the two groups. RESULTS: There were 1.3% cycles with an OMR < 30% and 22.16% of all oocytes retrieved (12.87 per cycle in average) were immature. Primary infertility, longer duration of infertility, larger BMI, more previous assisted reproductive times, less oocytes retrieved were risk factors for decreased OMR. Compared with long agonist protocol, patients received antagonist protocol for COH had a higher incidence of decreased OMR. The fertilization rate and subsequent embryo development of oocytes in Group A were worse than Group B. Implantation rate and clinical pregnancy rate were both lower in Group A than Group B. CONCLUSION: Primary infertility, duration of infertility, BMI, previous assisted reproductive times, number of oocytes retrieved and COH protocol were found to be factors inducing decreased OMR. Patients with decreased OMR had worse clinical outcomes.

Telmisartan protects chronic intermittent hypoxic mice via modulating cardiac renin-angiotensin system activity.

BACKGROUND: To explore the effects of chronic intermittent hypoxia (CIH), which mimics sleep apnea syndrome, on the cardiac renin angiotensin system (RAS), and to investigate the cardiac protection of an angiotensin receptor blocker (ARB)telmisartan (TERT) against CIH. METHODS: 32 healthy male C57B6J mice were randomly divided into CIH, ARB, blank and air control groups. CIH lasted for 12 weeks. Cardiac angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE 2) and angiotensin II (Ang II) were evaluated by immunohistochemistry. Myocardial apoptosis were assessed by TUNEL assay and myocardial cell ultrastructure were observed under transmission electron microscope. RESULTS: Cardiac ACE expression was higher in the CIH group than in blank and air control groups, which was decreased with TERT treatment. TERT treatment elevated the expression of cardiac ACE 2 and Ang II compared with CIH group. Myocardial cell and capillary endothelial cell apoptosis, mitochondrial injury were most severe in CIH groups, which were mitigated with TERT treatment. CONCLUSIONS: CIH changes the expression of cardiac ACE, ACE2 and Ang II, which may cause myocardial damage. TERT protects mice from CIH-linked cardiac damage via modulating the activity of RAS in the hearts.

Comparative microarray analyses of mono(2-ethylhexyl)phthalate impacts on fat cell bioenergetics and adipokine network.

Cellular accumulation of mono(2-ethylhexyl)phthalate (MEHP) has been recently demonstrated to disturb fat cell energy metabolism; however, the underlying mechanism remained unclear. The study aimed to determine how MEHP influenced fat cell transcriptome and how the changes might contribute to bioenergetics. Because of the pivotal role of PPARγ in energy metabolism of fat cells, comparative microarray analysis of gene expression in 3T3-L1 adipocytes treated with both MEHP and rosiglitazone was performed. Pathway enrichment analysis and gene ontology (GO) enrichment analysis revealed that both treatments caused up-regulation of genes involved in PPAR signaling/energy metabolism-related pathways and down-regulation of genes related to adipokine/inflammation signals. MEHP/rosiglitazone-treated adipocytes exhibited increased levels of lipolysis, glucose uptake, and glycolysis; the gene expression profiles provided molecular basis for the functional changes. Moreover, MEHP was shown to induce nuclear translocation and activation of PPARγ. The similarity in gene expression and functional changes in response to MEHP and rosiglitazone suggested that MEHP influenced bioenergetics and adipokine network mainly via PPARγ. Importantly, adipokine levels in C57BL/6J mice with di(2-ethylhexyl)phthalate (DEHP) treatments provided in vivo evidence for microarray results. On the basis of correlation between gene expression and functional assays, possible involvements of genes in bioenergetics of MEHP-treated adipocytes were proposed.

Mono(2-ethylhexyl)phthalate accumulation disturbs energy metabolism of fat cells.

Phthalates are lipophilic and tend to accumulate in adipose tissue, an important regulator of energy balance and glucose homeostasis. The study aimed to determine whether cellular phthalate accumulation influenced fat cell energy metabolism. Following a 3-day treatment with adipogenesis-inducing medium and a 2-day treatment with adipogenesis-maintaining medium, 3T3-L1 cells differentiated into adipocytes in the presence of a phthalate at a clinically relevant concentration (30-300 µM) for another 6 days. Two phthalates, di(2-ethylhexyl)phthalate and di-n-butylphthalate, and their metabolites, mono(2-ethylhexyl)phthalate (MEHP) and mono-n-butylphthalate, were used here. The phthalate treatments caused no marked effect on cytotoxicity and adipogenesis. Only the MEHP-treated adipocytes were found having smaller lipid droplets; MEHP accumulated in cells in a dose- and time-dependent manner. The MEHP-treated adipocytes exhibited significant increases in lipolysis and glucose uptake; quantitative real-time polymerase chain reaction (qPCR) analysis revealed correlated changes in expression of marker genes involved in adipogenesis, lipid metabolism, and glucose uptake. Analysis of oxygen consumption rate (a mitochondrial respiration indicator) and extracellular acidification rate (a glycolysis indicator) indicated a higher energy metabolism in the adipocytes. qPCR analysis of critical genes involved in mitochondrial biogenesis and/or energy metabolism showed that expression of peroxisome proliferator-activated receptor γ coactivator-1α, sirtuin 3, and protein kinase A were significantly enhanced in the MEHP-treated adipocytes. In vitro evidence of MEHP impacts on lipolysis, glucose uptake/glycolysis, and mitochondrial respiration/biogenesis demonstrates that MEHP accumulation disturbs energy metabolism of fat cells.

Serum C-reactive protein level in COPD patients stratified according to GOLD 2011 grading classification.

BACKGROUND AND OBJECTIVE: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 grading classification has been used to evaluate the severity of patients with chronic obstructive pulmonary disease (COPD). However, little is known about the relationship between the systemic inflammation and this classification. We aimed to study the relationship between serum CRP and the components of the GOLD 2011 grading classification. METHODS: C-reactive protein (CRP) levels were measured in 391 clinically stable COPD patients and in 50 controls from June 2, 2015 to October 31, 2015 in the First Affiliated Hospital of Xiamen University. The association between CRP levels and the components of the GOLD 2011 grading classification were assessed. RESULTS: Correlation was found with the following variables: GOLD 2011 group (0.240), age (0.227), pack year (0.136), forced expiratory volume in one second % predicted (FEV1%; -0.267), forced vital capacity % predicted (-0.210), number of acute exacerbations in the past year (0.265), number of hospitalized exacerbations in the past year (0.165), British medical Research Council dyspnoea scale (0.121), COPD assessment test score (CAT, 0.233). Using multivariate analysis, FEV1% and CAT score manifested the strongest negative association with CRP levels. CONCLUSIONS: CRP levels differ in COPD patients among groups A-D based on GOLD 2011 grading classification. CRP levels are associated with several important clinical variables, of which FEV1% and CAT score manifested the strongest negative correlation.

Genome characterization of sugarcane yellow leaf virus from China reveals a novel recombinant genotype.

Sugarcane yellow leaf virus (SCYLV; genus Polerovirus, family Luteoviridae) is a recombinant virus associated with yellow leaf disease, a serious threat to sugarcane in China and worldwide. Among the nine known SCYLV genotypes existing worldwide, COL, HAW, REU, IND, CHN1, CHN2, BRA, CUB and PER, the last five have been reported in China. In this study, the complete genome sequences (5,880 nt) of GZ-GZ18 and HN-CP502 isolates from the Chinese provinces of Guizhou and Hainan, respectively, were cloned, sequenced and characterized. Phylogenetic analysis showed that, among 29 SCYLV isolates described worldwide, the two Chinese isolates clustered together into an independent clade based on the near-complete genome nucleotide (ORF0-ORF5) or amino acid sequences of individual genes, except for the MP protein (ORF4). We propose that the two isolates represent a novel genotype, CHN3, diverging from other genotypes by 1.7-13.6 % nucleotide differences in ORF0-ORF5, and 2.7-28.1 %, 1.8-20.4 %, 0.5-5.1 % and 2.7-15.9 % amino acid differences in P0 (ORF0), RdRp (RNA-dependent RNA polymerase) (ORF1+2), CP (coat protein) (ORF3) and RT (readthrough protein) (ORF3+5), respectively. CHN3 was closely related to the BRA, HAW and PER genotypes, differing by 1.7-3.8 % in the near-complete genome nucleotide sequence. Recombination analysis further identified CHN3 as a new recombinant strain, arising from the major parent CHN-HN1 and the minor parent CHN-GD-WY19. Recombination breakpoints were distributed mostly within the RdRp region in CHN3 and the four significant recombinant genotypes, IND, REU, CUB and BRA. Recombination is considered to contribute significantly to the evolution and emergence of such new SCYLV variants.

Serum uric acid is inversely associated with lung function in US adults.

The relationship between serum uric acid and lung function has been controversial. This study aims to determine whether there is an independent relationship between serum uric acid and lung function in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012. Serum uric acid was considered the exposure variable, and lung function (FEV1 and FVC) was the outcome variable. Multivariable linear regression was conducted with adjustments for potential confounders. The total number of participants from NHANES (2007-2012) was 30,442, of which 7514 were included in our analysis after applying exclusion criteria. We observed that serum uric acid was negatively associated with FEV1 and FVC after adjusting for confounders (ß for FEV1 [- 24.77 (- 36.11, - 13.43)] and FVC [- 32.93 (- 47.42, - 18.45)]). Similarly, serum uric acid showed a negative correlation with FEV1 and FVC after adjusting for confounding variables both in male and female populations. The relationship between serum uric acid and FEV1 and FVC remained consistent and robust in various subgroups within both male and female populations, including age, race, BMI, alcohol consumption, smoking status, and income-poverty ratio. Serum uric acid is negatively associated with FEV1 and FVC in the US general healthy population. This negative relationship is significant in both the male and female populations.

PI3Kα inhibitor GNE-493 triggers antitumor immunity in murine lung cancer by inducing immunogenic cell death and activating T cells.

Phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer, playing pivotal roles in the pathophysiology of both malignant and immune cells. The impact of PI3K inhibitors on the tumor microenvironment (TME) within lung cancer remains largely unknown. In this study, we explored the regulatory effects of GNE-493, an innovative dual inhibitor of PI3K and mammalian target of rapamycin (mTOR), on the TME of lung cancer. First, through the analysis of The Cancer Genome Atlas-lung squamous cell carcinoma (LUSC) cohort, we found PIK3CA to be related to CD8 T cells, which may affect the overall survival rate of patients by affecting CD8 function. We herein demonstrated that GNE-493 can significantly inhibit tumor cell proliferation and promote cell apoptosis while increasing the expression of the immunogenic death-related molecules CRT and HSP70 using in vitro cell proliferation and apoptosis experiments on the murine KP lung cancer cell line and human A549 lung cancer cell line. Next, through the establishment of an orthotopic tumor model in vivo, it was found that after GNE-493 intervention, the infiltration of CD4+ and CD8+ T cells in mouse lung tumor was significantly increased, and the expression of CRT in tumors could be induced to increase. To explore the mechanisms underlying PI3K inhibition-induced changes in the TME, the gene expression differences of T cells in the control group versus GNE-493-treated KP tumors were analyzed by RNA-seq, and the main effector pathway of anti-tumor immunity was identified. The IFN/TNF family molecules were significantly upregulated after GNE-493 treatment. In summary, our findings indicate that GNE-493 promotes immunogenic cell death in lung cancer cells, and elucidates its regulatory impact on molecules associated with the adaptive immune response. Our study provides novel insights into how PI3K/mTOR inhibitors exert their activity by modulating the tumor-immune interaction.

Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

Paleoenvironmental changes in the coastal zone of the northwest South China Sea during the last 13 kyr.

Marine sediments in coastal zones serve as valuable archives for understanding the history of silicate chemical weathering and summer monsoon rainfall in source areas, providing insights into terrigenous climate and environmental evolution. In this study, we investigated the grain size, clay minerals, and geochemistry of sediments retrieved from core KZK01 in the coastal zone of the northwest South China Sea during the past 13 thousand years before present (kyr BP). Our findings demonstrated that the illite crystallinity index served as a reliable proxy for assessing the intensity of chemical weathering in the source area. Moreover, it distinctly recorded significant climatic events such as the Younger Dryas and Bond events during the Holocene. The dominant driver of the regional East Asian summer monsoon was identified as summer solar radiation in the Northern Hemisphere at low latitudes. Cold climate events exhibited global consistency, potentially influenced by the presence of ice sheets at high latitudes. Lastly, our records revealed a distinct transition at 9.0 kyr, highlighting significant impacts of the Qiongzhou Strait and sea level rise on regional climate dynamics.

Identification of active compounds of traditional chinese medicine derived from maxing shigan decoction for COVID-19 treatment: a meta-analysis and in silico study.

BACKGROUND: Coronavirus 2019 (COVID-19) poses a serious threat to human health. In China, traditional Chinese medicine (TCM), mainly based on the Maxing Shigan decoction (MXSGD), is used in conjunction with western medicine to treat COVID-19. RESEARCH DESIGN AND METHODS: We conducted a network meta-analysis to investigate whether MXSGD-related TCM combined with western medicine is more effective in treating COVID-19 compared to western medicine alone. Additionally, using network pharmacology, cross-docking, and molecular dynamics (MD) simulation to explore the potential active compounds and possible targets underlying the therapeutic effects of MXSGD-related TCM. RESULTS: MXSGD-related TCM combined with western medicine was better for treating COVID-19 compared to western medicine alone. Network pharmacological analysis identified 43 shared ingredients in the MXSGD-related TCM prescriptions and 599 common target genes. Cross-docking of the 43 compounds with 154 proteins that matched these genes led to the identification of 60 proteins. Pathway profiling revealed that the active ingredients participated in multiple signaling pathways that contribute to their efficacy. Molecular docking and MD simulation demonstrated that MOL007214, the most promising molecule, could stably bind to the active site of SARS-CoV-2 3CLpro. CONCLUSION: This study demonstrates the important role of MXSGD-related TCM in the treatment of COVID-19.