Epigenetic regulation of stem cells in lung cancer oncogenesis and therapy resistance.

Epigenetics plays an important role in regulating stem cell signaling, as well as in the oncogenesis of lung cancer and therapeutic resistance. Determining how to employ these regulatory mechanisms to treat cancer is an intriguing medical challenge. Lung cancer is caused by signals that cause aberrant differentiation of stem cells or progenitor cells. The different pathological subtypes of lung cancer are determined by the cells of origin. Additionally, emerging studies have demonstrated that the occurrence of cancer treatment resistance is connected to the hijacking of normal stem cell capability by lung cancer stem cells, especially in the processes of drug transport, DNA damage repair, and niche protection. In this review, we summarize the principles of the epigenetic regulation of stem cell signaling in relation to the emergence of lung cancer and resistance to therapy. Furthermore, several investigations have shown that the tumor immune microenvironment in lung cancer affects these regulatory pathways. And ongoing experiments on epigenetics-related therapeutic strategies provide new insight for the treatment of lung cancer in the future.

Comparing T- and B-cell responses to COVID-19 vaccines across varied immune backgrounds.

The emergence of adapted variants of the SARS-CoV-2 virus has led to a surge in breakthrough infections worldwide. A recent analysis of immune responses in people who received inactivated vaccines has revealed that individuals with no prior infection have limited resistance to Omicron and its sub-lineages, while those with previous infections exhibit a significant amount of neutralizing antibodies and memory B cells. However, specific T-cell responses remain largely unaffected by the mutations, indicating that T-cell-mediated cellular immunity can still provide protection. Moreover, the administration of a third dose of vaccine has resulted in a marked increase in the spectrum and duration of neutralizing antibodies and memory B cells in vivo, which has enhanced resistance to emerging variants such as BA.2.75 and BA.2.12.1. These results highlight the need to consider booster immunization for previously infected individuals and the development of novel vaccination strategies. The rapid spread of adapted variants of the SARS-CoV-2 virus presents a significant challenge to global health. The findings from this study underscore the importance of tailoring vaccination strategies based on individual immune backgrounds and the potential need for booster shots to combat emerging variants. Continued research and development are crucial to discovering new immunization strategies that will effectively protect public health against the evolving virus.

Impact of the COVID-19 pandemic on cancer healthcare utilization in southwestern China on March 2021.

BACKGROUND: Oncological care has been disrupted worldwide during the COVID-19 pandemic. We aimed to quantify the long-term impact of the pandemic on cancer care utilization and to examine how this impact varied by sociodemographic and clinical factors in southwestern China, where the Dynamic Zero-COVID Strategy was implemented. This strategy mainly included lockdowns, stringent testing, and travel restrictions to prevent the spread of COVID-19. METHOD: We identified 859,497 episodes of the utilization of cancer care from electronic medical records between January 1, 2019, and March 31, 2021, from the cancer center of a tertiary hospital serving an estimated population of 8.4 million in southwestern China. Changes in weekly utilization were evaluated via segmented Poisson regression across service categories, stratified by cancer type and sociodemographic factors. RESULTS: A sharp reduction in utilization of in-person cancer services occurred during the first week of the pandemic outbreak in January 2020, followed by a quick rebound in February 2020. Although there were few COVID-19 cases from March 2020 until this analysis, the recovery of most in-person services was slow and remained incomplete as of March 31, 2021. The exceptions were outpatient radiation and surgery, which increased and exceeded pre-pandemic levels, particularly among lung cancer patients; meanwhile, telemedicine utilization increased substantially after the onset of the pandemic. Care disruptions were most prominent for women, rural residents, uninsured, and breast cancer patients. CONCLUSIONS: As of March 2021, despite few COVID-19 cases, the COVID-19 pandemic has had a strong and continuing impact on in-person oncology care utilization in southwestern China under the Dynamic Zero-COVID Strategy. Equitable and timely access to cancer care requires adjustment in strict policies for COVID-19 prevention and control, as well as targeted remedies for the most vulnerable populations during and beyond the pandemic. Future studies should monitor the long-term effects of the COVID-19 pandemic and response strategies on cancer care and outcomes.

An effector of 'Candidatus Liberibacter asiaticus' manipulates autophagy to promote bacterial infection.

Autophagy functions in plant host immunity responses to pathogen infection. The molecular mechanisms and functions used by the citrus Huanglongbing (HLB)-associated intracellular bacterium 'Candidatus Liberibacter asiaticus' (CLas) to manipulate autophagy are unknown. We identified a CLas effector, SDE4405 (CLIBASIA_04405), which contributes to HLB progression. Transgenic SDE4405 in Wanjincheng orange (Citrus sinensis) promotes CLas proliferation and symptom expression via suppressing host immunity response. SDE4405 interacts with ATG8-family proteins (ATG8s) and their interactions activate autophagy in Nicotiana benthamiana. The occurrence of autophagy is also significantly enhanced in SDE4405-transgenic citrus plants. Interrupting NbATG8s-SDE4405 interaction by silencing NbATG8s reduces Pseudomonas syringae pv. tomato strain DC3000ΔhopQ1-1 (Pst DC3000ΔhopQ1-1) proliferation in N. benthamiana, and transient overexpression of CsATG8c and SDE4405 in citrus promotes Xanthomonas citri subsp. citri (Xcc) multiplication, suggesting SDE4405-ATG8s interaction negatively regulates plant defense. These data show the role of the CLas effector protein in manipulating autophagy and provide new insights into the molecular interaction between CLas and citrus.

Programming inactive RNA-binding small molecules into bioactive degraders.

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

Heme oxygenase-1 determines the cell fate of ferroptotic death of alveolar macrophages in COPD.

Background: Despite an increasing understanding of chronic obstructive pulmonary disease (COPD) pathogenesis, the mechanisms of diverse cell populations in the human lung remain unknown. Using single-cell RNA sequencing (scRNA-Seq), we can reveal changes within individual cell populations in COPD that are important for disease pathogenesis and characteristics. Methods: We performed scRNA-Seq on lung tissue obtained from donors with non-COPD and mild-to-moderate COPD to identify disease-related genes within different cell types. We testified the findings using qRT-PCR, immunohistochemistry, immunofluorescence and Western blotting from 25 additional subjects and RAW 264.7 macrophages. Targeting ferroptosis with the ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine or HO-1 inhibitor zinc protoporphyrin was administered in the experimental cigarette smoke COPD mouse model. Results: We identified two populations of alveolar macrophages (AMs) in the human lung that were dysregulated in COPD patients. We discovered that M2-like AMs modulate susceptibility to ferroptosis by disrupting lipid and iron homeostasis both in vivo and in vitro. The discrepancy in sensitivity to ferroptosis can be determined and regulated by HO-1. In contrast, M1-like AMs showed the ability to attenuate oxidative stress and exert resistance to ferroptosis. In addition, the expression of genes within M2-like AMs is also involved in defects in phagocytosis and lysosome distortion. This ferroptotic phenotype was ameliorated by antiferroptotic compounds, iron chelators and HO-1 inhibitors. During COPD, the accumulation of lipid peroxidation drives ferroptosis-sensitive M2-like AMs, while M1-like AMs show characteristics of ferroptosis resistance. Ferroptotic M2 AMs lose their anti-inflammatory and repair functions but provoke inflammatory responses, resulting in consistent inflammation and tissue damage in the presence of M1 AMs in COPD. Conclusion: Appropriate interventions in ferroptosis can reduce the occurrence of infections and acute onset, and delay the COPD process.

Development and evaluation of a data-driven integrated management app for perioperative adverse events: protocol for a mixed-design study.

INTRODUCTION: A patient record review study conducted in 2006 in a random sample of 21 Dutch hospitals found that 51%-77% of adverse events are related to perioperative care, while Centers for Disease Control and Prevention data in USA in 2013 estimated that the medical error is the third-leading cause of mortality. To capitalise on the potential of apps to enhance perioperative medical quality, there is a need for interventions developed in consultation with real-world users designed to support integrated management for perioperative adverse events (PAEs). This study aims: (1) to access the knowledge, attitude and practices for PAEs among physicians, nurses and administrators, and to identify the needs of healthcare providers for a mobile-based PAEs tool; (2) to develop a data-driven app for integrated PAE management that meets those needs and (3) to test the usability, clinical efficacy and cost-effectiveness of the developed app. METHODS AND ANALYSIS: We will adopt an embedded mixed-methods research technique; qualitative data will be used to assess user needs and app adoption, while quantitative data will provide crucial insights to establish the demand for the app, and measure the app effects. Phase 1 will enrol surgery-related healthcare providers from the West China Hospital and identify their latent demand for mobile-based PAEs management using a self-designed questionnaire underpinned by the knowledge, attitude and practice model, as well as expert interviews. In phase 2, we will develop the app for integrated PAE management and test its effectiveness and sustainability. In phase 3, the effects on the total number and severity of reported PAEs will be evaluated using Poisson regression with interrupted time-series analysis over a 2-year period, while users' engagement, adherence, process evaluation and cost-effectiveness will be evaluated using quarterly surveys and interviews. ETHICS AND DISSEMINATION: The West China Hospital of Sichuan University's Institutional Review Board authorised this study after approving the study protocol, permission forms and questionnaires (number: 2022-1364). Participants will be provided with study information, and informed written consent will be obtained. Study findings will be disseminated through peer-reviewed publications and conference presentations.

PRMT5 up-regulation improves myocardial hypertrophy by mediating E2F-1/NF-κB/NLRP3 pathway.

Various protein arginine methyltransferases (PRMTs) have been demonstrated to be aberrantly expressed in cardiovascular disease. This study aimed to investigate the role of PRMT5 in myocardial hypertrophy. Levels of fibrosis markers, NLRP3-ASC-Caspase1, inflammatory factors, myocardial hypertrophy markers and oxidative stress markers were determined in cardiomyocytes. Overexpression or knockdown models of PRMT5 and E2F-1 were constructed, and pharmacological intervention with NF-κB was determine the function of the PRMT5/E2F-1/NF-κB pathway in myocardial hypertrophy. Results shows that PRMT5 was down-regulated in the TAC rat model as well as in an in-vitro model of Ang II-induced myocardial hypertrophy. Overexpression of PRMT5 dramatically reduced Ang II-induced myocardial hypertrophy, fibrosis, inflammatory response, and oxidative stress, whereas knockdown of PRMT5 had the opposite effect. PRMT5 overexpression restrained E2F-1 expression and impaired NF-κB phosphorylation and NLRP3-ASC-Caspase1 inflammasome activation. Mechanistically, PRMT5 knockdown contributed to E2F-1 expression, but E2F-1 knockdown or NF-κB inhibition reversed PRMT5 knockdown-mediated myocardial hypertrophy. PRMT5 attenuated NLRP3 inflammasome activation and ameliorates angiotensin II-induced myocardial hypertrophy by regulating the E2F-1/NF-κB pathway.

In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate.

A deep and detailed understanding of drug-dendrimer conjugates key properties is needed to define the critical quality attributes that affect drug product performance. The characterization must be executed both in the formulation media and in biological matrices. This, nevertheless, is challenging on account of a very limited number of suitable, established methods for characterizing the physicochemical properties, stability, and interaction with biological environment of complex drug-dendrimer conjugates. In order to fully characterize AZD0466, a drug-dendrimer conjugate currently under clinical development by AstraZeneca, a collaboration was initiated with the European Nanomedicine Characterisation Laboratory to deploy a state-of-the-art multi-step approach to measure physicochemical properties. An incremental complexity characterization approach was applied to two batches of AZD0466 and the corresponding dendrimer not carrying any drug, SPL-8984. Thus, the aim of this work is to guide in depth characterization efforts in the analysis of drug-dendrimer conjugates. Additionally, it serves to highlight the importance of using the adequate complementary techniques to measure physical and chemical stability in both simple and biological media, to drive a complex drug-dendrimer conjugate product from discovery to clinical development.

Performance of radiomics models derived from different CT reconstruction parameters for lung cancer risk prediction.

BACKGROUND: This study analysed the performance of radiomics features extracted from computed tomography (CT) images with different reconstruction parameters in differentiating malignant and benign pulmonary nodules. METHODS: We evaluated routine chest CT images acquired from 148 participants with pulmonary nodules, which were pathologically diagnosed during surgery in West China Hospital, including a 5 mm unenhanced lung window, a 5 mm unenhanced mediastinal window, a 5 mm contrast-enhanced mediastinal window and a 1 mm unenhanced lung window. The pulmonary nodules were segmented, and 1409 radiomics features were extracted for each window. Then, we created 15 cohorts consisting of single windows or multiple windows. Univariate correlation analysis and principal component analysis were performed to select the features, and logistic regression analysis was performed to establish models for each cohort. The area under the curve (AUC) was applied to compare model performance. RESULTS: There were 75 benign and 73 malignant pulmonary nodules, with mean diameters of 18.63 and 19.86 mm, respectively. For the single-window setting, the AUCs of the radiomics model from the 5 mm unenhanced lung window, 5 mm unenhanced mediastinal window, 5 mm contrast-enhanced mediastinal window and 1 mm unenhanced lung window were 0.771, 0.808, 0.750, and 0.771 in the training set and 0.711, 0.709, 0.684, and 0.674 in the test set, respectively. Regarding the multiple-window setting, the radiomics model based on all four windows showed an AUC of 0.825 in the training set and 0.743 in the test set. Statistically, the 15 models demonstrated comparable performances (P > 0.05). CONCLUSION: A single chest CT window was acceptable in predicting the malignancy of pulmonary nodules, and additional windows did not statistically improve the performance of the radiomics models. In addition, slice thickness and contrast enhancement did not affect the diagnostic performance.

A structural equation modelling analysis: interprofessional team collaboration, organizational career management, and post competency of community nurses.

BACKGROUND: With the advent of an ageing society and an increase in the prevalence of chronic diseases, the role of primary health care has become increasingly important and reliant on multidisciplinary collaboration. As members of this interprofessional cooperative team, community nurses play a dominant role. Thus, the post competencies of community nurses study deserve our attention. In addition, organizational career management can affect nurses in some ways. This study aims to examine the current situation and relationship among interprofessional team collaboration, organizational career management and post-competency of community nurses. METHODS: A survey was conducted among 530 nurses in 28 community medical institutions from November 2021 to April 2022 in Chengdu, Sichuan Province, China. Descriptive analysis was used for analysis, and a structural equation model was used to hypothesize and verify the model. A total of 88.2% of respondents met the inclusion criteria and did not meet the exclusion criteria. The main reason nurses gave for not participating was that they were too busy. RESULTS: Among the competencies on the questionnaire, ensuring quality and helping roles scored the lowest. The teaching-coaching and diagnostic functions played a mediating role. Nurses with greater seniority and those who were transferred to administrative departments had lower scores, and the difference was statistically significant (p < 0.05). In the structural equation model, CFI = 0.992 and RMSEA = 0.049, which shows that the model fit well, suggesting that organizational career management had no statistically significant effect on post competency (ß = -0.006, p = 0.932) but that interprofessional team collaboration had a statistically significant effect on post competency (ß = 1.146, p < 0.001) and organizational career management had a statistically significant effect on interprofessional team collaboration (ß = 0.684, p < 0.001). CONCLUSIONS: Attention should be given to the improvement of community nurses' post competency in ensuring quality and performing helping, teaching-coaching, and diagnostic roles. Moreover, researchers should focus on the decline in community nurses' abilities, particularly for those with greater seniority or in administrative roles. The structural equation model shows that interprofessional team collaboration is a complete intermediary between organizational career management and post competency.

In situ structure of actin remodeling during glucose-stimulated insulin secretion using cryo-electron tomography.

Actin mediates insulin secretion from the pancreatic ß-cell through a remodeling process. Previous studies have been hampered by limited resolution, providing an ambiguous depiction of actin remodeling as a process that begins with depolymerization into actin monomers, followed by repolymerization into actin filaments. Here, we report the in situ structure of actin remodeling in INS-1E ß-cells during glucose-stimulated insulin secretion at nanoscale resolution. We demonstrate that actin remodeling occurs at the cell periphery rather than in the cell interior. The actin filament network at the cell periphery exhibits three marked differences after remodeling compared to those under basal conditions. First, approximately 12% of actin filaments reorient, their angle changing from 0-45° to 45-90° relative to the plasma membrane. Second, the actin filament network remains predominantly as cell-stabilizing bundles but partially reconfigures into a less compact arrangement. Third, actin filaments anchored to the plasma membrane reorganize from a "netlike" to a "blooming" architecture, featuring radial projections emanating from their anchor points. Remodeling precedes the transport of insulin secretory granulesto the plasma membrane and their release from it. Furthermore, the density of actin filaments and microtubules around insulin secretory granules is lowered after remodeling compared to the basal conditions, as expected for the subsequent granule transport and release. Finally, actin filaments and microtubules are more densely packed than under basal conditions. These findings advance our structural and functional understanding of actin remodeling during glucose-stimulated insulin secretion in pancreatic ß-cells.

Design, Synthesis, and Antitumor Activity of Potent and Selective EGFR L858R/T790M Inhibitors and Identification of a Combination Therapy to Overcome Acquired Resistance in Models of Non-small-cell Lung Cancer.

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for the treatment of non-small-cell lung cancer (NSCLC). Here, we report the identification, structure optimization, and structure-activity relationship studies of quinazoline derivatives as novel selective EGFR L858R/T790M inhibitors. The most promising compound, 28f, exhibited strong inhibitory activity against EGFR L858R/T790M (IC50 = 3.5 nM) and greater than 368-fold selectivity over EGFR WT (IC50 = 1290 nM), a 6.7-fold improvement over osimertinib. Furthermore, 28f effectively inhibited downstream signaling pathways and induced apoptosis in mutant cells. In the H1975 xenograft in vivo model, 28f exhibited a good tumor suppressive effect. Furthermore, the combination of 28f with the ACK1 inhibitor dasatinib produced synergistic antiproliferative efficacy with 28f in 28f-resistant cells and in vivo. In conclusion,28f could become a candidate drug for the treatment of NSCLC, and the combination of 28f and dasatinib is expected to overcome EGFR resistance.

PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration.

Extrachromosomal circular DNAs (eccDNAs) participate in tumorigenesis and tumor progression. However, the role and mechanism of eccDNAs have yet to be elucidated in non-small cell lung cancer (NSCLC). In our research, three surgically matched NSCLC tissue samples, NSCLC cell lines (H1299, A549, and H460), and a normal lung cell line (MRC-5) were used as study objects. High-throughput eccDNA sequencing and bioinformatics analysis were performed to study the distribution pattern and level of eccDNA expression. The upregulated candidate eccDNA-encoding PLCG2 was validated by routine PCR. Plasmid transfection, RNA interference, qRT‒PCR and western blotting experiments were used to verify the expression level of PLCG2. Our results showed that the chromosome distribution, length distribution, and genomic annotation of the eccDNAs were comparable between the NSCLC and normal groups. Nevertheless, there were no significant differences in eccDNAs between NSCLC tissues and matched normal lung tissues. The eccDNA derived from PLCG2 was upregulated in NSCLC cells. TCGA analysis and immunohistochemistry showed that PLCG2 was highly expressed in lung cancer tissues and tended to be associated with poor outcome. We also demonstrated that PLCG2 can promote metastasis through the regulation of mitochondrial respiration. These results suggested that PLCG2 identified by eccDNA sequencing acts as an oncogene and might be a new biomarker for NSCLC diagnosis and prognosis evaluation.

Risk of second primary lung cancer in patients with thyroid cancer: a meta-analysis based on big population studies.

BACKGROUND: Previous studies have revealed that the number of cancer survivors developing a second primary malignancy is increasing, especially among thyroid cancer patients, and lung cancer is still the main cause of cancer death. Therefore, we aimed to investigate the risk of second primary lung cancer (SPLC) in patients with thyroid cancer. METHODS: We searched the PubMed, Web of Science, Embase, and Scopus databases up to November 24, 2021, for relevant research and merged the standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) to evaluate the risk of developing SPLC in patients with thyroid cancer. RESULTS: Fourteen studies involving 1480,816 cases were included in our meta-analysis. The pooled result demonstrated that thyroid cancer patients may have a higher risk of SPLC than the general population (SIR = 1.21, 95% CI: 1.07-1.36, P < 0.01, I2 = 81%, P < 0.01). Subgroup analysis stratified by sex indicated that female patients may have a markedly higher risk of SPLC than male patients (SIR = 1.65, 95% CI: 1.40-1.94, P < 0.01, I2 = 75%, P < 0.01). CONCLUSIONS: Thyroid cancer patients are more likely to develop SPLC than the general population, especially women. However, other risk factors must be investigated, and more prospective studies are needed to confirm our results.Registration: International Prospective Register of Systematic Reviews: No. CRD42021285399.

Identification of priority pathogens for aetiological diagnosis in adults with community-acquired pneumonia in China: a multicentre prospective study.

BACKGROUND: Community-acquired pneumonia (CAP) is a major public health challenge worldwide. However, the aetiological and disease severity-related pathogens associated with CAP in adults in China are not well established based on the detection of both viral and bacterial agents. METHODS: A multicentre, prospective study was conducted involving 10 hospitals located in nine geographical regions in China from 2014 to 2019. Sputum or bronchoalveolar lavage fluid (BALF) samples were collected from each recruited CAP patient. Multiplex real-time PCR and bacteria culture methods were used to detect respiratory pathogens. The association between detected pathogens and CAP severity was evaluated. RESULTS: Among the 3,403 recruited eligible patients, 462 (13.58%) had severe CAP, and the in-hospital mortality rate was 1.94% (66/3,403). At least one pathogen was detected in 2,054 (60.36%) patients, with two or more pathogens were co-detected in 725 patients. The ten major pathogens detected were Mycoplasma pneumoniae (11.05%), Haemophilus influenzae (10.67%), Klebsiella pneumoniae (10.43%), influenza A virus (9.49%), human rhinovirus (9.02%), Streptococcus pneumoniae (7.43%), Staphylococcus aureus (4.50%), adenovirus (2.94%), respiratory syncytial viruses (2.35%), and Legionella pneumophila (1.03%), which accounted for 76.06-92.52% of all positive detection results across sampling sites. Klebsiella pneumoniae (p < 0.001) and influenza viruses (p = 0.005) were more frequently detected in older patients, whereas Mycoplasma pneumoniae was more frequently detected in younger patients (p < 0.001). Infections with Klebsiella pneumoniae, Staphylococcus aureus, influenza viruses and respiratory syncytial viruses were risk factors for severe CAP. CONCLUSIONS: The major respiratory pathogens causing CAP in adults in China were different from those in USA and European countries, which were consistent across different geographical regions over study years. Given the detection rate of pathogens and their association with severe CAP, we propose to include the ten major pathogens as priorities for clinical pathogen screening in China.

Mitigation mechanism of zinc oxide nanoparticles on cadmium toxicity in tomato.

Cadmium (Cd) pollution seriously reduces the yield and quality of vegetables. Reducing Cd accumulation in vegetables is of great significance for improving food safety and sustainable agricultural development. Here, using tomato as the material, we analyzed the effect of foliar spraying with zinc oxide nanoparticles (ZnO NPs) on Cd accumulation and tolerance in tomato seedlings. Foliar spraying with ZnO NPs improved Cd tolerance by increasing photosynthesis efficiency and antioxidative capacity, while it reduced Cd accumulation by 40.2% in roots and 34.5% in leaves but increased Zn content by 33.9% in roots and 78.6% in leaves. Foliar spraying with ZnO NPs also increased the contents of copper (Cu) and manganese (Mn) in the leaves of Cd-treated tomato seedlings. Subsequent metabonomic analysis showed that ZnO NPs exposure alleviated the fluctuation of metabolic profiling in response to Cd toxicity, and it had a more prominent effect in leaves than in roots. Correlation analysis revealed that several differentially accumulated metabolites were positively or negatively correlated with the growth parameters and physiol-biochemical indexes. We also found that flavonoids and alkaloid metabolites may play an important role in ZnO NP-alleviated Cd toxicity in tomato seedlings. Taken together, the results of this study indicated that foliar spraying with ZnO NPs effectively reduced Cd accumulation in tomato seedlings; moreover, it also reduced oxidative damage, improved the absorption of trace elements, and reduced the metabolic fluctuation caused by Cd toxicity, thus alleviating Cd-induced growth inhibition in tomato seedlings. This study will enable us to better understand how ZnO NPs regulate plant growth and development and provide new insights into the use of ZnO NPs for improving growth and reducing Cd accumulation in vegetables.

Cell Features Reconstruction from Gene Association Network of Single Cell.

Gene expression as an unstable form of cell characterization has been widely used for single-cell analyses. Although there are cell-specific networks (CSN) to explore stable gene associations within a single cell, the amount of information in CSN is huge and there is no method to measure the interaction level between genes. Therefore, this paper presents a two-level approach to reconstructing single-cell features, which transforms the original gene expression feature into the gene ontology feature and gene interaction feature. Specifically, we first squeeze all CSNs into a cell network feature matrix (CNFM) by fusing the global position and neighborhood influence of genes. Next, we propose a computational method of gene gravitation based on CNFM to quantify the extent of gene-gene interaction, and we can construct a gene gravitation network for single cells. Finally, we further design a novel index of gene gravitation entropy to quantitatively evaluate the level of single-cell differentiation. The experiments on eight different scRNA-seq datasets show the effectiveness and broad application prospects of our method.

Cost-effectiveness evaluation based on two models of first-line atezolizumab monotherapy and chemotherapy for advanced non-small cell lung cancer with high-PDL1 expression.

Background: Atezolizumab may provide clinical benefits to patients with advanced non-small cell lung cancer (NSCLC). However, the price of atezolizumab is relatively high, and its economic outcomes have remained unclear. In this study, we used two models to examine the cost-effectiveness of initial atezolizumab monotherapy versus chemotherapy for patients with PD-L1 high-expressing EGFR and ALK wild-type advanced NSCLC in the context of the Chinese healthcare system. Methods: Partitioned Survival model and Markov model were performed to evaluate the cost-effectiveness of first-line single-agent atezolizumab versus platinum-based chemotherapy for patients with advanced NSCLC with PD-L1 high-expressing EGFR and ALK wild-type disease. Clinical outcomes and safety information were obtained from the most recent data from the IMpower110 trial, while cost and utility values were obtained from Chinese hospitals and relevant literature. Total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed to explore model uncertainty. Scenario analyses were also conducted for the Patient Assistance Program (PAP) and various provinces in China. Results: In the Partitioned Survival model, the total cost of atezolizumab was $145,038, providing 2.92 LYs and 2.39 QALYs, while the total cost of chemotherapy was $69,803, providing 2.12 LYs and 1.65 QALYs. The ICER for atezolizumab versus chemotherapy was $102,424.83/QALY; in the Markov model, the ICER was $104,806.71/QALY. Atezolizumab was not cost-effective at the WTP threshold of three times China's per capita gross domestic product (GDP). Sensitivity analysis showed that the cost of atezolizumab, the utility of PFS, and the discount rate had a significant impact on ICER; PAP significantly reduced ICER, but atezolizumab was still not cost-effective in China. Conclusion: First-line monotherapy with atezolizumab for patients with PD-L1 high-expressing EGFR and ALK wild-type advanced NSCLC was estimated to be less cost-effective than chemotherapy in terms of the Chinese healthcare system; offering PAP increased the likelihood that atezolizumab would be cost-effective. In some areas of China with higher levels of economic development, atezolizumab was likely to be cost-effective. To improve the cost-effectiveness of atezolizumab, drug prices would need to be reduced.