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Abstract Background In recent years, clinicians often encounter patients with multiple pulmonary nodules in their clinical practices. As most of these ground glass nodules (GGNs) are small in volume and show no spicule sign, it is difficult to use Mayo Clinic Model to make early diagnosis of lung cancer accurately, especially in large numbers of nonsmoking women who have no tumor history. Other clinical models are disadvantaged by a relatively high false-positive or false-negative rate. Therefore, there is an urgent need to establish a new model of predicting malignancy or benignity of pulmonary GGNs for the sake of making accurate and early diagnosis of lung cancer. Methods Included in this study were GGNs surgically resected from patients who were admitted to Yiwu Central Hospital from January 2018 to March 2024, including both male and female patients, there is no gender specific issue. The nature of all these GGN tissues was confirmed pathologically. The case data were statistically analyzed to establish a mathematical prediction model, the prediction performance of which was verified by the pathological results. Results Altogether 261 GGN patients met the inclusion criteria. Using the results of logistic regression analysis, a mathematical prediction equation was established as follows: Malignant probability (mP) = ex/ (1 + ex); when mP was > 0.5, the GGN was considered as malignant, and when mP was ≤ 0.5, it was considered as benign. x= -2.46 + 1.032*gender + 1.85*mGGN + 1.40*VCS-0.0027*mean CT value of the nodule + 0.078*maximum diameter of the nodule, where e represents the natural logarithm; if the patient was a female, gender = 1 (otherwise = 0); if the pulmonary nodule was a mixed GGN, mGGN = 1 (otherwise = 0); if the pulmonary nodule had vascular convergence sign, VCS = 1 (otherwise = 0). The prediction performance of the mathematical prediction model was verified as follows: the negative prediction value was 0.97156 and the positive prediction value was 0.3800 in the model group versus 1 and 0.25 in the verification group. Conclusion In this study, we identified female gender, mGGN, VCS, mean CT value and maximum nodule diameter as five key factors for predicting malignancy or benignity of pulmonary nodules, based on which we established a mathematical prediction model. This novel innovation may provide a useful auxiliary tool for predicting malignancy and benignity of pulmonary nodules, especially in women patients.

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, particularly when diagnosed at an unresectable stage. Traditional treatments for advanced HCC have limited efficacy, prompting the exploration of combination therapies. This systematic review and meta-analysis evaluate the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in patients with unresectable HCC.MethodsA comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, including studies up to June 2024. Randomized controlled trials (RCTs) comparing combination therapy (PD-1/PD-L1 inhibitors with anti-angiogenic agents) to monotherapy or standard treatments in unresectable HCC patients were included. Data were synthesized using random-effects models, with pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs).ResultsFive Phase III RCTs involving 1515 patients were included. Combination therapy significantly improved OS (HR: 0.71, 95% CI: 0.60-0.85) and PFS (HR: 0.64, 95% CI: 0.53-0.77) compared to monotherapy or standard treatments. The pooled OR for ORR was 1.27 (95% CI: 1.57-2.11), indicating a higher response rate with combination therapy. However, the risk of AEs was also higher in the combination therapy group (RR: 1.04, 95% CI: 1.02-1.06). Subgroup analyses revealed consistent benefits across different types of PD-1/PD-L1 inhibitors and anti-angiogenic agents, with no significant publication bias detected.ConclusionsThe combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents offers significant benefits in improving OS and PFS in patients with unresectable HCC, although it is associated with an increased risk of adverse events.

BackgroundThe study of long non-coding RNAs (lncRNAs) has gained significant attention due to their roles in regulating gene expression and their potential as diagnostic biomarkers. This systematic review and meta-analysis aimed to evaluate the diagnostic value of high-expression lncRNAs in liver disease patients, including those with hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).MethodsA comprehensive literature search was conducted across multiple electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library, up to July 2024. Studies were included if they investigated the expression of lncRNAs in liver disease patients and evaluated their diagnostic performance. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess the quality of included studies. Pooled sensitivity, specificity, diagnostic odds ratios (DOR), and summary receiver operating characteristic (SROC) curves were calculated using a bivariate random-effects model.ResultsNine studies involving 888 samples were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 2.01 (95% CI: 1.71–2.36), indicating a significant association between high lncRNA expression and poor liver disease outcomes. Subgroup analyses revealed a pooled odds ratio (OR) of 1.99 (95% CI: 1.53–2.60) for tissue samples and 8.62 (95% CI: 1.16–63.71) for blood samples, suggesting a stronger diagnostic value for blood-based lncRNAs. The funnel plots indicated minimal publication bias, and sensitivity analyses confirmed the robustness of the findings.ConclusionHigh-expression lncRNAs show significant potential as diagnostic biomarkers for liver diseases, offering non-invasive, accurate, and timely diagnostic information. Despite the promising results, further research is needed to standardize detection methods, elucidate the biological functions of lncRNAs, and validate their clinical utility in diverse patient populations. Integrating lncRNA biomarkers with traditional diagnostic approaches could enhance diagnostic accuracy and improve patient management and outcomes in liver disease.

Summary: Background: Effective monitoring and management are crucial during long-term home noninvasive positive pressure ventilation (NPPV) in patients with hypercapnic chronic obstructive pulmonary disease (COPD). This study investigated the benefit of Internet of Things (IOT)-based management of home NPPV. Methods: This multicenter, prospective, parallel-group, randomized controlled non-inferiority trial enrolled patients requiring long-term home NPPV for hypercapnic COPD. Patients were randomly assigned (1:1), via a computer-generated randomization sequence, to standard home management or IOT management based on telemonitoring of clinical and ventilator parameters over 12 months. The intervention was unblinded, but outcome assessment was blinded to management assignment. The primary outcome was the between-group comparison of the change in health-related quality of life, based on severe respiratory insufficiency questionnaire scores with a non-inferiority margin of −5. This study is registered with Chinese Clinical Trials Registry (No. ChiCTR1800019536). Findings: Overall, 148 patients (age: 72.7 ± 6.8 years; male: 85.8%; forced expiratory volume in 1 s: 0.7 ± 0.3 L; PaCO2: 66.4 ± 12.0 mmHg), recruited from 11 Chinese hospitals between January 24, 2019, and June 28, 2021, were randomly allocated to the intervention group (n = 73) or the control group (n = 75). At 12 months, the mean severe respiratory insufficiency questionnaire score was 56.5 in the intervention group and 50.0 in the control group (adjusted between-group difference: 6.26 [95% CI, 3.71–8.80]; P

In an attempt to improve the utilization efficiency of multi-energy coupling in park-level integrated energy system (PIES), promote wind power consumption and reduce carbon emissions, a low-carbon economic operation optimization model of PIES integrating flexible load and carbon trading mechanism is constructed. Firstly, according to the characteristics of load response, the demand response is divided into four types: which can be shifted, transferred, reduced and replaced. Secondly, the PIES basic architecture is given by considering the combined heat and power generation coupling equipment, new energy and flexible load in the park. Finally, introducing the ladder-type carbon trading mechanism into the system and minimize the total operating cost, the low-carbon economic operation optimization model of PIES is established. The YALMIP toolbox and CPLEX solver are used to solve the example, the simulation results show that the participation of electrical and thermal coupled scheduling and flexible electric or thermal loads can significantly reduce the system operating cost, reduce the load peak-to-valley difference and relieve peak power consumption pressure.

Abstract Background Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC. Methods In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). Results A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2–34) months. The median PFS time was 14.1 (2–34) months, the median OS time was 16.9 (2–34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3–4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. Conclusion Screening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.

The expansion of the construction land scale has been vital in supporting rapid economic development and meeting social needs. However, the spatial heterogeneity in the effect of construction land scale on carbon emission intensity at the county level remains underexplored. Therefore, comprehensively investigating the relation between the construction land transfer scale and carbon emission intensity holds substantial research value. Using panel data from 2007 to 2021, this study analyzes the spatiotemporal differentiation characteristics of carbon emission intensity and the effect of construction land scale on carbon emission intensity at the county level in Jiangsu Province, China. The findings reveal that carbon emission intensity at the county level in Jiangsu Province generally exhibits a continuous downward trend over time and a spatial distribution characterized by a gradual decrease from the southern counties to the central and northern counties. Moreover, there is a significant positive relation between the construction land transfer scale and carbon emission intensity, a conclusion supported by robustness tests. Furthermore, mediating analysis indicates that reduction of the construction land transfer scale exhibits a significant promoting effect on green technology innovation and industrial structure upgrading, which, in turn, has a significant inhibitory effect on carbon emission intensity. The impact of the construction land transfer scale from different sources, supply methods, types, and of county economic strength on carbon emission intensity has significant heterogeneity.

Abstract Background Pulmonary cryptococcosis (PC) is a fungal infection that can have a variable prognosis depending on several factors. The objective of this study was to analyse the characteristics of pulmonary lesions and identify prognostic factors in patients with PC who were human immunodeficiency virus (HIV) -negative and underwent antifungal treatment. Methods The study enrolled patients diagnosed with PC who were negative for HIV. Symptoms, CT characteristics of pulmonary lesions, serum cryptococcal capsular antigen (CrAg) titre, underlying diseases, and duration of antifungal treatment were evaluated over a 2-year follow-up. Results A total of 63 patients (40 men and 23 women) with a mean age of 50.4 years were included. Half of the patients (50.8%) were asymptomatic, and the most common symptoms were cough (44.4%), expectoration (27.0%), and fever (17.5%). Pulmonary lesions were mainly present in the peripheral and lower lobes of the lung, with 35 cases classified as nodular-type lesions and 28 cases classified as mass-type lesions. At the first, third, sixth, 12th, and 24th-month follow-ups, the median proportion of residual pulmonary lesions were 59.6%, 29.9%, 12.2%, 9.6%, and 0.0%, respectively. During antifungal treatment, the lesions of 33 patients achieved complete response, while the remaining 30 patients did not. Compared with the non-CR group, the CR group had a lower baseline serum CrAg titre (median, 1:20 vs 1:80, P

Abstract Gas hydrate mechanical stability under pressure is critically important in energy supply, global warming, and carbon-neutral technologies. The stability of these polyhedral guest–host crystals under increasing pressure is affected by host cage type and face connectivity as well as guest gas occupancy. The geometry-imposed cage connectivity generates crystal lattices that include inclusion-matrix material composite structures. In this paper, we integrate Density Functional Theory simulations with a polyhedral-inspired composite material model that quantifies stability limits, failure modes, and the impact of the type of cage occupancy. DFT reveals the existence of two failure mechanisms under increasing pressure: (i) a multistep lattice breakdown under total occupancy and under only large cage occupancy and (ii) a single-step breakdown under zero occupancy as well as with only small cage occupancy. The DFT-composite model predicts optimal occupancy pathways to generate strength and critical occupancy pathways to promote decomposition.

Abstract Aims The co‐morbidities contribute to the inferior prognosis of COVID‐19 patients. Recent reports suggested that the higher co‐morbidity rate between COVID‐19 and heart failure (HF) leads to increased mortality. However, the common pathogenic mechanism between them remained elusive. Here, we aimed to reveal underlying molecule mechanisms and genetic correlation between COVID‐19 and HF, providing a new perspective on current clinical management for patients with co‐morbidity. Methods The gene expression profiles of HF (GSE26887) and COVID‐19 (GSE147507) were retrieved from the GEO database. After identifying the common differentially expressed genes (|log2FC| > 1 and adjusted P

Ticlopidine exerts its anti-platelet effects mainly by antagonizing platelet p2y12 receptors. Previously, a few studies have shown that ticlopidine can induce liver injury, but the exact mechanism of hepatotoxicity remains unclear. Oxidative stress, metabolic disorders, hepatocyte apoptosis, lipid peroxidation, and inflammatory responses can all lead to hepatic liver damage, which can cause hepatotoxicity. In this study, in order to deeply explore the potential molecular mechanisms of ticlopidine -induced hepatotoxicity, we used zebrafish as a model organism to comprehensively evaluate the hepatotoxicity of ticlopidine and its associated mechanism. Three days post-fertilization, zebrafish larvae were exposed to varying concentrations (1.5, 1.75 and 2 μg/mL) of ticlopidine for 72 h, in contrast, adult zebrafish were exposed exposure to 4 μg/mL of ticlopidine for 28 days. Ticlopidine-exposed zebrafish larvae showed changes in liver morphology, shortened body length, and delayed development of the swim bladder development. Liver tissues of ticlopidine-exposed zebrafish larvae and adults stained with Hematoxylin & Eosin revealed vacuolization and increased cellular interstitial spaces in liver tissues. Furthermore, using Oil Red O and periodic acid-Schiff staining methods and evaluating different metabolic enzymes of ticlopidine-exposed zebrafish larvae and adults suggested abnormal liver metabolism and liver injury in both ticlopidine-exposed zebrafish larvae and adults. Ticlopidine also significantly elevated inflammation and oxidative stress and reduced hepatocyte proliferation. During the rescue intervention using N-acetylcysteine, we observed significant improvement in ticlopidine-induced morphological changes in the liver, shortened body length, delayed swim bladder development, and proliferation of liver tissues showed significant improvement. In conclusion, ticlopidine might inhibit normal development and liver proliferation in zebrafish by upregulation of oxidative stress levels, thus leading to embryonic developmental toxicity and hepatotoxicity. In this study, we used zebrafish as a model organism to elucidate the developmental toxicity and hepatotoxicity induced by ticlopidine upregulation of oxidative stress signaling pathway in zebrafish, providing a theoretical basis for clinical application.

Abstract Background Liver transplantation is one of the most effective treatments for end-stage liver disease. Split liver transplantation (SLT) can effectively improve the utilization efficiency of grafts. However, split liver transplantation still faces shortcomings and is not widely used in surgery. How to improve the effective transplantation volume of split liver transplantation and promote the postoperative recovery of patients has important clinical significance. Methods In our study, the donor’s liver was split into the extended right graft and left lateral sector, and the IV segment occur ischemia. To guarantee the functional graft size, and avoid complications, we reconstructed the IV segment portal vein and left portal vein. And we analyzed the operation time, intraoperative bleeding, liver function, and postoperative complications. Results In our research, 14 patients underwent IV segment portal vein reconstruction, and 8 patients did not undergo vascular reconstruction. We found that the ischemic area of the IV segment decreased significantly after IV segment portal vein reconstruction. We found that there was no significant difference in operation time and postoperative complications between the patients of the groups. There were significant differences in ALT on the 1st day and albumin on the 6th day after the operation. Conclusion It indicates that IV segment reconstruction in SLT surgery can alleviate the graft ischemic and promote the recovery of liver function after the operation. And, IV segment reconstruction as a novel operating procedure may be widely used in SLT.

IntroductionTo assist mental health care providers with the assessment of depression, research to develop a standardized, accessible, and non-invasive technique has garnered considerable attention. Our study focuses on the application of deep learning models for automatic assessment of depression severity based on clinical interview transcriptions. Despite the recent success of deep learning, the lack of large-scale high-quality datasets is a major performance bottleneck for many mental health applications.MethodsA novel approach is proposed to address the data scarcity problem for depression assessment. It leverages both pretrained large language models and parameter-efficient tuning techniques. The approach is built upon adapting a small set of tunable parameters, known as prefix vectors, to guide a pretrained model towards predicting the Patient Health Questionnaire (PHQ)-8 score of a person. Experiments were conducted on the Distress Analysis Interview Corpus - Wizard of Oz (DAIC-WOZ) benchmark dataset with 189 subjects, partitioned into training, development, and test sets. Model learning was done on the training set. Prediction performance mean and standard deviation of each model, with five randomly-initialized runs, were reported on the development set. Finally, optimized models were evaluated on the test set.ResultsThe proposed model with prefix vectors outperformed all previously published methods, including models which utilized multiple types of data modalities, and achieved the best reported performance on the test set of DAIC-WOZ with a root mean square error of 4.67 and a mean absolute error of 3.80 on the PHQ-8 scale. Compared to conventionally fine-tuned baseline models, prefix-enhanced models were less prone to overfitting by using far fewer training parameters (

AbstractWe introduce a neuro-symbolic natural logic framework based on reinforcement learning with introspective revision. The model samples and rewards specific reasoning paths through policy gradient, in which the introspective revision algorithm modifies intermediate symbolic reasoning steps to discover reward-earning operations as well as leverages external knowledge to alleviate spurious reasoning and training inefficiency. The framework is supported by properly designed local relation models to avoid input entangling, which helps ensure the interpretability of the proof paths. The proposed model has built-in interpretability and shows superior capability in monotonicity inference, systematic generalization, and interpretability, compared with previous models on the existing datasets.

Sensorineural deafness becomes an inevitable worldwide healthy problem, yet the current curative therapy is limited. Emerging evidences demonstrate mitochondrial dysfunction plays a vital role of in the pathogenesis of deafness. Reactive oxygen species (ROS)-induced mitochondrial dysfunction combined with NLRP3 inflammasome activation is involved in cochlear damage. Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement of autophagy can reduce oxidative stress, inhibit cell apoptosis, and protect auditory cells. In addition, we further discuss the interplays linking ROS generation, NLRP3 inflammasome activation, and autophagy underlying the pathogenesis of deafness, including ototoxic drugs-, noise- and aging-related hearing loss.

BackgroundAlthough rare, ERBB2 exon 16 skipping mutations (ERBB2ΔEx16) have been implicated in resistance to anti-HER2 and anti-EGFR targeted agents. Our study investigated the prevalence and clinical significance of ERBB2ΔEx16 in Chinese pan-cancer patients.MethodsWe retrospectively screened 40996 patients, spanning 19 cancer types, who had available genomic profiles acquired with DNA-based next-generation sequencing (NGS). We characterized the clinical and molecular features of the ERBB2ΔEx16-positive patients. Furthermore, we also analyzed a pan-cancer dataset from the Cancer Genome Atlas (TCGA; n=8705).ResultsA total of 22 patients were detected with ERBB2ΔEx16, resulting in an overall prevalence rate of 0.054% (22/40996). Of them, 16 patients had lung cancer (LC; 0.05%, 16/30890), five patients had gastric cancer (GC; 0.35%, 5/1448), and one patient had ovarian cancer (0.12%, 1/826). Among the 16 LC patients, ERBB2ΔEx16 was detected in four treatment-naïve EGFR/ALK-negative patients and 12 EGFR-positive patients after the onset of resistance to EGFR tyrosine kinase inhibitors (TKIs). The treatment-naïve patients harbored no LC-associated oncogenic drivers except ERBB2 amplification, suggesting a potential oncogenic role for ERBB2ΔEx16. Consistently, ERBB2ΔEx16+ patients from TCGA data also carried no known drivers despite various concurrent alterations. In the 12 EGFR TKI-resistant LC patients, relative variant frequencies for ERBB2ΔEx16 were lower than in untreated patients, suggesting ERBB2ΔEx16 as secondary alterations following TKI treatment and thereby implicating ERBB2ΔEx16 in mediating therapeutic resistance.ConclusionsOur study identified an overall ERBB2ΔEx16 prevalence rate of 0.054% and provided insights into the clinical implications of ERBB2ΔEx16 in Chinese pan-cancer patients.

We used mouse CRC cell line (MC38) to establish a heterotopic mouse model, and applied [89Zr]-labeled PD-L1 antibody KN035 for PET imaging. Attenuated Salmonella typhimurium 3261 was used as an anti-tumor vaccine, and the combined anti-tumor immunotherapy with bivalent genetic vaccine and anti-PD1 antibody Nivolumab was conducted. MicroPET was performed to observe the changes of tumor tissues and expression of PD-L1. We found that the recombinant double-gene plasmids were stably expressed in COS7 cells. Study results showed the combined immunotherapy improved the effectiveness over genetic vaccine alone. This study supports that combination of genetic vaccines and anti-immunocheckpoint immunotherapy can inhibit MC38 tumor growth.

Currently, conventional neoadjuvant therapy or postoperative adjuvant therapy, such as chemotherapy and radiation therapy, can only bring limited survival benefits to gastric cancer (GC). Median survival after palliative chemotherapy is also low, at about 8–10 months. Immunotargeting is a new option for the treatment of GC, but has not been widely replicated. The highly immunosuppressed tumor microenvironment (TME) discounts the efficacy of immunotherapy for GC. Therefore, new strategies are needed to enhance the immune response of the TME. This paper reviewed the relationship between microorganisms and GC, potential links between microorganisms and immunotherapy and research of microorganisms combined immunotherapy.

Abstract The development of high‐performance individual marking taggants is of great significance. However, the interaction between taggant and skin is not fully understood, and a standard for marking taggants has yet to be realized. To achieve a highly retentive, anti‐interference, and covert individual marking fluorescent taggant, Mn2+‐doped NaYF4:Yb/Er upconversion nanoparticles (UCNPs), are surface‐functionalized with polyethyleneimine (PEI) to remarkably enhance the interaction between the amino groups and skin, and thus to facilitate the surface adhesion and chemical penetration of the taggant. Electrostatic interaction between PEI600‐UCNPs and skin as well as remarkable penetration inside the epidermis is responsible for excellent taggant retention capability, even while faced with robust washing, vigorous wiping, and rubbing for more than 100 cycles. Good anti‐interference capability and reliable marking performance in real cases are ensured by an intrinsic upconversion characteristic with a distinct red luminescent emission under 980 nm excitation. The present methodology is expected to shed light on the design of high‐performance individual marking taggants from the perspective of the underlying interaction between taggant and skin, and to help advance the use of fluorescent taggants for practical application, such as special character tracking.

Abstract Background The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma. Methods A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients. Results Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence. Conclusions The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

Abstract Background An adverse role for obstructive sleep apnea (OSA) in cancer aggressiveness and mortality has recently emerged from clinical and animal studies, and the reasons have not been fully determined. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis. So far, the relationship between OSA and lung CSCs has not been explored. Method In the present study, we established an orthotopic mouse model of primary lung cancer and utilized chronic intermittent hypoxia (CIH) exposure to mimic OSA status. Results We observed that CIH endows lung cancer with greater metastatic potential, evidenced by increased tumor growth, tumor seeding, and upregulated CSC-related gene expression in the lungs. Notably, the transcription factor BTB and CNC homology 1 (Bach1), a key factor in responding to conditions of oxidative stress, is increased in lung cancer after CIH exposure in vitro and in vivo. Meanwhile, exposing lung cancer cells to CIH promoted cell proliferation, clonal diversity, induced stem-like cell marker expression, and gave rise to CSCs at a relatively higher frequency. Furthermore, the increase of mitochondrial ROS (mtROS) and CSC-marker expression induced by CIH exposure was abolished in Bach1 shRNA-treated lung cancer cells. Conclusions Our results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.

This paper proposes novel single and double integral inequalities with arbitrary approximation order by employing shifted Legendre polynomials and Cholesky decomposition, and these inequalities could significantly reduce the conservativeness in stability analysis of linear systems with interval time-varying delays. The coefficients of the proposed single and double integral inequalities are determined by using the weighted least-squares method. Also former well-known integral inequities, such as Jensen inequality, Wirtinger-based inequality, auxiliary function-based integral inequalities, are all included in the proposed integral inequalities as special cases with lower-order approximation. Stability criterions with less conservatism are then developed for both constant and time-varying delay systems. Several numerical examples are given to demonstrate the effectiveness and benefit of the proposed method.

The aim is to diagnose COVID-19 earlier and to improve its treatment by applying medical technology, the “COVID-19 Intelligent Diagnosis and Treatment Assistant Program (nCapp)” based on the Internet of Things. Terminal eight functions can be implemented in real-time online communication with the “cloud” through the page selection key. According to existing data, questionnaires, and check results, the diagnosis is automatically generated as confirmed, suspected, or suspicious of 2019 novel coronavirus (2019-nCoV) infection. It classifies patients into mild, moderate, severe or critical pneumonia. nCapp can also establish an online COVID-19 real-time update database, and it updates the model of diagnosis in real time based on the latest real-world case data to improve diagnostic accuracy. Additionally, nCapp can guide treatment. Front-line physicians, experts, and managers are linked to perform consultation and prevention. nCapp also contributes to the long-term follow-up of patients with COVID-19. The ultimate goal is to enable different levels of COVID-19 diagnosis and treatment among different doctors from different hospitals to upgrade to the national and international through the intelligent assistance of the nCapp system. In this way, we can block disease transmission, avoid physician infection, and epidemic prevention and control as soon as possible.

Context Xiaoyaosan (XYS), a traditional Chinese medicine (TCM), has been widely used to relieve a variety of disorders caused by depression. Objective This study evaluates the effect of XYS against tumour metastasis in a chronic restraint stress mouse model. Methods and materials Forty C57BL/6J mice were randomly divided into four groups, including blank-control (BC), blank-stress (BS), XYS-control (XC) and XYS-stress (XS). BS and XS groups were exposed to immobilization stress for 2 h per day for 28 days commencing seven days before tumour cell injection. XC and XS groups were given a gavage of XYS (1516.67 mg/kg) before chronic immobilization stress. Mice were injected with HT-29 colon cancer cells in the spleen to produce liver metastasis. After 28 days of injecting with HT-29 cells, flow cytometry, western blot, PCR and immunohistochemical staining were performed to uncover the role of chronic restraint stress and XYS in the liver metastasis of colon cancer. Results Metastatic liver weight of mice in XS group (3.33 ± 0.18 g) was significantly lower than BS group (4.01 ± 0.27 g). Chronic restraint stress significantly increased CD11b+F4/80+ and CD11b+GrloLy6Chi cell infiltration. XYS treatment significantly decreased the CD11b+F4/80+ tumour-associated macrophage (TAM) population and CD11b+GrloLy6Chi myeloid-derived suppressor cell (MDSC). TGF-β, IL-6, MMP-9 and VEGF in spleen tumours significantly decreased in XYS group. XYS also reduced VEGF and CD31 in hepatic metastatic tissue, which were elevated by chronic restraint stress. Conclusions XYS may successfully inhibit chronic-stress-induced liver metastasis. Results suggest that XYS may have therapeutic value for colorectal cancer treatment.

BackgroundThe aim of this study was to explore the source and morphology of a small supernumerary marker chromosome (sSMC) from karyotype analysis of a patient with a unique case of mosaic Turner syndrome. The study findings will provide technical reference and genetic counseling for similar cases.Case PresentationA female patient with 46,X,+mar karyotype was diagnosed by genetic karyotype analysis. Genetic methods including fluorescence in situ hybridization (FISH) and copy number variation sequencing (CNV-seq) based on low-depth whole-genome sequencing were used to explore the source and morphology of sSMC. FISH technology showed that 56.5% of the cells were X and 43.5% of the cells were XY. CNV-seq detection found that the sSMC was chrY, implying that the patient's karyotype was mos 45,X[58.6%]/46,XY[41.4%]. Retrospective karyotype analysis indicated that the female patient's sSMC was inherited from her father's small chrY. Customized FISH probe of Yq12 microdeletion was positive, indicating that the sSMC was a del(Y)(q12). Based on the results of genetic diagnosis, the specialist doctor gave a comprehensive genetic consultation and ordered regular follow-up examinations.ConclusionsThe findings of the current study showed that the chromosome description of the unique Turner case was mos 45,X[56.5%]/46,X,del(Y)(q12)[43.5%]. FISH technology played a key role in diagnosis of mosaicism. The terminal deletion of mosaic chrY provided a scientific and an accurate explanation for masculinity failure and abnormal sexual development of the current case.

Methane gas hydrates (GHs) are polyhedral crystalline guest-host materials found under high pressure and low-temperature conditions, which can serve as an energy source. Previous work on methane GH material physics was limited to simple linear models, which only involves second-order elasticity. However, this is not fully suited to high-stress load conditions in technological applications and fundamental material physics. For other material systems, it has been demonstrated that third-order elasticity and pressure derivatives of second-order elasticity have a strong and hence significant correlation. To narrow a critical theory-simulation gap in gas hydrates materials research, in this work we expand prior work from second-order elastic constants (SOECs) to third-order elastic constants (TOECs). By using the open-source Python tool Elastic3rd and the DFT calculation software Vienna Ab initio Simulation Package (VASP), we found that the non-linear fitting involving TOECs gave a better overall prediction and a smaller root-mean-square deviation on pressure-strain evaluation when compared with linear fitting. In addition, the non-linear fitting provides robust results on the piezo-effect on the shear constant C _44 and the ductile-to-brittle transition (P = −0.5 GPa). These results are not achievable from previous work based on a linear model and these findings prove that non-linear models, including TOECs, are needed under high pressures. In addition, this research includes a detailed analysis of the calculation of TOECs and mechanical properties to study pressure stability limits and ductile-brittle transitions. Together the results, findings, and analyses from this work are a novel and significant contribution to the material physics knowledge of gas hydrates and hydrogen-bonded crystalline materials.

Nowadays, the contradiction between strict construction land supply restriction and excessive construction land demand is extremely prominent. Construction land reduction (CLR) is a policy innovation for economically developed regions designed to solve the tight constraints of the construction land quota as urban development continues in China, however, it leads to a lack of spatial justice. In this study, we address a gap in land use regulation literature regarding regional economic development in fast-developing nations by presenting a quantitative investigation of spatial justice in Shanghai, China. We theoretically analyze the connotation of spatial justice in CLR and its influence on residents’ policy acceptance of CLR. Based on theoretical analysis and using household questionnaires from JJ Town in W District, Shanghai, China, we investigate how spatial justice affects residents’ policy acceptance of CLR through an ordered probit model. The results show that (1) spatial justice strengthens residents’ policy acceptance of CLR; (2) both policy familiarity and participation are important influencing factors that contribute to residents’ policy acceptance of CLR; (3) age, education, household income, the contracting land scale and household population structure also affect residents’ policy acceptance of CLR. (4) Robustness tests support the above findings. Thus, in the process of CLR, it is essential to fully consider the realization of spatial justice to ensure the development of remote suburbs, especially the regions experiencing a net reduction in their construction land.

Abstract Li‐CO2 battery has attracted extensive attention and research due to its super high theoretical energy density and its ability to fix greenhouse gas CO2. However, the slow reaction kinetics during discharge/charge seriously limits its development. Hence, a simple cation exchange strategy is developed to introduce Ru atoms onto a Co3O4 nanosheet array grown on carbon cloth (SA Ru‐Co3O4/CC) to prepare a single atom site catalyst (SASC) and successfully used in Li‐CO2 battery. Li‐CO2 batteries based on SA Ru‐Co3O4/CC cathode exhibit enhanced electrochemical performances including low overpotential, ultra high capacity, and long cycle life. Density functional theory calculations reveal that single atom Ru as the driving force center can significantly enhance the intrinsic affinity for key intermediates, thus enhancing the reaction kinetics of CO2 reduction reaction in Li‐CO2 batteries, and ultimately optimizing the growth pathway of discharge products. In addition, the Bader charge analysis indicates that Ru atoms as electron‐deficient centers can enhance the catalytic activity of SA Ru‐Co3O4/CC cathode for the CO2 evolution reaction. It is believed that this work has important implications for the development of new SASCs and the design of efficient catalyst for Li‐CO2 batteries.

Background: So far, no study has investigated the effects of plasma transfusion in the patients with sepsis, especially in the terms of prognosis. Therefore, we aimed to explore the association of early fresh frozen plasma (FFP) transfusion with the outcomes of patients with sepsis.Methods: We performed a cohort study using data extracted from the Medical Information Mart for Intensive Care III database (v1.4). External validation was obtained from the First Affiliated Hospital of Wenzhou Medical University, China. We adopted the Sepsis-3 criteria to extract the patients with sepsis and septic shock. The occurrence of transfusion during the first 3-days of intensive care unit (ICU) stay was regarded as early FFP transfusion. The primary outcome was 28-day mortality. We assessed the association of early FFP transfusion with the patient outcomes using a Cox regression analysis. Furthermore, we performed the sensitivity analysis, subset analysis, and external validation to verify the true strength of the results.Results: After adjusting for the covariates in the three models, respectively, the significantly higher risk of death in the FFP transfusion group at 28-days [e.g., Model 2: hazard ratio (HR) = 1.361, P = 0.018, 95% CI = 1.054–1.756] and 90-days (e.g., Model 2: HR = 1.368, P = 0.005, 95% CI = 1.099–1.704) remained distinct. Contrarily, the mortality increased significantly with the increase of FFP transfusion volume. The outcomes of the patients with sepsis with hypocoagulable state after early FFP transfusion were not significantly improved. Similar results can also be found in the subset analysis of the septic shock cohort. The results of external validation exhibited good consistency.Conclusions: Our study provides a new understanding of the rationale and effectiveness of FFP transfusion for the patients with sepsis. After recognizing the evidence of risk-benefit and cost-benefit, it is important to reduce the inappropriate use of FFP and avoid unnecessary adverse transfusion reactions.

Number 3 Prescription (WD-3) is an herbal remedy used in traditional Chinese medicine that has been shown to improve the outcomes of patients with advanced colon and gastric cancers. This study aimed to investigate the effect of WD-3 on proliferation, glycolysis, and hexokinase 2 expression in breast cancer cells. Four breast cancer cell lines (MDA-MB-231, BT-549, MCF-7, and MCF-7/ADR-RES) were treated with different concentrations of WD-3 compared with blank control (phosphate-buffered saline). Each of the breast cancer cell lines was also divided into WD-3, paclitaxel, and blank control group. Cell proliferation and morphology were assessed by MTT assay, nuclear Hoechst 33258 staining, or immunofluorescence. Apoptosis was analyzed by flow cytometry. High performance liquid chromatography was used for measurement of ATP, ADP, and AMP. Hexokinase 2 expression was analyzed by Western blot and quantitative reverse transcription PCR. WD-3 inhibited proliferation and increased apoptosis in all four breast cancer cell lines, in a dose-dependent manner. ATP and EC (energy charge) were significantly decreased in WD-3-treated BT-549 and MDA-MB-231 cells. WD-3 significantly downregulated the protein and mRNA expression of hexokinase II in BT-549 cells, however, not in the other three breast cancer cell lines. Our findings indicate that WD-3 targets the glycolytic pathway in breast cancer cells to exert its antitumor activity.

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants, which is characterized by alveolar and vascular dysplasia and increased vascular permeability. Hyperoxia is a critical factor in the pathogenesis of BPD, hyperoxia-induced acute lung injury (HALI) model has similar pathological manifestations as human BPD, therefore, may provide insight into the pathogenesis of human BPD. Studies have shown that Twist1 regulates pulmonary vascular permeability of LPS-induced lung injury through the Ang-Tie2 pathway. However, the effect of Twist1 pathway on vascular permeability in HALI has not been reported.Methods: We randomly exposed newborn rats to the room air or hyperoxia for 14 days. Lung histopathology, immunofluorescence, vascular permeability, mRNA and protein expression was assessed on day 1,7,14.Results: Our results verified that hyperoxia caused alveolar and vascular developmental disorders and increased pulmonary vascular permeability, which was consistent with previous findings. In hyperoxia-exposed rat lungs, the expressions of Twist1, Ang1, Tie1, Tie2, and pTie2 were significantly reduced, whereas the expression of Ang2 was significantly increased. Next, we observed a significant down-regulation of the Akt/Foxo1 pathway.Conclusion: In HALI, the pulmonary microvascular permeability was increased, accompanied by changes in Twist1-Tie2 pathway which combined to Angs, and downregulation of Tie1 and Akt/Foxo1 pathway.

Abstract Background Biomaterials could affect the inflammation reaction and wound healing via the activation and polarization of macrophages. However, the influence of iRoot SP and mineral trioxide aggregate (MTA) on macrophage polarization under inflammatory conditions was not reported although these two root filling materials have been applied extensively in patients undergoing endodontic treatment. Therefore, the present study aimed to explore the mechanism how iRoot SP and MTA affect the cell behavior of RAW 264.7 macrophages when stimulated by lipopolysaccharide (LPS) in vitro. Methods The gene expression of three main related pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) was examined by quantitative real-time polymerase chain reaction (qRT-PCR) in RAW 264.7 macrophages when stimulated by iRoot SP and MTA in the presence of LPS. The protein expression of the M1 and M2 phenotype specific markers, CD11c and CD206, was assessed by immunofluorescence and flow cytometry in RAW 264.7 macrophages. Results LPS promoted the expression of IL-1β, TNF-α, and IL-6 in RAW 264.7 macrophages as compared to the control group. Both iRoot SP and MTA were significantly able to enhance the expression of IL-1β, TNF-α, and IL-6 in RAW 264.7 macrophages as compared to LPS group. LPS could increase the expression of CD11c as compared to the control group while iRoot SP and MTA were able to enhance the expression of both CD11c and CD206 as compared to LPS group. Conclusions iRoot SP and MTA could potentially promote the release of pro-inflammatory cytokines in RAW 264.7 macrophages and induce into M1/M2 phenotype when cultured with LPS.

Voltage control of magnetism in ferromagnetic semiconductor is appealing for spintronic applications, which is yet hindered by compound formation and low Curie temperature. Here, Nie et al. report electric-field control of ferromagnetism in MnxGe1−xnanomeshes with a Curie temperature above 400 K and controllable giant magnetoresistance.

BACKGROUND: PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines. Loss of Shp2 promotes hepatocellular carcinoma (HCC), suggesting that PTPN11 functions as a tumor suppressor in HCC tumorgenesis. The aim of this study was to evaluate the effects of the short tandem repeat (STR) polymorphism (rs199618935) within 3'UTR of PTPN11 on HCC susceptibility in Chinese populations. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the associations in 400 patients from Jiangsu province of China, validating the findings in an additional 305 patients from Shanghai of China. Unconditional logistic regression was used to analyze the association between rs199618935 and HCC risk. Additional biochemical investigations and in-silico studies were used to evaluate the possible functional significance of this polymorphism. Logistic regression analysis showed that compared with individuals carrying shorter alleles (11 and 12 repeats), those subjects who carry longer alleles (13 and 14 repeats) had a significantly decreased risk of HCC [adjusted odds ratio (OR) = 0.63, 95% confidence interval (CI) = 0.53-0.76, P = 2.00 × 10(-7)], with the risk decreased even further in those carrying allele 15 and 16 (adjusted OR = 0.46, 95% CI = 0.34-0.62, P = 1.00 × 10(-7)). Biochemical investigations showed that longer alleles of rs199618935 conferred higher PTPN11 expression in vivo and in vitro. The altered luciferase activities in reporter gene system suggested that STR regulation of PTPN11 expression could be a transcriptional event. Finally, in-silico prediction revealed that different alleles of rs199618935 could alter the local structure of PTPN11 mRNA. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings suggested that the STR polymorphism within PTPN11 contributes to hepatocarcinogenesis, possibly by affecting PTPN11 expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our findings.