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Abstract Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD.

Abstract Stem cell-derived exosomes exert comparable therapeutic effects to those of their parental stem cells without causing immunogenic, tumorigenic, and ethical disadvantages. Their therapeutic advantages are manifested in the management of a broad spectrum of diseases, and their dosing versatility are exemplified by systemic administration and local delivery. Furthermore, the activation and regulation of various signaling cascades have provided foundation for the claimed curative effects of exosomal therapy. Unlike other relevant reviews focusing on the upstream aspects (e.g., yield, isolation, modification), and downstream aspects (e.g. phenotypic changes, tissue response, cellular behavior) of stem cell-derived exosome therapy, this unique review endeavors to focus on various affected signaling pathways. After meticulous dissection of relevant literature from the past five years, we present this comprehensive, up-to-date, disease-specific, and pathway-oriented review. Exosomes sourced from various types of stem cells can regulate major signaling pathways (e.g., the PTEN/PI3K/Akt/mTOR, NF-κB, TGF-β, HIF-1α, Wnt, MAPK, JAK-STAT, Hippo, and Notch signaling cascades) and minor pathways during the treatment of numerous diseases encountered in orthopedic surgery, neurosurgery, cardiothoracic surgery, plastic surgery, general surgery, and other specialties. We provide a novel perspective in future exosome research through bridging the gap between signaling pathways and surgical indications when designing further preclinical studies and clinical trials.

Abstract TDP-43 is implicated in the dynamic formation of nuclear bodies and stress granules through phase separation. In diseased states, it can further condense into pathological aggregates in the nucleus and cytoplasm, contributing to the onset of amyotrophic lateral sclerosis. In this study, we evaluate the effect of graphene quantum dots (GQDs) with different functional groups on TDP-43’s phase separation and aggregation in various cellular locations. We find that halogen atom-doped GQDs (GQDs-Cl, Cl-GQDs-OH) penetrate the nuclear envelope, inhibiting the assembly of TDP-43 nuclear bodies and stress granules under oxidative stress or hyperosmotic environments, and reduce amyloid aggregates and disease-associated phosphorylation of TDP-43. Mechanistic analysis reveals GQDs-Cl and Cl-GQDs-OH modulate TDP-43 phase separation through hydrophobic and electrostatic interactions. Our findings highlight the potential of GQDs-Cl and Cl-GQDs-OH in modulating nuclear protein condensation and pathological aggregation, offering direction for the innovative design of GQDs to modulate protein phase separation and aggregation.

Abstract The shortage of organs for transplantation emphasizes the urgent need for alternative solutions. Xenotransplantation has emerged as a promising option due to the greater availability of donor organs. However, significant hurdles such as hyperacute rejection and organ ischemia–reperfusion injury pose major challenges, largely orchestrated by the complement system, and activated immune responses. The complement system, a pivotal component of innate immunity, acts as a natural barrier for xenotransplantation. To address the challenges of immune rejection, gene-edited pigs have become a focal point, aiming to shield donor organs from human immune responses and enhance the overall success of xenotransplantation. This comprehensive review aims to illuminate strategies for regulating complement networks to optimize the efficacy of gene-edited pig xenotransplantation. We begin by exploring the impact of the complement system on the effectiveness of xenotransplantation. Subsequently, we delve into the evaluation of key complement regulators specific to gene-edited pigs. To further understand the status of xenotransplantation, we discuss preclinical studies that utilize gene-edited pigs as a viable source of organs. These investigations provide valuable insights into the feasibility and potential success of xenotransplantation, offering a bridge between scientific advancements and clinical application.

BackgroundThe first-line treatment for advanced hepatocellular carcinoma has evolved significantly. This study aimed to identify the most beneficial regimen.MethodsA systematic search was conducted from July 2012 to August 2024 across the following four databases: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. This search focused on phase III prospective randomized controlled trials that compared first-line treatment for advanced hepatocellular carcinoma.ResultsSeventeen studies involving 10322 patients were included in this network meta-analysis. Of the studies we included, twelve studies were global multicenter clinical studies, four were initiated in China, and one was initiated in Korea. The results of our statistical analysis suggest that Hepatic artery infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) demonstrated significant overall survival (OS) benefits compared with most treatments, including various immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). In terms of OS, HAIC had shown similar efficacy with sorafenib plus FOLFOX (HR, 0.88; 95% CI: 0.37-2.09) and transcatheter arterial chemoembolization (TACE) combined with lenvatinib (HR, 0.69; 95% CI: 0.30-1.56). Notably, immune-related treatments, such as ICIs combined with anti-VEGF therapies, also showed improved OS compared with anti-VEGF-TKIs alone. In terms of progression-free survival (PFS), HAIC-FO outperformed anti-VEGF-TKI monotherapy, ICI monotherapy, and several ICI combinations. However, it was not superior to lenvatinib plus TACE or lenvatinib plus pembrolizumab. Based on the Surface Under the Cumulative Ranking Curve (SUCRA) values, HAIC-FO was ranked the most effective in terms of OS (SUCRA = 0.961) and objective response rate (ORR) (SUCRA = 0.971). The results of the subgroup analysis suggested that HAIC-FO achieved the best OS benefit in the macrovascular invasion (MVI) and extrahepatic spread (EHS) subgroup (SUCRA = 0.99) and that tremelimumab combined with durvalumab achieved the best OS benefit in the Asian subgroup (SUCRA = 0.88).ConclusionThis systematic review and network meta-analysis suggest that HAIC-based therapies may become a potential first-line treatment option for advanced HCC, especially for patients in Mainland China with MVI and EHS. Additionally, immune-related treatments may be more suitable for Asian populations.

Abstract Background Hyperuricemia and low level of high-density lipoprotein cholesterol (HDL-C) are both risk factors for coronary artery disease (CAD). The uric acid to HDL-C ratio (UHR) has recently been identified as a new inflammatory and metabolic biomarker. However, the relationship between the UHR and coronary culprit plaques has not been fully investigated in patients with acute coronary syndrome (ACS). Methods A total of 346 patients with ACS were enrolled in this study. Culprit lesion characteristics were assessed by optical coherence tomography (OCT). Logistic regression and linear correlation analyses were performed to assess the association between the UHR and culprit plaques. The predictive value of the UHR was investigated by receiver operating characteristic (ROC) curve analysis. Results The percentages of typical culprit plaques, including ruptures, erosions and thrombi, were greater in the high-UHR subgroup than those in the low-UHR subgroup. A positive relationship was also found between the UHR and diameter stenosis (r = 0.160, P = 0.003) and between the UHR and area stenosis (r = 0.145, P = 0.007). The UHR was found to be independently associated with plaque rupture, erosion and thrombus. Furthermore, ROC analysis suggested that the UHR had a better predictive value than low-density lipoprotein cholesterol. Conclusions An elevated UHR level was independently related to the occurrence rate of culprit plaques. The UHR is a simple and easily acquired parameter for detecting culprit plaques in patients with ACS.

Abstract Ultrasound is an acoustic wave which can noninvasively penetrate the skull to deep brain regions, enabling neuromodulation. However, conventional ultrasound’s spatial resolution is diffraction-limited and low-precision. Here, we report acoustic nanobubble-mediated ultrasound stimulation capable of localizing ultrasound’s effects to only the desired brain region in male mice. By varying the delivery site of nanobubbles, ultrasound could activate specific regions of the mouse motor cortex, evoking EMG signaling and limb movement, and could also, separately, activate one of two nearby deep brain regions to elicit distinct behaviors (freezing or rotation). Sonicated neurons displayed reversible, low-latency calcium responses and increased c-Fos expression in the sub-millimeter-scale region with nanobubbles present. Ultrasound stimulation of the relevant region also modified depression-like behavior in a mouse model. We also provide evidence of a role for mechanosensitive ion channels. Altogether, our treatment scheme allows spatially-targetable, repeatable and temporally-precise activation of deep brain circuits for neuromodulation without needing genetic modification.

BackgroundSleep quality is one of the important factors affecting soldiers’ task performance. ObjectiveTo explore the effects of mindful attention awareness, burnout, and occupational stress on sleep quality among soldiers in plateau areas. MethodsA total of 1090 soldiers were selected from four units in plateau areas by cluster sampling method and were asked to participate a cross-sectional questionnaire survey using the Pittsburgh Sleep Quality Index (PQSI), Occupational Stress Inventory (OSI), Maslach Burnout Inventory-General Survey (MBI-GS), and Mindful Attention Awareness Scale (MAAS). Correlation analysis, regression analysis, and mediated effect test were conducted for the study. ResultsOf the 1090 soldiers recruited, 1082 soldiers returned valid questionnaires, and the valid recovery rate was 99.26%. The median (P25, P75) score of PSQI was 4.00 (2.00,7.00), the median score of OSI was 26.00 (17.00, 34.00), the median score of MBI-GS was 3.53 (3.13, 4.00), and the median score of MAAS was 71.00 (59.00, 82.00). The burnout and mindful attention awareness levels varied among military personnel of different age groups (P

Abstract Purposes Radiotherapy can induce tumor cell autophagy, which might impair the antitumoral effect. This study aims to investigate the effect of autophagy inhibition on the targeted radionuclide therapy (TRT) efficacy of 131I-FAP-2286 in pancreatic cancer. Methods Human pancreatic cancer PANC-1 cells were exposed to 131I-FAP-2286 radiotherapy alone or with the autophagy inhibitor 3-MA. The autophagy level and proliferative activity of PANC-1 cells were analyzed. The pancreatic cancer xenograft-bearing nude mice were established by the co-injection of PANC-1 cells and pancreatic cancer-associated fibroblasts (CAFs), and then were randomly divided into four groups and treated with saline (control group), 3-MA, 131I-FAP-2286 and 131I-FAP-2286 + 3-MA, respectively. SPECT/CT imaging was performed to evaluate the bio-distribution of 131I-FAP-2286 in pancreatic cancer-bearing mice. The therapeutic effect of tumor was evaluated by 18F-FDG PET/CT imaging, tumor volume measurements, and the hematoxylin and eosin (H&E) staining, and immunohistochemical staining assay of tumor tissues. Results 131I-FAP-2286 inhibited proliferation and increased the autophagy level of PANC-1 cells in a dose-dependent manner. 3-MA promoted 131I-FAP-2286-induced apoptosis of PANC-1 cells via suppressing autophagy. SPECT/CT imaging of pancreatic cancer xenograft-bearing nude mice showed that 131I-FAP-2286 can target the tumor effectively. According to 18F-FDG PET/CT imaging, the tumor growth curves and immunohistochemical analysis, 131I-FAP-2286 TRT was capable of suppressing the growth of pancreatic tumor accompanying with autophagy induction, but the addition of 3-MA enabled 131I-FAP-2286 to achieve a better therapeutic effect along with the autophagy inhibition. In addition, 3-MA alone did not inhibit tumor growth. Conclusions 131I-FAP-2286 exposure induces the protective autophagy of pancreatic cancer cells, and the application of autophagy inhibitor is capable of enhancing the TRT therapeutic effect.

Abstract Doxorubicin (DOX) is a popular and potent anticancer drug, but its cardiotoxicity limits its clinical application. Shikonin has a wide range of biological functions, including antioxidant and anti-inflammatory effects. The aim of this study was to investigate the effects of shikonin on DOX-induced cardiac injury and to identify the underlying mechanisms. Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration. Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis. Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In conclusion, shikonin alleviates DOX-induced cardiotoxicity by inhibiting Mst1 and activating Nrf2. Shikonin may be used to treat DOX-induced cardiac injury.

Aim Tripterygium wilfordii Hook F (TwHF) has been shown to substantially reduce proteinuria in patients with diabetic kidney disease (DKD); however, the effect of TwHF on renal outcomes in DKD remains unknown. Accordingly, we aimed to establish the effects of TwHF on renal outcomes in patients with DKD.Methods Overall, 124 patients with DKD, induced by type 2 diabetes mellitus, with 24-h proteinuria > 2 g, and an estimated glomerular filtration rate > 30 mL/min/1.73 m2 were retrospectively investigated. The renal outcomes were defined as doubling serum creatinine levels or end-stage kidney disease. Kaplan-Meier curves and Cox regression analyses were performed to analyze prognostic factors for renal outcomes.Results By the end of the follow-up, renal outcomes were observed in 23 and 11 patients in the non-TwHF and TwHF groups, respectively (p = 0.006). TwHF significantly reduced the risk of renal outcomes (adjusted hazard ratio [HR] 0.271, 95% confidence interval [CI] 0.111–0.660, p = 0.004) in patients with chronic kidney disease (CKD) G3 (adjusted HR 0.274, 95%CI 0.081–0.932, p = 0.039). Based on the Kaplan-Meier analysis, 1- and 3-year proportions of patients without renal outcomes were significantly lower in the non-TwHF group than those in the TwHF group (92.8% vs. 95.5% and 47.2% vs. 76.8%, respectively; p = 0.0018).Conclusion In DKD patients with severe proteinuria, TwHF could prevent DKD progression, especially in patients with CKD G3. A randomized clinical trial is needed to elucidate the benefits of TwHF on renal outcomes in patients with DKD.

Over the past decades, cancer immunotherapy has encountered challenges such as immunogenicity, inefficiency, and cytotoxicity. Consequently, exosome-based cancer immunotherapy has gained rapid traction as a promising alternative. Exosomes, a type of extracellular vesicles (EVs) ranging from 50 to 150 nm, are self-originating and exhibit fewer side effects compared to traditional therapies. Exosome-based immunotherapy encompasses three significant areas: cancer vaccination, co-inhibitory checkpoints, and adoptive T-cell therapy. Each of these fields leverages the inherent advantages of exosomes, demonstrating substantial potential for individualized tumor therapy and precision medicine. This review aims to elucidate the reasons behind the promise of exosome-based nanoparticles as cancer therapies by examining their characteristics and summarizing the latest research advancements in cancer immunotherapy.

A diagnosis based on multiple nuclear medicine imaging (NMI) was more comprehensive in approaching the nature of pathological changes. In this research, a method to realize triple NMIs within one day was developed based on the reasonable arrangements of 68Ga-RGD PET/CT specialized on neovascularization, 99mTc-HL-91 SPECT/CT specialized on hypoxia and 18F-FDG PET/CT specialized on tumor metabolism. Feasibility was verified in evaluating the therapeutic effects of transarterial embolization (TAE) performed on rabbit models with VX2 tumor. Radiation dosimetry was carried out to record the radiation exposure from multiple injections of radiopharmaceuticals. In results, the one-day examination of triple NMIs manifested the diversity of the postoperative histological changes, including the local neovascularization induced by embolization, hypoxic state of embolized tissues, and suppression of tumor metabolism. More importantly, radiation dosage from radiopharmaceuticals was limited below 5.70 ± 0.90 mSv. In conclusion, the strong timeliness and complementarity of one-day examination of triple nuclear medicine imaging made it clinically operative and worthy of popularizing. There was flexibility in combining distinct NMIs according to the clinical demands, so as to provide comprehensive information for diagnosis.

In the quest to address the critical shortage of donor organs for transplantation, xenotransplantation stands out as a promising solution, offering a more abundant supply of donor organs. Yet, its widespread clinical adoption remains hindered by significant challenges, chief among them being immunological rejection. Central to this issue is the role of the complement system, an essential component of innate immunity that frequently triggers acute and chronic rejection through hyperacute immune responses. Such responses can rapidly lead to transplant embolism, compromising the function of the transplanted organ and ultimately causing graft failure. This review delves into three key areas of xenotransplantation research. It begins by examining the mechanisms through which xenotransplantation activates both the classical and alternative complement pathways. It then assesses the current landscape of xenotransplantation from donor pigs, with a particular emphasis on the innovative strides made in genetically engineering pigs to evade complement system activation. These modifications are critical in mitigating the discordance between pig endogenous retroviruses and human immune molecules. Additionally, the review discusses pharmacological interventions designed to support transplantation. By exploring the intricate relationship between the complement system and xenotransplantation, this retrospective analysis not only underscores the scientific and clinical importance of this field but also sheds light on the potential pathways to overcoming one of the major barriers to the success of xenografts. As such, the insights offered here hold significant promise for advancing xenotransplantation from a research concept to a viable clinical reality.

The role of cellular senescence in age-related diseases has been fully recognized. In various age-related-chronic lung diseases, the function of alveolar epithelial cells (AECs) is impaired and alveolar regeneration disorders, especially in bronchopulmonary dysplasia，pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), cancer, etc. Except for age-related-chronic lung diseases, an increasing number of studies are exploring the role of cellular senescence in developmental chronic lung diseases, which typically originate in childhood and even in the neonatal period. This review provides an overview of cellular senescence and lung diseases from newborns to the elderly, attempting to draw attention to the relationship between cellular senescence and developmental lung diseases.

Background: The potential effects of the very effective cystic fibrosis triple combination drug, Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pregnancy on prenatal development of offspring remain largely unknown. Research question: We aimed to investigate the fetal tissue distribution pattern of maternally administered ETI by placental transfer in the rat fetuses. Study design and methods: Sprague Dawley pregnant rats were administered ETI (6.7 mg/kg/d elexacaftor + 3.5 mg/kg/d tezacaftor + 25 mg/kg/d ivacaftor) traced with [3 H]-ivacaftor in single dose acute experiments (intraperitoneal injection) or treated orally with ETI (the same dose) for 7 days in sub-chronic experiments. Fetal tissue samples were collected at embryonic day (E) 19 and analyzed using liquid scintillation counting for acute experiments or liquid chromatography-mass spectrometry for sub-chronic experiments. Results: On day E19, after acute exposure, the entry of ivacaftor into fetal brain (brain/plasma concentration ratios 100%). However, after sub-chronic exposure, the entry of all 3 components into the developing brain was comparably extensive as into other tissues (tissue/plasma ratios, 260 – 1000%). Each component of ETI accumulated in different fetal tissues to approximately equal extent. Inter-litter differences on fetal drug distribution were found in cortex for ivacaftor, muscle for tezacaftor and cortex and mid/hindbrain for elexacaftor. Fetal plasma concentrations of ETI (ng/mL) were variable between litters. The entry of ivacaftor and tezacaftor into adult brain appeared to be restricted (

Head and neck cancer (HNC) is the seventh most prevalent cancer globally, often characterized by chemo-resistance and immunosuppression, which significantly hampers treatment efficacy. Cold atmospheric plasma (CAP) has recently emerged as a promising adjuvant oncotherapy with substantial potential and advantages. In this study, Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. We aimed to investigate the effects of CAPPZ2 on various types of HNC cells and elucidate the underlying mechanisms. In addition, we endeavored to examine the efficacy of combining CAPPZ2 with chemotherapy drugs (i.e., cisplatin) or immune checkpoint blockade (ICB, i.e., PD1 antibody) in HNC treatment. Firstly, the results demonstrated that CAPPZ2 exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promoting apoptosis and autophagy. Secondly, using transcriptomic sequencing, Western blotting, and quantitative real-time PCR, the mechanisms underlying CAPPZ2 treatment in vitro was presumed to be a multitargeted blockade of major cancer survival pathways, such as redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling. Lastly, combinatorial thearpy containing CAPPZ2 and cisplatin or PD-1 antibody significantly suppressed tumor growth and prolonged recipient survival in vivo. Collectively, the synergistic effects of CAPPZ2 and cisplatin or PD-1 antibody could serve as a promising solution to enhance head and neck tumor elimination.

Abstract Background Gaucher disease (GD) is a rare autosomal recessive inherited, lysosomal storage disoder that involves liver, spleen, lung, bone, bone marrow even central nervous. However, GD associated membranoproliferative glomerulonephritis (MPGN) is seldom reported. Case presentation Here we described a case of 35-year-old man suffering from GD with hepatosplenomegaly, ascites, bone destruction, myelofibrosis and MPGN. Renal biopsy revealed MPGN and Gaucher cells presented in the glomeruli capillaries. β-glucosidase activity was 1.95nmol/1 h/mg and gene detection demonstrated that one homozygous pathogenic variant Leu483Pro in GBA. He received the treatment of oral prednisone and mycophenolate mofetil and his ascites and renal outcomes had been significantly improved. Conclusions Therapy of prednisone and mycophenolate mofetil may be an optional choice for patients with Gaucher disease who have no opportunity to use enzyme treatment.

Background: Vascular health is increasingly recognized for its roles in the pathogenesis and progression of Alzheimer’s disease (AD). The objective of this study was to investigate effects of exercise training, dose, and cardiorespiratory fitness (CRF) on neurotrophic factors in community-dwelling, older adults with mild-to-moderate AD dementia. Methods: This was a pilot blood ancillary study of the FIT-AD trial. Participants in the parent study were randomized to 6-month aerobic exercise (AEx) or stretching control. For this ancillary study, resting plasma brain-derived neurotrophic factor (BDNF), irisin, fibroblast growth factor-21 (FGF-21), and insulin-like growth factor-1 (IGF-1) biomarkers were assessed at baseline, 3, and 6 months. Estimates of within- and between- group effect sizes were calculated (Cohen’s d). Relationships of biomarker change with dose and CRF change were explored with multivariable linear regression and repeated measures correlations. Results: The sample (n = 26, 18 AEx/8 stretching) averaged 77.6 ± 6.9 years old, with the majority being male (65.4%), and non-Hispanic White (92.3%); between-group effect sizes were generally small except for irisin (d = −0.44)), AEx group relative to stretching group. Associations of dose and changes in CRF with changes in neurotrophic biomarker were weak (r2 ≤ 0.025). Conclusions: The effects of exercise on BDNF, irisin, IGF-1, and FGF-21 were heterogeneous in AD. Our findings need validation in future, adequately powered exercise studies in AD.

Abstract Background The excellent physicochemical and biomedical properties make silk fibroin (SF) suitable for the development of biomedical materials. In this research, the silk fibroin microspheres (SFMS) were customized in two size ranges, and then carried gold nanoparticles or doxorubicin to evaluate the performance of drug loading and releasing. Embolization efficiency was evaluated in rat caudal artery and rabbit auricular artery, and the in vivo distribution of iodinated SFMS (125I/131I-SFMS) after embolization of rat hepatic artery was dynamically recorded by SPECT. Transhepatic arterial radioembolization (TARE) with 131I-SFMS was performed on rat models with liver cancer. The whole procedure of selective internal radiation was recorded with SPECT/CT, and the therapeutic effects were evaluated with 18 F-FDG PET/CT. Lastly, the enzymatic degradation was recorded and followed with the evaluation of particle size on clearance of sub-micron silk fibroin. Results SFMS were of smooth surface and regular shape with pervasive pores on the surface and inside the microspheres, and of suitable size range for TAE. Drug-loading functionalized SFMS with chemotherapy or radio-sensitization, and the enhanced therapeutic effects were proved in treating HUH-7 cells as lasting doxorubicin release or more lethal radiation. For artery embolization, SFMS effectively blocked the blood supply; when 131I-SFMS serving as the embolic agent, the good labeling stability and embolization performance guaranteed the favorable therapeutic effects in treating in situ liver tumor. At the 5th day post TARE with 37 MBq/3 mg 131I-SFMS per mice, tumor activity was quickly inhibited to a comparable glucose metabolism level with surrounding normal liver. More importantly, for the fragments of biodegradable SFMS, smaller sized SF ( 800 nm) entered the liver within 72 h for further metabolism. Conclusion The feasibility of SFMS as degradable TARE agent for liver cancer was primarily proved as providing multiple therapeutic potentials. Graphical abstract

Agricultural production contributes to the increase in global carbon emissions. It is crucial to improve output and reduce carbon emissions in the context of agricultural modernization, for which improved carbon emission efficiency is key. However, the role of agricultural modernization in promoting agricultural carbon emission efficiency is not clear. Hence, the aim of this article is to analyze the spatiotemporal evolution of agricultural modernization and agricultural carbon emission efficiency in China from 2000 to 2019 and to reveal the relationship between agricultural modernization and agricultural carbon emission efficiency. The results showed that (1) in China, the overall level of agricultural modernization has been steadily increasing, and the regional differences are widening, showing a spatial pattern characterized by a gradual decline from the eastern and central regions to the western region. (2) China’s agricultural carbon emission efficiency continues to grow but has not achieved a data envelopment analysis (DEA) effect, with the eastern and western regions having higher agricultural carbon efficiency than the central region. The regional differences first narrow and then expand. (3) Agricultural modernization significantly promotes agricultural carbon emission efficiency in both the province and the neighboring provinces, and the interprovincial spillover effect exceeds the direct effect within the province. A nonlinear correlation exists between agricultural modernization and agricultural carbon emission efficiency.

An accurate analysis of the relationship between humans and the land in oasis areas is essential for the formulation of policies for differentiated oasis urban development and resource management measures. Therefore, researchers have conducted numerous studies based on the linear relationship between “people and land” in oasis areas. To address this gap, this paper takes the Wuwei oasis as an example and re-examines the impact of human activities on the sustainability of natural capital from a new research perspective (nonlinear perspective). The study selected four variables, namely planted forests, scientific R&D investment, urbanization, and population density, as the main human activities affecting the Wuwei oasis area. The NARDL model, the nonlinear Granger causality test, is employed to investigate the interactions between the variables and the oasis natural capital in both the short and long term. The results indicate the following: (1) During the study period, the consumption of natural capital in the Wuwei oasis has been increasing annually and has long exceeded the local ecological carrying capacity. (2) In the short term, planting forests is the most beneficial human activity. The most beneficial human activity is the planting of trees, while in the long term, scientific R&D investment has the most positive effect on enhancing the oasis’ resource reserves. (3) Urbanization, population density, and planted forest land all have a direct effect on the sustainable development of natural resources in the oasis. The findings of the study indicate that the application of scientific and technological innovation to promote the sustainable development of resources and the environment is a more reliable approach for oasis cities with a high degree of industrialization.

Abstract Background Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease in preterm infants with pathological characteristics of arrested lung development. DNA double-strand breaks (DSBs) are a serious manifestation of oxidative stress damage, but little is known about the role of DSBs in BPD. The current study set out to detect DSB accumulation and cell cycle arrest in BPD and study the expression of genes related to DNA damage and repair in BPD through DNA damage signaling pathway-based PCR array to determine a suitable target to improve arrested lung development associated with BPD. Methods DSB accumulation and cell cycle arrest were detected in a BPD animal model and primary cells, then a DNA damage signaling pathway-based PCR array was used to identify the target of DSB repair in BPD. Results DSB accumulation and cell cycle arrest were shown in BPD animal model, primary type II alveolar epithelial cells (AECII) and cultured cells after exposure to hyperoxia. Of the 84 genes in the DNA damage-signaling pathway PCR array, eight genes were overexpressed and 11 genes were repressed. Rad1, an important protein for DSB repair, was repressed in the model group. Real-time PCR and western blots were used to verify the microarray results. Next, we confirmed that silencing Rad1 expression aggravated the accumulation of DSBs and cell cycle arrest in AECII cells, whereas its overexpression alleviated DSB accumulation and cell cycle arrest. Conclusions The accumulation of DSBs in AECII might be an important cause of alveolar growth arrest associated with BPD. Rad1 could be an effective target for intervention to improve this arrest in lung development associated with BPD.

The properties of asphalt binder play an essential role in the design life of asphalt pavement. Analysis of asphalt mechanical behaviors based on the chemical structures provides the theoretical basis for the improvement of asphalt performance in service life. Intermolecular interactions have a significant impact on the macroscopic properties of asphalt, a colloidal material, resulting in the parameters characterizing asphalt molecular structures fail to directly connect with mechanical properties of asphalt. This paper introduces the supramolecular theory, presents a brief review of existing supramolecular models and research methods of asphalt, aiming to explore a new methodology for the investigation between asphalt microstructures and macroscopic properties. Results showed the supramolecular theory focuses on the intermolecular interactions, providing more accurate indicators for the investigation on the asphalt supramolecules. Supramolecular analysis of asphalt has proposed feasible methods and established favorable connections with asphalt properties, giving a new view of understanding asphalt microstructure and a new approach to capture mechanical behaviors of asphalt.

Abstract Malignant breast cancer (BC) remains incurable mainly due to the cancer cell metastasis, which is mostly related to the status of Estrogen receptor alpha (ERα). However, our understanding of the mechanisms through which ERα regulates cancer cell metastasis remains limited. Here we identified a miR-29a-PTEN-AKT axis as a downstream signaling pathway of ERα governing breast cancer progression and metastasis. Two estrogen response element (ERE) half sites were identified in the promoter and enhancer regions of miR-29a, which mediated transcriptional regulation of miR-29a by ERα. Low level of miR-29a showed association with reduced metastasis and better survival in ERα+ luminal subtype of BC. In contrast, high level of miR-29a was detected in ERα- triple negative breast cancer (TNBC) in association with distant metastasis and poor survival. miR-29a overexpression in BC tumors increased the number of circulating tumor cells and promoted lung metastasis in mice. Targeted knockdown of miR-29a in TNBC cells in vitro or administration of a nanotechnology-based anti-miR-29a delivery in TNBC tumor-bearing mice in vivo suppressed cellular invasion, EMT and lung metastasis. PTEN was identified as a direct target of miR-29a, inducing EMT and metastasis via AKT signaling. A small molecular inhibitor of AKT attenuated miR-29a-induced EMT. These findings demonstrate a novel mechanism responsible for ERα-regulated breast cancer metastasis, and reveal the combination of ERα status and miR-29a levels as a new risk indicator in BC.

Cardiovascular disease remains the leading cause of death and morbidity worldwide. Inflammatory responses after percutaneous coronary intervention led to neoathrosclerosis and in-stent restenosis and thus increase the risk of adverse clinical outcomes. In this work, a metabolism reshaped surface is engineered, which combines the decreased glycolysis promoting, M2-like macrophage polarization, and rapid endothelialization property. Anionic heparin plays as a linker and mediates cationic SEMA4D and VEGF to graft electronically onto PLL surfaces. The system composed by anticoagulant heparin, immunoregulatory SEMA4D and angiogenic VEGF endows the scaffold with significant inhibition of platelets, fibrinogen and anti-thrombogenic properties, also noteworthy immunometabolism reprogram, anti-inflammation M2-like polarization and finally leading to rapid endothelializaiton performances. Our research indicates that the immunometabolism method can accurately reflect the immune state of modified surfaces. It is envisioned immunometabolism study will open an avenue to the surface engineering of vascular implants for better clinical outcomes.

Purpose: The combination of near-infrared (NIR) and positron emission tomography (PET) imaging presents an opportunity to utilize the benefits of dual-modality imaging for tumor visualization. Based on the observation that fibroblast activation protein (FAP) is upregulated in cancer-associated fibroblasts (CAFs) infiltrating all solid tumors, including head and neck squamous cell carcinoma (HNSCC), we developed the novel PET/NIR probe [68Ga]Ga-FAP-2286-ICG. Preclinically, the specificity, biodistribution and diagnostic properties were evaluated.Methods: Cell uptake assays were completed with the U87MG cell to evaluate the specificity of the [68Ga]Ga-FAP-2286-ICG. The tumor-targeting efficiency, biodistribution and optimal imaging time window of the [68Ga]Ga-FAP-2286-ICG were studied in mice bearing U87MG xenografts. HNSCC tumor-bearing mice were used to evaluate the feasibility of [68Ga]Ga-FAP-2286-ICG for tumor localization and guided surgical resection of HNSCC tumors.Results: The in vitro experiments confirmed that [68Ga]Ga-FAP-2286-ICG showed good stability, specific targeting of the probe to FAP, and the durable retention effect in high-expressing FAP tumors U87MG cell. Good imaging properties such as good tumor uptake, high tumor-to-background ratios (5.44 ± 0.74) and specificity, and tumor contouring were confirmed in studies with mice bearing the U87MG xenograft. PET/CT imaging of the probe in head and neck cancer-bearing mice demonstrated specific uptake of the probe in the tumor with a clear background. Fluorescence imaging further validated the value of the probe in guiding surgical resection and achieving precise removal of the tumor and residual lesions.Conclusion: In a preclinical model, these attractive [68Ga]Ga-FAP-2286-ICG PET/NIR imaging acquired in head and neck cancer make it a promising FAP-targeted multimodal probe for clinical translation.

Oxygen therapy is common during the neonatal period to improve survival, but it can increase the risk of oxygen toxicity. Hyperoxia can damage multiple organs and systems in newborns, commonly causing lung conditions such as bronchopulmonary dysplasia and pulmonary hypertension, as well as damage to other organs, including the brain, gut, and eyes. These conditions are collectively referred to as newborn oxygen radical disease to indicate the multi-system damage caused by hyperoxia. Hyperoxia can also lead to changes in metabolic pathways and the production of abnormal metabolites through a process called metabolic reprogramming. Currently, some studies have analyzed the mechanism of metabolic reprogramming induced by hyperoxia. The focus has been on mitochondrial oxidative stress, mitochondrial dynamics, and multi-organ interactions, such as the lung–gut, lung–brain, and brain–gut axes. In this article, we provide an overview of the major metabolic pathway changes reported in hyperoxia-associated neonatal diseases and explore the potential mechanisms of metabolic reprogramming. Metabolic reprogramming induced by hyperoxia can cause multi-organ metabolic disorders in newborns, including abnormal glucose, lipid, and amino acid metabolism. Moreover, abnormal metabolites may predict the occurrence of disease, suggesting their potential as therapeutic targets. Although the mechanism of metabolic reprogramming caused by hyperoxia requires further elucidation, mitochondria and the gut–lung–brain axis may play a key role in metabolic reprogramming.

Hierarchical porous carbon spheres (HPCS) were synthetized utilizing tannic acid as biomass source and Zn2+ as cross-linking agent. Metal Zn2+ prove to be pivotal in the preparation of materials, which can promote the formation of spherical structure and make materials have both micropores and mesopores. The adsorbent has regular spherical shape, specific surface areas of>1000 m2/g, the maximum adsorption capacity (qmax) of methylene blue is 697 mg/g. It has stable adsorption performance in a broad pH environment (3–11), and the methylene blue removal remains at 91.9% after five cycles. The hierarchical porous structure is beneficial to the immobilization process of methylene blue, and hydrogen bonding, π-π interaction and electrostatic attraction are the main forces for the immobilization of methylene blue. This research offers a promising way for the exploration of biomass-based materials for efficacious dye removal.

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.

The impact of vaccination on the outcomes of dialysis patients with Omicron infections in China remains unknown. This study aimed to examine the relationship between vaccination and hospitalization as well as all-cause mortality. We included patients who had undergone maintenance hemodialysis (HD) for at least three months at our center. The follow-up period spanned from December 2022 to February 2023. We assessed the connections between vaccination and hospitalization as well as all-cause mortality using univariable and multivariable logistic regression models. Receiver operating characteristic (ROC) curves were used to assess the diagnostic accuracy for hospitalization and all-cause mortality. Ultimately, a total of 427 HD patients with confirmed SARS-CoV-2 infections were included. The patients had a mean age of 54 years, and 59.4% of them were male. Prior to the investigation, 108 patients had received vaccinations, with 81 of them having completed or received booster vaccinations. Throughout the follow-up period, 81 patients were admitted to the hospital, and 39 patients died. Multivariable logistic regression revealed that vaccination significantly decreased all-cause mortality (OR 0.25, 95% CI 0.07–1.94, P = .04). Moreover, completed or booster vaccinations were effective in reducing the hospitalization rate (OR 0.41, 95%CI 0.17–0.99, P = .047). It is noteworthy that both unvaccinated and vaccinated individuals experienced mild symptoms, and the hospitalization rates were relatively low in both groups. Despite the reduced pathogenicity of Omicron compared to previous strains in dialysis patients, both vaccinated and unvaccinated, vaccination still provides benefits for improving the prognosis.

Abstract Background Soil salinization is a worldwide environmental problem, especially in the arid and semiarid regions of northeastern China, which are heavily affected by soda saline–alkaline stress. At present, there is an urgent need to improve the soda saline–alkaline stress tolerance of rice. Results Stress-associated proteins are involved in regulating the abiotic stresses in plants. There are 18 members of the rice stress-associated protein (OsSAP) gene family. In this study, the expression levels of OsSAP6 in leaves and roots were upregulated with increasing NaHCO3 stress duration. OsSAP6 was located in nucleus and cytoplasm. The bud length and total root length of OsSAP6 overexpression rice were significantly longer than those of Lj11 (Oryza sativa longjing11) during germination stage, and the survival rates, plant height and malondialdehyde content at the seedling stage showed tolerance growth of saline–alkaline stress. The expression of OsCu/Zn-SOD, OsAPX2, and OsCAT1 in transgenic lines was increased significantly under SAE (soda saline–alkali soil eluent) stress. OsSAP6 interacts with OsPK5 according to yeast two-hybrid screening and luciferase complementation experiments. The expression of OsPK5 increased under NaHCO3 and H2O2 stress, and the overexpression of OsPK5 in rice improved soda saline–alkaline tolerance. Conclusion Overexpression of OsSAP6 in rice significantly enhanced saline–alkaline tolerance compared with the wild type. It is speculated that OsSAP6 responds to soda salinity stress and interacts with OsPK5 to positively regulate soda saline–alkaline tolerance through ROS homeostasis. This study revealed the features of OsSAP6 involved in response to soda saline–alkaline stress and the interaction with OsPK5, which provided resources for breeding aimed at improving the soda saline–alkaline stress tolerance of rice.

Abstract Background Alzheimer’s disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-β42 and Aβ40 (Aβ42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). Methods This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20–50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aβ42, Aβ40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen’s d, and linear mixed models. Resultss The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and −0.001 (0.010) for Aβ42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and −0.020 (0.279) pg/mL and −0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [−0.33, 1.19]) and t-tau in cycling (−0.35 [−0.87, 0.17]). Conclusions Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. Trials registration ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 2013

Abstract Deregulation of NEK2(NIMA-related serine/threonine 2) confers chemotherapeutic resistance to apoptosis and is closely correlated with poor prognosis in hepatocellular carcinoma (HCC). Here, we find that nanoparticles are prepared through hemisynthesis from natural nitidine chloride (NC) with enhanced antitumor activity. Nitidine chloride nanoparticle (TPGS-FA/NC) treatment show good therapy effect in Li-7 hepatocellular carcinoma cells. Additionally, molecular docking technologies are aimed at NEK2 protein (PDB ID: 6SGD) to analyze the detailed binding interactions with the potent target. NC participates in interactions with Asp159 residue. These studies advance the understanding of the modification of nitidine chloride substituent and provide useful drug design information for liver cancer treatment.

Abstract Head and neck squamous cell carcinomas (HNSCCs) are often aggressive, making advanced disease very difficult to treat using contemporary modalities, such as surgery, radiation therapy, and chemotherapy. However, targeted therapy, e.g., cetuximab, an epidermal growth factor receptor inhibitor, has demonstrated survival benefit in HNSCC patients with locoregional failure or distant metastasis. Molecular imaging aims at various biomarkers used in targeted therapy, and nuclear medicine-based molecular imaging is a real-time and non-invasive modality with the potential to identify tumor in an earlier and more treatable stage, before anatomic-based imaging reveals diseases. The objective of this comprehensive review is to summarize recent advances in nuclear medicine-based molecular imaging for HNSCC focusing on several commonly radiolabeled biomarkers. The preclinical and clinical applications of these candidate imaging strategies are divided into three categories: those targeting tumor cells, tumor microenvironment, and tumor angiogenesis. This review endeavors to expand the knowledge of molecular biology of HNSCC and help realizing diagnostic potential of molecular imaging in clinical nuclear medicine.

Abstract Background Stemness of CD133+EPCAM+ hepatocellular carcinoma cells ensures cancer resistance to apoptosis,which is a challenge to current liver cancer treatments. In this study, we evaluated the tumorcidal activity of a novel nanoparticle of nitidine chloride (TPGS-FA/NC, TPGS-FA: folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate, NC: nitidine chloride), against human hepatocellular carcinoma (HCC) cell line Huh7 growth in vitro and in vivo. Methods Huh7 cells were treated with TPGS-FA/NC. Cell proliferation was assessed using MTT and colony assays. The expression of cell markers and signaling proteins was detected using western blot analyses. A sphere culture technique was used to enrich cancer stem cells (CSC) in Huh7 cells. TPGS-FA/NC (7.5, 15, 30, 60, 120 μg/mL) dose-dependently inhibited the proliferation of HCC cells, which associated with a reduction in AQP3 and STAT3 expression. Importantly,TPGS-FA/NC (10, 20, and 40 μg/mL) significantly reduced the EpCAM+/CD133+cell numbers, suppressed the sphere formation. The in vivo antitumor efficacy of TPGS-FA/NC was proved in Huh7 cell xenograft model in BALB/c nude mice, which were administered TPGS-FA/NC(4 mg· kg − 1· d − 1, ig) for 2 weeks. Results TPGS-FA/NC dose-dependently suppressed the AQP3/STAT3/CD133 axis in Huh7 cells. In Huh7 xenograft bearing nude mice, TPGS-FA/NC administration markedly inhibited Huh7 xenograft tumor growth . Conclusions TPGS-FA/NC inhibit HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the clinical therapy of hepatocellular carcinoma.

Chlamydia trachomatis, one species of Chlamydia spp., has the greatest impact on human health and is the main cause of bacterial sexually transmitted diseases and preventable blindness among all Chamydia spp. species. The obligate intracellular parasitism and unique biphasic developmental cycle of C. trachomatis are the main barriers for the development of tools of genetic manipulation. The past decade has witnessed significant gains in genetic manipulation of C. trachomatis, including chemical mutagenesis, group II intron-based targeted gene knockout, fluorescence-reported allelic exchange mutagenesis (FRAEM), CRISPR interference (CRISPRi) and the recently developed transposon mutagenesis. In this review, we discuss the current status of genetic manipulations of C. trachomatis and highlights new challenges in the nascent field of Chlamydia genetics.

White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic–ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague−Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7–21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.

The WRKY gene family in plants regulates the plant’s response to drought through regulatory networks and hormone signaling. AfWRKY20 (MT859405) was cloned from Amorpha fruticosa (A. fruticosa) seedlings using RT-PCR. The binding properties of the AfWRKY20 protein and the W-box (a DNA cis-acting element) were verified both in vivo and in vitro using EMSA and Dual-Luciferase activity assays. RT-qPCR detected that the total expression level of AfWRKY20 in leaves and roots was 22 times higher in the 30% PEG6000 simulated drought treatment compared to the untreated group. Under the simulated drought stress treatments of sorbitol and abscisic acid (ABA), the transgenic tobacco with the AfWRKY20 gene showed enhanced drought resistance at the germination stage, with significantly increased germination rate, green leaf rate, fresh weight, and root length compared to the wild-type (WT) tobacco. In addition, the superoxide dismutase (SOD) activity, chlorophyll content, and Fv/Fm ratio of AfWRKY20 transgenic tobacco were significantly higher than those of the WT tobacco under natural drought stress, while the malondialdehyde (MDA) content and 3,3′-diaminobenzidine (DAB) and nitroblue tetrazolium (NBT) staining levels were lower. The expression levels of oxidation kinase genes (NbSOD, NbPOD, and NbCAT) in transgenic tobacco under drought stress were significantly higher than those in WT tobacco. This enhancement in gene expression improved the ability of transgenic tobacco to detoxify reactive oxygen species (ROS). The survival rate of transgenic tobacco after natural drought rehydration was four times higher than that of WT tobacco. In summary, this study revealed the regulatory mechanism of AfWRKY20 in response to drought stress-induced ABA signaling, particularly in relation to ROS. This finding provides a theoretical basis for understanding the pathways of WRKY20 involved in drought stress, and offers genetic resources for molecular plant breeding aimed at enhancing drought resistance.

Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.

Abstract Excess mental stress may harm health, and even accelerate cancer initiation and progression. One fourth of breast cancer patients suffer mental stress including anxiety, sadness, or depression, which negatively affect prognosis and survival. However, the regulatory mechanism is yet to be determined. Herein, we applied unpredictable stress stimuli to the breast tumor-bearing mice to establish a xenograft model of breast cancer suffering mental stress, followed by behavioral tests, tumor growth tracking, immune analysis, miRNA screening, and tumor cell proliferation analysis as well. As a result, increased stress hormone levels in serum, decreased percentage of T and NK cells in both blood and tumor samples and accelerated tumor growth in vivo were observed in the mice exposed to mental stress. Promoted cell proliferation was observed in both primary tumor cells derived from the stressed mice and 4T1 breast cancer cells treated with stress hormone corticosterone. In addition, a subset of miRNAs including miR-326, 346, 493, 595, 615, and 665 were identified through a miRNA screening with downregulation in tumors of the stressed mice. CCND1 was identified as a common target gene of miR-346 and miR-493, the top two most significantly downregulated miRNAs by stress exposure. The stress-miRNA-CCND1 signaling regulation of the tumor cell proliferation was further validated in 4T1 cells treated with corticosterone in vitro. GO terms and KEGG pathways analyses on the target genes of miR-346 and miR-493 revealed their involvement in the regulation of human cancer and neuron system, indicating the importance of non-coding genome in mediating the mental stress-induced cancer regulation. In conclusion, this study not only explored immune and nonimmune mechanisms through which mental stress exposure contributes to tumor growth in breast cancer, but also suggested a new therapeutic strategy for cancer patients suffering mental stress.

BackgroundSentinel lymph node (SLN) biopsy has been widely recognized as an excellent surgical and staging procedure for early-stage breast cancer, and its development has greatly improved the detection of micrometastases. However, the axillary treatment of micrometastasis has been the subject of much debate.MethodsWe identified 427,131 women diagnosed with breast cancer from 2010 to 2018 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients whose nodal status was micrometastases (pTxN1miM0) were classified into two groups: the SLNB only group and SLNB with complete ALND group, and we used these classifications to carry out propensity-score matching (PSM) analysis. The primary and secondary endpoints were OS and BCSS, respectively. We then implemented the Kaplan-Meier method and Cox proportional hazard model and used Fine and Gray competitive risk regression to identify factors associated with the risk of all-cause mortality.ResultsAfter the PSM, 1,833 pairs were included in total. The SLNB with complete ALND showed no significant difference in OS (HR=1.04, 95% CI: 0.84-1.28, P=0.73) or BCSS (HR= 1.03, 95% CI: 0.79-1.35, P=0.82) compared to the SLNB only group, and axillary treatment was not associated with breast cancer-specific death (BCSD) (HR=1.13, 95% CI: 0.86-1.48, P=0.400) or other cause-specific death (OCSD) (HR=0.98, 95% CI:0.70-1.38, P=0.920). There was no statistically significant difference in the cumulative incidence of BCSD (Grey’s test, P=0.819) or OCSD (Grey’s test, P=0.788) for between the two groups either. For different molecular subtypes, patients in the SLNB only group showed no statistically significant differences from those in the SLNB with complete ALND group with Luminal A (HR=1.00, 95% CI:0.76-1.32, P=0.98) or Luminal B (HR=0.82, 95% CI:0.42-1.62, P=0.55) but similar OS to HER2-enriched (HR=1.58, 95% CI:0.81-3.07, P=0.19) or triple negative breast cancers (HR=1.18, 95% CI:0.76-1.81, P=0.46).ConclusionsOur results suggest that in early breast cancer patients with micrometastasis, complete ALND does not seem to be required and that SLNB suffices to control locoregional and distant disease, with no significant adverse effects on survival compared to complete ALND.

BackgroundBronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA).MethodsWe used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate

Transarterial embolization (TAE) is a personalized technology that offers precise delivery of chemotherapeutic drugs or selective internal radiation therapy for hepatocellular carcinoma (HCC). Beta-emitting radionuclide embolisms for TAE (β-based TARE) are commonly used in the clinic via inducing biochemical lethality on tumor cells, while alpha-emitting radionuclides-based embolisms for TAE (α-based TARE) are still under study. The feeding artery plays a key role in tumor growth, metastasis, and recurrence. In this research, the auricular central arteries (ACAs) of rabbits were embolized with silk fibroin-based microspheres (SFMs) or SFMs integrated with α (Ra-223) or β (I-131) radionuclides to investigate the influence on vessels. TARE-induced tissue necrosis and the following neovascularization were measured by pathological analysis and 68Ga-DOTA-RGD PET/CT. The results showed that, compared to I-131, Ra-223 enhanced the growth inhibition of human hepatoma cells Huh-7 and induced more DNA double-strand breaks in vascular smooth muscle cells. Unlike β-based TARE, which mainly led to extensive necrosis of surrounding tissues, α-based TARE induced irreversible necrosis of a limited area adjacent to the embolized vessels. RGD PET revealed the inhibition on neovascularization in α-based TARE (SUVmax = 0.053 ± 0.004) when compared with normal group (SUVmax = 0.099 ± 0.036), the SFMs-lipiodol group (SUVmax = 0.240 ± 0.040), and β-based TARE (SUVmax = 0.141 ± 0.026), owing to the avoidance of the embolism-induced neovascularization. In conclusion, α-based TARE provided a promising strategy for HCC treatments via destroying the embolized vessels and inhibiting neovascularization.

Abstract Background Apolipoprotein (Apo) A1 and Apo B are strongly associated with the risk of atherosclerotic cardiovascular disease (ASCVD). However, the relationship between the Apo B/A1 ratio and the morphology of coronary vulnerable plaques has not been fully elucidated in patients with ASCVD. Methods A total of 320 patients with ASCVD undergoing percutaneous coronary intervention were enrolled and assigned into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) group. The morphology of culprit plaque was analyzed by intravascular optical coherence tomography. Association between the Apo B/A1 ratio and coronary vulnerable plaques were evaluated using logistic regression models and receiver operator characteristic (ROC) curve analyses. Results The Apo B/A1 ratio was higher in ACS patients than CCS patients (0.77 ± 0.28 vs. 0.64 ± 0.22, P

Abstract Objectives To explore the correlations among social isolation and symptoms of anxiety and depression among patients with breast cancer in China and to further verify the mediating role of social support in social isolation and symptoms of depression or anxiety. Design A cross‐sectional survey. Settings The cluster sampling method was conducted for 456 female inpatients diagnosed with breast cancer at the Tumor Hospital Affiliated of Harbin Medical University from April 2019–September 2019. Methods Pearson correlation analysis was used for identifying correlations among all the variables. Mediation effect analysis was used to examine the role of social support in social isolation and symptoms of depression or anxiety. Results The results showed a prevalence of 73.26% and 70.44% for anxiety and depression symptoms in patients with breast cancer, respectively. Anxiety was significantly negatively correlated with social support (r = −.334, p

Abstract Objective: Breast cancer (BC) is becoming the leading cause of cancer-related death in women all over the word. Identification of diagnostic biomarkers for early detection of BC is one of the most effective ways to reduce the mortality.Methods: Plasma samples from BC patients (n = 120) and normal controls (n = 50) were collected to determine the differentially expressed circulating miRNAs in BC patients. Binary logistic regression was applied to develop miRNA diagnostic models. Receiver operating characteristic (ROC) curves were applied to calculate the area under the curve (AUC). MMTV-PYMT mammary tumor mice were used to validate the expression change of those circulating miRNAs. Plasma samples from patients with other tumor types were collected to determine the specificity of the model in diagnosis of BC.Results: In the screening phase, 5 circulating miRNAs (miR-16, miR-17, miR-19b, miR-27a, and miR-106a) were identified as the most significantly upregulated miRNAs in plasma of BC patients. In consistence, the 5 miRNAs showed upregulation in the circulation of additional 80 BC patients in a tumor stage-dependent manner. Application of a tumor-burden mice model further confirmed upregulation of the 5 miRNAs in circulation. Based on these data, five models with diagnostic potential of BC were developed. Among the 5 miRNAs, miR-19b ranked at the top position with the highest specificity and the biggest contribution. In combination with miR-16 and miR-106a, a miR-19b-based 3-circulating miRNA model was selected as the best for further validation. Taken the samples together, the model showed 92% of sensitivity and 90% of specificity in diagnosis of BC. In addition, three other tumor types including prostate cancer, thyroid cancer and colorectal cancer further verified the specificity of the BC diagnostic model. Conclusion: The current study developed a miR-19b-based 3-miRNA model holding potential for diagnosis of BC using blood samples.

The worldwide incidence of head and neck cancer (HNC) exceeds half a million cases annually, and up to half of the patients with HNC present with advanced disease. Surgical resection remains the mainstay of treatment for many HNCs, although radiation therapy, chemotherapy, targeted therapy, and immunotherapy might contribute to individual patient’s treatment plan. Irrespective of which modality is chosen, disease prognosis remains suboptimal, especially for higher staging tumors. Cold atmospheric plasma (CAP) has recently demonstrated a substantial anti-tumor effect. After a thorough literature search, we provide a comprehensive review depicting the oncological potential of CAP in HNC treatment. We discovered that CAP applies to almost all categories of HNC, including upper aerodigestive tract cancers, head and neck glandular cancers and skin cancers. In addition, CAP is truly versatile, as it can be applied not only directly for superficial or luminal tumors but also indirectly for deep solid organ tumors. Most importantly, CAP can work collaboratively with existing clinical oncotherapies with synergistic effect. After our attempts to elaborate the conceivable molecular mechanism of CAP’s anti-neoplastic effect for HNC, we provide a brief synopsis of recent clinical and preclinical trials emphasizing CAP’s applicability in head and neck oncology. In conclusion, we have enunciated our vision of plasma oncology using CAP for near future HNC treatment.