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Abstract Background Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune conditions that affect the central nervous system. The contribution of peripheral abnormalities to the disease's pathogenesis is not well understood. Methods To investigate this, we employed a multi-omics approach analyzing blood samples from 52 NMOSD patients and 46 healthy controls (HC). This included mass cytometry, cytokine arrays, and targeted metabolomics. We then analyzed the peripheral changes of NMOSD, and features related to NMOSD's disease severity. Furthermore, an integrative analysis was conducted to identify the distinguishing characteristics of NMOSD from HC. Additionally, we unveiled the variations in peripheral features among different clinical subgroups within NMOSD. An independent cohort of 40 individuals with NMOSD was utilized to assess the serum levels of fibroblast activation protein alpha (FAP). Results Our analysis revealed a distinct peripheral immune and metabolic signature in NMOSD patients. This signature is characterized by an increase in monocytes and a decrease in regulatory T cells, dendritic cells, natural killer cells, and various T cell subsets. Additionally, we found elevated levels of inflammatory cytokines and reduced levels of tissue-repair cytokines. Metabolic changes were also evident, with higher levels of bile acids, lactates, triglycerides, and lower levels of dehydroepiandrosterone sulfate, homoarginine, octadecadienoic acid (FA[18:2]), and sphingolipids. We identified distinctive biomarkers differentiating NMOSD from HC and found blood factors correlating with disease severity. Among these, fibroblast activation protein alpha (FAP) was a notable marker of disease progression. Conclusions Our comprehensive blood profile analysis offers new insights into NMOSD pathophysiology, revealing significant peripheral immune and metabolic alterations. This work lays the groundwork for future biomarker identification and mechanistic studies in NMOSD, highlighting the potential of FAP as a marker of disease progression.

Abstract Background Somatic copy number alterations (SCNAs) are pivotal in cancer progression and patient prognosis. Dysregulated long non-coding RNAs (lncRNAs), modulated by SCNAs, significantly impact tumorigenesis, including colorectal cancer (CRC). Nonetheless, the functional significance of lncRNAs induced by SCNAs in CRC remains largely unexplored. Methods The dysregulated lncRNA LOC101927668, induced by copy number amplification, was identified through comprehensive bioinformatic analyses utilizing multidimensional data. Subsequent in situ hybridization was employed to ascertain the subcellular localization of LOC101927668, and gain- and loss-of-function experiments were conducted to elucidate its role in CRC progression. The downstream targets and signaling pathway influenced by LOC101927668 were identified and validated through a comprehensive approach, encompassing RNA sequencing, RT-qPCR, Western blot analysis, dual-luciferase reporter assay, evaluation of mRNA and protein degradation, and rescue experiments. Analysis of AU-rich elements (AREs) within the mRNA 3’ untranslated region (UTR) of the downstream target, along with exploration of putative ARE-binding proteins, was conducted. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and dual-luciferase reporter assays were employed to elucidate potential interacting proteins of LOC101927668 and further delineate the regulatory mechanism between LOC101927668 and its downstream target. Moreover, subcutaneous xenograft and orthotopic liver xenograft tumor models were utilized to evaluate the in vivo impact of LOC101927668 on CRC cells and investigate its correlation with downstream targets. Results Significantly overexpressed LOC101927668, driven by chr7p22.3-p14.3 amplification, was markedly correlated with unfavorable clinical outcomes in our CRC patient cohort, as well as in TCGA and GEO datasets. Moreover, we demonstrated that enforced expression of LOC101927668 significantly enhanced cell proliferation, migration, and invasion, while its depletion impeded these processes in a p53-dependent manner. Mechanistically, nucleus-localized LOC101927668 recruited hnRNPD and translocated to the cytoplasm, accelerating the destabilization of RBM47 mRNA, a transcription factor of p53. As a nucleocytoplasmic shuttling protein, hnRNPD mediated RBM47 destabilization by binding to the ARE motif within RBM47 3'UTR, thereby suppressing the p53 signaling pathway and facilitating CRC progression. Conclusions The overexpression of LOC101927668, driven by SCNAs, facilitates CRC proliferation and metastasis by recruiting hnRNPD, thus perturbing the RBM47/p53/p21 signaling pathway. These findings underscore the pivotal roles of LOC101927668 and highlight its therapeutic potential in anti-CRC interventions.

Abstract Background Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC. Methods DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR. Results DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway. Conclusions We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.

Abstract Heart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.

Soil quality is closely related to the evolution of forest ecosystems, especially in the context of global warming; therefore, it is essential to study the changes in soil quality caused by the invasion of moso bamboo in its habitat. In this study, we selected plantation forests and natural secondary forests with typical vegetation of the northern subtropics, Quercus acutissima plantation (QAP) and oak secondary forest (OSF), collected plant community and soil physicochemical data, and established a soil quality index (SQI) to assess how moso bamboo invasion affects soil quality. In addition, the mechanisms driving the moso bamboo invasion effects on soil quality were investigated using a partial least squares structural equation model (PLS-SEM). The results demonstrated that: (1) Moso bamboo invasion significantly affected community structure and soil physicochemical properties, there were inconsistent changes in soil physicochemical indicators in oak forests of different origins, and in general the effects of moso bamboo expansion on soil physicochemical properties were concentrated in the topsoil (0–20 cm). (2) Soil bulk density (BD), total soil porosity (TSP), total nitrogen (TN), and available potassium (AK) comprised the minimum data set (MDS) used to calculate the SQI, and the SQI of oak forests of different origins ranged from 0.48 to 1, and the invasion of moso bamboo led to a significant decrease in the SQI of the surface layer of QAP. A redundancy analysis (RDA) showed that soil quality assessment factors were closely related to community structure and the PLS-SEM indicated that moso bamboo invasion indirectly affected surface soil quality through its effects on community and soil factors. The results showed that moso bamboo invasion had different effects on oak forests of different origins. They also showed that soil quality was strongly affected by aboveground biomass (AGB), the tree Shannon-Wiener index (TH'), and available potassium (AK).

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

Sinomenine hydrochloride is an excellent drug with anti-inflammatory, antioxidant, immune-regulatory, and other functions. Atopic dermatitis is an inherited allergic inflammation that causes itchiness, redness, and swelling in the affected area, which can have a significant impact on the life of the patient. There are many therapeutic methods for atopic dermatitis, and sinomenine with immunomodulatory activity might be effective in the treatment of atopic dermatitis. In this study, the atopic dermatitis model was established in experimental mice, and physical experiments were carried out on the mice. In the experiment, sinomenine hydrochloride liposomes-in-hydrogel as a new preparation was selected for delivery. In this case, liposomes were dispersed in the colloidal hydrogel on a mesoscopic scale and could provide specific transfer properties. The results showed that the sinomenine hydrochloride-loaded liposomes-in-hydrogel system could effectively inhibit atopic dermatitis.

As a potent zinc chelator, hydroxamic acid has been applied in the design of inhibitors of zinc metalloenzyme, such as histone deacetylases (HDACs). A series of hydroxamic acids with HDAC inhibitory activities were subjected to the QSRR (Quantitative Structure–Retention Relationships) study. Experimental data in combination with calculated molecular descriptors were used for the development of the QSRR model. Specially, we employed PCA (principal component analysis) to accomplish dimension reduction of descriptors and utilized the principal components of compounds (16 training compounds, 4 validation compounds and 7 test compounds) to execute GA (genetic algorithm)-BP (error backpropagation) algorithm. We performed double cross-validation approach for obtaining a more convincing model. Moreover, we introduced molecular interaction-based features (molecular docking scores) as a new type of molecular descriptor to represent the interactions between analytes and the mobile phase. Our results indicated that the incorporation of molecular interaction-based features significantly improved the accuracy of the QSRR model, (R2 value is 0.842, RMSEP value is 0.440, and MAE value is 0.573). Our study not only developed QSRR model for the prediction of the retention time of hydroxamic acid in HPLC but also proved the feasibility of using molecular interaction-based features as molecular descriptors.

Cyclin-dependent kinase 2 (CDK2) regulates the progression of the cell cycle and is critically associated with tumor growth. Selective CDK2 inhibition provides a potential therapeutic benefit against certain tumors. Purines and related heterocycle (e.g., R-Roscovitine) are important scaffolds in the development of CDK inhibitors. Herein, we designed a new series of 2-aminopurine derivatives based on the fragment-centric pocket mapping analysis of CDK2 crystal structure. Our results indicated that the introduction of polar substitution at the C-6 position of purine would be beneficial for CDK2 inhibition. Among them, compound 11l showed good CDK2 inhibitory activity (IC50 = 19 nM) and possessed good selectivity against other CDKs. Further in vitro tests indicated that compound 11l possesses anti-proliferation activity in triple-negative breast cancer (TNBC) cells. Moreover, molecular dynamics simulation suggested the favorable binding mode of compound 11l, which may serve as a new lead compound for the future development of CDK2 selective inhibitors.

Abstract Background The study aimed to investigate the clinical and genetic features of Rahman syndrome caused by HIST1H1E gene mutations. Methods We retrospectively analyzed the clinical information and genetic testing results of a Rahman syndrome family in an outpatient clinic in August 2020 and summarized the clinical characteristics of the HIST1H1E gene mutations in conjunction with peer‐reviewed reports. Results A 4‐year‐old boy was diagnosed with severe developmental delay and with specific features (large head, full cheeks, high hairline, low‐set ear, sparse eyebrows, and short neck) similar to his mother (mild intellectual disability, high hairline, reduced hair, ptosis, sagging skin, and hyperkeratosis) and premature aging. Trio whole exome sequencing (WES) revealed a novel maternal c.368dup (p.G124Rfs*72) heterozygous mutation in the HIST1H1E gene. There have been only a few reported cases with mainly de novo mutations. Only six peer‐reviewed articles in English and one in Chinese have been published regarding this syndrome. From 48 children with Rahman syndrome, 21 were males and 27 were females encompassing 25 mutations in the HIST1H1E gene. All mutations located in C‐terminal tail were frameshift mutations leading to premature protein termination. Conclusion Rahman syndrome, caused by the HIST1H1E gene mutation, is a rare autosomal dominant disorder in which the patient has an unusual facial appearance with high hairline and full cheeks, and clinical manifestations of mild to severe intellectual disability, motor delay and speech delay. Genetic testing may assist in the diagnosis of these patients. This diagnosis will permit early speech rehabilitation to improve their quality of life.

Miscanthus sinensis is a C4 perennial grass species that is widely used as forage, ornamental grass and bioenergy crop due to its broad adaption and great biological traits. Recent studies indicated that M. sinensis could also grow in marginal lands which were contaminated with heavy metals, and exhibited important ecological restoration potential. In this study, transcriptome characterization of candidate genes related to chromium (Cr) uptake, transport and accumulation in M. sinensis were employed to investigate the molecular mechanism of plant tolerance to heavy metal stress. The result showed that following treatment of 200 mg/L of Cr, plant roots could accumulate most Cr and localize mainly in cell walls and soluble fractions, whereas Cr in stems and leaves was primarily in soluble fractions. A total of 83,645 differentially expressed genes (DEGs) were obtained after the treatment. Many genes involved in heavy metal transport, metal ion chelation and photosynthesis were found to be Cr-induced DEGs. Co-expression and weighted correlation network analysis revealed that Glutathion metabolism and ABC transporters pathways play an important role in Cr tolerance of M. sinensis. A hypothesis schematic diagram for the Cr uptake, transport and accumulation of M. sinensis cells were suggested, which could provide a molecular and genetic basis for future candidate genes validation and breeding of such crops.

Ovarian cancer (OC) is one of the most fatal diseases among women all around the world. It is highly lethal because it is usually diagnosed at an advanced stage which may reduce the survival rate greatly. Even though most of the patients are treated timely and effectively, the survival rate is still low due to the high recurrence rate of OC. With a large number of genome-wide association analysis (GWAS)-discovered risk regions of OC, expression quantitative trait locus (eQTL) analyses can explore candidate susceptible genes based on these risk loci. However, a large number of OC-related genes remain unknown. In this study, we proposed a novel gene prediction method based on different omics data and deep learning methods to identify OC causal genes. We first employed graph attention network (GAT) to obtain a compact gene feature representation, then a deep neural network (DNN) is utilized to predict OC-related genes. As a result, our model achieved a high AUC of 0.761 and AUPR of 0.788, which proved the accuracy and effectiveness of our proposed method. At last, we conducted a gene-set enrichment analysis to further explore the mechanism of OC. Finally, we predicted 245 novel OC causal genes and 10 top related KEGG pathways.

Pulmonary arterial hypertension (PAH) is defined as elevation of mean pulmonary arterial pressure to ≥25 mmHg within the low pressure pulmonary circulatory system. PAH is characterized by obstructive vascular remodeling, partially due to excessive pulmonary arterial smooth muscle cell (PASMC) proliferation. Puerarin is a natural flavonoid isolated from the herb Radix puerariae, which has been widely used for the treatment of cardiovascular and cerebrovascular disorders and diabetes. However, how puerarin mediates autophagy in the progression of pulmonary vascular remodeling is unclear. In this study, we explored the effects of puerarin in a hypoxic pulmonary hypertension (PH) rat model using immunohistochemistry, and morphometric analyses of right ventricle. In addition, cell counting kit 8 assay, western blotting and flow cytometry were employed to test cell proliferation in PASMCs, and then autophagy was tested with mRFP-GFP-LC3 fluorescence microscopy and Western blot. We found that puerarin could alleviate hypoxia-induced PH in rats and improved pulmonary histopathology, and also reduced the expression of autophagy markers in vivo and in vitro. Moreover, puerarin also ameliorated hypoxia-induced PASMC proliferation in an autophagy-dependent manner. Overall, these findings demonstrated that puerarin could prevent hypoxia-induced PH in rats, possibly via reducing autophagy and suppressing cell proliferation. Keywords: Puerarin, Hypoxia, Pulmonary artery hypertension, Autophagy, Proliferation

The purpose of this study was to prepare and evaluate kaempferol-loaded carbopol polymer (acrylic acid) hydrogel, investigate its antioxidant activity in vitro, and compare the effects on drug release under different pH conditions. Drug release studies were conducted in three different pH media (pH 3.4, 5.4, and 7.4). The kaempferol-loaded hydrogel was prepared by using carbopol 934 as the hydrogel matrix. The morphology and viscosity of the preparation were tested to understand the fluidity of the hydrogel. The antioxidant activity of the preparation was studied by scavenging hydrogen peroxide and 2,2-diphenyl-1-picrilhidrazil (DPPH) radicals in vitro and inhibiting the production of malondialdehyde in mouse tissues. The results showed that kaempferol and its preparations had high antioxidant activity. In vitro release studies showed that the drug release at pH 3.4, 5.4, and 7.4 was 27.32 ± 3.49%, 70.89 ± 8.91%, and 87.9 ± 10.13%, respectively. Kaempferol-loaded carbopol hydrogel displayed greater swelling and drug release at higher pH values (pH 7.4).

White clover is an important temperate legume forage with high nutrition. In the present study, 448 worldwide accessions were evaluated for the genetic variation and polymorphisms using 22 simple sequence repeat (SSR) markers. All the markers were highly informative, a total of 341 scored bands were amplified, out of which 337 (98.83%) were polymorphic. The PIC values ranged from 0.89 to 0.97 with an average of 0.95. For the AMOVA analysis, 98% of the variance was due to differences within the population and the remaining 2% was due to differences among populations. The white clover accessions were divided into different groups or subgroups based on PCoA, UPGMA, and STRUCTURE analyses. The existence of genetic differentiation between the originally natural and introduced areas according to the PCoA analysis of the global white clover accessions. There was a weak correlation between genetic relationships and geographic distribution according to UPGMA and STRUCTURE analyses. The results of the present study will provide the foundation for future breeding programs, genetic improvement, core germplasm collection establishment for white clover.

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH, NM_014362.3) gene mutation can cause HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series have investigated the relationship between metabolites and clinical phenotypes or the effects of treatment, although 34 patients with HIBCH mutations from 27 families have been reported. The purpose of this study was to analyze the phenotypic spectrum, follow-up results, metabolites, and genotypes of patients with HIBCH deficiency presenting with Leigh/Leigh-like syndrome and explore specific metabolites related to disease diagnosis and prognosis through retrospective and longitudinal studies. Applying next-generation sequencing, we identified eight patients with HIBCH mutations from our cohort of 181 cases of genetically diagnosed Leigh/Leigh-like syndrome. Six novel HIBCH mutations were identified: c.977T>G [p.Leu326Arg], c.1036G>T [p.Val346Phe], c.750+1G>A, c.810-2A>C, c.469C>T [p.Arg157*], and c.236delC [p.Pro79Leufs*5]. The Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) was employed to assess disease progression and clinical outcomes. The non-invasive approach of metabolite analysis showed that levels of some were associated with clinical phenotype severity. Five (5/7) patients presented with elevated C4-OH in dried blood spots, and the level was probably correlated with the NPMDS scores during the peak disease phase. 2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients and elevated S-(2-caboxypropyl)cysteamine in urine was found in three patients (3/3). The median age at initial presentation was 13 months (8–18 months), and the median follow-up was 2.3 years (range 1.3–7.2 years). We summarized and compared with all reported patients with HIBCH mutations. The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties. We administered drug and dietary treatment. During follow-up, five patients responded positively to treatment with a significant decrease in NPMDS scores. Our research is the largest case series of patients with HIBCH mutations.

Histone deacetylases (HDACs) regulate the acetylation status of histones and structural status of chromatin. The chromatin structure becomes relaxed after inhibition of HDAC, leading to DNA exposed to DNA disrupting agents, and eventually causing DNA dysfunction. Recently, more and more dual inhibitors targeting DNA and HDACs have been reported to be applied to cancer treatment. In this review, we describe the current status of dual inhibitors targeting DNA and HDACs, summarize their pharmacological characters, and predict their further trend in the field.

Congenital myasthenic syndromes (CMSs) are a group of inherited disorders caused by genetic defects in neuromuscular junctions. Mutations in CHAT, encoding choline acetyltransferase, cause congenital myasthenic syndrome with episodic apnea (CMS-EA), a rare autosomal recessive disease characterized by respiratory insufficiency with cyanosis and apnea after infections, fever, vomiting, or excitement. To date, no studies have reported deletions comprised of multiple exons. Here, using next generation sequencing, we identified compound heterozygous mutations, namely a large maternally inherited deletion, including exons 4, 5, and 6, and a paternally inherited missense variant (c.914T>C [p.Ile305Thr]) in CHAT in a Chinese patient with a severe phenotype of CMS-EA. Furthermore, the large deletion was also validated by real-time fluorescence quantitative polymerase chain reaction. The patient was a 10-month-old boy, who presented with a weak cry and feeding difficulties soon after birth, ptosis at 4 months old, episodic apnea after fever at 9 months old, and respiratory insufficiency with cyanosis and apnea that required intubation after a respiratory tract infection at 10 months old. Unfortunately, he died in the Pediatric Intensive Care Unit soon after hospitalization. The patient’s elder sister had similar clinical manifestations, and she died prior to the age of 2 months old without a diagnosis. Genotype-phenotype correlation analysis revealed that loss-of-function mutations in exons 4–6 of CHAT might cause more severe CMS-EA. To our knowledge, this is the first study to show compound heterozygous CHAT mutations consisting of a large deletion and missense mutation in a patient with CMS-EA.

Zinc oxide (ZnO) possesses superior chemical and physical properties so that it can occupy an essential position in the application of nanostructures. In this paper, ZnO nano-rod arrays were synthesized by a simple one-step hydrothermal approach with the assistance of cetyl trimethyl ammonium bromide (CTAB). Exposure of the {0001} facets could be controlled by adjusting the amount of CTAB and the maximum exposure of the {0001} facets of ZnO nanorods is obtained at 1.2 g of CTAB. The photocurrent, EIS, and PL measurements support the facile charge transfer with minimum recombination of the photogenerated excitons of the ZnO nano-rod arrays obtained at 1.2 g of CTAB. Consequently, the obtained ZnO nano-rod arrays at the optimal CTAB of 1.2 g exhibit an excellent photocatalytic degradation rate of 99.7% for rhodamine B (RhB), while the degradation rate of RhB by the ZnO obtained without CTAB is only 35%.

Background and objective This study aims to explore the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) on the lymphangiogenesis of lung cancer with EGFR mutation, as well as to determine the function of EGFR targeted therapy in relation to the inhibition of lymphangiogenesis during lung cancer treatment. Methods The EGFR double mutant lung cancer cell line NCI-H1975 is used to construct lung cancer xenograft models. The models are divided into two groups: the solvent control group and the EGFR-TKI treatment group. Each group includes five mice. The inhibitory effect of EGFR-TKI on the growth of transplanted tumors was observed. Immunohistochemical method and lymphatic endothelium specific antibody D2-40 were used in the experiment to observe the influence of EGFR-TKI on lymphangiogenesis in lung cancer. Results The weight and relative volume of tumors in the EGFR-TKI treated group were less than those in the solvent control group. The average lymphatic vessel density of EGFR-TKI-treated mice was 6.44 per case. This value was 10.70 per case in the solvent control group. Lower density of lymphangiogenesis was found in the EGFR-TKI treated group (P=0.023). The area and longest diameter of neonatal lymphatic vessel of the EGFR-TKI treated group were less than those of the solvent control group. Moreover, EGFR-TKI exhibited no significant effect on the invasion of tumor cells into the lymphatic vessel (P=0.519). Conclusion EGFR-TKI can inhibit lymphangiogenesis in EGFR mutant lung cancer while suppressing vessel diameter and expansion area.

Artemisinin and its main active metabolite dihydroartemisinin, clinically used antimalarial agents with low host toxicity, have recently shown potent anticancer activities in a variety of human cancer models. Although iron mediated oxidative damage is involved, the mechanisms underlying these activities remain unclear. In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners. It decreased iron uptake and disturbed iron homeostasis in cancer cells, which were independent of oxidative damage. Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane. The regulation of dihydroartemisinin to transferrin receptor-1 could be reversed by nystatin, a cholesterol-sequestering agent but not the inhibitor of clathrin-dependent endocytosis. Dihydroartemisinin also induced transferrin receptor-1 palmitoylation and colocalization with caveolin-1, suggesting a lipid rafts mediated internalization pathway was involved in the process. Also, nystatin reversed the influences of dihydroartemisinin on cell cycle and apoptosis related genes and the siRNA induced downregulation of transferrin receptor-1 decreased the sensitivity to dihydroartemisinin efficiently in the cells. These results indicate that dihydroartemisinin can counteract cancer through regulating cell-surface transferrin receptor-1 in a non-classical endocytic pathway, which may be a new action mechanism of DHA independently of oxidative damage.

The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3), and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144), were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega). The detailed in-vitro (cell level) and in-vivo (animal model) studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V-FITC assay), G2/M cell cycle arrest (PI staining analysis) and also dose-dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu). Mechanistic studies (both in vitro and in vivo) revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS)-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent) data analysis (GEO accession number: GSE25317). In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer.

While scientific knowledge acquisition is a vital premise for citizens' self-protection against COVID-19, the impact of anti-intellectualism on scientific information seeking has yet to be fully examined. Based on a cross-sectional survey, this study investigated the association of distrust and stigmatization forms of antiintellectualism (i.e. AID vs. AIS) with the Planned Risk Information Seeking Model (PRISM) in predicting Chinese netizens' information seeking about SARS-CoV-2 variants. The statistical results show that AIS is positively associated with seeking-related subjective norms and perceived control, indicating that it may boost a sense of self-empowerment. However, AIS is negatively related to affective risk response and the knowledge-sufficiency threshold, suggesting its possible link to overconfidence and trust in government. AID was found to be negatively associated with seeking-related attitudes and perceived control. Because AIS is far more popular than AID among respondents, its contradictory health implications should be brought into the vision of health communicators. [ABSTRACT FROM AUTHOR]