Super Resolution of Pulmonary Nodules Target Reconstruction Using a Two-Channel GAN Models.

RATIONALE AND OBJECTIVES: To develop a Dual generative-adversarial-network (GAN) Cascaded Network (DGCN) for generating super-resolution computed tomography (SRCT) images from normal-resolution CT (NRCT) images and evaluate the performance of DGCN in multi-center datasets. MATERIALS AND METHODS: This retrospective study included 278 patients with chest CT from two hospitals between January 2020 and June 2023, and each patient had all three NRCT (512×512 matrix CT images with a resolution of 0.70 mm, 0.70 mm,1.0 mm), high-resolution CT (HRCT, 1024×1024 matrix CT images with a resolution of 0.35 mm, 0.35 mm,1.0 mm), and ultra-high-resolution CT (UHRCT, 1024×1024 matrix CT images with a resolution of 0.17 mm, 0.17 mm, 0.5 mm) examinations. Initially, a deep chest CT super-resolution residual network (DCRN) was built to generate HRCT from NRCT. Subsequently, we employed the DCRN as a pre-trained model for the training of DGCN to further enhance resolution along all three axes, ultimately yielding SRCT. PSNR, SSIM, FID, subjective evaluation scores, and objective evaluation parameters related to pulmonary nodule segmentation in the testing set were recorded and analyzed. RESULTS: DCRN obtained a PSNR of 52.16, SSIM of 0.9941, FID of 137.713, and an average diameter difference of 0.0981 mm. DGCN obtained a PSNR of 46.50, SSIM of 0.9990, FID of 166.421, and an average diameter difference of 0.0981 mm on 39 testing cases. There were no significant differences between the SRCT and UHRCT images in subjective evaluation. CONCLUSION: Our model exhibited a significant enhancement in generating HRCT and SRCT images and outperformed established methods regarding image quality and clinical segmentation accuracy across both internal and external testing datasets.

Fabrication of Eco-Friendly Hydrolyzed Ethylene-Maleic Anhydride Copolymer-Avermectin Nanoemulsion with High Stability, Adhesion Property, pH, and Temperature-Responsive Releasing Behaviors.

In this study, novel amphiphilic polymer emulsifiers for avermectin (Avm) were synthesized facilely via the hydrolysis of ethylene-maleic anhydride copolymer (EMA) with different agents, and their structures were confirmed by various techniques. Then, water-based Avm-nanoemulsions were fabricated with the emulsifiers via phase inversion emulsification process, and superior emulsifier was selected via the emulsification effects. Using the superior emulsifier, an optimal Avm-nanoemulsion (defined as Avm@HEMA) with satisfying particle size of 156.8 ± 4.9 nm, encapsulation efficiency (EE) of 69.72 ± 4.01% and drug loading capacity (DLC) of 54.93 ± 1.12% was constructed based on response surface methodology (RSM). Owing to the emulsifier, the Avm@HEMA showed a series of advantages, including high stability, ultraviolet resistance, low surface tension, good spreading and high affinity to different leaves. Additionally, compared to pure Avm and Avm-emulsifiable concentrate (Avm-EC), Avm@HEMA displayed a controlled releasing feature. The encapsulated Avm was released quite slowly at normal conditions (pH 7.0, 25 °C or 15 °C) but could be released at an accelerated rate in weak acid (pH 5.5) or weak alkali (pH 8.5) media or at high temperature (40 °C). The drug releasing profiles of Avm@HEMA fit the Korsmeyer-Peppas model quite well at pH 7.0 and 25 °C (controlled by Fickian diffusion) and at pH 7.0 and 10 °C (controlled by non-Fickian diffusion), while it fits the logistic model under other conditions (pH 5.5 and 25 °C, pH 8.5 and 25 °C, pH 7.0 and 40 °C).

Assessment of aortic and peripheral arterial stiffness in patients with knee osteoarthritis by ultrasound Doppler derived pulse wave velocity.

Information regarding regional arterial stiffness assessment in osteoarthritis (OA) was scarce and sometimes contradictory. We aimed to investigate the aortic, lower limb peripheral arterial stiffness and their associations with knee OA. Patients with primary knee OA and matched non-OA controls were prospectively enrolled from two medical centers in China. The carotid-femoral pulse wave velocity (cfPWV) and femoral-ankle pulse wave velocity (faPWV) were measured using a novel ultrasound technique. A total of 238 participants (including 128 patients with knee OA and 110 controls) were included. In OA patients, cfPWV was significantly higher than that of non-OA controls (9.40 ± 1.92 vs 8.25 ± 1.26 m/s, P < 0.0001). However, faPWV measurements in OA patients (12.10 ± 2.09 m/s) showed no significant difference compared with that of the controls (11.67 ± 2.52 m/s, P = 0.130). Multiple regression analysis revealed that cfPWV was independently associated with knee OA (P < 0.0001) after adjusting for the confounding factors including age, gender, smoking, mean blood pressure, body mass index, heart rate, high-sensitivity C-reactive protein and lipids profiles. In contrast, faPWV did not show independent association with knee OA (P = 0.372) when after adjusting for confounding factors. In addition, Spearman's correlation analysis showed cfPWV had a significant correlation with Kellgren-Lawrence score (rs = 0.2333, P = 0.008), but no correlation was founded between faPWV with Kellgren-Lawrence score (rs = 0.1624, P = 0.067) in OA patients. This study demonstrated that stiffening of aorta, but not lower limb arteries, was independently associated with knee OA. Our findings may call for further implementation of routine aortic stiffness assessments so as to evaluate cardiovascular risk in patients with OA.

Identification of the chemical composition of distiller's grain polyphenols and their effects on the fecal microbial community structure.

Distiller grains are the main by-products of Baijiu production and are usually discarded, ignoring their abundant functional phytochemicals. The free and bound polyphenols from distiller grains were extracted and their potential effect on modulating fecal microbiota was investigated using in vitro fecal fermentation. The results showed that 34 polyphenols were quantified from distiller grains. The antioxidant activity was positively correlated with quercetin, myricetin, epicatechin, and naringenin. The abundance of Bifidobacterium, Ruminobacterium, Lactobacillus, Akkermansia, and butyrate-producing bacteria was enhanced by distiller's grain polyphenols by approximately 10.66-, 6.39-, 7.83-, 2.59-, and 7.74-fold, respectively. Moreover, the production of short-chain fatty acids (SCFAs), especially acetic, butyric, and propionic acid, was promoted (increased 1.99-, 1.71-, and 1.34-fold, respectively). Correlated analysis revealed quercetin, daidzein, and kaempferol as the key polyphenols by analyzing the effects on gut microbiota and SCFAs. This study could provide a reference for converting distiller grains into high-nutrient functional food ingredients and feeds.

Effect of free and bound polyphenols from Rosa roxburghii Tratt distiller's grains on moderating fecal microbiota.

Rosa roxburghii Tratt distiller's grains (R. roxburghii DGs), the main by-product of wine processing, showed functional value and potential for high-value usage which benefited from their rich polyphenols. In this study, the free and bound polyphenols from R. roxburghii DGs were extracted and their potential effect on modulating fecal microbiota was investigated using in vitro fecal fermentation. The free polyphenols (26.32-26.45 mg GAE/g) showed higher antioxidant activity compared to the bound polyphenols (8.76-9.01 mg GAE/g). The free and bound polyphenols significantly improved the fecal microbiota community structure and enhanced short chain fatty acids concentrations after the stimulated colonic fermentation for 24 h. Furthermore, the effect of R. roxburghii DGs polyphenols on modulating fecal microbiota was primarily attributed to quercetin, catechin, kaempferol, cyanidin and baicalin. This research suggests that R. roxburghii DGs are a promising source of natural antioxidants and prebiotic foods.

Hypoglycemic effect of Lactobacillus plantarum-fermented mulberry pomace extract in vitro and in Caenorhabditis elegans.

Mulberry pomace is rich in phytochemicals, but there are few studies on its utilization as a by-product. Natural foods containing phytochemicals can alleviate the toxic effects of excessive glucose intake. In this study, we investigated the protective effect of Lactobacillus plantarum-fermented mulberry pomace extract (FMPE) under hyperglycemic conditions. The phenolic compounds and α-glucosidase inhibition of FMPE were determined using UPLC-MS and chemical models. Furthermore, Caenorhabditis elegans was a model system to study the hypoglycemic effects. The results showed that the polyphenolics and α-glucosidase inhibition were improved during fermentation. Three phenolic components (cyanidin, 2,4,6-trihydroxybenzaldehyde, and taxifolin) were important variables for α-glucosidase inhibition. FMPE and the three key compound treatments reduced the glucose content and reactive oxygen species (ROS) level in Caenorhabditis elegans. The protective mechanism occurred by activating DAF-16/FOXO and SKN-1/Nrf2. This study suggests that Lactobacillus plantarum-fermentation was a potential way to utilize mulberry pomace polyphenols as hypoglycemic food ingredients.

Maslinic acid attenuates UVB-induced oxidative damage in HFF-1 cells.

BACKGROUND: Oxidative damage is one of the major mechanisms of ultraviolet B (UVB)-induced damage to the skin. Maslinic acid (MA) is a natural compound of pentacyclic triterpene acids. It has been proved to have anti-inflammatory and antioxidant properties. OBJECTIVE: This study aimed to explore the effects of MA on oxidative damage in human foreskin fibroblast cells (HFF-1) and the potential molecular mechanisms. METHODS: A specific dose of UVB radiation was used to induce oxidative damage in HFF-1. Based on this, we performed measurements of cell proliferation, reactive oxygen species (ROS) levels, antioxidant enzyme activity, inflammation-related mediators, and NF-κB nuclear localization with or without the addition of MA. RESULTS: MA significantly promoted cell proliferation viability at 10 and 20 µM. The addition of MA 24 h before UVB irradiation was more effective at enhancing cell proliferation and also produced lower ROS levels compared to co-cultured fibroblasts and MA for 24 h after irradiation. However, there was no statistically significant difference between groups at concentrations of 10 and 20 µM. The pretreatment group with MA had elevated superoxide dismutase and catalase activities, decreased IL-6 generation, and lowered mRNA levels of IL-6, TNF-α and MMP3 in comparison with the UVB-irradiated group without additional MA. Meanwhile, the nuclear translocation of NF-κB and the degradation of IκB were inhibited by MA pretreatment. CONCLUSION: Taken together, these findings suggest that MA may alleviate UVB-induced oxidative damage in HFF-1 by inhibiting the nuclear translocation of NF-κB.

Construction of Circadian Clock Signature for Tumor Microenvironment in Predicting Survival for Cutaneous Melanoma.

OBJECTIVE: We explored circadian clock-related genes (CCRG) to establish a risk model and identify associations with the tumor immune microenvironment in cutaneous melanoma (CM). METHODS: Circadian clock genes were downloaded from Circadian Gene Database. To explore CM-related circadian clock genes, we combined multivariate cox regression associated with least absolute shrinkage and selection operator (LASSO) regression in the Cancer Genome Atlas (TCGA) and validated it in the GSE65904 dataset. Time-dependent receiver operating characteristic curve (ROC) and Kaplan-Meier analysis were calculated to determine a CCRG risk score model. In addition, the overall survival nomograms of clinicopathological factors and circadian clock-related gene signatures. Additionally, we evaluated the connection between circadian clock-related genes with immune checkpoint inhibitors and immune cell infiltration. RESULTS: Two circadian clock-related signatures were established. The risk model included SEMA4D (p<0.001, HR: 0.709, 95% CI: 0.581 to 0.867) and SOD-2 (p=0.009, HR: 0.790, 95% CI: 0.663 to 0.944) in patients with TCGA melanoma. The risk model was based on two CCRGs enriched in base excision repair, glycosylphosphatidyl (GPI), and one carbon of the folate pathway. The overall survival was lower in the high-risk group. In addition, the circadian-clock signature may be able to evaluate the immunotherapy response. CONCLUSIONS: We developed and validated a circadian signature to characterize the clinical significance and tumor microenvironment of cutaneous melanoma, revealing that circadian rhythms may impact cutaneous melanoma.

Protective effects of di-caffeoylquinic acids from Artemisia selengensis Turcz leaves against monosodium urate-induced inflammation via the modulation of NLRP3 inflammasome and Nrf2 signaling pathway in THP-1 macrophages.

Artemisia selengensis Turcz (AST) as a common vegetable is rich in di-caffeoylquinic acids (di-CQAs) and has been reported to possess multiple health benefits. However, whether di-CQAs from AST leaf extracts (ASTE) could alleviate gout inflammation is still unknown. Herein, this study explored the inhibitory mechanism of ASTE on gout inflammation in THP-1 macrophages. Results suggested that ASTE suppressed the secretion and mRNA levels of inflammatory cytokines including interleukin-18, interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Pretreatment with ASTE inhibited lipopolysaccharide-induced of IκBα degradation, p65 phosphorylation and up-regulation of Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome proteins. Moreover, ASTE inhibited monosodium urate-induced the up-regulation of active caspase-1 and interleukin-1ß, promoted nuclear factor E2-related factor2 (Nrf2) to translocate into the nucleus, reducing the generation of MSU-induced reactive oxygen species. These results suggested that ASTE alleviated gout inflammation via inhibiting NLRP3 inflammasome activation and activating Nrf2 signaling pathway. PRACTICAL APPLICATIONS: Artemisia selengensis Turcz (AST) as a common vegetable in China belongs to genus Artemisia, which are rich in di-caffeoylquinic acids. This study aimed to investigate the effect of ASTE on alleviating gout inflammation and whether NLRP3 inflammasome and Nrf2 signaling pathways are involved in the protection of ASTE against gout inflammation. Our findings are significant for developing di-CQAs from AST by-products as an effective functional food for preventing gout.

Modulation of Gut Microbiota by Lactobacillus casei Fermented Raspberry Juice In Vitro and In Vivo.

The aim of this study was to investigate the modulation of gut microbiota by fermented raspberry juice (FRJ) both in vitro and in vivo. Results showed that total phenolic content and antioxidant activities of FRJ reached the highest after fermentation for 42 h. Seventeen phenolic compounds were contained in FRJ, mainly including ellagic acid (496.64 ± 2.91 µg/g) and anthocyanins (total concentration: 387.93 µg/g). FRJ modulated the gut microbiota into a healthy in vitro status, with increase of valeric and isovaleric acids production. In healthy mice, all FRJ treatments improved the production of acetic, butyric and isovaleric acids as well as the gene expression of ZO-1, Claudin-1, Claudin-4, Ocdudin, E-cadherin and Muc-2. Moreover, variable gut microbial compositions were found among the groups fed diet-supplemented the different doses of FRJ, within low and median doses of FRJ may regulate the microbiota to a healthier state compared to the high dose supplementation. This study indicated that fermentation is a potential way to produce plant-based juices, which could reshape the gut microbiota and improve the host health.

Construction of a Ferroptosis-Related Gene Signature for Predicting Survival and Immune Microenvironment in Melanoma Patients.

OBJECTIVE: In this research, we studied the genes associated with ferroptosis to develop a prognostic model and find out an association with tumor immune microenvironment in skin cutaneous melanoma (SKCM) patients. METHODS: To find SKCM-related ferroptosis genes, we used Cox regression and LASSO approach on 60 genes related to ferroptosis and SKCM-related RNA-seq. Following that, a ferroptosis-related gene signature was created. Time-dependent ROC curve and Kaplan-Meier analysis were calculated to determine its capability of prediction. Besides, several assessments were used to evaluate overall survival (OS), accompanied by the creation of a nomogram for the clinicopathologic factors and the ferroptosis-related gene signature we established. We also investigated the relationship between ferroptosis-related gene signature with three immune checkpoints and immune cell infiltration. RESULTS: Our prognostic model included two genes (ALOX5, CHAC1). In both TCGA and GEO cohorts, OS was lower in high-risk category. Using our gene signature, we can reliably predict OS. Additionally, our gene signature can predict immune cell infiltration and SKCM immunotherapy response. CONCLUSION: Our gene signature has shown to be a reliable predictor of OS, reflect the immune microenvironment, and predict the effectiveness of immunotherapy for SKCM patients.

Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer.

BACKGROUND: The expression of programmed cell death ligand 1(PD-L1) is related to the efficacy of immune checkpoint inhibitors on patients with non-small cell lung cancer (NSCLC), but tumor tissue (TT) samples are difficult to obtain, and initial TT samples are difficult to reflect the spatial-temporal heterogeneity. Therefore, we explored the feasibility of separating circulating tumor cells (CTCs) and detecting PD-L1 expression on CTCs. PATIENTS AND METHODS: Peripheral blood specimens were sampled from 66 NSCLC patients, and CTCs were separated by membrane filtration based on size. For 59 patients with paired TT specimens, the expression of PD-L1 in their CTCs and TTs was determined using the immunohistochemistry and immunocytochemistry based on 28-8 antibody, respectively. The PD-L1 expression in TTs was set as a gold standard for calculation of sensitivity, specificity, consistency, positive predictive value (PPV), and negative predictive value (NPV), and the Cohen kappa coefficient for CTCs and paired TTs was calculated. In addition, the T-test, Chi-square test, and Mann-Whitney U-test were adopted to analyze the correlation of clinical pathological features and prognosis with PD-L1 expression. RESULTS: Sensitivity, specificity, concordance, PPV and NPV of detecting PD-L1 in CTCs of the 41 initial treated patients were 88.89%, 73.91%, 80%, 72.73% and 89.47%, respectively, and the Cohen kappa coefficient of CTC and paired TTs was 0.613. The univariate analysis of survival showed that the progression-free survival time of initial treated patients with positive PD-L1 expression was shorter than that of those with negative PD-L1 expression in CTCs or TTs (P>0.05), and the positive PD-L1 expression in CTCs or TTs had nothing to do with age, sex, smoking status, histological type, and stage (P > 0.05). CONCLUSION: The study confirms the feasibility of CTC PD-L1 detection in peripheral blood and lays a foundation for exploring real-time and individualized immunotherapy molecular biomarkers.

A novel device to capture circulating tumor cells: Quantification and molecular analysis in lung cancer patients.

Here, we describe a novel microfilter device to capture circulating tumor cells in an efficient and low-cost manner. Then, we validated the safety and clinical utility of the novel microfilter device. We next performed mutation analysis from circulating tumor cells collected from lung cancer patients using this new device. Our results indicate that this microfilter system can be used to investigate the genome landscape of circulating tumor cells collected from lung cancer patients. Further, our results highlight a proof-of-concept demonstration indicating that circulating tumor cell can be used for mutation profiling during tumor evolution, therapy prediction, and monitoring, with immediate clinical applicability.

Fermented blueberry pomace ameliorates intestinal barrier function through the NF-κB-MLCK signaling pathway in high-fat diet mice.

The barrier-improving functions of fermented blueberry pomace (FBP) and its potential mechanism were investigated in this study. Polyphenols and the approximate composition of FBP were evaluated according to the National Standard of the People's Republic of China and the UPLC-MS system. Male C57BL/6 mice were fed a control diet (CD) or a high-fat diet (HFD) with or without FBP supplementation. Oxidative stress, inflammation, histological morphology and the expression of functional proteins in the small intestine of mice were evaluated using the enzyme linked immunosorbent assay (ELISA), quantitative polymerase chain reaction (qPCR) and western blotting. The content of protein, fat, soluble dietary fiber, insoluble dietary fiber and carbohydrates (non-dietary fiber) was 114.5 ± 1.5 g kg-1, 5.0 ± 0.2 g kg-1, 48.0 ± 0.1 g kg-1, 360.3 ± 2.2 g kg-1 and 423 g kg-1 (by difference), respectively. Thirty-six polyphenols were identified in FBP. FBP improved the growth of mice and attenuated hepatic and intestinal oxidative stress. Intestinal inflammation was significantly reduced through the decrease of tumor necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) as well as an increase of interleukin-10 (IL-10). FBP supplementation significantly improved the intestinal morphology and barrier function, potentially by mediating the NF-κB-MLCK signaling pathway. The supplementation of FBP in HFD mice enhanced the intestinal barrier function. This suggested that polyphenol-rich by-products might provide a similar health effect in HFD individuals.

Isoflavone biochanin A, a novel nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element activator, protects against oxidative damage in HepG2 cells.

Isoflavones are one group of the major flavonoids and possess multiple biological activities due to their antioxidant properties. However, a clear antioxidant mechanism of dietary isoflavones is still remained to be answered. In this study, the effects of isoflavones on the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway and the underlying molecular mechanisms were investigated. Results showed that isoflavones are potential Nrf2-ARE activators while their activities were structure dependent. Biochanin A (BCA), an O-methylated isoflavone with low direct antioxidant activity, can effectively protect HepG2 cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage via activation of the Nrf2 signaling, and thereby the induction of downstream cytoprotective enzymes including NAD(P)H quinone oxidoreductase-1, heme oxygenasae-1, and glutamate-cysteine ligase catalytic subunit. A molecular docking study revealed that BCA could directly bind into the pocket of Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a cytoplasmic suppressor of Nrf2, to facilitate Nrf2 activation. The upstream mitogen-activated protein kinase (MAPK) pathways were also involved in the activation of Nrf2 signaling. These findings indicate that the protective actions of dietary isoflavones against oxidative damage may be at least partly due to their ability to enhance the intracellular antioxidant response system by modulating the Nrf2-ARE signaling pathway.

Ailanthone induces autophagic and apoptotic cell death in human promyelocytic leukemia HL-60 cells.

Ailanthone, which is extracted from the traditional Chinese medicinal plant Ailanthus altissima, has been thoroughly demonstrated to have anti-tumor, anti-HIV, anti-inflammatory, anti-malarial, anti-allergic and anti-microbial activities. However, the anti-proliferative effects of ailanthone on HL-60 cells and potential mechanisms underlying those effects have not been reported. In the present study, we demonstrated the potent cytotoxicity of ailanthone against HL-60 cells. Annexin V-APC/7-ADD staining assay indicated that ailanthone increased the number of apoptotic cells in a dose-dependent manner. PI staining showed that ailanthone increased the percentage of G0/G1-phase cells in a dose-dependent manner. Acridine orange staining suggested that ailanthone induced the formation of acidic vesicular organelles in HL-60 cells and pretreatment with BaF-A1 could attenuate this process. Western blotting showed that ailanthone up-regulated the protein expression levels of beclin-1 and LC3-II and down-regulated those of LC3-I and p62 in a dose-dependent manner. Use of BaF-A1 showed that the anti-proliferative effects of ailanthone on HL-60 cells may be partly attributable to the induction of autophagy-mediated apoptosis by MTT assay and annexin V-APC/7-ADD staining assay.

Detection and monitoring of driver mutations by next-generation sequencing in squamous cell lung cancer patient and possible predictive biomarker of third generation EGFR-tyrosine kinase inhibitors.

Driver mutation detection and the development of targeted drugs have significantly improved survival of advanced lung adenocarcinoma patients with driver mutations. However, we still lack understanding of druggable mutations in patients with advanced squamous cell lung cancer (SQCLC). Less than 10% of SQCLC patients have EGFR gene mutations, thus we have limited knowledge of biological molecular changes with first generation EGFR-tyrosine kinase inhibitor (TKI) resistance. We report a case of an SQCLC patient treated with first-line platinum-doublet chemotherapy. After disease progression, the patient was administered first generation EGFR-TKI gefitinib based on next generation sequencing results. After five months, a second biopsy was performed and both the tumor and plasma samples indicated an acquired EGFR exon 20 T790M mutation. The patient was subsequently administered AZD9291, which resulted in disease control for a time. Our results indicate that a TP53 exon 8 mutation might act as a negative predictive biomarker for third generation EGFR-TKIs.