A Preliminary Study Using High-Frequency Ultrasound to Evaluate Vulvar Skin With Lichenoid Vulvar Dermatoses.

BACKGROUND: Lichenoid vulvar dermatoses (LVD) are inflammatory diseases primarily affecting the vulva and anus. This study aims to evaluate the skin changes in patients with LVD using high-frequency ultrasound. METHODS: Forty-five patients with LVD, who attended Henan Provincial People's Hospital from November 2021 to March 2024, were selected. According to the pathological conclusions, patients were divided into two groups: the vulvar lichen sclerosus (VLS) group (n = 24) and the vulvar lichen simplex chronicus (VLSC) group (n = 21). Thirty age- and BMI-matched healthy women were selected as the control group. We assessed the epidermal thickness, subepidermal low echogenic band (SLEB) thickness, dermal thickness, and vascular index (VI) among the three groups. Receiver operating characteristic curve (ROC) analysis was performed to determine the diagnostic efficacy of these ultrasound parameters for LVD. Binary logistic regression was used to investigate risk factors influencing LVD pathology in VLS patients. RESULTS: Epidermal thickness, SLEB thickness, dermal thickness, and VI were increased in the VLS and VLSC groups compared to the control group (p < 0.05). There were no statistically significant differences in ultrasound parameters between the VLS and VLSC groups (p > 0.05). The ROC curves showed that the area under the curve (AUC) value for the dermis (AUC = 0.882) was the largest for VLS, and VI (AUC = 0.917), it was the largest for VLSC. Binary logistic regression indicated that having an allergic disease was a risk factor for VLS between VLS and VLSC groups (OR = 6.797, p = 0.028). CONCLUSION: High-frequency ultrasound can detect thickening of the skin and increasing VI in patients with LVD, which can be helpful in the evaluation and management of LVD.

Dietary supplementation of ß-1, 3-glucan improves the intestinal health of white shrimp (Litopenaeus vannamei) by modulating intestinal microbiota and inhibiting inflammatory response.

The phenomenon of intestinal dysfunction is widely observed in white shrimp (Litopenaeus vannamei) culture, and ß-1,3-glucan has been confirmed to be beneficial in intestinal health with a lack understanding of its underlying mechanism. Proteobacteria, Firmicutes, and Actinobacteria served as the predominant phyla inhabiting the intestine of white shrimp, whilst a significant variation in their proportion was recorded in shrimp fed with basal and ß-1,3-glucan supplementation diets in this study. Dietary supplementation of ß-1,3-glucan could dramatically increase the microbial diversity and affect microbial composition, concurrent with a notable reduction in the ratio of opportunistic pathogen Aeromonas, gram-negative microbes, from Gammaproteobacteria compared to the basal diet group. The benefits for microbial diversity and composition by ß-1,3-glucan improved the homeostasis of intestinal microbiota through the increase of specialists' number and inhibition of microbial competition caused by Aeromonas in ecological networks; afterward, the inhibition of Aeromonas by ß-1,3-glucan diet dramatically suppressed microbial metabolism related to lipopolysaccharide biosynthesis, followed by a conspicuous decrease in the intestinal inflammatory response. The improvement of intestinal health referred to the elevation in intestinal immune and antioxidant capacity, ultimately contributing to the growth of shrimp fed ß-1,3-glucan. These results suggested that ß-1,3-glucan supplementation improved the intestinal health of white shrimp through the modulation of intestinal microbiota homeostasis, the suppression of intestinal inflammatory response, and the elevation of immune and antioxidant capacity, and subsequently promoted the growth of white shrimp.

Response of Intestinal Microbiota to the Variation in Diets in Grass Carp (Ctenopharyngodon idella).

The intestinal microbiota is important for the nutrient metabolism of fish and is significantly influenced by the host's diet. The effect of ryegrass and commercial diets on the intestinal microbiota of grass carp was compared in this study. In comparison to ryegrass, artificial feed significantly reduced the microbial diversity in the intestine, which was measured by a decrease in the observed OTUs, ACE, Shannon, and the InvSimpson index. Although grass carp fed with ryegrass and artificial feed shared a dominant phyla Firmicutes and Proteobacteria, the microbial composition was clearly distinguishable between the two groups. In grass carp fed with ryegrass, Alphaproteobacteria, Gammaproteobacteria, and Actinobacteria predominated, whereas Bacilli was significantly higher in the artificial feed group due to an increase in Weissella and an unassigned Bacillales bacteria, as well as a significant increase in a potential pathogen: Aeromonas australiensis. Grass carp fed with ryegrass exhibited a more complex ecological network performed by the intestinal bacterial community, which was dominated by cooperative interactions; this was also observed in grass carp fed with artificial feed. Despite this, the increase in A. australiensis increased the competitive interaction within this ecological network, which contributed to the vulnerable perturbation of the intestinal microbiota. The alteration of the microbial composition through diet can further affect microbial function. The intestinal microbial function in grass carp fed with ryegrass was rich in amino acids and exhibited an increased energy metabolism in order to compensate for a low-nutrient diet intake, while the artificial feed elevated the microbial lipid metabolism through the promotion of its synthesis in the primary and secondary bile acids, together with a notable enhancement of fatty acid biosynthesis. These results indicated that diet can affect the homeostasis of the intestinal microbiota by altering the microbial composition and the interspecific interactions, whilst microbial function can respond to a variation in diet.

Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα.

Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation.

The expression landscape of JAK1 and its potential as a biomarker for prognosis and immune infiltrates in NSCLC.

BACKGROUND: Janus-activated kinase-1 (JAK1) plays a crucial role in many aspects of cell proliferation, differentiation, apoptosis and immune regulation. However, correlations of JAK1 with prognosis and immune infiltration in NSCLC have not been documented. METHODS: We analyzed the relationship between JAK1 expression and NSCLC prognosis and immune infiltration using multiple public databases. RESULTS: JAK1 expression was significantly decreased in NSCLC compared with that in paired normal tissues. JAK1 overexpression indicated a favourable prognosis in NSCLC. In subgroup analysis, high JAK1 expression was associated with a preferable prognosis in lung adenocarcinoma (OS: HR, 0.74, 95% CI from 0.58 to 0.95, log-rank P = 0.017), not squamous cell carcinoma. In addition, data from Kaplan-Meier plotter revealed that JAK1 overexpression was associated with a preferable prognosis in male and stage N2 patients and patients without distant metastasis. Notably, increased levels of JAK1 expression were associated with an undesirable prognosis in patients with stage 1 (OS: HR, 1.46, 95% CI from 1.06 to 2.00, P = 0.02) and without lymph node metastasis (PFS: HR, 2.18, 95% CI from 1.06 to 4.46, P = 0.029), which suggests that early-stage NSCLC patients with JAK1 overexpression may have a bleak prognosis. Moreover, multiple immune infiltration cells, including NK cells, CD8 + T and CD4 + T cells, B cells, macrophages, neutrophils, and dendritic cells (DCs), in NSCLC were positively correlated with JAK1 expression. Furthermore, diverse immune markers are associated with JAK1 expression. CONCLUSIONS: JAK1 overexpression exhibited superior prognosis and immune infiltration in NSCLC.

Elevated exosome-derived miRNAs predict osimertinib resistance in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. Recently, the drug resistance information transmitted by exosomal miRNAs has attracted much attention. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored. METHODS: We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients. RESULTS: Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 and miR-3913-5p expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-3913-5p was associated with TNM stage, platelet count, tumor marker carcinoembryonic antigen, and distant metastases. In patients with EGFR exon 21 L858R mutation, the increased expression levels of miR-184 and miR-3913-5p derived from serum exosomes indicated osimertinib resistance. Similarly, for T790M-positive patients, the level of exosome-derived miR-3913-5p can be used as a predictive marker for osimertinib resistance. CONCLUSIONS: The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.

Omarigliptin Prevents TNF-α-Induced Cellular Senescence in Rat Aorta Vascular Smooth Muscle Cells.

Cellular senescence is one of the most significant factors involved in aging and age-related diseases. Senescence of vascular smooth muscle cells (VSMCs) adversely affects the function of the cardiovascular system and contributes to the development of atherosclerosis, hypertension, and other cardiovascular diseases. Glucagon-like peptide-1 (GLP-1) is an important incretin hormone involved in insulin release and vascular tone. GLP-1 is quickly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Omarigliptin is a new DPP-4 inhibitor that has demonstrated anti-inflammatory and antioxidative stress properties. In the present study, we investigated the effects of the selective DPP-4 inhibitor omarigliptin (OMG) on VSMCs exposed to insult from tumor necrosis factor-α (TNF-α), one of the main inflammatory signaling molecules involved in cellular senescence. We found that OMG could suppress TNF-α-induced expression of pro-inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, and IL-8) and inhibit oxidative stress by reducing the production of H2O2 and protein carbonyl. OMG ameliorated the increase in senescence-associated ß-galactosidase (SA-ß-gal) and telomerase activity induced by TNF-α. The plasminogen activator inhibitor-1 (PAI-1)/p53/p21 pathway is a key inducer of cellular senescence. OMG ameliorated the acetylation of p53 at lysine 382 (K382) and subsequent activation of p21 via inhibition of PAI-1. Importantly, our experiments revealed that blockage of silent information-regulator 1 (SIRT1) abolished the inhibitory effects of OMG on p53 acetylation, SA-ß-gal activity, and telomerase activity in VSMCs. These results suggest that OMG may have the potential to delay or prevent the progression of age-related cardiovascular diseases by modulating the activity of SIRT1.

Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults.

BACKGROUND: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. OBJECTIVE: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. METHODS: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30-44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. RESULTS: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-ß negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. CONCLUSION: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis.

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. These effects provide a novel mechanism by which mTORC1 signaling impairs the function of MNK2 and thereby decreases eIF4E phosphorylation. MNK2[S74A] knock-in cells show enhanced phosphorylation of eIF4E and S6K1 (i.e., increased mTORC1 signaling), enlarged cell size, and increased invasive and transformative capacities. MNK2[Ser74] phosphorylation was inversely correlated with disease progression in human prostate tumors. MNK inhibition exerted anti-proliferative effects in prostate cancer cells in vitro. These findings define a novel feedback loop whereby mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, allowing reciprocal regulation of these two oncogenic pathways.

Dilated conditional GAN for bone suppression in chest radiographs with enforced semantic features.

PURPOSE: The purpose of this essay is to improve computer-aided diagnosis of lung diseases by the removal of bone structures imagery such as ribs and clavicles, which may shadow a clinical view of lesions. This paper aims to develop an algorithm to suppress the imaging of bone structures within clinical x-ray images, leaving a residual portrayal of lung tissue; such that these images can be used to better serve applications, such as lung nodule detection or pathology based on the radiological reading of chest x rays. METHODS: We propose a conditional Adversarial Generative Network (cGAN) (Mirza and Osindero, Conditional generative adversarial nets, 2014.) model, consisting of a generator and a discriminator, for the task of bone shadow suppression. The proposed model utilizes convolutional operations to expand the size of the receptive field of the generator without losing contextual information while downsampling the image. It is trained by enforcing both the pixel-wise intensity similarity and the semantic-level visual similarity between the generated x-ray images and the ground truth, via optimizing an L-1 loss of the pixel intensity values on the generator side and a feature matching loss on the discriminator side, respectively. RESULTS: The framework we propose is trained and tested on an open-access chest radiograph dataset for benchmark. Results show that our model is capable of generating bone-suppressed images of outstanding quality with a limited number of training samples (N = 272). CONCLUSIONS: Our approach outperforms current state-of-the-art bone suppression methods using x-ray images. Instead of simply downsampling images at different scales, our proposed method mitigates the loss of contextual information by utilizing dilated convolutions, which gains a noticeable quality improvement for the outputs. On the other hand, our experiment shows that enforcing the semantic similarity between the generated and the ground truth images assists the adversarial training process and achieves better perceptual quality.

Comparison between closed pleural biopsy and medical thoracoscopy for the diagnosis of undiagnosed exudative pleural effusions: a systematic review and meta-analysis.

BACKGROUND: Exudative pleural effusion (EPE) is a common diagnostic challenge. The utility of medical thoracoscopy (MT) and closed pleural biopsy (CPB) to aid in the diagnosis of EPE has been reported in many published studies. Herein, we perform a systematic review and meta-analysis to compare the diagnostic yield and safety of CPB and MT in EPE. METHODS: Four databases were searched for studies reporting the diagnostic yield of CPB and MT for EPE. The quality of the included studies was evaluated according to the quality assessment of diagnostic accuracy studies (QUADAS) tool. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and complication risks were compared between the two groups. RESULTS: Ten studies dealing with CPB and twenty-three studies dealing with MT for the diagnosis of EPE were included in this meta-analysis. Pooled sensitivity, specificity, PLR, NLR and DOR of CPB group was 77%, 99%, 32.55, 0.22, 165.71, respectively, while pooled sensitivity, specificity, PLR, NLR and DOR of MT group was 93%, 100%, 10.82, 0.08, 162.81, respectively. The area under the summary receiver operating characteristic (SROC) curve of CPB and MT were both 0.97. The ability of CPB to diagnose non-malignant diseases was like MT (69% vs. 68%), while the ability was lower than that of MT to diagnose malignant diseases (72% vs. 92%). The pooled diagnostic accuracy of CPB and MT for mesothelioma was 26% (95% CI, 14-38%) and 42% (95% CI, 22-62%) (P<0.001), respectively. The rate of complications with CBP was lower than that reported for MT. CONCLUSIONS: CBP is a relatively accurate tool with a lower complication rate compared to MT in the diagnosis of EPE, especially in diagnosing non-malignant diseases. We confirm the utility of MT in the diagnostic workup of malignancy (especially mesothelioma); however, in selected cases, CPB could be used as the first diagnostic approach with a favorable safety profile.

Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-ß Load.

BACKGROUND/OBJECTIVE: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-ß load (NAL). METHODS: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n = 65) and ≥1.35 (n = 35) was classified as high NAL. RESULTS: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOEɛ4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aß42/40 ratio (AUC = 0.829). CONCLUSION: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

Plasma transferrin and hemopexin are associated with altered Aß uptake and cognitive decline in Alzheimer's disease pathology.

BACKGROUND: Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts. METHODS: Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures. RESULTS: Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit ß (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOEε4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment. CONCLUSIONS: In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.

Personality factors and cerebral glucose metabolism in community-dwelling older adults.

Personality factors have been associated with Alzheimer's disease (AD) and dementia, but they have not been examined against markers of regional brain glucose metabolism (a primary measure of brain functioning) in older adults without clinically diagnosed cognitive impairment. The relationship between personality factors derived from the five-factor model and cerebral glucose metabolism determined using positron emission tomography (PET) with [18F]-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET) was examined in a cohort of 237 non-demented, community-dwelling older adults aged 60-89 years (M ± SD = 73.76 ± 6.73). Higher neuroticism and lower scores on extraversion and conscientiousness were significantly associated with decreased glucose metabolism in brain regions typically affected by AD neuropathological processes, including the hippocampus and entorhinal cortex. Furthermore, while there were significant differences between apolipoprotein E (APOE) ε4 allele carriers and non-carriers on 18F-FDG-PET results in the neocortex and other brain regions (p < 0.05), there was no significant difference between carriers and non-carriers on personality factors and no significant interactions were found between APOE ε4 carriage and personality factors on brain glucose metabolism. In conclusion, we found significant relationships between personality factors and glucose metabolism in neural regions more susceptible to AD neuropathology in older adults without clinically significant cognitive impairment. These findings support the need for longitudinal research into the potential mechanisms underlying the relationship between personality and dementia risk, including measurement of change in other AD biomarkers (amyloid and tau imaging) and how they correspond to change in personality factors. Future research is also warranted to determine whether timely psychological interventions aimed at personality facets (specific aspects or characteristics of personality factors) can affect imaging or other biomarkers of AD resulting in delay or ideally preventing the onset of the cognitive impairment.

Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with increasing mortality in China. Angiogenesis is crucial for tumor formation, development and metastasis in HCC. Previous studies indicated that high expression levels of elongation factor 2 kinase (eEF2K), a protein kinase that negatively regulates the elongation stage of translation, were associated with poor prognosis of HCC. Here, we show that pharmacological inhibition or knockdown of eEF2K in highly metastatic liver cancer cells inhibits their colony forming and migratory capacities, as well as reducing their invasiveness. Importantly, knocking down eEF2K by lentiviral directed shRNA prevented tumor growth and angiogenesis of HCC in mice. Silencing of eEF2K in endothelial cells (HUVECs) led to a reduction in vascularization, evidenced by a decrease in capillary-like structures in the matrigel. Notably, knocking down eEF2K reduced the expression of angiogenesis-related growth factors in liver cancer cells and the expression of growth factor receptors on HUVECs, and thus restricted signaling crosstalk that promotes angiogenesis between HCC cells and endothelial cells. We also showed that silencing of eEF2K effectively reduced protein levels of SP1/KLF5 transcription factors and hence decreased the levels of bound SP1/KLF5 to the VEGF promoter, resulted in a decrease in VEGF mRNA expression. Knocking down eEF2K also led to a striking decrease in the phosphorylation of PI3K/Akt and STAT3, indicating inactivation of these tumorigenic pathways. Taken together, our data suggest that eEF2K contributes to angiogenesis and tumor progression in HCC via SP1/KLF5-mediated VEGF expression, as well as the subsequent stimulation of PI3K/Akt and STAT3 signaling.

Structural core of the executive control network: A high angular resolution diffusion MRI study.

Executive function (EF) is a set of cognitive capabilities considered essential for successful daily living, and is negatively affected by ageing and neurodegenerative conditions. Underpinning EF performance are functional nodes in the executive control network (ECN), while the structural connectivity underlying this network is not well understood. In this paper, we evaluated the structural white matter tracts that interconnect the ECN and investigated their relationship to the EF performance. Using high-angular resolution diffusion MRI data, we performed tractography analysis of structural connectivity in a cognitively normal cohort (n = 140), specifically targeting the connectivity between ECN nodes. Our data revealed the presence of a strongly-connected "structural core" of the ECN comprising three components: interhemispheric frontal connections, a fronto-parietal subnetwork and fronto-striatal connections between right dorsolateral prefrontal cortex and right caudate. These pathways were strongly correlated with EF performance (p = .003). Post-hoc analysis of subregions within the significant ECN connections showed that these effects were driven by a highly specific subset of interconnected cortical regions. The structural core subnetwork of the functional ECN may be an important feature crucial to a better future understanding of human cognition and behaviour.

Plasma neurofilament light chain and amyloid-ß are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease.

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-ß; Aß), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aß correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aß concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. RESULTS: A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aß40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aß42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aß load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aß and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. CONCLUSIONS: The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aß seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

Ultrasensitive Detection of Plasma Amyloid-ß as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer's Disease.

BACKGROUND: Aberrant amyloid-ß (Aß) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aß load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aß deposition, attractive candidates for investigation as surrogate markers. OBJECTIVE: Investigation of plasma Aß as a surrogate marker for brain Aß deposition in cognitively normal elderly individuals. METHODS: Plasma Aß40 and Aß42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aß deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aß was compared between 32 participants assessed to have low brain Aß load (Aß-, SUVR <1.35) and 63 assessed to have high brain Aß load (Aß+, SUVR ≥1.35). RESULTS: Plasma Aß42/Aß40 ratios were lower in the Aß+ group compared to the Aß-group. Plasma Aß40 and Aß42 levels were not significantly different between Aß-and Aß+ groups, although a trend of higher plasma Aß40 was observed in the Aß+ group. Additionally, plasma Aß42/Aß40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aß+ participants being distinguished from Aß-participants based on an area under the receiver operating characteristic curve shown to be 78%. CONCLUSION: Plasma Aß ratios in this study are a potential biomarker for brain Aß deposition and therefore, for preclinical AD. However, this method to measure plasma Aß needs further development to increase the accuracy of this promising AD blood biomarker.