LC3-dependent extracellular vesicles promote M-MDSC accumulation and immunosuppression in colorectal cancer.

For a long time, myeloid-derived suppressor cells (MDSCs) dilated in circulation system of colorectal cancer (CRC) patients have been puzzling clinicians. Various evidence shows that MDSCs constitute the bulk of immunosuppression in CRC, which is related to tumor growth, adhesion, invasion, metastasis, and immune escape. However, the mechanisms underlying these cells formation remain incompletely understood. In this study, we reported that CRC cell-derived LC3-dependent extracellular vesicles (LDEVs)-mediated M-MDSCs formation via TLR2-MYD88 pathway. Furthermore Hsp60 was the LDEVs surface ligand that triggered these MDSCs induction. In clinical studies, we reported that accumulation of circulating M-MDSCs as well as IL-10 and arginase1 secretion were reliant upon the levels of tumor cell-derived LDEVs in CRC patients. These findings indicated how local tumor cell-derived extracellular vesicles influence distal hematopoiesis and provided novel justification for therapeutic targeting of LDEVs in patients with CRC.

FBXO43 promotes cell cycle progression in cancer cells through stabilizing SKP2.

FBXO43 is a member of the FBXO subfamily of F-box proteins, known to be a regulatory hub during meiosis. A body of data showed that FBXO43 is overexpressed in a number of human cancers. However, whether and how FBXO43 affects cell cycle progression and growth of cancer cells remain elusive. In this study, we provide first piece of evidence, showing a pivotal role of FBXO43 in cell cycle progression and growth of cancer cells. Specifically, FBXO43 acts as a positive cell cycle regulator with an oncogenic activity in variety types of human cancer, including non-small cell lung cancer, hepatocellular carcinoma and sarcoma. Mechanistically, FBXO43 interacts with phosphorylated SKP2 induced by AKT1, leading to reduced SKP2 auto-ubiquitylation and subsequent proteasome degradation. Taken together, our study demonstrates that FBXO43 promotes cell cycle progression by stabilizing SKP2, and FBXO43 could serve as a potential anti-cancer target.

Multiple Immunomodulatory Strategies Based on Targeted Regulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Immune Homeostasis against Hepatocellular Carcinoma.

Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients' overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.

The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis.

Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene's transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2's protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.

The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and suicidal ideation in adults: a population-based study in the United States.

BACKGROUND: The ratio of non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) (NHHR) serves as a reliable lipid indicator associated with atherogenic characteristics. Studies have indicated a potential connection between suicidality and lipid metabolism. This research aims to investigate any possible association between the NHHR and the emergence of suicidal ideation within the confines of the study. METHODS: This study examined the association between NHHR levels and suicidal ideation using data from the National Health and Nutrition Examination Survey (NHANES), conducted in the United States spanning 2005 and 2016. Calculation of the NHHR corresponds to the proportion of HDL-C to Non-HDL-C. The Patient Health Questionnaire-9's ninth question was implemented for assessing suicidal ideation. Using subgroup analysis, smooth curve fitting, and multivariate logistic regression analysis, the research was conducted. RESULTS: Encompassing a cohort of 29,288 participants, the analysis identified that 3.82% of individuals reported suicidal ideation. After using multivariable logistic regression and thorough adjustments, elevated NHHR levels were significantly and positively associated with a heightened likelihood of suicidal ideation, according to the findings (odds ratio [OR] = 1.06; 95% confidence interval [CI]: 1.02-1.11; P = 0.0048). Despite extensive adjustment for various confounding factors, this relationship remained consistent. An inverted U-shaped curve was utilized to illustrate the link between NHHR and suicidal ideation among nonsmokers; the curve's inflection point was situated at 7.80. Subgroup analysis and interaction tests (all P for interaction > 0.05) demonstrated that there was no significant influence of the following variables on this positive relationship: age, sex, race, body mass index, education level, married status, hypertension, diabetes, and smoking status. CONCLUSION: Significantly higher NHHR levels were associated with an elevated likelihood of suicidal ideation. Based on these results, it is probable that NHHR may serve as a predictive indicator of suicidal ideation, emphasizing its potential utility in risk assessment and preventive strategies.

The effects of glucocorticoid plus intravenous immunoglobulin (IVIG) vs IVIG alone on platelet activation in children with Kawasaki disease.

BACKGROUND: Even though intravenous immunoglobulin (IVIG) is a current treatment for Kawasaki disease (KD), 10-20% of patients require additional therapy. This study seeks to investigate the therapeutic effects of glucocorticoids plus IVIG on KD and to ascertain the subsequent effect on platelet activation during the acute phase. METHODS: A total of 32 children with KD were randomly classified into two groups: the experimental group (16 cases) and the control group (16 cases). The control group was exposed to IVIG (2 g/kg), whereas children in the experimental group were treated with IVIG (2 g/kg) + glucocorticoid. Peripheral venous blood samples were obtained from all participants before treatment as well as three days post-treatment to test platelet activation levels with procaspase activating compound-1 (PAC-1) antibody, Toll-like receptor 4 (TLR4), interleukin-6 (IL- 6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and C-reactive protein (CRP). Fever duration posttreatment was documented for both groups. Additionally, the coronary arteries in both groups were evaluated during three months of treatment. RESULTS: After treatment, the experimental group had remarkably lower levels of TNF-α, CRP, PCT, IL-6, PAC- 1, and TLR4 relative to the control group. The fever persistence rate was considerably elevated in the control group compared to the experimental group (log-rank, P=0.024). In addition, the z-score of coronary artery size dropped after IVIG + glucocorticoids treatment compared to the control group, although this difference was not significant. CONCLUSIONS: The IVIG + glucocorticoids can quickly mitigate the inflammatory response and platelet activation. Moreover, it can also improve clinical symptoms in children with KD.

Limitations of ALA-PDT as a reliable therapy for AK in clinical practice.

BACKGROUND: Numerous clinical studies have demonstrated the effectiveness of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) in treating actinic keratosis (AK). This therapy has achieved an average lesion clearance rate of approximately 80 % and has also shown to produce satisfactory cosmetic outcomes. However, in our clinical practice, the utilization and adherence to ALA-PDT treatment among AK patients has been lower than anticipated, possibly due to various factors. OBJECTIVE: The objectives of this study are twofold: (1) To analyze the actual therapeutic effects of ALA-PDT treatment on AK lesions in clinical practice; and (2) To identify the factors that hinder acceptance of ALA-PDT therapy among AK patients with large area or multiple lesions situated on the head and face. METHOD: This study included a group of 20 AK patients, comprising 15 females and 5 males, with an age range of 57-87 years. All patients received a complete course of ALA-PDT therapy, consisting of 3-6 treatments. The study analyzed various factors, including the cure rate, recurrence rate, cosmetic effects, and adverse reactions following treatment. To investigate the factors affecting the acceptance of ALA-PDT treatment among AK patients with large or multiple lesions on the head and face, we also examined a separate group of 43 AK patients. This group included individuals who either had incomplete courses of ALA-PDT treatment or declined the therapy for the first time. The factors potentially influencing patients' acceptance of PDT were analyzed based on the outcomes of these investigations. RESULT: Among the 20 patients who completed the full course of ALA-PDT treatment, the cure rate was 95 % (19/20). The recurrence rates at 1 month, 3 months, and 6 months were 0 %, 5 %, and 10 %, respectively. Out of the 19 cured patients, only 2 experienced heavy pigmentation, and no scarring was reported 1-3 months post-treatment. Based on the survey of 43 patients who either had an incomplete course of ALA-PDT treatment or declined the therapy initially, several factors were identified as limiting their choice of PDT therapy. These factors include: (1) Intolerable adverse effects of treatment. (2) Higher treatment cost than expected. (3) Inconvenient transportation. (4) Coexistence of other senile diseases. (5) Unsatisfactory clinical efficacy observed. (6) Inadequate understanding of AK. (7) Lost to follow-up. CONCLUSION: The study concludes that ALA-PDT is a beneficial and aesthetically pleasing treatment for AK patients, particularly those with extensive or multiple lesions on the head and face. However, various factors can impede the selection of ALA-PDT therapy, potentially depriving patients of the most suitable option. The study aims to assist dermatologists and AK patients in considering treatment plans and exploring alternative options. Overall, the findings of this study may provide valuable guidance for improving treatment outcomes and patient satisfaction.

Primary choledocholithiasis occurrence and recurrence is synergetcally modulated by the bile microbiome and metabolome alternations.

AIMS: Primary choledocholithiasis is a common digestive disease with high morbidity and relapse. However, the compositions and functions of the bile microbial ecosystem and the pathogenesis of microfloral regulation of host metabolism resulting in stone formation are poorly understood. MAIN METHODS: Biliary samples collected from patients with acute cholangitis induced by benign biliary stricture (nonlithiasis group, n = 17) and primary choledocholithiasis (lithiasis group, n = 33) were subjected to multiomics analyses. Furthermore, clinicopathological features collected over a 24-month follow-up period were examined to evaluate the predictive value of candidate microbes. KEY FINDINGS: Five alpha diversity indices of the bile microbiome were significantly decreased in the lithiasis group. Furthermore, we identified 49 differential bile flora between the two groups, and the relative abundances of 6 bacteria, Actinobacteria, Actinobacteriota, Staphylococcales, Micrococcales, Altererythrobacter and Carnobacteriaceae, were associated with primary choledocholithiasis relapse conditions. Multiomics analyses showed that specific changes in disease-related bacterial taxa were closely related to metabolite variation (low-molecular weight carboxylic acids, sterol liquid and acylcarnitine), which might reflect disease prognosis. According to microbiomic and metabolomic pathway analyses, we revealed that bacterial infections, microbiota-derived amino acid metabolites and secondary bile acid-related pathways were significantly enriched in the stone-formation group, suggesting a novel host-microbial metabolic mechanism of primary choledocholithiasis. SIGNIFICANCE: Our study first indicates bile host-microbial dysbiosis modulates the abnormal accumulation of metabolites might further disrupt calcium homeostasis and generate insoluble saponification. Additionally, we determined the predictive value of Actinomycetes phylum reduction for recurrence in primary common bile duct stone patients.

The E3 ubiquitin ligase TRIM17 promotes gastric cancer survival and progression via controlling BAX stability and antagonizing apoptosis.

Tripartite motif 17 (TRIM17) belongs to a subfamily of the RING-type E3 ubiquitin ligases, and regulates several cellular processes and pathological conditions including cancer. However, its potential function in gastric cancer (GC) remains obscure. Here, we have found TRIM17 mRNA and protein levels are both upregulated in human GC compared with normal specimens, and TRIM17 upregulation indicates poor survival for GC patients. Functionally, TRIM17 was found to act as an oncogene by promoting the proliferation and survival of GC cell lines AGS and HGC-27. Mechanistically, TRIM17 acts to interact with BAX and promote its ubiquitination and proteasomal degradation, leading to a deficiency in BAX-dependent apoptosis in GC cells in the absence and presence of apoptosis stimuli. Moreover, TRIM17 and BAX expression levels are inversely correlated in human GC specimens. Our data thus suggest TRIM17 contributes to gastric cancer survival through regulating BAX protein stability and antagonizing apoptosis, which provides a promising therapeutic target for GC treatment and a biomarker for prognosis.

FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation.

FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.

Predictive Models for Colon Adenocarcinoma Diagnosis, Prognosis, and Immune Microenvironment Based on 2 Hypoxia-Related Genes: KDM3A and ENO3.

Background: Hypoxia is known to play a critical role in tumor occurrence, progression, prognosis, and therapy resistance. However, few studies have investigated hypoxia markers for diagnosing and predicting prognosis in colon adenocarcinoma (COAD). This study aims to identify a hypoxia genes-based biomarker for predicting COAD patients' prognosis and response to immunotherapy on an individual basis. Methods: Hypoxia-related genes were extracted from the Molecular Signatures Database. Gene expression, clinical data, and mutation data of COAD were collected retrospectively from the Cancer Genome Atlas, the Gene Expression Omnibus, and the International Cancer Genome Consortium databases. Univariate and multivariate cox regression, and the least absolute shrinkage and selection operator method were used to select the genes most associated with the prognosis of COAD patients. Kaplan-Meier survival analysis, receiver operating characteristic curves, calibration curves, and decision curve analyses were performed to validate the efficacy of the signature in predicting the prognosis of COAD patients. EdU incorporation assays, cell survival assays, western blot assays, and trans-well invasion assays were performed to further confirm the function of the screened genes in tumorigenesis. Results: ENO3 and KDM3A were identified as key genes for constructing prognostic and diagnostic signatures, which were found to be independent risk factors for predicting the prognosis and diagnosis of COAD patients. Using these signatures, COAD patients could be stratified into high-risk and low-risk groups, with the latter exhibiting better overall survival outcomes. Moreover, the high-risk group displayed elevated levels of immune checkpoint genes and tumor mutation burden, indicating that these patients may benefit from immune checkpoint inhibitor therapy. Conclusion: The signature developed in this study demonstrates excellent efficacy in prognosticating the outcomes of COAD patients. Moreover, it can serve as a valuable tool for clinicians to identify COAD patients who are suitable for ICI therapy.

MEX3A determines in vivo hepatocellular carcinoma progression and induces resistance to sorafenib in a Hippo-dependent way.

BACKGROUND: Hepatocellular carcinoma (HCC) is most common malignant tumor worldwide, and one of the most lethal malignancies. MEX3A, RNA-binding protein, is profoundly implicated in tumor initiation and progression. But its role and potential mechanism in HCC remains fully unclear. METHODS: The expression of MEX3A in HCC was analysis using the data derived from the Cancer Genome Atlas (TCGA) dataset and further confirmed by HCC samples and cells lines. The roles of MEX3A in the proliferation, migration and sorafenib resistance were detected both in vitro and vivo. In addition, the underline mechanism was investigated. RESULTS: In this study, MEX3A expression was upregulated in HCC tissue and cell lines. Knockdown or overexpression of MEX3A disturbed the proliferation, migration and apoptosis of HCC cells by modulating the activation of Hippo signaling pathway. The expression of MEX3A was negatively associated with sorafenib sensitivity and upregulated in sorafenib resistant HCC cells. MEX3A knockdown facilitated the expression of WWC1, a negative modulator of Hippo signaling pathway, and led to increase of the phosphorylation of LATS1 and YAP1. Pharmacological inhibition of LATS1 or WWC1 overexpression alleviated the proliferative and migrated suppression and increased sorafenib sensitivity, whereas WWC1 inhibition using genetic interference strategy showed opposite trend in MEX3A knockdown HCC cells. Importantly, MEX3A knockdown led to growth and lung metastasis inhibition using xenograft model established by means of subcutaneous or tail vein injection. In addition, a combination of MEX3A knockdown and WWC1 overexpression dramatically enhances the growth inhibition of sorafenib in vivo. CONCLUSION: MEX3A may facilitate HCC progression and hinder sorafenib sensitivity via inactivating Hippo signaling. The present study suggested that targeting MEX3A can be served as a novel therapeutic strategy for HCC.

In vivo anti-hepatitis B activity of Artemisia argyi essential oil-loaded nanostructured lipid carriers. Study of its mechanism of action by network pharmacology and molecular docking.

BACKGROUND: Hepatitis B virus (HBV) infection remains a major global health burden, due to the increasing risk of complications, such as cirrhosis and hepatocellular carcinoma. Novel anti-HBV agents are critical required. Our previous study suggested that Artemisia argyi essential oil (AAEO) significantly inhibited the replication of HBV DNA and especially the secretion of hepatitis B antigen in vitro. PURPOSE: The aim of this study was to prepare AAEO loaded nanostructured lipid carriers (AAEO-NLCs) for the delivery of AAEO to the liver, investigated the therapeutic benefits of AAEO-NLCs against HBV in a duck HBV (DHBV) model and explored its potential mechanism. STUDY DESIGN AND METHODS: AAEO-NLCs were prepared by hot homogenization and ultrasonication method. The DHBV-infected ducks were treated with AAEO (4 mg/kg), AAEO-NLCs (0.8, 4, and 20 mg/kg of AAEO), and lamivudine (20 mg/kg) for 15 days. The DHBV DNA levels in the serum and liver were measured by quantitative Real-Time PCR. Pharmacokinetics and liver distribution were performed in rats after oral administration of AAEO-NLCs and AAEO suspension. The potential antiviral mechanism and active compounds of AAEO were investigated by network pharmacology and molecular docking. RESULTS: AAEO-NLCs markedly inhibited the replication of DHBV DNA in a dose-dependent manner and displayed a low virologic rebound following withdrawal the treatment in DHBV-infected ducks. Moreover, AAEO-NLCs led to a more pronounced reduction in viral DNA levels than AAEO suspension. Further investigations of pharmacokinetics and liver distribution in rats confirmed that NLCs improved the oral bioavailability and increased the liver exposure of AAEO. The potential mechanisms of AAEO against HBV explored by network pharmacology were associated with signaling pathways related to immune response, such as tumor necrosis factor, nuclear factor kappa B, and sphingolipid signaling pathways. Furthermore, a total of 16 potential targets were obtained, including prostaglandin-endoperoxide synthase-2 (PTGS2), caspase-3, progesterone receptor, etc. Compound-target docking results confirmed that four active compounds of AAEO had strong binding interactions with the active sites of PTGS2. CONCLUSIONS: AAEO-NLCs displayed potent anti-HBV activity with improved oral bioavailability and liver exposure of AAEO. Thus, it may be a potential therapeutic strategy for the treatment of HBV infection.

Machine Learning Classifier for Preoperative Prediction of Early Recurrence After Bronchial Arterial Chemoembolization Treatment in Lung Cancer Patients.

RATIONALE AND OBJECTIVES: Bronchial arterial chemoembolization (BACE) was deemed as an effective and safe approach for advanced standard treatment-ineligible/rejected lung cancer patients. However, the therapeutic outcome of BACE varies greatly and there is no reliable prognostic tool in clinical practice. This study aimed to investigate the effectiveness of radiomics features in predicting tumor recurrence after BACE treatment in lung cancer patients. MATERIALS AND METHODS: A total of 116 patients with pathologically confirmed lung cancer who received BACE treatment were retrospectively recruited. All patients underwent contrast-enhanced CT within 2 weeks before BACE treatment and were followed up for more than 6 months. We conducted a machine learning-based characterization of each lesion on the preoperative contrast-enhanced CT images. In the training cohort, recurrence-related radiomics features were screened by least absolute shrinkage and selection operator (LASSO) regression. Three predictive radiomics signatures were built with linear discriminant analysis (LDA), support vector machine (SVM) and logistic regression (LR) algorithms, respectively. Univariate and multivariate LR analyses were performed to select the independent clinical predictors for recurrence. The radiomics signature with best predictive performance was integrated with the clinical predictors to form a combined model, which was visualized as a nomogram. The performance of the combined model was assessed by receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). RESULTS: Nine recurrence-related radiomics features were screened out, and three radiomics signatures (RadscoreLDA, RadscoreSVM and RadscoreLR) were built based on these features. Patients were classified into the low-risk and high-risk groups based on the optimal threshold of three signatures. Progression-free survival (PFS) analysis showed that patients of low-risk group achieved longer PFS than patients of high-risk group (P < 0.05). The combined model including RadscoreLDA and independent clinical predictors (tumor size, carcinoembryonic antigen and pro-gastrin releasing peptide) achieved the best predictive performance for recurrence after BACE treatment. It yields AUCs of 0.865 and 0.867 in the training and validation cohorts, with accuracy (ACC) of 0.804 and 0.750, respectively. Calibration curves indicated that the probability of recurrence predicted by the model fits well with the actual recurrence probability. DCA showed that the radiomics nomogram was clinically useful. CONCLUSION: The radiomics and clinical predictors-based nomogram can predict tumor recurrence after BACE treatment effectively, which allowing oncologists to identify potential recurrence and enable better patient management and clinical decision-making.

Association of Cerebral Hemodynamics and Cognitive Function in Adult Patients with Moyamoya Disease: A Three-Dimensional Pseudo-Continuous Arterial Spin Labeling Study.

OBJECTIVE: Cognitive dysfunction is a serious complication of moyamoya disease (MMD) in adults, and reduced cerebral blood flow (CBF) might be the potential cause. We aimed to explore the correlation between cerebral hemodynamics and cognitive function in adults with MMD by using three-dimensional pseudo-continuous arterial spin labeling (3D-pCASL). METHODS: A total of 24 MMD patients with a history of cerebral infarction, 25 asymptomatic MMD patients, and 25 healthy controls were prospectively enrolled in this study. All participants were performed 3D-pCASL, and cognitive function was evaluated with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment Scale (MoCA), and the Trail Making Test Part A (TMTA). The correlation between cerebral hemodynamics and cognitive function was explored in the region of interest-based analysis. RESULTS: Compared with healthy controls, both CBF and cognition decreased in adult MMD. In the infarction group, the MMSE and MoCA scores correlated with CBF of the right anterior cerebral artery (P = 0.037 and 0.010, respectively) and the left middle cerebral artery (MCA) cortical territories (P = 0.002 and 0.001, respectively), and the TMTA time-consuming has a negative correlation with CBF of the right and left MCA cortical territories (P = 0.044 and 0.010, respectively); in the asymptomatic group, the MMSE and MoCA scores correlated with CBF of the left MCA cortical territory (P = 0.032 and 0.029, respectively). CONCLUSIONS: The 3D-pCASL can find the hypoperfusion area of CBF in adults with MMD, and hypoperfusion in specific brain regions may cause cognitive dysfunction even in asymptomatic patients.

Case report: Gene mutation analysis and skin imaging of isolated café-au-lait macules.

Background: Café-au-lait macules (CALMs) are common birthmarks associated with several genetic syndromes, such as neurofibromatosis type 1 (NF1). Isolated CALMs are defined as multiple café-au-lait macules in patients without any other sign of NF1. Typical CALMs can have predictive significance for NF1, and non-invasive techniques can provide more accurate results for judging whether café-au-lait spots are typical. Objectives: The study aimed to investigate gene mutations in six Chinese Han pedigrees of isolated CALMs and summarize the characteristics of CALMs under dermoscopy and reflectance confocal microscopy (RCM). Methods: In this study, we used Sanger sequencing to test for genetic mutations in six families and whole exome sequencing (WES) in two families. We used dermoscopy and RCM to describe the imaging characteristics of CALMs. Results: In this study, we tested six families for genetic mutations, and two mutations were identified as novel mutations. The first family identified [NC_000017.11(NM_001042492.2):c.7355G>A]. The second family identified [NC_000017.11(NM_001042492.2):c.2739_2740del]. According to genotype-phenotype correlation analyses, proband with frameshift mutation tended to have a larger number of CALMs and a higher rate of having atypical CALMs. Dermoscopy showed uniform and consistent tan-pigmented network patches with poorly defined margins with a lighter color around the hair follicles. Under RCM, the appearance of NF1 comprised the increased pigment granules in the basal layer and significantly increased refraction. Conclusion: A new heterozygous mutation and a new frameshift mutation of NF1 were reported. This article can assist in summarizing the properties of dermoscopy and RCM with CALMs.

Evaluation of a continuous-time random-walk diffusion model for the differentiation of malignant and benign breast lesions and its association with Ki-67 expression.

The purpose of the current study was to evaluate the performance of a continuous-time random-walk (CTRW) diffusion model for differentiating malignant and benign breast lesions and to consider the potential association between CTRW parameters and the Ki-67 expression. Sixty-four patients (46.2 ± 11.4 years) with breast lesions (29 malignant and 35 benign) were evaluated with the CTRW model, intravoxel incoherent motion model, and diffusion-weighted imaging. Echo planar diffusion-weighted imaging was conducted using 13 b-values (0-3000 s/mm2 ). Three CTRW model parameters, including an anomalous diffusion coefficient Dm , and two parameters related to temporal and spatial diffusion heterogeneity, α and ß, respectively, were obtained, and had MRI b-values of 0-3000 s/mm2 . Receiver operating characteristic (ROC) analysis was conducted to determine the sensitivity, specificity, and diagnostic accuracy of CTRW parameters for differentiating malignant from benign breast lesions. In malignant breast lesions, the CTRW parameters Dm , α, and ß were significantly lower than the corresponding parameters of benign breast lesions. In the malignant breast lesion group, the CTRW parameter Dm was significantly lower in high Ki-67 expression than in low Ki-67 expression. In ROC analysis, the combination of CTRW parameters (Dm , α, ß) demonstrated the highest area under the curve value (0.985) and diagnostic accuracy (94.23%) in differentiating malignant and benign breast lesions. The CTRW model effectively differentiated malignant from benign breast lesions. The CTRW diffusion model offers a new way for noninvasive assessment of breast malignancy and better understanding of the proliferation of malignant lesions.

Development of Henoch-Schoenlein purpura in a child with idiopathic hypereosinophilia syndrome with multiple thrombotic onset: A case report.

BACKGROUND: The incidence of pulmonary embolism (PE) in children is low, but its mortality is high. Hypereosinophilic syndrome (HES) is a group of diseases caused by an abnormal increase in eosinophilic granulocytes resulting in multiple-organ dysfunction. The urgent event of thromboembolism in the pulmonary region provoked by eosinophils in idiopathic HES (IHES) is relatively unusual. This article reports a case of IHES with multiple PEs and left leg venous thrombosis as the first manifestation. One month later, the patient developed Henoch-Schonlein purpura (HSP), which is very rare. CASE SUMMARY: We report the case of a 12-year-old boy who was admitted to the hospital with dyspnea, left leg pain, and aggravation. He had bilateral PE and left leg venous embolism with mild eosinophilia. Low-molecular-weight heparin and urokinase were given. At the same time, the interventional department was contacted about filter implantation, followed by urokinase thrombolysis. The left leg thrombus was aspirated under ultrasound guidance. He was discharged from the hospital on rivaroxaban. One month later, he developed a rash on both legs and ankle pain consistent with HSP, with severe eosinophilia and motor and sensory disturbances. The patient was diagnosed with IHES with multiple embolisms complicated by HSP after excluding other causes of the eosinophil elevation. After glucocorticoid treatment, the symptoms were relieved, but the patient later developed purpura nephritis. CONCLUSION: We report a rare and life-threatening case of IHES with multiple embolisms associated with HSP. A mild elevation of eosinophils early in the disease leads to difficulties in diagnosis and delayed treatment.

Characterization of Microvascular Invasion in Hepatocellular Carcinoma Using Computational Modeling of Interstitial Fluid Pressure and Velocity.

BACKGROUND: Most solid tumors show increased interstitial fluid pressure (IFP), and this increased IFP is an obstacle to treatment. A noninvasive model for measuring IFP in hepatocellular carcinoma (HCC) is an unresolved issue. PURPOSE: To develop a noninvasive model to measure IFP and interstitial fluid velocity (IFV) in HCC and to characterize the microvascular invasion (MVI) status by using this model. STUDY TYPE: Retrospective. POPULATION: A total of 97 HCC patients (mean age 57.6 ± 10.9 years, 77.3% males), 53 of them with MVI and 44 of them without MVI. FIELD STRENGTH/SEQUENCE: A 3-T, three-dimensional spoiled gradient-recalled echo. ASSESSMENT: MVI was defined as microscopic vascular invasion of small vessels within the peritumoral liver tissue. The volumes of interest (VOIs) were manually delineated and enclosed the tumor lesion and healthy liver parenchyma, respectively. The extended Tofts model (ETM) was used to estimate permeability parameters from all the VOIs. Subsequently, the continuity partial differential equation (PDE) was implemented and IFP and IFV were acquired. STATISTICAL TESTS: Wilcoxon signed-ranks tests, histogram analysis, Mann-Whitney U test, Fisher's exact test, least absolute shrinkage and selection operator (LASSO) logistic regression, receiver operating characteristic (ROC) curve analysis with the area under the curve (AUC), Youden index, DeLong test, and Benjamini-Hochberg correction. A P value <0.05 was considered statistically significant. RESULTS: The HCC lesions exhibited elevated IFP and reduced IFV. There were no significant differences in any measured demographic and clinical features between the MVI-positive and MVI-negative groups, except for tumor size. Nine IFP histogram analysis-derived parameters and seven IFV histogram analysis-derived parameters could be used to characterize the MVI status. LASSO regression selected five features: IFP maximum, IFP 10th percentile, IFP 90th percentile, IFV SD, and IFV 10th percentile. The combination of these features showed the highest AUC (0.781) and specificity (77.3%). DATA CONCLUSION: A noninvasive IFP and IFV measurement model for HCC was developed. Specific IFP- and IFV-derived parameters exhibited significant association with the MVI status. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Proteomic analysis of DZIP3 interactome and its role in proliferation and metastasis in gastric cancer cells.

Gastric cancer is a serious malignant tumor in the world, accounting for the third cause of cancer death worldwide. The pathogenesis of gastric cancer is very complex, in which epigenetic inheritance plays an important role. In our study, we found that DZIP3 was significantly up-regulated in gastric cancer tissues as compared to adjacent normal tissue, which suggested it may be play a crucial part in gastric cancer. To clarify the mechanism of it, we further analyzed the interacting proteome and transcriptome of DZIP3. An association between DZIP3 and some epigenetic regulators, such as CUL4B complex, was verified. We also present the first proteomic characterization of the protein-protein interaction (PPI) network of DZIP3. Then, the transcriptome analysis of DZIP3 demonstrated that knockdown DZIP3 increased a cohort of genes, including SETD7 and ZBTB4, which have essential role in tumors. We also revealed that DZIP3 promotes proliferation and metastasis of gastric cancer cells. And the higher expression of DZIP3 is positively associated with the poor prognosis of several cancers. In summary, our study revealed a mechanistic role of DZIP3 in promoting proliferation and metastasis in gastric cancer, supporting the pursuit of DZIP3 as a potential target for gastric cancer therapy.