Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells.

Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction and exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact with the MMP-7 prodomain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and the strongest ability to disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, suggesting that this inhibitory effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. Together, these data suggest that, in addition to inhibiting mTOR signaling, everolimus exerts anticancer activity by interfering with the interaction of MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon cancer.NEW & NOTEWORTHY The utility of cancer therapeutics targeting the proteolytic activities of MMPs is limited because MMPs are widely distributed throughout the body and involved in many different aspects of cell functions. This work specifically targets the activation of MMP-7 through its interaction with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this interaction, demonstrating a novel role for everolimus in inhibiting mTOR signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.

Prevalence and progression rate of interstitial lung abnormalities detected on thoracic CT: a systematic review and meta-analysis.

OBJECTIVES: To estimate the pooled prevalence and progression rate of ILAs and identify the risk factors for radiological progression. MATERIALS AND METHODS: An EMBASE and PubMed search was undertaken, identifying all studies meeting the inclusion criteria performed before May 10, 2023. Random effect models were used to estimate pooled prevalence, ILA progression rates, and odds ratio for radiological progression based on radiological subtype. Subgroup analyses were performed to compare the general and high-risk populations for lung cancer. The quality of the included studies was evaluated using the risk of bias assessment tool for non-randomized studies. RESULTS: We analyzed 19 studies (241,541 patients) and 10 studies (1317 patients) for the pooled prevalence and progression rate of ILA, respectively. The pooled ILA prevalence was 9.7% (95% CI, 6.1-13.9%). The pooled prevalence was 6.8% (95% CI, 3.1-11.6%) and 7.1% (95% CI, 2.2-14.4%) in the general (six studies) and high-risk population for lung cancer (six studies), respectively. The pooled progression rate was 47.1% (95% CI, 29.1-65.5%). The pooled progression rate was 64.2% (95% CI, 45.0-81.2%, five studies) and 31.0% (95% CI, 8.2-60.5%, five studies) for longer (≥ 4.5 years) and shorter follow-up periods (< 4.5 years), respectively (p = 0.009). Fibrotic ILAs were significantly associated with a higher progression probability (combined OR, 5.55; 95% CI, 1.95-15.82). CONCLUSIONS: The prevalence of ILAs was approximately 9.7%. Approximately half of the patients exhibited radiological progression, with the rate increasing over a longer follow-up period. Fibrotic ILA was a significant risk factor for radiological progression. CLINICAL RELEVANCE STATEMENT: The prevalence of interstitial lung abnormalities (ILAs) is approximately 9.7%, with about half exhibiting progression; a longer follow-up duration and fibrotic ILAs are associated with a higher progression rate. KEY POINTS: ILAs are increasingly recognized as important, but few population data are available. ILAs exhibited a pooled prevalence of 9.7% with a progression rate of 47.1%. Fibrotic ILAs were associated with increased progression likelihood.

Urinary tract dilation classification system for predicting surgical management and urinary tract infection in neonates and young infants: a systematic review and meta-analysis.

BACKGROUND: The urinary tract dilation classification system has recently been developed to ensure a unified approach to describe urinary tract dilation in neonates and young infants. However, the predictive value of this system for surgical intervention or urinary tract infection (UTI) has not yet been evaluated in a meta-analysis. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the utility of a postnatal urinary tract dilation classification system for predicting surgical management or a UTI occurrence. MATERIALS AND METHODS: As the urinary tract dilation classification system was introduced in 2014, we searched Embase and PubMed databases for studies published between January 2014 and December 2022. Original articles that reported surgical interventions or UTI episodes according to postnatal urinary tract dilation grades were included. The pooled odds ratio (OR) was calculated, using either the fixed-effects or random-effects model, given the lower urinary tract dilation grades as the base category. The quality of the included studies was evaluated using the Newcastle-Ottawa scale. RESULTS: Of the 285 articles reviewed, eight (comprising 2,165 children) were included in the analysis. The studies were of medium-to-high quality. Pooled analysis demonstrated that urinary tract dilation P3 (combined OR, 21.41; 95% confidence interval [CI], 15.72-29.17) and urinary tract dilation P2-P3 (combined OR, 65.17; 95% CI, 33.08-128.38) were associated with surgical intervention. The urinary tract dilation P3 (combined OR, 2.11; 95% CI, 1.56-2.85) and urinary tract dilation P2-P3 (combined OR, 3.36; 95% CI, 2.43-4.63) were associated with UTI episodes. CONCLUSION: The postnatal urinary tract dilation classification system is useful for predicting the need for surgical management and UTI episodes in infants with hydronephrosis.

Deep learning-based fully automatic Risser stage assessment model using abdominal radiographs.

BACKGROUND: Artificial intelligence has been increasingly used in medical imaging and has demonstrated expert level performance in image classification tasks. OBJECTIVE: To develop a fully automatic approach for determining the Risser stage using deep learning on abdominal radiographs. MATERIALS AND METHODS: In this multicenter study, 1,681 supine abdominal radiographs (age range, 9-18 years, 50% female) obtained between January 2019 and April 2022 were collected retrospectively from three medical institutions and graded manually using the United States Risser staging system. A total of 1,577 images from Hospitals 1 and 2 were used for development, and 104 images from Hospital 3 for external validation. From each radiograph, right and left iliac crest patch images were extracted using the pelvic bone segmentation model DeepLabv3 + with the EfficientNet-B0 encoder trained with 90 digitally reconstructed radiographs from pelvic computed tomography scans with a pelvic bone mask. Using these patch images, ConvNeXt-B was trained to grade according to the Risser classification. The model's performance was evaluated using accuracy, area under the receiver operating characteristic curve (AUROC), and mean absolute error. RESULTS: The fully automatic Risser stage assessment model showed an accuracy of 0.87 and 0.75, mean absolute error of 0.13 and 0.26, and AUROC of 0.99 and 0.95 on internal and external test sets, respectively. CONCLUSION: We developed a deep learning-based, fully automatic segmentation and classification model for Risser stage assessment using abdominal radiographs.

Emerging role of syndecans in maintaining homeostasis of colon epithelium during inflammation.

The syndecans are a family of transmembrane proteoglycans that are widespread in mammalian tissues. Located at the cell surface membrane, they contribute to modulating the composition of the extracellular matrix via glycosaminoglycan chains (GAGs) attached to their extracellular domains. Syndecans can interact with a variety of extracellular ligands through their core proteins and GAGs, and may also transmit signals through their transmembrane domain to regulate intracellular functions. These properties enable syndecan to modulate glycocalyx formation, epithelial cell-to-cell connections for cell barrier formation, and epithelial cell-lamina propria interactions in the colon epithelium, all of which are crucial for the homeostasis of this tissue. Inflammation induces structural alterations of the colon epithelium, and accumulating evidence suggests that syndecan expression might play important regulatory functions during inflammation. This review summarizes the possible roles of syndecans in maintaining tissue homeostasis in the colon epithelium, especially under inflammation.

Substituted Syndecan-2-Derived Mimetic Peptides Show Improved Antitumor Activity over the Parent Syndecan-2-Derived Peptide.

We previously showed that a synthetic peptide (S2-P) corresponding to a portion of the human syndecan-2 (SDC2) sequence can bind to the pro-domain of matrix metalloproteinase-7 (MMP-7) to inhibit colon cancer activities. Since S2-P had a relatively weak binding affinity for the MMP-7 pro-domain, we herein modified the amino acid sequence of S2-P to improve the anticancer potential. On the basis of the interaction structure of S2-P and MMP-7, four peptides were generated by replacing amino acids near Tyr 51, which is critical for the interaction. The SDC2-mimetic peptides harboring an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-D) or with an Ala-to-Phe substitution at the N-terminal side of Tyr 51 and an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-FE) showed improved interaction affinities for the MMP-7 pro-domain. Compared to S2-P, S2-FE was better able to inhibit the SDC2-MMP-7 interaction, the cell surface localization of MMP-7, the gelatin degradation activity of MMP-7, and the cancer activities (cell migration, invasion, and colony-forming activity) of human HCT116 colon cancer cells in vitro. In vivo, S2-FE inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a xenograft mouse model. Together, these data suggest that S2-FE could be useful therapeutic anticancer peptides for colon cancer.

Diagnostic performance of adult-based ATA and ACR-TIRADS ultrasound risk stratification systems in pediatric thyroid nodules: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the diagnostic performance of adult-based "American College of Radiology- Thyroid Imaging Reporting And Data System" (ACR-TIRADS) and "American Thyroid Association" (ATA) in the pediatric population. METHODS: MEDLINE/PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for articles investigating the diagnostic performance of each stratification system (ACR-TIRADS or ATA) and evaluated them according to three aspects: (a) the risk of malignancy in each category; (b) diagnostic performance using the classic indicators (sensitivity, specificity); and (c) diagnostic performance regarding fine needle aspiration/biopsy recommendation. In addition to pathologic diagnosis, we allowed imaging follow-up as the reference standard for benign nodules. RESULTS: Eight articles (1036 thyroid nodules) were included. For ACR-TIRADS, the pooled risk of malignancy in category was as follows: category 5 (59.3%); 4 (20.7%); 3 (11.0%); 2 (6.0%), and 1 (5.5%). For nodules of high suspicion of malignancy (category 4 or 5), the pooled sensitivity and specificity were 0.84 and 0.64. For ATA, the pooled risk of malignancy was as follows: category 5 (55.4%); 4 (34.2%); 3 (12.2%); and 2 (7.5%). For nodules of high suspicion of malignancy (category 4 or 5), the pooled sensitivity and specificity were 0.90 and 0.50. For category 5 nodules, the pooled specificity was significantly higher in ACR-TIRADS (p = 0.02). For ACR-TIRADS, the missed malignancy rate was 21.7% and the unnecessary biopsy rate was 62.7%. Information was not sufficient for this calculation with ATA. CONCLUSIONS: The diagnostic performance of ACR-TIRADS and ATA in the pediatric population was somewhat modest. Large studies are mandatory for further validation and future amendments. KEY POINTS: • The pooled sensitivity and specificity for highly suspicious nodules (category 4 or 5) for ACR-TIRADS were 0.84 and 0.64, and for ATA were 0.90 and 0.50, respectively. • When applying ACR-TIRADS for children, the pooled missed malignancy rate (21.7%) and unnecessary biopsy rates (62.7%) are still reasonably high. Insufficient information was available to perform these calculations for the ATA system. • Current risk stratification systems, especially ACR-TIRADS, require modification by focusing more on increasing the sensitivity and decreasing the missed malignancy rate. Lowering size cut-off for biopsy would be a reasonable option.

Predictors of failed enema reduction in children with intussusception: a systematic review and meta-analysis.

OBJECTIVE: To identify predictors of failed enema reduction in children with intussusception. METHODS: PubMed and EMBASE were searched for all studies published over a 20-year time frame, prior to March 25, 2020. Original articles that reported predictors of failed enema reduction were included. The pooled odds ratio (OR) for successful enema reduction according to various features was calculated. The combined estimates were meta-analytically pooled by random-effects modeling. The risk of bias was assessed using the National Institute of Health Quality Assessment Tool. This review was registered to the PROSPERO (CRD42020190178). RESULTS: A total of 38 studies, comprising 40,133 cases, were included. The shorter duration of symptoms (< 24 h; combined OR, 3.812; 95% CI, 2.150-6.759) and abdominal pain (combined OR, 2.098; 95% CI, 1.405-3.133) were associated with the success (all p < 0.001). Age < 1 year (combined OR, 0.385; 95% CI, 0.166-0.893; p = 0.026), fever (combined OR, 0.519; 95% CI, 0.371-0.725; p < 0.001), rectal bleeding (combined OR, 0.252; 95% CI, 0.165-0.387; p < 0.001), and vomiting (combined OR, 0.497; 95% CI, 0.372-0.664; p < 0.001) were associated with the failed reduction. The ascites (combined OR, 0.127; 95% CI, 0.044-0.368; p = 0.001), left-sided intussusception (combined OR, 0.121; 95% CI, 0.058-0.252; p < 0.001), and trapped fluid (combined OR, 0.179; 95% CI, 0.061-0.525; p = 0.017) on US were associated with the failed reduction. CONCLUSIONS: Successful predictors for intussusception reduction have been summarized. This evidence can help identify patients who are more likely to fail non-operative reduction and could be potential surgical candidates. KEY POINTS: • A shorter duration of symptoms and presence of abdominal pain were associated with increased probability of success. • Age (less than 1 year), presence of fever, rectal bleeding, vomiting, and presence of ascites, left-sided intussusception, or trapped fluid on ultrasonography were associated with decreased probability of success. • This study suggests that various clinical and ultrasonography predictors would help identify patients who are more likely to fail nonoperative reduction and identify potential preoperative candidates.

Outcome of staging chest CT and identification of factors associated with lung metastasis in children with hepatoblastoma.

OBJECTIVES: To evaluate the outcome of staging chest CT and to identify clinicoradiological factors predictive of lung metastasis in patients with hepatoblastoma based on the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system. METHODS: This bi-center study retrospectively identified patients diagnosed with hepatoblastoma between January 1998 and September 2019 in two tertiary hospitals. The primary outcome was the proportion of the patients who had lung metastasis at staging chest CT. The diagnostic accuracy of staging chest CT was calculated based on the 2017 PRETEXT criteria. The secondary outcome was the identification of factors predictive of lung metastasis using multivariable logistic regression. RESULTS: In total, 123 patients (median age, 1 year; interquartile range, 0-4 years; 59 female) were included. Among those, 28% (35/123; 95% confidence interval [CI], 21-37%) had lung metastasis at staging chest CT. The overall accuracy of staging chest CT was 96.8%. The proportion of lung metastasis in patients with stage I, II, III, and IV was 0%, 24% (12 of 49; 95% CI, 14-38%), 23% (9 of 40; 95% CI, 12-38%), and 56% (14 of 25; 95% CI, 37-73%), respectively. Multifocality (adjusted odds ratio, 6.7; 95% CI, 2.7-17.5; p < .001) and male sex (adjusted odds ratio, 3.1; 95% CI, 1.2-8.6; p = .02) were associated with the presence of lung metastasis. CONCLUSIONS: Twenty-eight percent of the patients with hepatoblastoma had lung metastasis at staging chest CT. Multifocality and male sex were predictive factors for lung metastasis on staging chest CT. KEY POINTS: • The proportion of lung metastasis in patients with hepatoblastoma was 28%. • The overall accuracy of staging chest CT was 97% based on the 2017 PRETEXT system. • Hepatic tumor multifocality and male sex were predictors of lung metastasis.

Prevalence of brain MRI findings in children with nonacquired growth hormone deficiency: a systematic review and meta-analysis.

PURPOSE: To verify and integrate the prevalence and phenotype of abnormalities in the sellar region in patients with growth hormone deficiency (GHD) using MRI data. METHODS: We searched PubMed and EMBASE up to December 14, 2020. The inclusion criteria were as follows: (1) pediatric patients diagnosed with nonacquired GHD and (2) detailed data sufficient to assess the proportion of sellar and parasellar abnormalities on brain MRI scans. Finally, thirty-two studies with 39,060 children (mean or median age, 3.4-14.1 years) were included. The number and type of MRI findings from all included studies were pooled by two authors. The heterogeneity across studies was evaluated with the Q test or the inconsistency index (I2) statistic. Subgroup analyses were performed according to the type of GHD (isolated GHD [IGHD] vs. multiple pituitary hormone deficiency [MPHD]), MRI magnet, geographical region, and cutoff serum growth hormone (GH) level. RESULTS: The pooled proportion of sellar and parasellar abnormalities was 58.0% (95% CI, 47.1-68.6%; I2, 98.2%). The MPHD group showed a higher proportion of sellar and parasellar abnormalities and pituitary stalk interruption syndrome than the IGHD group (91.4% vs. 40.1%, P<0.001; 65.3% vs. 20.1%, P<0.001). The patients in studies with low peak GH levels on stimulation tests were more associated with severe MR abnormalities (cutoff GH ≤ 5 µg/l vs. cutoff GH = 10 µg/l; 72.8 % vs. 38.0%; P<0.001). CONCLUSION: The types and incidence of MRI abnormalities of the sellar region differ significantly between the IGHD and MPHD groups.

Assessment of native liver fibrosis using ultrasound elastography and serological fibrosis indices in children with biliary atresia after the Kasai procedure.

BACKGROUND: Validated non-invasive examinations are necessary to monitor liver fibrosis in children with biliary atresia (BA) after the Kasai procedure. PURPOSE: To evaluate the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE), transient elastography (TE), and the serologic biomarkers of aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for evaluating native liver fibrosis in children with BA. MATERIAL AND METHODS: We retrospectively reviewed same-day 2D-SWE and TE liver stiffness (LS) measurements of 63 patients with BA who underwent the Kasai procedure. The APRI and FIB-4 score were computed. Hepatic fibrosis was categorized into three clinical categories based on the ultrasound (US) hepatic morphology and clinical manifestations of liver cirrhosis: I, pre-cirrhotic liver state (n = 15); II, US and/or clinical signs of liver cirrhosis with compensated liver function (n = 27); and III, liver cirrhosis with decompensated liver function (n = 21). We compared area under the receiver operating characteristic curve (AUC) data among 2D-SWE, TE, APRI, and FIB-4 score. Combined evaluation of serologic fibrosis indices and US elastography was conducted and AUCs of combinations were analyzed. RESULTS: 2D-SWE, TE, APRI, and FIB-4 score showed good to excellent diagnostic accuracy for differentiating clinical categories (AUCs 0.779-0.955). AUC values were significantly increased after adding TE to FIB-4 score for detecting liver cirrhosis (P = 0.02). CONCLUSION: 2D-SWE, TE, APRI, and FIB-4 score are accurate non-invasive markers for monitoring native liver fibrosis in patients with BA. Combined use of serologic markers and US elastography could yield more accurate diagnoses of liver fibrosis than serologic markers alone.

Technical Performance of Acoustic Radiation Force Impulse Imaging for Measuring Renal Parenchymal Stiffness: A Systematic Review and Meta-Analysis.

OBJECTIVES: To estimate the technical performance of acoustic radiation force impulse (ARFI) imaging (two-dimensional shear wave elastography [2D-SWE] and point shear wave elastography [p-SWE]) for measuring renal parenchymal stiffness. METHODS: EMBASE and PubMed databases were searched for studies reporting technical performance of ARFI imaging in terms of technical failure, interobserver agreement, and/or intraobserver agreement. The proportion of technical failure and intraclass correlation coefficients (ICCs) for interobserver and intraobserver agreement was pooled. The pooled estimates of native and transplanted kidneys were obtained separately. Meta-regression and subgroup analyses were conducted to explore heterogeneity. RESULTS: Twenty-four studies (2993 patients) were included. The pooled proportions of technical failure were 4.3% (95% confidence interval [CI] 2.2-8.5%) and 6.6% (95% CI 4.0-10.7%) in native and transplanted kidneys, respectively. The pooled ICCs of interobserver agreement were 0.70 (95% CI 0.68-0.83) and 0.81 (95% CI 0.68-0.89), indicating moderate and good agreement in native and transplanted kidneys, respectively. The pooled ICC showed good (0.77; 95% CI 0.49-0.91) intraobserver agreement in native kidneys. Regarding interobserver agreement in transplanted kidneys, ROI location (mid pole only versus others) was a significant factor of heterogeneity (P = .04). CONCLUSIONS: The ARFI-based SWE techniques show good technical performance for measuring renal parenchymal stiffness. The wide range of SWE protocols necessitates development of standardized guidelines on the use of renal ARFI imaging.

Syndecan Transmembrane Domain Specifically Regulates Downstream Signaling Events of the Transmembrane Receptor Cytoplasmic Domain.

Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.

Glucosamine improves survival in a mouse model of sepsis and attenuates sepsis-induced lung injury and inflammation.

The aim of the current study was to investigate the effects of glucosamine (GlcN) on septic lethality and sepsis-induced inflammation using animal models of mice and zebrafish. GlcN pretreatment improved survival in the cecal ligation and puncture (CLP)-induced sepsis mouse model and attenuated lipopolysaccharide (LPS)-induced septic lung injury and systemic inflammation. GlcN suppressed LPS-induced M1-specific but not M2-specific gene expression. Furthermore, increased expressions of inflammatory genes in visceral tissue of LPS-injected zebrafish were suppressed by GlcN. GlcN suppressed LPS-induced activation of mitogen-activated protein kinase (MAPK) and NF-κB in lung tissue. LPS triggered a reduction in O-GlcNAc levels in nucleocytoplasmic proteins of lung, liver, and spleen after 1 day, which returned to normal levels at day 3. GlcN inhibited LPS-induced O-GlcNAc down-regulation in mouse lung and visceral tissue of zebrafish. Furthermore, the O-GlcNAcase (OGA) level was increased by LPS, which were suppressed by GlcN in mouse and zebrafish. OGA inhibitors suppressed LPS-induced expression of inflammatory genes in RAW264.7 cells and the visceral tissue of zebrafish. Stable knockdown of Oga via short hairpin RNA led to increased inducible nitric oxide synthase (iNOS) expression in response to LPS with or without GlcN in RAW264.7 cells. Overall, our results demonstrate a protective effect of GlcN on sepsis potentially through modulation of O-GlcNAcylation of nucleocytoplasmic proteins.

Comparison of 2-Dimensional Shear Wave Elastographic Measurements Using ElastQ Imaging and SuperSonic Shear Imaging: Phantom Study and Clinical Pilot Study.

OBJECTIVES: To compare the feasibility and clinical applicability of ElastQ imaging (Philips Healthcare, Best, the Netherlands) with that of SuperSonic shear imaging (SSI; SuperSonic Imagine, Aix-en-Provence, France) using an elastographic phantom and a pilot study of patients. METHODS: Two-dimensional shear wave elastography measurement was performed by ElastQ imaging and SSI by 2 radiologists. An elastographic phantom with 5 target elasticities at 2 acquisition depths was used. The coefficients of variation and intraclass correlation coefficients (ICCs) were evaluated for repeatability and interobserver agreement, respectively. The mean elasticities of the systems at each target were compared. The proportions of measurements that were out of the range of expected values and measurement errors were calculated to determine accuracy. Liver stiffness (LS) was measured by both systems in 27 children and young adult patients with various liver diseases. RESULTS: Both systems provided high repeatability in elasticity measurements of phantom targets (coefficients of variation, 0.69%-15.82%), and there was excellent interobserver agreement (ICC, 0.992). Most (90%) mean elasticities of targets were significantly different between the techniques (P ≤ .002) and acquisition depths (P ≤ .004). ElastQ imaging had significantly lower proportions of out-of-range measurements and measurement errors (P ≤ .003) than SSI. In patients with liver disease, LS measurements of the systems were strongly correlated (ρ = 0.955; P < .001) and had excellent agreement (ICC, 0.951; P < .001). CONCLUSIONS: ElastQ imaging had comparably good results in terms of repeatability, interobserver agreement, and accuracy in the phantom model compared with SSI. The pilot patient study showed strong correlations in LS values between the systems.

Diagnostic Performance of Ultrasound Elastography and Serologic Fibrosis Indices for Evaluation of Hepatic Involvement in Wilson Disease.

OBJECTIVES: To investigate the diagnostic value of transient elastography (TE), 2-dimensional (2D) shear wave elastography (SWE), and the serologic fibrosis indices aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for Wilson disease (WD). METHODS: We retrospectively identified patients with a diagnosis of WD who underwent TE and 2D SWE on the same day. Their APRI and FIB-4 scores were calculated. Hepatic involvement was classified into 5 clinical categories (I-V) based on the laboratory findings, hepatic morphologic characteristics on ultrasound (US) imaging, and clinical symptoms of cirrhosis: I, normal (n = 17); II, only biochemical abnormality (n = 15); III, altered hepatic morphologic characteristics (n = 10); IV, compensated liver cirrhosis (n = 3); and V, decompensated liver cirrhosis (n = 0). We compared the area under the receiver operating characteristic curve (AUROC) data for TE, 2D SWE, the APRI, and the FIB-4 score. A combined assessment of the serologic markers and US elastography was performed, and the AUROCs of the combinations were compared. RESULTS: Forty-five patients were included in the study (median age, 16.0 years; range, 3-35 years). Transient elastography, 2D SWE, and APRI were comparable in distinguishing the clinical categories (AUROC, 0.799-0.928). The FIB-4 score showed lower diagnostic value in distinguishing clinical category I from the other categories (AUROC, 0.647). Combining the serologic markers and US elastography significantly increased the AUROC value of the FIB-4 score (with TE and 2D SWE, P = .01 and .02). CONCLUSIONS: Transient elastography and 2D SWE showed excellent diagnostic accuracy for differentiating the clinical categories of hepatic involvement. The APRI showed better diagnostic performance than the FIB-4 score. The assessment of hepatic manifestations in WD can be improved by combining US elastography with serologic indices.

Correction to: Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1.

Following publication of the original article [1], the authors have re-evaluated the authorship for this article. The updated author group is.

Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells.

We investigated the regulatory effect of glucosamine (GlcN) for the production of nitric oxide (NO) and expression of inducible NO synthase (iNOS) under various glucose conditions in macrophage cells. At normal glucose concentrations, GlcN dose dependently increased LPS-stimulated production of NO/iNOS. However, GlcN suppressed NO/iNOS production under high glucose culture conditions. Moreover, GlcN suppressed LPS-induced up-regulation of COX-2, IL-6, and TNF-α mRNAs under 25 mm glucose conditions yet did not inhibit up-regulation under 5 mm glucose conditions. Glucose itself dose dependently increased LPS-induced iNOS expression. LPS-induced MAPK and IκB-α phosphorylation did not significantly differ at normal and high glucose conditions. The activity of LPS-induced nuclear factor-κB (NF-κB) and DNA binding of c-Rel to the iNOS promoter were inhibited under high glucose conditions in comparison with no significant changes under normal glucose conditions. In addition, we found that the LPS-induced increase in O-GlcNAcylation as well as DNA binding of c-Rel to the iNOS promoter were further increased by GlcN under normal glucose conditions. However, both O-GlcNAcylation and DNA binding of c-Rel decreased under high glucose conditions. The NF-κB inhibitor, pyrrolidine dithiocarbamate, inhibited LPS-induced iNOS expression under high glucose conditions but it did not influence iNOS induction under normal glucose conditions. In addition, pyrrolidine dithiocarbamate inhibited NF-κB DNA binding and c-Rel O-GlcNAcylation only under high glucose conditions. By blocking transcription with actinomycin D, we found that stability of LPS-induced iNOS mRNA was increased by GlcN under normal glucose conditions. These results suggest that GlcN regulates inflammation by sensing energy states of normal and fuel excess.

Exogenous Sodium Pyruvate Stimulates Adipogenesis of 3T3-L1 Cells.

We investigated the effects of exogenous sodium pyruvate (SP) on adipocyte differentiation, lipid accumulation, and the mRNA expression levels of adipogenesis-related genes in 3T3-L1 pre-adipocytes. Differentiation of pre-adipocytes was induced by MDI (3-isobutyl-1-methylxanthine: IBMX, dexamethasone: DEX, and insulin), in the presence or absence of SP. Adipogenesis was stimulated by SP in a concentration-dependent manner. SP also induced the expression of genes encoding aP2, GLUT4, and adiponectin, but had no effect on cell proliferation. Exogenous glucose did not promote adipogenesis or lipid accumulation. 2-deoxy-D-glucose inhibited adipogenesis initiated by MDI, but failed to influence the effects of SP on adipogenesis, whereas 3-bromopyruvate inhibited adipogenesis regardless of whether SP was present. The pro-adipogenic properties of SP were limited to the early events of adipogenesis. To determine whether SP mimics the adipogenic action of dexamethasone or insulin, we examined the effects of SP on adipogenesis with combinations of IBMX, DEX, and insulin. SP did not improve incomplete lipid accumulation observed in cells grown under IBMX-, DEX-, or insulin-free conditions. Insulin-stimulated ERK1/2 phosphorylation was diminished by SP, while phosphorylation of Akt was increased, correlating with increased glucose uptake in response to insulin. We also observed that SP stimulated immediate early expression of C/EBPß and C/EBPδ. The PPARγ antagonist GW9662 inhibited adipogenesis. Our findings highlight the adipogenic function of exogenous SP by stimulating early events of adipogenesis.

Interaction of Ets-1 with HDAC1 represses IL-10 expression in Th1 cells.

IL-10 is a multifunctional cytokine that plays a crucial role in immunity and tolerance. IL-10 is produced by diverse immune cell types, including B cells and subsets of T cells. Although Th1 produce IL-10, their expression levels are much lower than Th2 cells under conventional stimulation conditions. The potential role of E26 transformation-specific 1 (Ets-1) transcription factor as a negative regulator for Il10 gene expression in CD4(+) T cells has been implicated previously. In this study, we investigated the underlying mechanism of Ets-1-mediated Il10 gene repression in Th1 cells. Compared with wild type Th1 cells, Ets-1 knockout Th1 cells expressed a significantly higher level of IL-10, which is comparable with that of wild type Th2 cells. Upregulation of IL-10 expression in Ets-1 knockout Th1 cells was accompanied by enhanced chromatin accessibility and increased recruitment of histone H3 acetylation at the Il10 regulatory regions. Reciprocally, Ets-1 deficiency significantly decreased histone deacetylase 1 (HDAC1) enrichment at the Il10 regulatory regions. Treatment with trichostatin A, an inhibitor of HDAC family, significantly increased Il10 gene expression by increasing histone H3 acetylation recruitment. We further demonstrated a physical interaction between Ets-1 and HDAC1. Coexpression of Ets-1 with HDAC1 synergistically repressed IL-10 transcription activity. In summary, our data suggest that an interaction of Ets-1 with HDAC1 represses the Il10 gene expression in Th1 cells.