Rap1 prevents fusions between long telomeres in fission yeast.

The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length regulation. Previous studies have addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a mutagenesis screen in combination with high-throughput sequencing to identify several amino acid positions in Rap1 that have key roles in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner, whereby longer telomeres are prone to undergoing end fusions, while telomeres within the normal length range are sufficiently protected. The protection of long telomeres is in part dependent on their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrate that long telomeres represent a challenge for the maintenance of genome integrity, thereby providing an explanation for species-specific upper limits on telomere length.

Prognostic significance of multiparametric flow cytometry minimal residual disease at two time points after induction in pediatric acute myeloid leukemia.

BACKGROUND: Prompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses. METHODS: MFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol. RESULTS: Using a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy. CONCLUSIONS: The TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

Coronary artery calcification in Takayasu's arteritis: clinical characteristics and risk factors.

OBJECTIVES: Coronary artery calcification (CAC) is frequently observed in Takayasu's arteritis (TAK). Our objective is to calculate the prevalence and severity of CAC in TAK, while evaluating the influence of traditional cardiovascular risk factors, glucocorticoid exposure, and disease activity on CAC. METHODS: This retrospective study involved 155 TAK patients. We measured the Agatston score by coronary computed tomography angiography (CCTA) and categorised all patients into groups with or without CAC (41 vs. 114) to compare clinical characteristics and ancillary findings between the two groups. RESULTS: Among the TAK patients, a total of 41 TAK patients (26.45%) exhibited CAC. Age of onset, disease duration, history of hypertension, history of hyperlipidaemia, Numano V and glucocorticoid use emerged as the independent risk factors for developing CAC in TAK (OR [95% CI] 1.084[1.028-1.142], p=0.003; 1.005 [1.001-1.010], p=0.020; 4.792 [1.713-13.411], p=0.003; 4.199 [1.087-16.219], p=0.037; 3.287 [1.070-10.100], p=0.038; 3.558[1.269-9.977], p=0.016). Nonetheless, CAC was not associated with disease activity. Moreover, the extent of calcification score in TAK showed a positive correlation with the number of traditional cardiovascular risk factors. CONCLUSIONS: We recommend CCTA screening for Numano V classified TAK patients. Glucocorticoid usage significantly escalates the risk of CAC. Therefore, in cases of effectively controlled disease, the inclusion of immunosuppressants aimed at reducing glucocorticoid dosage is advisable.

Long Non-coding RNA RP11-252C15.1 is a Potential Biomarker of Prognosis and Hallmark for Leukemogenesis in Children with B-cell Precursor Acute Lymphoblastic Leukemia.

INTRODUCTION: Improved understanding of the prognostic biomarkers associated with childhood acute lymphoblastic leukemia (ALL) is needed for accurate risk group stratification. This study aimed to identify potential long-non coding RNA (lncRNA) markers and evaluate their prognostic value in children with ALL. METHODS: We selected 50 children with newly diagnosed ALL and 20 age-matched patients with idiopathic immune thrombocytopenia (controls). RNA sequencing was performed to identify differentially expressed lncRNAs between the ALL and control groups. Correlation analysis was performed to determine the relationships between candidate lncRNAs, clinical features, and the risk of leukemogenesis. RESULTS: A total of 1,019 differentially expressed lncRNAs were identified between the ALL and control groups. Reverse-transcriptase (RT-qPCR) revealed that lncRNA RP11-252C15.1 and lncRNA RP11-701P16.2 were significantly upregulated in patients with ALL. Furthermore correlation analysis showed that lncRNA RP11-252C15.1 and lncRNA RP11-701P16.2 represent potential predictors of leukemogenesis; however, only lncRNA RP11-252C15.1 was associated with clinical features and outcome in children with B-cell precursor ALL (BCP-ALL). In vitro experiments confirmed that lncRNA RP11-252C15.1 was significantly overexpressed in BCP-ALL cell lines and promoted proliferation, and repressed apoptosis in MHH-CALL-3 cells. CONCLUSION: LncRNA RP11-252C15.1 is a potential oncogene in BCP-ALL pathogenesis and a prognostic biomarker in children with BCP-ALL.

PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis.

Unlike other cell types, developing B cells undergo multiple rounds of somatic recombination and hypermutation to evolve high-affinity antibodies. Reflecting the high frequency of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. B lymphoid transcription factors (e.g., IKZF1 and PAX5) serve as metabolic gatekeepers by limiting glucose to levels insufficient to fuel transformation. We here identified aberrant expression of the lactonase PON2 in B cell acute lymphoblastic leukemia (B-ALL) as a mechanism to bypass metabolic gatekeeper functions. Compared to normal pre-B cells, PON2 expression was elevated in patient-derived B-ALL samples and correlated with poor clinical outcomes in pediatric and adult cohorts. Genetic deletion of Pon2 had no measurable impact on normal B cell development. However, in mouse models for BCR-ABL1 and NRASG12D-driven B-ALL, deletion of Pon2 compromised proliferation, colony formation, and leukemia initiation in transplant recipient mice. Compromised leukemogenesis resulted from defective glucose uptake and adenosine triphosphate (ATP) production in PON2-deficient murine and human B-ALL cells. Mechanistically, PON2 enabled glucose uptake by releasing the glucose-transporter GLUT1 from its inhibitor stomatin (STOM) and genetic deletion of STOM largely rescued PON2 deficiency. While not required for glucose transport, the PON2 lactonase moiety hydrolyzes the lactone-prodrug 3OC12 to form a cytotoxic intermediate. Mirroring PON2 expression levels in B-ALL, 3OC12 selectively killed patient-derived B-ALL cells but was well tolerated in transplant recipient mice. Hence, while B-ALL cells critically depend on aberrant PON2 expression to evade metabolic gatekeeper functions, PON2 lactonase activity can be leveraged as synthetic lethality to overcome drug resistance in refractory B-ALL.

Dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway.

DEAH-box helicase 15 (DHX15) is ATP-dependent RNA helicase which is known for its role in RNA metabolism. Recent studies reported DHX15 involves in the intestinal immunity. However, the role of DHX15 (or RNA helicase) in intestinal development is poorly understood. Here, we revealed an unidentified role for dhx15 in regulating zebrafish intestinal development. We found the profound intestinal defects in dhx15 knockout zebrafish. Decreased proliferation and increased apoptosis of the intestine cells were observed when dhx15 were deleted. Further RNA genome wide analysis and qRT-PCR analysis showed the Wnt signaling pathway is down-regulated in the dhx15 knockout zebrafish. Thus, we concluded that dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway. Here, we provided new insights into the role of dhx15 in intestinal development beyond its well-characterized role in intestinal immunity.

Enhanced Stress Stability in Flexible Co/Pt Multilayers with Strong Perpendicular Magnetic Anisotropy.

Due to the magnetoelastic coupling, the magnetic properties of many flexible magnetic films (such as Fe, Co, and Ni) are sensitive to mechanical stress, which deteriorates the performance of flexible magnetoelectronic devices. We show that by stacking Co and Pt alternatively to form multilayers with strong perpendicular magnetic anisotropy (PMA), both magnetic hysteresis and magnetic domain measurements reveal robust PMA against external stress. As the PMA weakens at increased Co thickness, the magnetic anisotropy is vulnerable to external stress. These results were understood based on a micromagnetic model, which suggests that the strength of magnetoelastic anisotropy with respect to initial effective magnetic anisotropy affects the stress-stability of the film. Although the stress coefficient of magnetoelastic anisotropy is enhanced at reduced Co thickness, the concomitant increase of initial effective magnetic anisotropy guarantees a robust PMA against external stress. Our results provide a route to constructing flexible magnetoelectronic devices with enhanced stress stability.

Elsinochrome A induces cell apoptosis and autophagy in photodynamic therapy.

Elsinochrome A (EA) is a perylene quinone natural photosensitizer, photosensitizer under light excitation generates reactive oxygen species (ROS) to induce apoptosis, so can be used for treating tumors, that is so-called photodynamic therapy (PDT). However, the molecular mechanism, especially related to apoptosis and autophagy, is still unclear. In this study, we aimed to explore the mechanism of EA-PDT-induced B16 cells apoptosis and autophagy. The action of EA-PDT on mitochondrial permeability transition pore (MPTP), mitochondrial membrane potential (MMP) and the mitochondrial function were researched by fluorescence technique and Extracellular Flux Analyzer. Illumina sequencing, tandem mass tags Quantitative Proteomics and Western Blot studied the mechanism at the gene and protein levels. The results indicated that EA-PDT had excellent phototoxicity in vitro. EA could bind to the mitochondria. EA-PDT for 5 min caused MPTP opening, MMP decreasing and abnormal mitochondrial function with a concentration-dependent characteristic. EA-PDT resulted in an increase intracellular ROS and the number of autophagosomes. Caspase2, caspase9 and tnf were upregulated, and bcl2, prkn, atg2, atg9 and atg10 were downregulated. Our results indicated that EA-PDT induced cell apoptosis and autophagy through the mediation of ROS/Atg/Parkin. This study can provide enlightenment for exploring potential targets of drug development for the PDT of melanoma.

Right Ventricular Function in Takayasu's Arteritis Patients With Pulmonary Artery Involvement Using MRI Feature Tracking.

BACKGROUND: Pulmonary artery involvement (PAI) is not rare in Takayasu arteritis (TA). Persistently elevated pulmonary arterial pressure in TA-PAI patients leads to pulmonary hypertension (PH), and eventually cardiac death. Thus, the early detection of right ventricular dysfunction before the onset of PH is important. PURPOSE: To explore the potential of right ventricular global peak longitudinal and circumferential strain (RVGLS and RVGCS, respectively) in detecting right ventricular myocardial damage in TA-PAI patients without PH. STUDY TYPE: Retrospective. POPULATION: One hundred and six TA patients (39.6 ± 13.9 years), of whom 52 were non-PAI and 54 were PAI patients (36 without PH and 18 with PH), along with 58 sex- and age-matched healthy volunteers (HVs) (36.7 ± 13.2 years). The involved arteries were validated by aorta magnetic resonance (MR) angiography and pulmonary artery computed tomography angiography. FIELD STRENGTH/SEQUENCE: 3 T/Cine imaging sequence with a steady-state free precession readout. ASSESSMENT: Cardiac MRI-derived parameters measured by two radiologists independently were compared among HVs, and TA patients with and without PAI. In addition, these indices were further compared among HVs, and TA-PAI patients with and without PH. STATISTICAL TESTS: Student's t test, one-way ANOVA analysis, Pearson and Spearman correlation analysis, and reproducibility analysis. A P-value of <0.05 was considered statistically significant. RESULTS: Although the TA-PAI patients without PH had a similar RV ejection fraction (RVEF) with HV (P = 0.348), RVGLS (non-PH 20.6 ± 3.7% vs. HV 24.0 ± 3.1%) was significantly lower and RVGCS (non-PH 14.8 ± 3.9% vs. HV 13.0 ± 2.7%) higher. The TA-PAI patients with PH had significantly poorer RVGLS (PH 13.5 ± 3.8% vs. non-PH 20.6 ± 3.7%) and RVGCS (PH 10.9 ± 3.2% vs. non-PH 14.8 ± 3.9%) than those without PH. DATA CONCLUSION: Right ventricular dysfunction was detected in the TA-PAI patients without PH. MR-feature tracking may be an effective method for detecting early cardiac damage in the TA-PAI patients without PH. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Characteristics of B cells and immunoglobulin profile in Takayasu's arteritis.

OBJECTIVES: Disorders of humoral immunity in Takayasu's arteritis (TAK) have not been well explored. This study describes the characteristics of B cells and immunoglobulin (Ig) profile in patients with TAK. METHODS: Peripheral B cell populations assessed using flow cytometry and serum Ig levels assessed using a biochemical analyser in 98 newly diagnosed patients with TAK were analysed and compared with those of 31 patients with systemic lupus erythematosus (SLE) and 60 healthy controls (HCs). CD19+ B cell and IgG infiltration to the aortic tissue was evaluated by immunohistochemical staining. RESULTS: The proportion of peripheral CD3-CD19+ B cells and levels of serum IgG in TAK were lower than those in SLE, but higher than those in HCs. CD3-CD19+ B cell counts were higher in TAK than in HCs. Serum IgG and IgG1 levels were higher in active TAK than in non-active TAK. In TAK, positive correlations of serum IgG levels with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, Kerr score, and Indian Takayasu Clinical Activity Score (ITAS2010, ITAS-A) were observed before immunotherapy. After 6 months of immunotherapy, serum Ig levels significantly decreased. Positive correlations between the changes in IgG levels and values of ESR, CRP, Kerr score, and ITAS-A were detected. Immunohistochemical staining confirmed CD19+ B cell and IgG infiltration to the aortic wall in patients with TAK. CONCLUSIONS: Enhanced B cells might contribute to the pathogenesis of TAK, and serum IgG levels could serve as a simple, useful biomarker to assess disease activity and monitor treatment response in TAK.

Erythropoietin relieves neuronal apoptosis in epilepsy rats via TGF-ß/Smad signaling pathway.

This study aimed to investigate the influence of recombinant human erythropoietin (rHuEPO) on pentylenetetrazol (PTZ)-induced neuronal apoptosis in epilepsy rats, and to explore the signaling pathways related to the action. Healthy Sprague-Dawley rats aged 8 weeks old were randomly divided into 5 groups, namely, control group, PTZ model group, PTZ + rHuEPO intervention group, PTZ + SB431542 + rHuEPO intervention group and PTZ + SB431542 (TGF-ß/Smad inhibitor) intervention group. The expressions of apoptotic proteins [tumor necrosis factor receptor 1 (TNFR1) and caspase-3] and the transforming growth factor-beta (TGF-ß)/Smad signaling pathway-related proteins [phosphorylated smad3 (p-smad3) and TGF-ß1] in the brain tissues were determined via Western blotting (WB). Epilepsy was successfully induced by PTZ in the rats. The results of the TUNEL assay showed that the intervention with rHuEPO could remarkably reduce the number of PTZ-induced apoptotic neurons in the hippocampus, while SB431542 inhibitor could attenuate the protective effect of rHuEPO against neuronal apoptosis (P<0.05). In addition, the intraperitoneal injection of 50 µg/kg rHuEPO could activate the TGF-ß/Smad signaling pathway, markedly up-regulate the expressions of TGF-ß1 and p-smad3 (P<0.05), down-regulate the expressions of apoptotic proteins TNFR1 and caspase-3 (P<0.01) and reduce neuronal apoptosis. Moreover, SB431542 was able to notably repress the protective effect of rHuEPO against neuronal apoptosis, and down-regulate the expressions of p-smad3 and TGF-ß1 (P<0.01). In conclusion, the inhibitory effect of rHuEPO on nerve cell apoptosis in epilepsy rats may be realized by activating the TGF-ß/Smad signaling pathway, thus relieving neuronal apoptosis and ameliorating the symptoms of epilepsy.

Platelet count as a potential predictor in refractory Takayasu arteritis.

Platelet parameters have been recognized as important markers for disease severity in various types of diseases. The aim of our study was to investigate whether platelet count could be used as a potential predictor of refractory Takayasu arteritis (TAK). In this retrospective study, fifty-seven patients were selected as development data group to identify the associated risk factors and potential predictors of refractory TAK. Ninety-two TAK patients were included in the validation data group to verify the predictive value of platelet count for refractory TAK. Refractory TAK patients had higher levels of platelet (PLT) than non-refractory TAK patients (305.5 vs. 272.0 × 109/L, P = 0.043). For PLT, the best cut-off value was 296.5 × 109/L to predict refractory TAK. Elevated PLT (> 296.5 × 109/L) was found to be statistically related to refractory TAK (OR [95%CI] 4.000 [1.233-12.974], p = 0.021). In the validation data group, the proportion of refractory TAK in patients with elevated PLT was significantly higher than that in patients with non-elevated PLT (55.6% vs. 32.2%, P = 0.037). The 1-, 3- and 5-year cumulative incidence of refractory TAK were 37.0%, 44.4% and 55.6% in patients with elevated PLT, respectively. Elevated PLT (p = 0.035, hazard ratio (HR) 2.106) was identified as a potential predictor of refractory TAK. Clinicians should pay close attention to platelet levels in patients with TAK. For TAK patients with PLT greater than 296.5 × 109/L, closer monitoring of the disease and comprehensive assessment of disease activity are recommended to be alert to the occurrence of refractory TAK.

Flexible Magnetic Sensors.

With the merits of high sensitivity, high stability, high flexibility, low cost, and simple manufacturing, flexible magnetic field sensors have potential applications in various fields such as geomagnetosensitive E-Skins, magnetoelectric compass, and non-contact interactive platforms. Based on the principles of various magnetic field sensors, this paper introduces the research progress of flexible magnetic field sensors, including the preparation, performance, related applications, etc. In addition, the prospects of flexible magnetic field sensors and their challenges are presented.

Minishelterins separate telomere length regulation and end protection in fission yeast.

The conserved shelterin complex is critical for chromosome capping and maintaining telomere length homeostasis. In fission yeast, shelterin is comprised of five proteins. Taz1, Rap1, and Poz1 function as negative regulators of telomere elongation, whereas Pot1 and Tpz1 are critical for end capping and telomerase recruitment. How the five proteins work together to safeguard chromosome ends and promote telomere length homeostasis is a matter of great interest. Using a combination of deletions, fusions, and tethers, we define key elements of shelterin important for telomere length regulation. Surprisingly, deletion of the entire Rap1 and Poz1 proteins does not impair telomere length regulation as long as a static bridge is provided between Taz1 and Tpz1. Cells harboring minishelterin display wild-type telomere length and intact subtelomeric silencing. However, protection against end fusions in G1 is compromised in the absence of Rap1. Our data reveal a remarkable plasticity in shelterin architecture and separate functions in length regulation and end protection.

[Comparison of detection rates of chromosome G-banding karyotype analysis and fluorescence in situ hybridization among children with sex chromosome mosaicisms].

OBJECTIVE: To explore the coincidence rate of G-banding karyotype analysis and fluorescence in situ hybridization (FISH) for the diagnosis of children with sex chromosome mosaicisms. METHODS: A retrospective analysis was carried out for 157 children with suspected sex chromosome abnormalities who had presented at Shenzhen Children's Hospital from April 2021 to May 2022. Interphase sex chromosome FISH and G-banding karyotyping results were collected. The coincidence rate of the two methods in children with sex chromosome mosaicisms was compared. RESULTS: The detection rates of G-banding karyotype analysis and FISH were 26.1% (41/157) and 22.9% (36/157) , respectively (P > 0.05). The results of G-banding karyotype analysis showed that 141 cases (89.8%) were in the sex chromosome homogeneity group, of which only 5 cases (3.5%) were inconsistent with the results of FISH. There were 16 cases (10.2%) in the sex chromosome mosaicism group, of which 11 cases (68.8%) were inconsistent with the results of FISH. There was a statistical difference between the two groups in the coincidence rate of the results of the two methods (P < 0.05). CONCLUSION: No significant difference was found between G-banding karyotype analysis and FISH in the detection rate of chromosome abnormalities. The coincidence rate in the mosaicism group was lower than that in the homogeneity group, and the difference was statistically significant. The two methods should be combined for clinical diagnosis.

Effect of perioperative application of dexmedetomidine on post-operative stress reaction, pain and prognostic adverse effects in patients undergoing gynaecological laparoscopy.

Introduction: The aim of this study was to analyse the effect of perioperative dexmedetomidine (DEX) application on stress response, post-operative pain and prognosis in patients undergoing gynaecologic laparoscopy. Patients and Methods: One hundred and sixty-eight patients admitted for gynaecologic laparoscopic surgery from May 2020 to November 2022 were included in the study. The patients were randomly divided into pre-operative DEX group (n = 56), intraoperative DEX group (n = 56) and post-operative DEX group (n = 56) according to the application of DEX in the perioperative period. The visual analogue scale (VAS), time awake, extubation time, pneumoperitoneum time, post-anaesthesia care unit (PACU) stay time and Richmond agitation-sedation scale score (RASS) were recorded. Results: Patients in both the pre-operative and intraoperative DEX groups had substantially shorter wakeup and extubation times than those in the post-operative DEX group. Patients in the pre-operative DEX group had considerably shorter wakeup and extubation times than those in the intraoperative DEX group, and their pneumoperitoneum time was significantly shorter than that of the post-operative DEX group (P < 0.001). The RASS scores of the pre-operative DEX group and intraoperative DEX group were significantly lower than those of the post-operative DEX group at 1 h, 6 h and 12 h after surgery. Meanwhile, at all time periods, the RASS scores of patients in the pre-operative DEX group were considerably lower than those in the intraoperative DEX group (P < 0.01). The VAS scores of patients in the pre-operative DEX group and intraoperative DEX group were evidently lower than those in the post-operative DEX group at 0.5 h, 2 h and 12 h postoperatively, and the VAS scores of patients in the pre-operative DEX group were markedly lower than those in the intraoperative DEX group (P < 0.001). The incidence of nausea and vomiting was significantly lower in the pre-operative DEX group than in the intraoperative DEX group and the post-operative DEX group at 0-2 h, >2-12 h and >12-24 h postoperatively (P < 0.001). The incidence of nausea and vomiting in the intraoperative DEX group was significantly lower than that in the post-operative DEX group from 0 to 2 h after surgery (P < 0.05). The incidence of adverse reactions was not significantly different amongst the three groups of patients (P > 0.05). Conclusion: Pre-operative and intraoperative application of DEX can help reduce post-operative pain and stress responses, help patients recover quickly after surgery and improve patient prognosis, especially the pre-operative application of DEX.

Comparison of Different Thoracic Aortic Wall Characteristics for Assessment of Disease Activity in Takayasu Arteritis: A Quantitative Study with 3.0 T Magnetic Resonance Imaging.

BACKGROUND: Determination of disease activity in Takayasu arteritis (TAK) is crucial for clinical management but challenging. The value of different magnetic resonance imaging (MRI) characteristics for the assessment of disease activity remains unclear. This study investigated the imaging findings of the thoracic aortic wall and elasticity by using a comprehensive 3.0 T MRI protocol. METHODS: We prospectively enrolled 52 consecutive TAK patients. TAK activity was recorded according to the ITAS2010. All the patients underwent thoracic aortic MRI. The luminal morphology of the thoracic aorta and its main branches were quantitatively evaluated using a contrast-enhanced magnetic resonance angiography (MRA) sequence. The maximum wall thickness of the thoracic aorta, postcontrast enhancement ratio, and aortic wall edema were analyzed in each patient through pre- and post-enhanced T1-weighted and T2-weighted imaging. Pulse-wave velocity (PWV) of the thoracic aorta was calculated using a four-dimensional flow technique. RESULTS: The majority of the 52 patients had type V disease (34.62%, 18/52). Among all the MRI indicators of the thoracic aorta, the area under the curve was the largest for the maximal wall thickness (0.804, 95% confidence interval [CI] = 0.667-0.941). The maximal wall thickness (93.33%, 95% CI = 68.1%-99.8%) exhibited the highest sensitivity with a cutoff value of 3.12 mm. Wall edema (84.00%, 95% CI = 63.9%-95.5%) presented the highest specificity. A positive correlation was noted between PWV and patients' age (r = 0.54, p < 0.001), disease duration (r = 0.52, p < 0.001), and the maximum wall thickness (r = 0.45, p = 0.001). CONCLUSIONS: MRI enabled the comprehensive assessment of aortic wall morphology and functional markers for TAK disease activity. Aortic maximal wall thickness was the most accurate indicator of TAK activity. The early phase was superior to the delay phase for aortic wall enhancement analysis for assessing TAK activity.

RNA helicase DHX15 decreases cell apoptosis by NF-κB signaling pathway in Burkitt lymphoma.

BACKGROUND: DHX15 is one of the RNA helicase family members involving in several biological processes. Studies have reported that overexpression of DHX15 is related to cancer progression. However, the role of DHX15 in Burkitt lymphoma (BL) and latent Epstein-Barr virus (EBV) infection remains to be elucidated. METHODS: Expression of DHX15 was measured in BL patient by immunohistochemical staining. In vitro study, a CCK-8 assay was used to analyze cell proliferation and flow cytometry was performed to assess cell cycle, apoptosis and mitochondria membrane potential. Members of NF-κB signaling pathway and apoptotic-related proteins expression were measured by western-blot. EBV latent infection products and RNA polymerase III transcripts expression were determined by quantitative real-time PCR and western-blot. In vivo study, HE, IHC, TUNEL and ISH assays were used to analyze the effect of DHX15 on subcutaneous tumor nodes formation. RESULTS: DHX15 was overexpressed in Burkitt lymphoma patients and tends to be associated with poor progression-free survival and poor overall survival. Knockdown of DHX15 significantly inhibited BL tumor growth, reduced cell proliferation, induced cell cycle arrest and increased cell apoptosis. Further analysis showed that canonical NF-κB signaling and its downstream targets, mitochondria and Caspase were involved in the increased cell apoptosis after DHX15 gene knockdown. Furthermore, knockdown of DHX15 reduced EBV latent infection products expression and inhibited RNA polymerase III activity. CONCLUSION: DHX15 may be an oncogene in the development of BL and a potential therapeutic target for the treatment of BL and latent EBV infection.

Synthesis, radiolabeling, and evaluation of a potent ß-site APP cleaving enzyme (BACE1) inhibitor for PET imaging of BACE1 in vivo.

The ß-site APP-cleaving enzyme 1 (BACE1) plays important roles in the proteolytic processing of amyloid precursor protein, and can be regarded as an important target for the diagnosis and treatment of AD. This study aimed to report the synthesis and evaluation of an 18F-labeled 2-amino-3,4-dihydroquinazoline analog as a potential BACE1 radioligand. A fluoropropyl side chain was introduced to the phenyl of this 3,4-dihydroquinazoline scaffold to generate the radioligand. Our preliminary data indicated that although the 2-amino-3,4-dihydroquinazoline scaffold possessed favorable in-vitro properties as a PET ligand, its poor brain uptake hindered the in-vivo imaging of BACE1. Further investigation would be required to optimize the scaffold for the development of a blood-brain-barrier-permeable BACE1-targeted PET ligand.

In vitro and in vivo evaluation of 211At-labeled fibroblast activation protein inhibitor for glioma treatment.

Glioma is the most common primary intracranial tumor without effective treatment. Positron emission tomography tracers labeled with 68Ga targeting fibroblast activation protein (FAP) have shown favorable characteristics in the diagnosis of glioma. However, to the best of our knowledge, FAP-targeted endoradiotherapy has never been explored in glioma. Hence, in this study, we investigated the therapeutic effect of 211At-labeled fibroblast activation protein inhibitor (FAPI) for glioma in vitro and in vivo. By astatodestannylation reaction, we prepared 211At-FAPI-04 with a radiochemical yield of 45 ± 6.7% and radiochemical purity of 98%. With good stability in vitro, 211At-FAPI-04 showed fast and specific binding to FAP-positive U87MG cells, and could significantly reduce the cell viability, arrested cell cycle at G2/M phase and suppressed cell proliferative efficacy. Biodistribution studies revealed that 6-fold higher accumulation in tumor sites was achieved by intratumoral injection in comparison with intravenous injection. In U87MG xenografts, 211At-FAPI-04 obviously suppressed the tumor growth and prolonged the median survival in a dose-dependent manner without obvious toxicity to normal organs. In addition, reduced proliferation and increased apoptosis were also observed after 211At-FAPI-04 treatment. All these results suggest that targeted alpha-particle therapy (TAT) mediated by 211At-FAPI-04 can provide an effective and promising strategy for the treatment of glioma.