Novel brd4 inhibitors with a unique scaffold exhibit antitumor effects

Since bromodomain containing 4 (brd4) has been considered as a prominent cancer target, numerous attempts have been made to develop potent brd4 bromodomain inhibitors. The present study provided a novel chemical scaffold which inhibited brd4 activity. Mid-throughput screening against brd4 bromodomain was performed using alpha-screen and homogeneous time-resolved fluorescence assays. Furthermore, cell cytotoxicity and xenograft assays were performed to examine if the compound was effective both in vitro and in vivo. As a result, it was revealed that compounds having naphthalene-1,4-dione scaffold inhibited the binding of bromodomain to acetylated histone. The compounds with naphthalene-1,4-dione had cytotoxic effects against the Ty82 cell line, a NUT midline carcinoma cell line, whose proliferation is dependent on brd4 activity. A10, one of the compounds with naphthalene-1,4-dione scaffold, also exhibited tumor growth inhibition effects in the xenograft assay. In addition, the compounds exhibited cytotoxic effects against gastric cancer cell lines which were resistant to I-BET-762, a BET bromodomain inhibitor. In conclusion, the novel scaffold to suppress brd4 activity was effective against cancer cells both in vitro and in vivo.     

Small bowel volvulus with a jejunal trichobezoar

Background

Small bowel volvulus caused by a jejunal trichobezoar is an extremely rare and life-threatening emergency in children.

Case characteristics

An 8-year-old girl with abdominal pain and persistent bilious vomiting.

Observation

The abdominal computed tomography scan showed a solitary intraluminal mass and a whirl sign, suggesting the small bowel volvulus. Emergency laparoscopic exploration revealed the rotated segment of small bowel loops by a jejunal trichobezoar.

Outcome

Satisfactory recovery after surgery.

Message

Trichobezoars should be considered in the differential diagnosis of abdominal pain and projectile vomiting in children.     

Expression of phosphorylcholine-specific B cells during murine development

The TEPC 15 (T15) clonotype, a putatively germline antibody specificity, does not appear in the neonatal B-cell repertoire until approximately 1 wk of age. This report extends this observation by the demonstration that (a) the T15 clonotype follows similar kinetics of appearance in germfree as well as conventionally-reared mice; (b) maternal influences and genetic background play a minor role in the development of the T15 clonotype since CBFI neonates raised by C57BL/6 or BALB/c mothers acquire the T15 clonotype at the same time in ontogeny as BALB/c neonates; (c) the lack of phosphorylcholine (PC)-specific B cells shortly after birth is reflected in a dearth of PC-binding cells in the neonate as well; and (d) no PC-specifc B cells are found in 19-day fetal liver or in bone marrow until 7 days of life, coincident with their appearance in the spleen. These findings, along with a previous report that PC-specific splenic B cells are tolerizable as late as day 10 after birth, confirm the invariant, late occurrence of the T15 clonotype and support a highly- ordered, rigorously predetermined mechanism for the acquisition of the B- cell repertoire. The results are discussed in light of other studies on the ontogeny of B-cell specificity, and in terms of the implications on the mechanism by which antibody diversity is generated.     

Inhibition of Mycoplasma pneumoniae by Actinomycin D

Growth of Mycoplasma pneumoniae was completely prevented by 0.06 mug of actinomycin D/ml, and 0.00375 mug/ml caused 90% inhibition. It thus appears that M. pneumoniae is more susceptible to actinomycin D than previously reported. Low concentrations (0.019 mug/ml) of the antibiotic primarily inhibited ribonucleic acid synthesis and high concentrations (20 mug/ml) inhibited both ribonucleic and deoxyribonucleic acid synthesis.     

Diffusion-weighted MRI of intracerebral hemorrhage clinically undifferentiated from ischemic stroke

This report describes diffusion-weighted MRI findings of some intracerebral hemorrhages clinically undifferentiated from ischemic stroke. We treated patients with characteristic features of intracerebral hemorrhages that could distinguish themselves from ischemic lesion on diffusion-weighted imaging. Therefore, we think diffusion-weighted imaging could be an emergency screening tool for ischemic stroke as an alternative to computed tomography, and the EP should be familiar with the diffusion-weighted imaging findings of intracerebral hemorrhage as well as cerebral infarction.     

Can preoperative MR imaging predict optic nerve invasion of retinoblastoma?

Purpose

To evaluate the accuracy of pre-operative MRI for the detection of optic nerve invasion in retinoblastoma.

Materials and methods

Institutional review board approval and informed consent were waived for this retrospective study. A total of 41 patients were included. Inclusion criteria were histologically proven retinoblastoma, availability of diagnostic-quality preoperative MR images acquired during the 4 weeks before surgery, unilateral retinoblastoma, and normal-sized optic nerve. Two radiologists retrospectively reviewed the MR images independently. Five imaging findings (diffuse mild optic nerve enhancement, focal strong optic nerve enhancement, optic sheath enhancement, tumor location, and tumor size) were evaluated against optic nerve invasion of retinoblastoma. The predictive performance of all MR imaging findings for optic nerve invasion was also evaluated by the receiver operating characteristic curve analysis.

Results

Optic nerve invasion was histopathologically confirmed in 24% of study population (10/41). The differences in diffuse mild enhancement, focal strong enhancement, optic sheath enhancement, and tumor location between patients with optic nerve invasion and patients without optic nerve invasion were not significant. Tumor sizes were 16.1 mm (SD: 2.2 mm) and 14.9 mm (SD: 3.6 mm) in patients with and without optic nerve involvement, respectively (P = 0.444). P-Values from binary logistic regression indicated that all five imaging findings were not significant predictors of tumor invasion of optic nerve. The AUC values of all MR imaging findings for the prediction of optic nerve invasion were 0.689 (95% confidence interval: 0.499–0.879) and 0.653 (95% confidence interval: 0.445–0.861) for observer 1 and observer 2, respectively.

Conclusion

Findings of MRI in patients with normal-sized optic nerves have limited usefulness in preoperatively predicting the presence of optic nerve invasion in retinoblastoma.     

Evaluation of knowledge-based reconstruction for magnetic resonance volumetry of the right ventricle after arterial switch operation for dextro-transposition of the great arteries

Right ventricular (RV) volume and function evaluation is essential in the follow-up of patients after arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA). Cardiac magnetic resonance (CMR) imaging using the Simpson’s method is the gold-standard for measuring these parameters. However, this method can be challenging and time-consuming, especially in congenital heart disease. Knowledge-based reconstruction (KBR) is an alternative method to derive volumes from CMR datasets. It is based on the identification of a finite number of anatomical RV landmarks in various planes, followed by computer-based reconstruction of the endocardial contours by matching these landmarks with a reference library of representative RV shapes. The purpose of this study was to evaluate the feasibility, accuracy, reproducibility and labor intensity of KBR for RV volumetry in patients after ASO for d-TGA. The CMR datasets of 17 children and adolescents (males 11, median age 15) were studied for RV volumetry using both KBR and Simpson’s method. The intraobserver, interobserver and intermethod variabilities were assessed using Bland–Altman analyses. Good correlation between KBR and Simpson’s method was noted. Intraobserver and interobserver variability for KBR showed excellent agreement. Volume and function assessment using KBR was faster when compared with the Simpson’s method (5.1?±?0.6 vs. 6.7?±?0.9 min, p?<?0.001). KBR is a feasible, accurate, reproducible and fast method for measuring RV volumes and function derived from CMR in patients after ASO for d-TGA.     

A New MRI Grading System for Cervical Foraminal Stenosis Based on Axial T2-Weighted Images

ObjectiveThe purpose of this study was to evaluate the reliability of a new magnetic resonance imaging (MRI) grading system for cervical neural foraminal stenosis (NFS).ResultsFor the distinction among the three individual grades at all six neural foramina, the ICC ranged from 0.68 to 0.73, indicating fair to good reproducibility. The percentage agreement ranged from 60.2% to 70.6%, and the kappa values (κ = 0.50-0.58) indicated fair to moderate agreement. The percentages of intraobserver agreement ranged from 85.4% to 93.8% (κ = 0.80-0.92), indicating near perfect agreement.ConclusionThe new MRI grading system shows sufficient interobserver and intraobserver agreement to reliably assess cervical NFS.     

Accuracy of Diffusion Tensor Imaging for Diagnosing Cervical Spondylotic Myelopathy in Patients Showing Spinal Cord Compression

ObjectiveTo assess the performance of diffusion tensor imaging (DTI) for the diagnosis of cervical spondylotic myelopathy (CSM) in patients with deformed spinal cord but otherwise unremarkable conventional magnetic resonance imaging (MRI) findings.ResultsThe MD, LD, and RD cut-off values were 1.079 × 10^-3, 1.719 × 10^-3, and 0.749 × 10^-3 mm²/sec, respectively, and that of FA was 0.475. Sensitivity, specificity, positive predictive value and negative predictive value were: 100 (4/4), 44.8 (13/29), 20 (4/20), and 100 (13/13) for MD; 100 (4/4), 27.6 (8/29), 16 (4/25), and 100 (8/8) for FA; 100 (4/4), 58.6 (17/29), 25 (4/16), and 100 (17/17) for MD∩FA; 100 (4/4), 68.9 (20/29), 30.8 (4/13), and 100 (20/20) for LD∩FA; and 75 (3/4), 68.9 (20/29), 25 (3/12), and 95.2 (20/21) for RD∩FA in percentage value. Diagnostic performance comparisons revealed significant differences only in specificity between FA and MD∩FA (p = 0.003), FA and LD∩FA (p < 0.001), FA and RD∩FA (p < 0.001), MD and LD∩FA (p = 0.024) and MD and RD∩FA (p = 0.024).ConclusionFractional anisotropy combined with MD, RD, or LD is expected to be more useful than FA and MD for diagnosing CSM in patients who show deformed spinal cords without signal changes on MRI.