DWI during CRT for HNC allows more accurate response prediction than anatomical imaging, correlating significantly with 2-year LRC.
• Whole-body MRI with diffusion weighting (WB-DWI/MRI) helps to assess the operability of suspected ovarian cancer. • Interobserver agreement is good for primary tumour characterisation, peritoneal and distant staging. • WB-DWI/MRI improves mesenteric/serosal metastatic spread assessment compared with CT and FDG-PET/CT. • Retroperitoneal/cervical-thoracic nodal staging using qualitative DWI criteria was reasonably accurate. • WB-DWI/MRI and FDG-PET/CT showed the highest diagnostic impact for detecting thoracic metastases.
The purpose of this study was to evaluate the accuracy of diffusion-weighted magnetic resonance imaging (DW-MRI) in differentiating HCC from benign cirrhotic lesions compared with conventional dynamic contrast-enhanced MRI. Fifty-five patients with cirrhosis underwent conventional and DW-MRI at 1.5 Tesla. Signal intensity ratios (SI(ratio)) of solid liver lesions to adjacent hepatic parenchyma were measured for b0, b100, b600 and b1000, and the apparent diffusion coefficients (ADC) were calculated. In 27 patients, imaging results were compared to histopathology, and in 28 patients, to imaging follow-up. Based on predetermined thresholds, sensitivity and specificity of DW-MRI and conventional MRI were compared. SI(ratio) was significantly different between malignant and benign lesions at all b-values (P < 0.0001). No significant difference in ADC was seen (P = 0.47). For detection of malignant lesions, DW-MRI with b600-SI(ratio) yielded a sensitivity of 95.2% compared to 80.6% for conventional MRI (P = 0.023) and a specificity of 82.7% compared to 65.4% (P = 0.064). The improved accuracy was most beneficial for differentiating malignant lesions smaller than 2 cm. DW-MRI with b600-SI(ratio) improved the detection of small HCC and the differentiation of pseudotumoral lesions compared with conventional MRI.
DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. Keywords: tumor suppressor; hearing loss; apoptosis; dfna5; cancer; GSEA INTRODUCTION DFNA5 first was discovered in a Dutch family with autosomal dominant hearing loss (HL). 1 Not much was known concerning its cellular function and how its function was related to HL. Recently, a novel mutation in DFNA5 has been identified in a Korean family, totaling five families with DFNA5 HL. 2 These families all have different genomic DFNA5 mutations, but in each case the DFNA5 mRNA transcript skips exon 8, resulting in a frameshift and a premature truncation of the protein. [1][2][3][4][5] These findings have led to the hypothesis that DFNA5-associated HL is attributable to a highly specific gain-of-function mutation, in which skipping of one exon causes disease while mutations in other parts of this gene may not result in HL at all. Further experimental evidence for this hypothesis was provided by the finding that transfection of mutant DFNA5 causes cell death in both yeast 6 and mammalian 7 cells and by the discovery of a new DFNA5 mutation. 8 The latter mutation truncated the protein in the fifth exon, but did not segregate with HL and was present in family members with normal hearing. The hypothesis was further corroborated by a mouse that lacked the Dfna5 protein. This knockout (KO) mouse did not display any HL and, as a consequence, was not a suitable animal model to study DFNA5-associated HL. 9 To date, little information is available on the physiological function of DFNA5. However, since its identification, the small num...
Apoptosis is an important physiological process. Normally, a healthy cell maintains a delicate balance between pro- and anti-apoptotic factors, allowing it to live and proliferate. It is thus not surprising that disturbance of this delicate balance may result in disease. It is a well known fact that apoptosis also contributes to several acquired forms of hearing impairment. Noise-induced hearing loss is the result of prolonged exposure to excessive noise, triggering apoptosis in terminally differentiated sensory hair cells. Moreover, hearing loss caused by the use of therapeutic drugs such as aminoglycoside antibiotics and cisplatin potentially may result in the activation of apoptosis in sensory hair cells leading to hearing loss due to the “ototoxicity” of the drugs. Finally, apoptosis is a key contributor to the development of presbycusis, age-related hearing loss. Recently, several mutations in apoptosis genes were identified as the cause of monogenic hearing impairment. These genes are TJP2, DFNA5 and MSRB3. This implies that apoptosis not only contributes to the pathology of acquired forms of hearing impairment, but also to genetic hearing impairment as well. We believe that these genes constitute a new functional class within the hearing loss field. Here, the contribution of apoptosis in the pathology of both acquired and genetic hearing impairment is reviewed.
The human BON-1 and QGP-1 cell lines are two frequently used models in pancreatic neuroendocrine tumor (PNET) research. Data on the whole-exome genetic constitution of these cell lines is largely lacking. This study presents, to our knowledge, the first wholeexome profile of the BON-1 and QGP-1 cell lines. Cell line identity was confirmed by short tandem repeat profiling. Using GTG-banding and a CytoSNP-12v2 Beadchip array, cell line ploidy and chromosomal alterations were determined in BON-1 and QGP-1. The exomes of both cell lines were sequenced on Ilumina's HiSeq next-generation sequencing (NGS) platform. Single-nucleotide variants (SNVs) and insertions and deletions (indels) were detected using the Genome Analysis ToolKit. SNVs were validated by Sanger sequencing. Ploidy of BON-1 and QGP-1 was 3 and 4 respectively, with long stretches of loss of heterozygosity across multiple chromosomes, which is associated with aggressive tumor behavior. In BON-1, 57 frameshift indels and 1725 possible protein-altering SNVs were identified in the NGS data. In the QGP-1 cell line, 56 frameshift indels and 1095 SNVs were identified. ATRX, a PNET-associated gene, was mutated in both cell lines, while mutation of TSC2 was detected in BON-1. A mutation in NRAS was detected in BON-1, while KRAS was mutated in QGP-1, implicating aberrations in the RAS pathway in both cell lines. Homozygous mutations in TP53 with possible loss of function were identified in both cell lines. Various MUC genes, implicated in cell signaling, lubrication and chemical barriers, which are frequently expressed in PNET tissue samples, showed homozygous proteinaltering SNVs in the BON-1 and QGP-1 cell lines.
Otosclerosis is an otodystrophy of the otic capsule and is a cause of conductive, mixed or sensorineural hearing loss in the 2nd to 4th decades of life. Otosclerosis is categorised into two types, fenestral and retrofenestral. Imaging plays an important role in the diagnosis and management of otosclerosis. High-resolution CT (HRCT) of the temporal bone using 1-mm (or less) thick sections is the modality of choice for assessment of the labyrinthine windows and cochlear capsules. MRI has limited application in the evaluation of the labyrinthine capsules but is useful for assessment of the cochlear lumen prior to cochlear implantation in patients with profound hearing loss. The treatment of fenestral otosclerosis is primarily surgical with stapedectomy and prosthesis insertion. Patients with retrofenestral otosclerosis and profound hearing loss are treated medically using fluorides, but may derive significant benefit from cochlear implantation. This pictorial review aims to acquaint the reader with the pathology and clinical features of otosclerosis, the classical imaging appearances on CT and MRI, a radiological checklist for preoperative CT evaluation of otosclerosis, imaging mimics and a few examples of post-stapedectomy imaging and complications.Teaching points• Otosclerosis causes conductive, sensorineural and mixed hearing loss in adults.• HRCT of the temporal bone is the diagnostic imaging modality of choice.• Stapedectomy is used to treat fenestral otosclerosis.• Fluorides and cochlear implantation are used to treat retrofenestral otosclerosis.
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