Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells.

Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.

Magnetic resonance imaging in patients diagnosed with papilledema: a comparison of 6 different high-resolution T1- and T2(*)-weighted 3-dimensional and 2-dimensional sequences.

PURPOSE: To evaluate visualization and signal characteristics of macroscopic changes in patients with ophthalmologically stated papilledema and to find a suitable high-resolution magnetic resonance imaging (MRI) protocol. METHOD: Nine consecutive patients with 12 ophthalmologically stated papilledemas underwent MRI of the head and orbits, which consisted of the following high-resolution sequences: 3-dimensional (3D), T2*-weighted (T2*w) constructive interference in steady-state sequence (CISS); 3D, T1-weighted (T1w) magnetization prepared-rapid gradient echo sequence (MP-RAGE) (with and without intravenous contrast medium); transverse 3D and 2-dimensional (2D) (2 mm), T2-weighted (T2w) turbo spin echo (TSE); transverse 2D (2 mm), contrast-enhanced T1w TSE with fat-suppression technique; and transverse 2D (5 mm), T2w TSE. A quantitative and qualitative evaluation of the papilla, optic nerve, optic nerve sheath, optic chiasm, and the brain was performed. The 6 high-resolution sequences were compared. RESULTS: The elevation of the optic disc into the optic globe in ophthalmologically stated papilledema was best visualized in T2w, 3D CISS sequence. The pathological contrast enhancement was best seen in T1w contrast-enhanced 2D TSE sequence with fat-suppression technique. The mean width of the optic nerve sheath directly behind the globe was 7.54 mm (+/- 1.05 mm) in the pathological eyes, compared to 5.52 mm (+/- 1.11 mm) in the normal eyes. In all patients, the cerebral indices calculated showed no signs of increased intracranial pressure or other abnormalities changing the volume of the brain or ventricles. The contrast of the orbital fat versus the optic nerve sheath, the optic nerve sheath versus the surrounding cerebrospinal fluid (CSF), the surrounding CSF versus the optic nerve, the optic chiasm versus the CSF, and the optic papilla versus the optic globe were best visualized in the 3D, T2*w CISS sequence. An enhancement of the swollen optic nerve head was best seen in all 12 cases in the T1w contrast-enhanced 2D TSE sequence with fat-suppression technique. CONCLUSION: An MRI protocol consisting of a 5-mm transverse T2w TSE sequence; a T2*w, 3D CISS sequence; a T1w, 3D MP-RAGE sequence with and without contrast medium; and a transverse T1w, (2-mm) 2D TSE sequence with fat-suppression technique with intravenous contrast medium is suitable to visualize the macroscopic changes in papilledema. In addition, this combination is an excellent technique for the examination of the orbits and the brain.

Magnetic resonance imaging-based virtual endoscopy of inner ear pathology.

OBJECTIVE: To study the feasibility of high-resolution magnetic resonance imaging (MRI)-based virtual endoscopy of the labyrinth to assess subtle inner ear pathology. STUDY DESIGN: A retrospective case review of patient with known inner ear pathology to determine the feasibility and clinical value of MRI-based virtual labyrinthoscopy. SETTING: Tertiary referral center. PATIENTS: Ten patients with symptoms of sensorineural hearing loss or vertigo who underwent high-resolution MRI between 1996 and 1999. INTERVENTION: Diagnostic image modality with three-dimensional (3-D) postprocessing to assess inner ear pathology. MAIN OUTCOME MEASURES: To evaluate how 3-D rendering with virtual labyrinthoscopy can depict subtle labyrinthine pathology. RESULTS: Cases with typical 3-D models and virtual labyrinthoscopic views are presented to illustrate this new image processing approach. CONCLUSION: The virtual endoscopic view of the labyrinth revealed subtle inner ear pathology. This 3-D postprocessing technique is able to render inner surface changes of tiny structures within the inner ear. It can be performed within a very short time using dedicated hybrid rendering techniques. It allows visualization of pathology in a comprehensive way for clinicians and is able to add 3-D information for troubleshooting in doubtful two-dimensional findings. We suggest the term virtual labyrinthoscopy for virtual intraluminal visualization of the labyrinth.

Vertigo and hearing disturbance as the first sign of a glioblastoma (World Health Organization grade IV).

OBJECTIVE: To describe vertigo and hearing disturbance as a first sign of glioblastoma. STUDY DESIGN: Case report. SETTING: Ear, Nose, and Throat Department of the University of Regensberg, Germany. Primary Care Center. PATIENTS: A patient with a left temporal glioblastoma. RESULTS: A 67-year-old man presented with a 2-month history of vertigo and hearing disturbance. Radiological imaging revealed a left temporal tumor with dural inflation and erosion of the petrous bone and superior semicircular duct. The surgery involved total resection of the tumor and resurfacing of the gap in the superior canal. The histopathological examination revealed World Health Trade Organization IV glioblastoma. Postoperatively, the debilitating symptoms were relieved and the patient received radiation therapy. Tumor progression indicated a recraniotomy and a mastoidectomy. The tumor was only partially resected, and required chemotherapy. It subsequently developed otoliquorrhea and required a remastoidectomy. Histopathology of a pathological fracture of the X thoracic vertebra revealed a metastasis of the known glioblastoma. The patient died from respiratory distress syndrome. CONCLUSION: To the best of our knowledge, we are presenting the first case with transdural infiltration of bony structures by a glioblastoma at the moment of diagnosis. The transdural spread could be via the sinus petrosus and along the nervous petrosus major in the petrosal bone. Superior canal dehiscence syndrome should be considered in the differential diagnosis of vertigo and hearing disturbance. Two different processes for the etiology of the superior canal dehiscence syndrome are discussed previously in the literature; however, we present a new entity with a tumor-cause dehiscence of the bone overlying the superior canal.

Uncommon lesions in the internal auditory canal (IAC): review of the literature and case report.

BACKGROUND: Despite the relatively frequent occurrence of multiple primary tumors, namely, 10% of intracranial tumors, metastasis is a rare occurrence within the internal auditory canal (IAC) and cerebellopontine angle (CPA). Intracanalicular metastases of adenocarcinoma are documented, but a primary adenocarcinoma remains unreported. We provide a review of uncommon lesions in the IAC and describe to our knowledge the first instance of a primary adenocarcinoma. CASE REPORT: A 60-year-old man presented with nausea and vomiting. Cranial computed tomography scan revealed bilateral nonspecific periventricular and subcortical vascular lesions. He presented 8 months later with left-sided tinnitus, progressive hearing loss, and attacks of vertigo. Magnetic resonance imaging (MRI) showed an extra-axial mass most likely representing a left-sided vestibular schwannoma with characteristic contrast enhancement in the IAC. The follow-up MRI showed an unchanged pattern of contrast enhancement. Due to progressive headaches and dizziness, the patient underwent a left transtemporal craniotomy with subtotal tumor resection. Histological examination revealed blennogenic cylindrical adenocarcinoma. The investigations for the primary tumor site were all negative. The patient's condition deteriorated gradually. MRI showed an increase of the residual tumor and meningeosis carcinomatosa, and cerebrospinal fluid (CSF) examination was positive for tumor cells. The patient was treated with intrathecal chemotherapy. He died of multiple organ failure. DISCUSSION: The discussion focuses on the incidence of extra-axial CPA and IAC lesions with their clinical presentations and their radiological findings. We address the issue of a possible regulation of CPA lesion laterality by asymmetrically expressed genes. In view of the sparse literature on treatment of single intracanalicular metastases, the review is broadened to the current treatment recommendations of single brain metastases. CONCLUSIONS: The differentiation between benign and malign lesions in the CPA and IAC is important, as it requires diverse treatment protocols. For the physician this differentiation represents a clinical and radiological challenge. For the developmental research the left-right asymmetry might be a field of research.

Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells.

Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma.

Magnetic resonance imaging, computed tomography, and conventional X-ray in 3 cases of symmelia.

BACKGROUND: Symmelia is a rare birth defect, often combined with severe malformations of the urogenital system and the lower gastrointestinal tract. Additionally, a deformed pelvis and various degrees of separation of the lower limbs are present. CASES: We report the examination findings of 3 autopsy specimens of symmelia using magnetic resonance imaging (MRI) and computed tomography (CT) with 3-dimensional (3D) reconstructions, and conventional X-ray. CONCLUSIONS: MRI and CT with the addition of 3D visualization can be used additionally with autopsy and conventional X-ray images in the investigation of such complex anatomical abnormalities.