A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer.

Glucose metabolism is remodeled in cancer, but the global pattern of cancer-specific metabolic changes remains unclear. Here we show, using the comprehensive measurement of metabolic enzymes by large-scale targeted proteomics, that the metabolism both carbon and nitrogen is altered during the malignant progression of cancer. The fate of glutamine nitrogen is shifted from the anaplerotic pathway into the TCA cycle to nucleotide biosynthesis, with this shift being controlled by glutaminase (GLS1) and phosphoribosyl pyrophosphate amidotransferase (PPAT). Interventions to reduce the PPAT/GLS1 ratio suppresses tumor growth of many types of cancer. A meta-analysis reveals that PPAT shows the strongest correlation with malignancy among all metabolic enzymes, in particular in neuroendocrine cancer including small cell lung cancer (SCLC). PPAT depletion suppresses the growth of SCLC lines. A shift in glutamine fate may thus be required for malignant progression of cancer, with modulation of nitrogen metabolism being a potential approach to SCLC treatment.

Metabolomic screening using ESI-FT MS identifies potential radiation-responsive molecules in mouse urine.

The demand for establishment of high-throughput biodosimetric methods is increasing. Our aim in this study was to identify low-molecular-weight urinary radiation-responsive molecules using electrospray ionization Fourier transform mass spectrometry (ESI-FT MS), and our final goal was to develop a sensitive biodosimetry technique that can be applied in the early triage of a radiation emergency medical system. We identified nine metabolites by statistical comparison of mouse urine before and 8 h after irradiation. Time-course analysis showed that, of these metabolites, thymidine and either thymine or imidazoleacetic acid were significantly increased dose-dependently 8 h after radiation exposure; these molecules have already been reported as potential radiation biomarkers. Phenyl glucuronide was significantly decreased 8 h after radiation exposure, irrespective of the dose. Histamine and 1-methylhistamine were newly identified by MS/MS and showed significant, dose-dependent increases 72 h after irradiation. Quantification of 1-methylhistamine by enzyme-linked immunosorbent assay (ELISA) analysis also showed a significant increase 72 h after 4 Gy irradiation. These results suggest that urinary metabolomics screening using ESI-FT MS can be a powerful tool for identifying promising radiation-responsive molecules, and that urinary 1-methylhistamine is a potential radiation-responsive molecule for acute, high-dose exposure.

Hepcidin-2 in mouse urine as a candidate radiation-responsive molecule.

We used high-performance liquid chromatography to separate urine obtained from whole-body gamma-irradiated mice (4 Gy) before analyzing each fraction with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to identify radiation-responsive molecules. We identified two candidates: hepcidin antimicrobial peptide 2 (hepcidin-2) and peptide fragments of kidney androgen-regulated protein (KAP). We observed that peak increases of hepcidin-2 in urine were delayed in a dose-dependent manner (1 Gy and above); however, the amount of KAP peptide fragments showed no correlation with radiation dose. In addition, an increase in hepcidin-2 after exposure to relatively low radiation doses (0.25 and 0.5 Gy, respectively) was biphasic (at 8-48 h and 120-168 h, respectively, after irradiation). The increase in hepcidin-2 paralleled an increase in hepcidin-2 gene (Hamp2) mRNA levels in the liver. These results suggest that radiation exposure directly or indirectly induces urinary excretion of hepcidin-2 at least in part by the upregulation of Hamp2 mRNA in the liver.

Long-term suppression of tremor by deep brain stimulation of the ventral intermediate nucleus of the thalamus combined with pallidotomy in hemiparkinsonian patients.

Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM) is a powerful surgical option in the treatment of tremor-predominant Parkinson's disease. However, its therapeutic efficacy depends on the tremor distribution. DBS is highly efficient in relief of distal appendicular tremor but not other types of tremor. Also, it is generally thought that DBS of the VIM has no significant beneficial effects on other motor symptoms of Parkinson's disease. We report two hemiparkinsonian patients, in whom unilateral VIM DBS combined with posteroventral pallidotomy produced long-lasting suppression of not only hand tremor, but also leg or jaw tremor and other motor symptoms.

De novo appearance of cerebellar cavernous malformation in a patient with moyamoya disease: case report and review of the literature.

The authors report a case of cerebellar cavernous malformation associated with moyamoya disease. An adolescent male with moyamoya disease had undergone bilateral direct and indirect extracranial-intracranial anastomosis at 11 years of age, and the course had been uneventful until MRI detected the appearance of a cavernous malformation in the cerebellum 3 years later. The lesion had grown, bled, and caused headache and disturbance of consciousness 2 years after the initial detection. The cavernous malformation was removed surgically and pathologically verified. The patient has recovered without any neurological deficits. This is a quite rare case with cavernous malformation which appeared in a moyamoya disease patient. The association of the two different vascular disorders in a young patient may suggest the existence of some interaction in the pathogenesis of these diseases. Since cavernous malformations with a de novo appearance may grow and become clinically significant, careful observation is necessary.

Moyamoya disease associated with midaortic syndrome.

We report a 1-year-old girl who presented moyamoya disease associated with midaortic syndrome. She had been treated for cardiac failure and severe hypertension due to midaortic syndrome until she suffered seizure and repeated cerebral ischemic attack. Cerebral angiography revealed stenosis of the bilateral internal carotid artery at its terminal portion. She was successfully treated with encephaloduroarteriosynangiosis, and ischemic attack ceased postoperatively. This is the first report of moyamoya disease with midaortic syndrome. Although cerebral ischemic attack has been effectively managed by encephaloduroarteriosynangiosis, renovascular hypertension is still difficult to control.

Rapidly enlarging chordoid meningioma with abundant mucin production.

This 77-year-old woman with a rapidly enlarging chordoid meningioma first noticed a growing, non-pulsatile, nonpainful soft mass in the left temporal region after a head trauma 2 years earlier. Neuroimaging showed a homogeneously enhanced osteolytic mass lesion in the left temporal bone. Surgery revealed an extradural tumor without significant adhesions. Histopathologically it was a meningioma with features reminiscent of chordoma. Most of the tumor cells contained mucin-rich chordoid elements. Immunohistochemically, the lesion was positive for vimentin and epithelial membranous antigen; it was negative for cytokeratin and S-100 protein. Based on these findings a diagnosis of chordoid meningioma was made. We posit that the rapid enlargement of the tumor over a relatively short period was attributable to its high mucin-producing activity.

Spontaneous dissecting aneurysms of anterior and middle cerebral artery associated with brain infarction: a case report and review of the literature.

BACKGROUND: Intracranial dissecting aneurysms have been reported with increasing frequency and are recognized as a common cause of stroke. In some reviews and case reports, attempts have been made to compare the outcomes of surgical and medical treatments. However, the appropriate management of dissecting aneurysms in the anterior circulation remains controversial, especially in patients who also manifest cerebral infarction. CASE DESCRIPTION: A 45-year-old male was diagnosed as having a dissecting aneurysm of the right middle cerebral artery (MCA) with cerebral infarction. In the course of conservative treatment, he developed a new cerebral infarction in the territory of the right anterior cerebral artery (ACA). Repeat cerebral angiograms revealed an increase in the aneurysmal dilatation of the right M2 and the appearance of a segmental dilatation of the right A2. He continued to be treated conservatively and his course was satisfactory. On subsequent angiograms, we observed resolution of the right A2 dissection and no further progression of the dilatation of the right M2. CONCLUSION: This is the first reported case of simultaneous idiopathic dissecting aneurysms of different major arterial branches in the anterior circulation. Our review of the literature disclosed 36 and 23 cases, respectively, of dissecting aneurysms of the ACA and MCA. Many previously reported patients with these dissecting aneurysms involving subarachnoid hemorrhage (SAH) underwent surgery, which resulted in better outcome. More than half of the patients with ACA and MCA dissecting aneurysms had cerebral infarction. All ACA dissecting aneurysms involving ischemia occurred in the A2 region. The outcomes of both surgical and conservative management were equally satisfactory. On the other hand, in patients with MCA dissecting aneurysms, the area of ischemia frequently involved the M1 region; in these patients, conservative treatment resulted in poor outcomes. Therefore, revascularization distal to the compromised artery should be considered in patients with MCA-dissecting aneurysms who have ischemia. Careful interpretation of serial angiograms and/or magnetic resonance (MR) images is necessary because of the possibility of disease progression. If the aneurysmal size increases or there is progression of ischemic symptoms in the course of conservative treatment, surgery must be urgently evaluated.