Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury

Recent evidence suggests oxygen as a powerful trigger for cell death in the immature white matter, leading to periventricular leukomalacia (PVL) as a cause of adverse neurological outcome in survivors of preterm birth. This oligodendrocyte (OL) death is associated with oxidative stress, upregulation of apoptotic signaling factors (i.e., Fas, caspase-3) and decreased amounts of neurotrophins. In search of neuroprotective strategies we investigated whether the polysulfonated urea derivative suramin, recently identified as a potent inhibitor of Fas signaling, affords neuroprotection in an in vitro model of hyperoxia-induced injury to immature oligodendrocytes. Immature OLs (OLN-93) were subjected to 80% hyperoxia (48 h) in the presence or absence of suramin (0, 30, 60, 120 microM). Cell death was assessed by flow cytometry (Annexin V, caspase-3 activity assay) and immunohistochemistry for activated caspase-3. Immunoblotting for the death receptor Fas, cleaved caspase-8 and the phosphorylated isoform of the serine-threonin kinase Akt (pAkt) was performed. Suramin lead to OL apoptosis and potentiated hyperoxia-induced injury in a dose-dependent manner. Immunoblotting revealed increased Fas and caspase-8 expression by suramin treatment. This effect was significantly enhanced when suramin was combined with hyperoxia. Furthermore, pAkt levels decreased following suramin exposure, indicating interference with neurotrophin-dependent growth factor signaling. These data indicate that suramin causes apoptotic cell death and aggravates hyperoxia-induced cell death in immature OLs. Its mechanism of action includes an increase of previously described hyperoxia-induced expression of pro-apoptotic factors and deprivation of growth factor dependent signaling components.     

Two types of mitochondrial crystals in diseased human skeletal muscle fibers

Mitochondrial crystalline inclusions, frequently found in mitochondrial myopathies, were analyzed by crystallographic techniques and computer-aided image processing. It could be shown that these structures were real crystals. There are two distinct types of crystal, which can be distinguished by shape, size, and pattern. So-called type I crystals are usually present in the intracristal space, whereas the type II crystals are preferentially located in the intermembrane space between outer and inner mitochondrial membranes. The unit cell dimensions were found to be 38 x 34 x 8 nm for the type I crystals and 20 x 17 x 8 nm for the type II crystals. These results strongly suggest that the crystals are composed of macromolecules, presumably proteins. Arguments are presented that indicate that type I crystals occur only in type 1 muscle fibers and type II crystals in type 2 muscle fibers.     

血清胸苷激酶1检测对恶性肿瘤诊断及疗效评估的意义

目的探讨血清胸苷激酶1（TK1）作为肿瘤细胞增殖标志物对恶性肿瘤诊断及疗效评估的意义。方法应用免疫印迹-增强化学发光法检测恶性肿瘤组（53例）治疗前后、体格检查组（49例）以及健康对照组（18名）的血清TK1水平。治疗前与治疗后比较用配对t检验,治疗前和后分别与健康对照组、体格检查组比较采用两独立样本均数比较t检验。结果恶性肿瘤组治疗前STK1为0．3—11．3（2．4±2．0）pmol／L;恶性肿瘤组治疗后STK1为0．3～5．0（0．9±0．8）pmol／L;体格检查组STK1为0．1～2．1（0．8±0．3）pmol／L;健康对照组STK1为0．5～1．2（0．7±0．2）pmol／L。恶性肿瘤组治疗前与治疗后之间STK1水平差异有统计学意义（t=5．257,P〈0．0001）。恶性肿瘤组治疗前与健康对照组和体格检查组STK1水平比较,差异均有统计学意义（t=3．568和5．460,P=0．001和〈0．0001）,而恶性肿瘤组治疗后与健康对照组和体格检查组STK1水平比较,差异均无统计学意义（t=1．056和0．715,P均〉0．05）。结论血清TK1检测细胞增殖有较高的特异性和灵敏度,对临床监测恶性肿瘤疗效和在体格检查中进行恶性肿瘤风险筛查具有重要意义。     

Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs. abnormal iron content in the brain

PURPOSE: To establish a baseline of phase differences between tissues in a number of regions of the human brain as a means of detecting iron abnormalities using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A fully flow-compensated, three-dimensional (3D), high-resolution, gradient-echo (GRE) susceptibility-weighted imaging (SWI) sequence was used to collect magnitude and phase data at 1.5 T. The phase images were high-pass-filtered and processed region by region with hand-drawn areas. The regions evaluated included the motor cortex (MC), putamen (PUT), globus pallidus (GP), caudate nucleus (CN), substantia nigra (SN), and red nucleus (RN). A total of 75 subjects, ranging in age from 55 to 89 years, were analyzed. RESULTS: The phase was found to have a Gaussian-like distribution with a standard deviation (SD) of 0.046 radians on a pixel-by-pixel basis. Most regions of interest (ROIs) contained at least 100 pixels, giving a standard error of the mean (SEM) of 0.0046 radians or less. In the MC, phase differences were found to be roughly 0.273 radians between CSF and gray matter (GM), and 0.083 radians between CSF and white matter (WM). The difference between CSF and the GP was 0.201 radians, and between CSF and the CN (head) it was 0.213 radians. For CSF and the PUT (the lower outer part) the difference was 0.449 radians, and between CSF and the RN (third slice vascularized region) it was 0.353 radians. Finally, the phase difference between CSF and SN was 0.345 radians. CONCLUSION: The Gaussian-like distributions in phase make it possible to predict deviations from normal phase behavior for tissues in the brain. Using phase as an iron marker may be useful for studying absorption of iron in diseases such as Parkinson's, Huntington's, neurodegeneration with brain iron accumulation (NBIA), Alzheimer's, and multiple sclerosis (MS), and other iron-related diseases. The phases quoted here will serve as a baseline for future studies that look for changes in iron content.     

Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG.

Recently, the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine (FLT) was suggested for imaging tumoral proliferation. In this prospective study, we examined whether (18)F-FLT better determines proliferative activity in newly diagnosed lung nodules than does (18)F-FDG. METHODS: Twenty-six patients with pulmonary nodules on chest CT were examined with PET and the tracers (18)F-FDG and (18)F-FLT. Tumoral uptake was determined by calculation of standardized uptake value (SUV). Within 2 wk, patients underwent resective surgery or had core biopsy. Proliferative activity was estimated by counting nuclei stained with the Ki-67-specific monoclonal antibody MIB-1 per total number of nuclei in representative tissue specimens. The correlation between the percentage of proliferating cells and the SUVs for (18)F-FLT and (18)F-FDG was determined using linear regression analysis. RESULTS: Eighteen patients had malignant tumors (13 with non-small cell lung cancer [NSCLC], 1 with small cell lung cancer, and 4 with pulmonary metastases from extrapulmonary tumors); 8 had benign lesions. In all visible lesions, mean (18)F-FDG uptake was 4.1 (median, 4.4; SD, 3.0; range, 1.0-10.6), and mean (18)F-FLT uptake was 1.8 (median, 1.2; SD, 2.0; range, 0.8-6.4). Statistical analysis revealed a significantly higher uptake of (18)F-FDG than of (18)F-FLT (Mann-Whitney U test, P < 0.05). (18)F-FLT SUV correlated better with proliferation index (P < 0.0001; r = 0.92) than did (18)F-FDG SUV (P < 0.001; r = 0.59). With the exception of 1 carcinoma in situ, all malignant tumors showed increased (18)F-FDG PET uptake. (18)F-FLT PET was false-negative in the carcinoma in situ, in another NSCLC with a low proliferation index, and in a patient with lung metastases from colorectal cancer. Increased (18)F-FLT uptake was related exclusively to malignant tumors. By contrast, (18)F-FDG PET was false-positive in 4 of 8 patients with benign lesions. CONCLUSION: (18)F-FLT uptake correlates better with proliferation of lung tumors than does uptake of (18)F-FDG and might be more useful as a selective biomarker for tumor proliferation.     

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.     

Malignant gastric outlet obstruction managed by endoscopic stenting: a prospective single-centre study

Objective. Endoscopic stenting for malignant gastric outlet obstruction was chosen as the primary strategy by which to palliate this complication, which is dominated by weight loss and anorexia. Advanced upper gastrointestinal tract cancers present late and life expectancy is limited. Only smaller multicentre studies point to endoscopic stenting as superior to surgery in terms of clinical outcome and cost. Material and methods. Forty-five consecutive patients with gastric outlet obstruction as a result of advanced upper GI-tract malignancy were enrolled in accordance with the intention-to-treat principle. All patients were offered endoscopic stenting. Oral intake before and after stenting was assessed using the gastric outlet obstruction score system (GOOSS). Various lengths of duodenal Hanaro® self-expanding nitinol stents were delivered through a therapeutic endoscope. Outcome criteria were successful deployment, clinical effect, length of stay in hospital, survival, need for re-intervention and complications. Results. Forty-one patients (91%) were successfully stented. The mean pre-procedure GOOSS improved significantly from 0.39 (95% CI 0.22–0.56) to 2.29 (95% CI 2.01–2.58) after stenting (p<0.0001). Twenty-six patients (63%) improved GOOSS at least one point, whereas 5 patients (12%) did not change GOOSS at all. Mean length of hospital stay was 13 days (95% CI 9–17 days). Mean survival was 121 days (95% CI 62–181 days). Two patients (4%; numbers 6 and 19) sustained perforation without fatalities. Three patients (7%) had stent migration. Procedure-related mortality was zero. Conclusions. Palliative stenting for advanced malignant upper GI-tract tumours at a tertiary Hepato-Pancreato-Biliary Unit is a safe, feasible and effective alternative to surgical bypass with a short hospital stay and prompt improvement of food intake.