Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma.

PURPOSE: Recent studies have shown that tissue factor (TF) may be involved in tumor angiogenesis and metastasis. The role of TF in hepatocellular carcinoma (HCC) was unknown. This study evaluated whether TF expression correlates with microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, tumor invasiveness, and prognosis in human HCC. EXPERIMENTAL DESIGN: Tissue samples were obtained from 58 specimens of resected HCC. Immunohistochemical expression of TF was examined, and tumor MVD was evaluated using CD34 as the endothelial marker. TF and VEGF protein levels in the tumor cytosol were quantified by ELISA. Clinicopathologic and follow-up data of patients were prospectively collected. RESULTS: The immunohistochemical expression of TF in the tumors correlated significantly with tumor MVD (P = 0.002). The median cytosolic TF protein level in the tumors was 720 pg/mg total protein (range, 67-2406 pg/mg total protein). A significant positive correlation was found between TF and VEGF levels in the tumor cytosol (r = 0.475, P < 0.001). High tumor cytosolic TF level was associated with venous invasion (P = 0.004), microsatellite nodules (P = 0.024), unencapsulated tumor (P = 0.007), and advanced tumor stage (P = 0.010). A higher than median tumor cytosolic TF level was an independent predictor of poor survival (risk ratio, 1.836; 95% confidence interval 1.130-5.312, P = 0.023). CONCLUSIONS: This study shows that TF is related to tumor angiogenesis and invasiveness in HCC. Evaluation of tumor TF expression may be useful as a prognostic indicator in patients with HCC.     

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial

Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m², achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place, but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites. Received: 21 July 1996 / Accepted: 20 January 1997     

A novel system for simultaneous monitoring of locomotor and sound activities in animals

This paper describes a PC-based system for simultaneous monitoring of locomotor and sound activities on small rodents. The displacement and location signals of the animal were first determined across consecutive video-frames, followed by marked data reduction to cater for long-term studies. At the same time, sounds generated by the animal were detected and the sound level was recorded as root-mean-square values at 1 s intervals. Preliminary data showed that such a multi-parametric monitor system could provide comprehensive information on the animal's activity.     

罗格列酮单用或者与阿伐他汀联合使用对于2型糖尿病患者心血管疾病的非传统标志物的作用

背景和目的:罗格列酮与阿伐他汀联合疗法已经被证实对于2型糖尿病患者的血糖控制以及脂质水平都有益处。本试验将通过检测罗格列酮与阿伐他汀联合疗法对于2型糖尿病患者的生物标记水平的作用来研究该联合疗法对血管炎的作用。方法:30例患有2型糖尿病和高脂血症的患者被纳入治疗。对这些患者给予罗格列酮单一疗法4mg/d,持续3个月,然后在接下来的3个月中给予这些患者阿伐他汀10mg/d作为联合疗法。在研究开始时,罗格列酮单一疗法之后以及罗格列酮与阿伐他汀联合治疗之后测量炎性生物标记物,包括高敏C-反应蛋白(hs-CRP)、基质金属蛋白酶9(MMP…     

Buchbesprechungen

Ohne Zusammenfassung     

Oligodynamische Metallwirkung und Hämolyse

Ohne ZusammenfassungAuszug aus einer Inaugural-Dissertation. Freiburg i. Br. 1924.     

Effects of Ambient Coarse,Fine, and Ultrafine Particles and Their Biological Constituents on Systemic Biomarkers: A Controlled Human Exposure Study

Background

Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers.

Objectives

We examined changes of blood and urinary biomarkers following exposures to three particle sizes.

Methods

Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5–10 μm; mean, 213 μg/m³) and fine (0.15–2.5 μm; mean, 238 μg/m³) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 μm; mean, 136 μg/m³) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences.

Results

One hour postexposure, for every 100-μg/m³ increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O_3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs.

Conclusions

Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress.

Citation

Liu L, Urch B, Poon R, Szyszkowicz M, Speck M, Gold DR, Wheeler AJ, Scott JA, Brook JR, Thorne PS, Silverman FS. 2015. Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study. Environ Health Perspect 123:534–540; http://dx.doi.org/10.1289/ehp.1408387     

Pre-operative grading of intracranial glioma.

AIM: To compare the accuracy of MR-determined cerebral blood volume (CBV) maps with SPECT imaging with thallium-201 in pre-operative grading of intracranial glioma. MATERIAL AND METHODS: Nineteen patients (7 female and 12 male, mean age 46.8 years) with intracranial gliomas were examined with MR perfusion imaging pre-operatively. Sixteen of these patients were also examined with SPECT imaging with thallium-201. The tumour to contralateral white matter NI (negative integral) and tracer uptake ratios were evaluated. The ratios in high-grade and low-grade tumours were compared. RESULTS: The maximum CBV ratios of grades I and II gliomas (2.958+/-2.217) were significantly lower than the maximum CBV ratio of grades III and IV (9.484+/-4.520), p<0.001. There was no statistical difference when CBV ratios of grades I and II (p=0.381), grades II and III (p=0.229) and grades III and IV (p=0.476) gliomas were compared. Thallium SPECT imaging showed no difference in tumour uptake ratio between low-grade and high-grade gliomas (p=0.299). CONCLUSION: MR-determined NI was useful for pre-operative grading of intracranial gliomas but SPECT thallium-201 imaging was not.     

Delayed portal vein thrombosis after experimental radiofrequency ablation near the main portal vein

BACKGROUND: Portal venous blood flow may protect adjacent tumour cells from thermal destruction with radiofrequency ablation (RFA). This study aimed to investigate the local effect of RFA on the main portal vein branch, and the completeness of cellular ablation in its vicinity, with or without a Pringle manoeuvre using a porcine model. METHODS: This was an in vivo study on 23 domestic pigs. RFA using a cooled-tip electrode was performed 5 mm from the left main portal vein branch under ultrasonographic guidance for 12 min with (n = 10) or without (n = 10) a Pringle manoeuvre. Ten pigs were killed 4 h after the procedure to study the early effects of RFA and ten others were killed 1 week later to determine any delayed effect. As a control, sham operations with a Pringle manoeuvre for 12 min were performed on three pigs. The flow velocity changes of portal vein and hepatic artery were measured using Doppler ultrasonography, and the completeness of cellular ablation around the portal vein was assessed qualitatively by histochemical staining and quantitatively by measuring intracellular levels of adenosine 5'-triphosphate (ATP). RESULTS: In the absence of the Pringle manoeuvre, there was no significant change in mean(s.d.) portal vein flow velocity before RFA (20.0(3.5) cm/s) and at 4 h (18.5(2.5) cm/s) (P = 0.210) and 1 week (19.5(2.2) cm/s) (P = 0.500) after the procedure. Gross and histological examination of the portal vein branches showed no damage without the Pringle manoeuvre. In all pigs that underwent RFA with a Pringle manoeuvre, the portal vein was occluded 1 week after the operation; histological examination of the affected portal vein showed severe thermal injury and associated venous thrombosis. The local effect of RFA on the hepatic artery was similar. With intact portal blood flow during RFA, complete ablation of liver tissue around the pedicle was demonstrated by histochemical staining and measurement of the intracellular ATP concentration. CONCLUSION: RFA was safe when applied close to the main portal vein branch without a Pringle manoeuvre, with complete cellular destruction. Use of the Pringle manoeuvre resulted in delayed portal vein and hepatic artery thrombosis and injury to the hepatic artery and bile duct.