Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.     

Chromium evaporation and oxidation characteristics of alumina-forming austenitic stainless steels for balance of plant applications in solid oxide fuel cells

The chromium (Cr) evaporation behavior of several different types of iron (Fe)-based AFA alloys and benchmark Cr₂O₃-forming Fe-based 310 and Ni-based 625 alloys was investigated for 500 h exposures at 800 °C to 900 °C in air with 10% H₂O. The Cr evaporation rates from alumina-forming austenitic (AFA) alloys were ~5 to 35 times lower than that of the Cr₂O₃-forming alloys depending on alloy and temperature. The Cr evaporation behavior was correlated with extensive characterization of the chemistry and microstructure of the oxide scales, which also revealed a degree of quartz tube Si contamination during the test. Long-term oxidation kinetics were also assessed at 800 to 1000 °C for up to 10,000 h in air with 10% H₂O to provide further guidance for SOFC BOP component alloy selection.     

In vivo evaluation of a mucoadhesive polymeric caplet for intravaginal anti-HIV-1 delivery and development of a molecular mechanistic model for thermochemical characterization

Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.

Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.

Results and discussion: There was a big deviation between the T_g of the polymeric caplet from the T_g's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.

Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents.     

Influence of device engineering on the analog and RF performances of SOI MOSFETs

This work presents a systematic comparative study of the influence of various process options on the analog and RF properties of fully depleted (FD) silicon-on-insulator (SOI), partially depleted (PD) SOI, and bulk MOSFET's with gate lengths down to 0.08 /spl mu/m. We introduce the transconductance-over-drain current ratio and Early voltage as key figures of merits for the analog MOS performance and the gain and the transition and maximum frequencies for RF performances and link them to device engineering. Specifically, we investigate the effects of HALO implantation in FD, PD, and bulk devices, of film thickness in FD, of substrate doping in SOI, and of nonstandard channel engineering (i.e., asymmetric Graded-channel MOSFETs and gate-body contacted DTMOS).     

Transjugular intrahepatic portosystemic shunts (TIPS) in children

The transjugular intrahepatic portosystemic shunt procedure is an accepted treatment for adults with complications of portal hypertension. We performed a retrospective review of all pediatric TIPS placements performed at the University of California, San Francisco between 1990 and 1996. Twelve procedures were attempted in nine children, with a mean age (+/- SD) of 9.4 +/- 3.9 years (range, 5 to 15 years) and a mean weight of 31 +/- 18 kg (range, 16 to 70 kg). The indications for TIPS placement were portal hypertension complicated by chronic variceal hemorrhage not controlled with sclerotherapy (n = 7) and hypersplenism with thrombocytopenia (n = 2). TIPS placement was successfully completed initially in seven of nine (78%) patients. Unfavorable vascular anatomy was the cause of failure in two cases. The seven patients who underwent successful TIPS placement were followed up for an average of 136 days (range, 1 to 800 days); two still have patent shunts, three underwent liver transplantation, one had a splenorenal shunt after stenosis, and one died of underlying liver disease. Variceal bleeding was controlled in four of five patients who successfully underwent TIPS placement. Shunt occlusion occurred in four patients; patency was restored by transjugular shunt revision in three, and a splenorenal shunt was performed in one.     

Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

Event-related desynchronization (ERD) patterns during verbal memory tasks: effect of age

Event-related desynchronization (ERD) was studied in 10 young (mean age = 19.1) and 10 older (mean age = 62.8) subjects during a verbal recognition task. The attention load of the task varied according to the difficulty of discriminating between targets and distractors. EEG recorded from 29 electrodes was used to compute ERD from 14 source derivations in 125 ms intervals. Thereafter, it was displayed as spatiotemporal maps. The results show that attention influences the characteristics of EEG desynchronization. In young subjects, ERD is more pronounced and more widespread when the attentional load is high. In the elderly, differences between the two attention conditions are less marked. ANOVA reveals main effects of attention and time. The significant 'attention x time x age group' interaction confirms the presence of different brain activation patterns in the two age groups in relation to attention load.     

Surgery for hepatoblastoma in children

In order to characterize the role of transforming growth factor-alpha (TGF alpha) during hepatocarcinogenesis, liver tissue was examined at 10, 16, and 19 weeks following initial 10-week diethylnitrosamine (50 mg l-1 drinking water) exposure in female Wistar rats. Liver tissue protein extracts were electrophoresed and transferred to nitrocellulose filters. Levels of tissue-derived TGF alpha and epidermal growth factor receptor (EGFr) were assessed using an anti-TGF alpha monoclonal antibody (Ab-1) and an anti-EGFr polyclonal antibody (AB-4), coupled with scanning densitometric quantification. Immunolocalization of TGF alpha was performed in Bouin's-fixed, paraffin-embedded liver tissue sections. The distribution and intensity of TGF alpha immunoreactivity varied according to the degree of dysplasia, severely dysplastic cells being strongly immunoreactive. At week 10, mild hepatocyte dysplasia and perivenular inflammation were evident, together with a corresponding increase in perivenular TGF alpha immunoreactivity. By week 16, foci of moderate to severe dysplasia were observed; at this stage, there was a decrease in perivenular immunoreactivity but a further increase in overall liver tissue TGF alpha levels. Some 'altered foci' and dysplastic nodules showed intense immunoreactivity for TGF alpha. At these time points, immunodetectable liver EGFr was found to decrease significantly in comparison with normal control tissue. TGF alpha immunoreactivity was observed in fully developed carcinomas at week 19, although some tumours were negative by immunohistochemistry. The up-regulation of immunodetectable TGF alpha and the concomitant down-regulation of EGFr demonstrated positive (P < 0.01) and negative (P < 0.001) correlations, respectively, with hepatocyte proliferation indices. These findings suggest that the TGF alpha/EGFr ligand receptor system may be important during tumour promotion and in the stimulation of continued proliferation in hepatocellular carcinomas.     

Temperament and substance abuse in schizophrenia: is there a relationship?

Dyspnea may be easily appreciated during exercise with dyspneic scales, but methodological standardisation still needs to be specified. Authors review the basic physiological mechanism relating dyspnea to indices obtained during a stress test. They propose to use the dyspnea/VE relationship. With the concept of dyspneic threshold (close to the ventilatory threshold) and the ramp that both could be modified (for instance by rehabilitation programmes including exercise training). Interpretation of dyspnea during an exercise test obviously needs to be integrated with other parameters studied during exercise.