Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator.

PURPOSE: The purpose of this study was to investigate the antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; NSC707545), a water-soluble benzoquinone ansamycin. EXPERIMENTAL DESIGN: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c. implanted Matrigel in mice. In vitro, the activity of 17-DMAG on endothelial cells (human umbilical vein endothelial cells; HUVEC) was tested in FGF-2; and vascular endothelial growth factor (VEGF)-induced proliferation and apoptosis, motility, and extracellular matrix invasion; and on the alignment of capillary like structures in Matrigel. The protein level of heat shock protein (Hsp)90 and client proteins was examined by Western blot in FGF-2 and VEGF-stimulated HUVEC. RESULTS: Daily oral administration of 17-DMAG affected the angiogenic response in Matrigel in a dose-dependent manner. The hemoglobin content in the Matrigel implants was significantly inhibited, and the histological analysis confirmed a decrease of CD31(+) endothelial cells and of structures organized in cord and erythrocyte-containing vessels. In vitro, the compound inhibited dose-dependently the migration and the extracellular matrix-invasiveness of HUVEC and their capacity to form capillary like structures in Matrigel. 17-DMAG treatment also inhibited FGF-2 and VEGF-induced HUVEC proliferation and resulted in apoptosis. Accordingly, the expression of Hsp90 direct client proteins (pAkt and c-Raf-1) or their downstream substrates including pERK was also affected. 17-DMAG consistently increased the expression of Hsp70. Throughout the study similar results were obtained with 17-allylamino-17-demethoxygeldanamycin (17-AAG; NSC330507), the analog compound currently undergoing clinical trials. CONCLUSIONS: We show that the Hsp90 targeting agents 17-DMAG and 17-AAG inhibit angiogenesis. The strong effects on endothelial cell functions, in vitro, indicate that the antiangiogenic activity of 17-DMAG/17-AAG could also be due to a direct effect on endothelial cells. The oral bioavailability of 17-DMAG might be of advantage in investigating the potential of this compound in clinical trials with antiangiogenic as well as antiproliferative endpoints.     

The Potential Application of Natural Clinoptilolite-Rich Zeolite as Support for Bacterial Community Formation for Wastewater Treatment

The aim of this study was to investigate the use of natural zeolite as support for microbial community formation during wastewater treatment. Scanning electron microscopy (SEM), thermal decomposition and differential thermogravimetric curves (TGA/DGT) techniques were used for the physicochemical and structural characterization of zeolites. The chemical characterization of wastewater was performed before and after treatment, after 30 days of using stationary zeolite as support. The chemical composition of wastewater was evaluated in terms of the products of nitrification/denitrification processes. The greatest ammonium (NH₄⁺) adsorption was obtained for wastewater contaminated with different concentrations of ammonium, nitrate and nitrite. The wastewater quality index (WWQI) was determined to assess the effluent quality and the efficiency of the treatment plant used, showing a maximum of 71% quality improvement, thus suggesting that the treated wastewater could be discharged into aquatic environments. After 30 days, NH₄⁺ demonstrated a high removal efficiency (higher than 98%), while NO₃⁺ and NO₂⁺ had a removal efficiency of 70% and 54%, respectively. The removal efficiency for metals was observed as follows (%): Mn > Cd > Cr > Zn > Fe > Ni > Co > Cu > Ba > Pb > Sr. Analysis of the microbial diversity in the zeolite samples indicated that the bacteria are formed due to the existence of nutrients in wastewater which favor their formation. In addition, the zeolite was characterized by SEM and the results indicated that the zeolite acts as an adsorbent for the pollutants and, moreover, as a support material for microbial community formation under optimal conditions. Comparing the two studied zeolites, NZ1 (particle size 1–3 mm) was found to be more suitable for wastewater treatment. Overall, the natural zeolite demonstrated high potential for pollutant removal and biomass support for bacteria community growth in wastewater treatment.     

Synthesis of novel cyclosiloxane monomers containing push–pull moieties and their anionic ring opening polymerization

The synthesis of three novel tetracyclosiloxane monomers modified either with a nitroaniline (NA) or with a Disperse Red 1 (DR1) push–pull group and their ring opening polymerization reaction in the presence of tetramethylammonium hydroxide are presented. The prepared monomers and polymers were characterized by different spectral methods and gel permeation chromatography. For the crystalline monomers, the structures were further proven by single crystal X-ray diffraction. Dynamic scanning calorimetry shows that the polymers that carry NA groups have a glass transition temperature (T_g) well below room temperature (RT), while the one that carries DR1 groups melts at 55 °C. The transition temperatures have a strong effect on permittivity as indicated by broadband impedance spectroscopy measurements conducted at different temperatures and frequencies. The polymers modified with NA groups have a high permittivity (maximum value of 17.3) at RT, suggesting the polar groups to be mobile and orientation polarization to be effective. However, the polar groups of the polymer modified with DR1 are frozen and thus cannot contribute to the permittivity via orientation polarization. Consequently, the permittivity is only 8.8 at RT, but increases to 22 above the melting temperature, where the dipoles are mobile. Because of the high dielectric permittivity and rather low T_g, the polymers modified with NA are attractive as active dielectric materials in actuators, capacitors, and stretchable electronics, whereas the polymer modified with DR1 may be of interest in nonlinear optical devices.

The synthesis of polysiloxanes modified with a nitroaniline or with a Disperse Red 1 push–pull group and their dielectric properties are reported.     

Temporomandibular Disorders in Burning Mouth Syndrome Patients: An Observational Study

BACKGROUND: Burning Mouth Syndrome (BMS) is a chronic disease characterized by absence of any lesions and burning of the oral mucosa associated to a sensation of dry mouth and/or taste alterations. The purpose of our study is to estimate signs and symptoms of Temporomandibular Disorders (TMD) in patients with BMS and to investigate for the existence of an association between BMS and TMD.MATERIALS AND METHODS: Forty-four BMS patients were enrolled; BMS subtype was established according to the classification of Lamey. After a gnathological evaluation, according to the protocol of the European Academy of Craniomandibular Disorders, patients were classified by RDC/TMD criteria. The data were compared and analyzed using a chi-square test to describe the existence of an association between BMS and TMD.RESULTS: 65.9% the BMS patients showed disorders classified as primary signs and symptoms of TMD according to RDC / TMD criteria, and 72.7% showed parafunctional habits. The chi-square test revealed a statistically significant association (p = 0.035) between BMS and TMD.CONCLUSION: The data suggest that there is a possible relationship not yet well understood between BMS and TMD, may be for neurophatic alterations assumed for BMS that could be also engaged in TMD pathogenesis.     

Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis

Transferrin receptor 2 (TfR2) is a membrane glycoprotein that mediates cellular iron uptake from holotransferrin. Homozygous mutations of this gene cause one form of hereditary hemochromatosis in humans. We recently reported that homozygous TfR2(Y245X) mutant mice, which correspond to the TfR2(Y250X) mutation in humans, showed a phenotype similar to hereditary hemochromatosis. In this study, we further analyzed the phenotype as well as iron-related gene expression in these mice by comparing the TfR2-mutant and wild-type siblings. Northern blot analyses showed that the levels of expression of hepcidin mRNA in the liver were generally lower, whereas those of duodenal DMT1, the main transporter for uptake of dietary iron, were higher in the TfR2-mutant mice as compared to the wild-type siblings. Expression of hepcidin mRNA in the TfR2 mutant mice remained low even after intraperitoneal iron loading. In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA. These results suggest that up-regulation of hepcidin expression by inflammatory stimuli is independent of TfR2 and that TfR2 is upstream of hepcidin in the regulatory pathway of body iron homeostasis.     

Soluble factors produced by activated CD4+ T cells modulate EBV latency

Following infection with Epstein-Barr virus (EBV), the virus is carried for life in the memory B-cell compartment in a silent state (latency I/0). These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental significance to identify how the different EBV expression patterns are established in the latently infected cell. In view of the prompt activatability of CD4(+) T cells in primary EBV infection, and their role in B-cell differentiation, we studied the involvement of CD4(+) T cells in the regulation of EBV latency. Lymphoblastoid cell lines (LCLs) were cocultured with autologous or allogeneic CD4(+) T cells. Activated T cells influenced the expression of two key viral proteins that determine the fate of the infected B cell. EBNA2 was down-regulated, whereas LMP1 was unregulated and the cells proliferated less. This was paralleled by the down-regulation of the latency III promoter (Cp). Experiments performed in the transwell system showed that this change does not require cell contact, but it is mediated by soluble factors. Neutralizing experiments proved that the up-regulation of LMP1 is, to some extent, mediated by IL21, but this cytokine was not responsible for EBNA2 down-regulation. This effect was partly mediated by soluble CD40L. We detected similar regulatory functions of T cells in in vitro-infected lymphocyte populations. In conclusion, our results revealed an additional mechanism by which CD4(+) T cells can control the EBV-induced B-cell proliferation.     

Decayed,missing and filled teeth index and dental anomalies in long-term survivors leukaemic children: A prospective controlled study

Objective: The aim of this prospective controlled study is the comparison between long-term children survived leukaemia and a control group in terms of the decayed, missing or filled permanent teeth (DMFT) and dental anomalies. Study design: Fifty-two long term children survived leukaemia, aged from 8 to 15 years (27 females, 25 males; mean age 11.5 years) were evaluated for the possible effects of the anti-leukaemic therapy on dental development and compared to a control group of 52 healthy children (27 females, 25 males, mean age 11 years). All long-term children who survived were at least 24 months in continuous complete remission. The study of the dental status with a routine oral examination and panoramic radiographs was performed. The DMFT (recorded according to the WHO criteria) and dental anomalies were registered and evaluated. Results: The results of this study evidence that long-term children survived leukaemia, in comparison with the control group, have an higher risk to develop dental caries and show a greater severity of dental anomalies including V-shaped roots, dental agenesis, microdontia, enamel dysplasias. Conclusions: Paediatric patients with haemathological diseases require a special attentions in dental care in addition to the antineoplastic treatment. Therefore, oral hygiene and oral health can be maintained thanks to a close cooperation between the paediatric oncohaematologists, pediatrics dental surgeons and dental hygienists. Key words:Paediatric leukaemia, dental anomalies, children.     

Benchtop evaluation of pressure barrier insufflator and standard insufflator systems

Background

Previous experimental research has reported minimal differences in pressure maintenance between different versions of standard insufflators (SI). However, a recent report identified potential clinical benefits with a valveless pressure barrier insufflator (PBI). We sought to perform a benchtop objective evaluation of SI and PBI systems.

Methods

A rigid box system with continuous pressure manometry was used to evaluate a PBI (Surgiquest Airseal) and two SIs (SI1 = Stryker PneumoSure High Flow Insufflator and SI2 = Storz SCB Thermoflator). Pressure maintenance of 15 mmHg was evaluated during experimental conditions of leakage from a 5 mm port site, leakage from a 12 mm port site, and continuous suction.

Results

With leakage from the 5 mm port site, the PBI maintained pressure of >13 mmHg whereas the pressures dropped moderately with the SI1 (7–13 mmHg) and SI2 insufflators (3–7 mmHg) and did not regain goal pressure until leakage was stopped. With leakage from 12 mm port site, the PBI pressure decreased to 9–11 mmHg, whereas the SI1 and SI2 lost insufflation pressures completely. The PBI maintained pressure of >11 mmHg during continuous suction while the SI1 and SI2 lost pressure entirely, and actually showed negative pressure from air suction into the rigid box system. When evaluated statistically with the mixed model repeated measures ANOVA, the SI1 and SI2 performed similarly while the PBI maintained increased pressure.

Conclusions

In the experimental rigid box system, the PBI more successfully maintained pressure in response to leakage and suction than SIs.