Mutation and protein expression of p53 in acquired immunodeficiency syndrome-related lymphomas

p53 mutations are found in a variety of neoplasia. B-immunoblastic lymphoma (BIBL) is a rapidly progressive, aggressive lymphoma. As patients with acquired immunodeficiency syndrome (AIDS) live longer, BIBL is becoming an increasing problem. We asked three questions in our study. What is the frequency of p53 mutations in BIBL? Is it more frequent in patients with AIDS? Can immunohistochemical staining of lymph nodes for expression of p53 substitute for mutational analysis of p53 to detect lymphomas with mutated p53? Exons 5, 6, 7, 8 of the p53 gene (hot-spots for mutations) were amplified and examined for mutations by single-strand conformation polymorphism (SSCP) analysis. Altered migration was observed in 7 of 52 BIBL samples. Of these, 4 of 25 were from individuals infected with human immunodeficiency virus (HIV) and 3 of 27 were not infected with HIV. Direct sequencing of amplified material confirmed the presence of mutations in exons 5, 7, 8 of p53. A total of 26 BIBL as well as other lymphoma/leukemia samples, stained strongly by immunohistochemistry with three antibodies directed against human p53. Five of 6 BIBL samples with p53 mutations stained strongly for p53, but 20 lymphoma samples with no detectable p53 mutations also stained strongly for p53. Of note, however, 10 hyperplastic, nonmalignant lymph nodes from individuals either infected or not infected with HIV had negligible staining for p53 protein. In conclusion, p53 mutations occur in about 14% BIBL samples; the frequency of p53 mutations in BIBL in individuals with and without AIDS was similar. Positive p53 immunohistochemistry did not correlate with detectable p53 mutations in the same tissue, but positive immunohistochemical staining for p53 was only found in neoplastic lymph nodes. This latter finding provides a strong warning that p53 immunochemistry with available reagents cannot be used to determine which tumors have mutations of p53.     

Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor γ (PPARγ) is expressed in breast cancer cells. Activation of PPARγ through a synthetic ligand, troglitazone (TGZ), and other PPARγ-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10⁻⁵ M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10⁻⁵ M) and ATRA (10⁻⁶ M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.     

Physico-chemical characterization and pharmacological evaluation of sulfated polysaccharides from three species of Mediterranean brown algae of the genus Cystoseira

Background

Seaweed polysaccharides are highly active natural substances having valuable applications. The present study was conducted to characterize the physico-chemical properties of sulphated polysaccharides from three Mediterranean brown seaweeds (Cystoseira sedoides, Cystoseira compressa and Cystoseira crinita) and to evaluate their anti-radical, anti-inflammatory and gastroprotective activities.

Methods

The different rates of neutral sugars, uronic acids, L-fucose and sulphate content were determined by colorimetric techniques. The different macromolecular characteristics of isolated fucoidans were identified by size exclusion chromatography equipped with a triple detection: multiangle light scattering, viscometer and differential refractive index detectors, (SEC/MALS/VD/DRI). Anti-inflammatory activity was evaluated, using the carrageenan-induced rat paw edema test in comparison to the references drugs Acetylsalicylate of Lysine and Diclofenac. The gastroprotective activity was determined using HCl/EtOH induced gastric ulcers in rats and to examine the antioxidant effect of fucoidans in the three species, the free radical scavenging activity was determined using 1,1-diphenyl-2-picrylhydrazyl.

Results

The pharmacological evaluation of the isolated fucoidans for their anti-inflammatory, and their gastroprotective effect established that these products from C. sedoides, C. compressa and C. crinita exhibited a significant anti-inflammatory activity at a dose of 50 mg/kg, i.p; the percentages of inhibition of the oedema were 51%, 57% and 58% respectively. And, at the same dose, these fucoidans from C. sedoides and C. compressa showed a significant decrease of the intensity of gastric mucosal damages compared to a control group by 68%, whereas, the fucoidan from C. crinita produced a less gastroprotective effect. Furthermore, the isolated fucoidans exhibited a radical scavenging activity.

Conclusion

The comparative study of fucoidans isolated from three species of the genus Cystoseira showed that they have similar chemicals properties and relatives anti-radical, anti-inflammatory and gastroprotective activities which are found to be promising.     

HIV,pathology and epigenetic age acceleration in different human tissues

GeroScience - Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their...     

Is 30-Day Mortality after Admission for Heart Failure an Appropriate Metric for Quality?

Background

The Centers for Medicare and Medicaid Services (CMS) model for publicly reporting national 30-day-risk-adjusted mortality rates for patients admitted with heart failure fails to include clinical variables known to impact total mortality or take into consideration the culture of end-of-life care. We sought to determine if those variables were related to the 30-day mortality of heart failure patients at Geisinger Medical Center.

Fabrication of novel electrochemical sensors based on modification with different polymorphs of MnO2 nanoparticles. Application to furosemide analysis in pharmaceutical and urine samples

A novel MnO₂ nanoparticles/chitosan-modified pencil graphite electrode (MnO₂ NPs/CS/PGE) was constructed using two different MnO₂ polymorphs (γ-MnO₂ and ε-MnO₂ nanoparticles). X-ray single phases of these two polymorphs were obtained by the comproportionation reaction between MnCl₂ and KMnO₄ (molar ratio of 5 : 1). The temperature of this reaction is the key factor governing the formation of the two polymorphs. Their structures were confirmed by powder X-ray diffraction (XRD), Fourier transform infrared (FTIR) and energy dispersive X-ray (EDX) analysis. Scanning electron microscopy (SEM) was employed to investigate the morphological shape of MnO₂ NPs and the surface of the bare and modified electrodes. Moreover, cyclic voltammetry and electrochemical impedance spectroscopy (EIS) were used for surface analysis of the modified electrodes. Compared to bare PGE, MnO₂ NPs/CS/PGE shows higher effective surface area and excellent electrocatalytic activity towards the oxidation of the standard K₃[Fe(CN)₆]. The influence of different suspending solvents on the electrocatalytic activity of MnO₂ was studied in detail. It was found that tetrahydrofuran (THF) is the optimum suspending solvent regarding the peak current signal and electrode kinetics. The results reveal that the modified γ-MnO₂/CS/PGE is the most sensitive one compared to the other modified electrodes under investigation. The modified γ-MnO₂/CS/PGE was applied for selective and sensitive determination of FUR. Under the optimized experimental conditions, γ-MnO₂/CS/PGE provides a linear response over the concentration range of 0.05 to 4.20 μmol L⁻¹ FUR with a low limit of detection, which was found to be 4.44 nmol L⁻¹ (1.47 ng mL⁻¹) for the 1^st peak and 3.88 nmol L⁻¹ (1.28 ng mL⁻¹) for the 2^nd one. The fabricated sensor exhibits a good reproducibility and selectivity and was applied successfully for the determination of FUR in its dosage forms and in spiked urine samples with good accuracy and precision.

A novel MnO₂ nanoparticles/chitosan-modified pencil graphite electrode (MnO₂ NPs/CS/PGE) was constructed using two different MnO₂ polymorphs (γ-MnO₂ and ε-MnO₂ nanoparticles).     

Rift Valley fever surveillance in mobile sheep flocks in the Nile Delta

Rift Valley fever (RVF) surveillance was carried out in the Nile Delta by monitoring mobile and stationary sheep flocks for antibodies to RVF virus. Sheep are known to be susceptible to RVF virus infection and experienced severe morbidity in 1977 and 1978 when RVF was epidemic in Egypt. Four hundred six sheep in 32 flocks were surveyed during 1984. Twenty-four sheep from 7 flocks had antibodies to RVF virus detected by hemagglutination inhibition and plaque reduction neutralization tests. Antibodies were found primarily in sheep greater than 3 years of age, although 1- and 2-year-old sheep were included in the sample. No seroconversion was observed among 177 seronegative sheep that were bled successively for a period of 10 months. These results indicate that epizootic RVF was probably not present in the Nile Delta during 1984.     

Dextrocardia, situs inversus and severe mitral stenosis in a pregnant woman: successful closed commissurotomy

A 16-weeks' pregnant woman with situs inversus and dextrocardia underwent successful closed commissurotomy for severe mitral stenosis. The electrocardiogram revealed sinus rhythm with right axis deviation and progressive diminishing of QRS amplitude towards the left precordial leads. The chest X-ray showed dextrocardia with situs inversus. Doppler echocardiography depicted severe mitral stenosis; the mitral valve area increased from 0.9 cm2 pre-operatively to 1.8 cm2 post-operatively with mild increase of mitral regurgitation from grade I to II post-valvotomy. She also had associated mild functional tricuspid insufficiency and moderate pulmonary hypertension. No thrombo-embolic complications occurred intra- or post-operatively. There was no evidence of either clinical or Doppler restenosis. The course of pregnancy was uneventful. At 39 weeks a healthy baby was vaginally delivered. The patient is still free of cardiac symptoms.