Three apoptotic genes are upregulated in a patient with Alzheimer's disease and well-differentiated squamous cell carcinoma

We report the case of a 74-year-old man with Alzheimer's disease (AD) and an extensive ulcerative lesion on the right ear. AD is a neurodegenerative disease with progressive loss of memory and cognitive deterioration. It has been suggested that apoptotic cell injury and eventually cell death is a major contributor to the AD neurodegenerative process. The ulcerative lesion was surgically excised and the histological analysis reported a well-differentiated squamous cell carcinoma. Caspase-3 (CASP3) plays an important role in neuronal death during nervous system development and under certain pathological conditions. Furthermore, in vitro and in vivo studies reported elevated expression and activation of CASP3 in models of AD. Molecular epidemiological studies suggest that CASP3 may contribute to head and neck squamous cell carcinoma susceptibility and disease progression and that increased CASP3 expression is associated with tumors of the head. Also poly (ADP-ribose) polymerase 1 (PARP1) and the leucine zipper downregulated in cancer 1 (LDOC1) genes play a proapoptotic role. We therefore evaluated the differential expression of LDOC1, PARP1, and CASP3 mRNA in peripheral blood leukocytes of our patient. We found increased expression of all these genes compared with the expression in control subjects.     

HPV16 E7-Dependent Transformation Activates NHE1 through a PKA-RhoA-Iinduced Inhibition of p38alpha

Background

Neoplastic transformation originates from a large number of different genetic alterations. Despite this genetic variability, a common phenotype to transformed cells is cellular alkalinization. We have previously shown in human keratinocytes and a cell line in which transformation can be turned on and followed by the inducible expression of the E7 oncogene of human papillomavirus type 16 (HPV16), that intracellular alkalinization is an early and essential physiological event driven by the up-regulation of the Na/⁺H⁺ exchanger isoform 1 (NHE1) and is necessary for the development of other transformed phenotypes and the in vivo tumor formation in nude mice.

Methodology

Here, we utilize these model systems to elucidate the dynamic sequence of alterations of the upstream signal transduction systems leading to the transformation-dependent activation of NHE1.

Principal Findings

We observe that a down-regulation of p38 MAPK activity is a fundamental step in the ability of the oncogene to transform the cell. Further, using pharmacological agents and transient transfections with dominant interfering, constitutively active, phosphorylation negative mutants and siRNA strategy to modify specific upstream signal transduction components that link HPV16 E7 oncogenic signals to up-regulation of the NHE1, we demonstrate that the stimulation of NHE1 activity is driven by an early rise in cellular cAMP resulting in the down-stream inhibition of p38 MAPK via the PKA-dependent phosphorylation of the small G-protein, RhoA, and its subsequent inhibition.

Conclusions

All together these data significantly improve our knowledge concerning the basic cellular alterations involved in oncogene-driven neoplastic transformation.     

A new abnormal human hemoglobin: Hb Prato (alpha 2 31 (B12) Arg leads to Ser beta 2).

An abnormal human hemoglobin was found in a hemolysate from a 5-year-old healthy child living in Prato (Tuscany, Italy). Strutctural studies demonstrated a previously unreported amino acid substitution, alpha 31 (B12) Arg leads to Ser (this is an alpha 1 beta 1 contact). The new variant has been named Hb Prato. It was unstable in isopropanol and heat-denaturation tests, but has normal functional properties, with respect to whole blood studies. Family studies indicated that the variant had been inherited from the mother, a 39-year-old woman of Sicilian extraction. Hb Prato occurs at 20 and 28% in hemolysates from the boy and woman, respectively.     

Pyruvate but not lactate prevents NADH-induced myoglobin oxidation

In this work, we investigated the influence of NADH on the redox state of myoglobin and the roles of pyruvate and lactate in this process. NADH increased the autoxidation rate of myoglobin. Both a drop in pH and partial deoxygenation markedly stimulated the autoxidation process and the influence of NADH. A correlation between met-Mb formation rate and NADH oxidation rate was always observed. The increased rate of Mb autoxidation caused by NADH was inhibited by catalase and pyruvate but not by l-lactate. The antioxidant activity versus H2O2 of both pyruvate and lactate was evidenced by chemiluminescence experiments. The antioxidant activity of lactate disappeared completely in the presence of myoglobin or apo-myoglobin, whereas it was only reduced for pyruvate. These results could be of interest in preventing autoxidation of myoglobin that can contribute to ischemia-reperfusion injury during infarction or high-intensity exercise.     

‘Salivary secretions’ of eriophyoids (Acari: Eriophyoidea): first results of an experimental model

This paper concerns an approach to direct collection of eriophyoid salivary secretions, and reports preliminary results on biological assays providing evidence for the presence of plant growth promoting substances in these secretions. Eleven species belonging to the Phytoptidae, Eriophyidae and Diptilomiopidae, characterized by different host–plant interactions, were studied by immersing mites into the following oils: condensate of cedar oil, oil for immersion lenses, two kinds of olive oil, -terpineol, hystolemon, vaseline oil, and soybean oil. Some species secreted small droplets of lipophobic substances at the tip of their mouthparts when they were immersed in objective lens oil. Mite mortality and percentage of secreting specimens depended on the species and the medium used. Aceria caulobia (Nalepa) was selected as the candidate for subsequent study, because this species displayed a higher percentage of secreting mites than the other species and numerous specimens were easily collected by means of an airflow and filtering device. The induced secretions were studied from January to June of 2000, 2001 and 2002. Rapid salivary bioassays were performed during the period of maximum induced secretion in 2001. They were evaluated using a wheat-coleoptile and an excised-radish-cotyledon growth test, respectively, for indole-3-acetic acid-like and cytokinin-like activity. The bioassays suggested the presence of chemicals with plant growth regulatory effects. A brief account of eriophyoid mortality in the oils was also given.     

Entrapment of protein protease inhibitors in red blood cells.

Aprotinin and alpha 1-proteinase inhibitor have been encapsulated in human red blood cells (RBC) by a dialysis technique that involves transient hypotonic haemolysis followed by isotonic resealing. Both protease inhibitors can be encapsulated to a considerable extent. These molecules are released only by haemolysis of the cells and that excludes the possibility of using loaded erythrocytes for a slow release of the inhibitor(s) in the blood stream. However, the stability of the two inhibitors, the evidence for the binding of aprotinin to RBC components, and the results showing inhibition of endogenous proteolytic activity indicate that the inhibitors may be valuable in blocking, at least partially, undesired intraerythrocytic proteolytic reactions.     

Hemoglobin components from trout (Salmo irideus): determination of their peroxidative activity

The peroxidative activity of trout hemoglobins, HbI and HbIV, which differ in their conformation, was compared with that of HbA. Artificial substrates (guaiacol and dopamine) and more physiological substrates such as model lipid membranes containing unsaturated fatty acids were used. The results indicate that all the hemoglobin molecules assayed show different levels of peroxidative activity. The capability to act as peroxidases is greater in HbIV than in HbI and HbA. In contrast, native globins did not show peroxidase activity. The different peroxidative activity of the Hbs is discussed in relation to stability both vs. protein oxidation and protein dissociation. The results confirm the view that hemoglobin may be of importance in establishing the life span of the erythrocyte itself.     

Genotypes and phenotypes of G6PD deficiency among Indonesian females across diagnostic thresholds of G6PD activity guiding safe primaquine therapy of latent malaria

BackgroundPlasmodium vivax occurs as a latent infection of liver and a patent infection of red blood cells. Radical cure requires both blood schizontocidal and hypnozoitocidal chemotherapies. The hypnozoitocidal therapies available are primaquine and tafenoquine, 8-aminoquinoline drugs that can provoke threatening acute hemolytic anemia in patients having an X-linked G6PD-deficiency. Heterozygous females may screen as G6PD-normal prior to radical cure and go on to experience hemolytic crisis.Methods & findingsThis study examined G6PD phenotypes in 1928 female subjects living in malarious Sumba Island in eastern Indonesia to ascertain the prevalence of females vulnerable to diagnostic misclassification as G6PD-normal. All 367 (19%) females having <80% G6PD normal activity were genotyped. Among those, 103 (28%) were G6PD wild type, 251 (68·4%) were heterozygous, three (0·8%) were compound heterozygotes, and ten (2·7%) were homozygous deficient. The variants Vanua Lava, Viangchan, Coimbra, Chatham, and Kaiping occurred among them. Below the 70% of normal G6PD activity threshold, just 18 (8%) were G6PD-normal and 214 (92%) were G6PD-deficient. Among the 31 females with <30% G6PD normal activity were all ten homozygotes, all three compound heterozygotes, and just 18 were heterozygotes (7% of those).ConclusionsIn this population, most G6PD heterozygosity in females occurred between 30% and 70% of normal (69·3%; 183/264). The prevalence of females at risk of G6PD misclassification as normal by qualitative screening was 9·5% (183/1928). Qualitative G6PD screening prior to 8-aminoquinoline therapies against P. vivax may leave one in ten females at risk of hemolytic crisis, which may be remedied by point-of-care quantitative tests.     

Patterns of Admixture and Population Structure in Native Populations of Northwest North America

The initial contact of European populations with indigenous populations of the Americas produced diverse admixture processes across North, Central, and South America. Recent studies have examined the genetic structure of indigenous populations of Latin America and the Caribbean and their admixed descendants, reporting on the genomic impact of the history of admixture with colonizing populations of European and African ancestry. However, relatively little genomic research has been conducted on admixture in indigenous North American populations. In this study, we analyze genomic data at 475,109 single-nucleotide polymorphisms sampled in indigenous peoples of the Pacific Northwest in British Columbia and Southeast Alaska, populations with a well-documented history of contact with European and Asian traders, fishermen, and contract laborers. We find that the indigenous populations of the Pacific Northwest have higher gene diversity than Latin American indigenous populations. Among the Pacific Northwest populations, interior groups provide more evidence for East Asian admixture, whereas coastal groups have higher levels of European admixture. In contrast with many Latin American indigenous populations, the variance of admixture is high in each of the Pacific Northwest indigenous populations, as expected for recent and ongoing admixture processes. The results reveal some similarities but notable differences between admixture patterns in the Pacific Northwest and those in Latin America, contributing to a more detailed understanding of the genomic consequences of European colonization events throughout the Americas.