PIK3CA mutations in advanced ovarian carcinomas

PIK3CA belongs to the phosphatidylinositol 3-kinases (PI3Ks) family, which play an important role in proliferation, adherence, transformation and cell survival through the PI3K/AKT signaling pathway. Somatic activating mutations of this gene have recently been detected in several types of cancers. In the present study, 109 advanced ovarian carcinomas were analyzed for PIK3CA mutations in exon 9 and exon 20 by direct sequencing. Activating missense mutations were observed in 4 of the 109 tumors in addition to one variant leading no change of the PIK3CA protein. Two of the cases with mutations were mucinous and clear cell tumors, suggesting that PIK3CA mutations are more common in these rare histological types.     

Postural effects on muscle nerve sympathetic activity in man

1. Pulse-synchronous bursts of multi-unit sympathetic activity (MSA) were recorded in peroneal muscle nerve fascicles in eight healthy subjects when lying, sitting and standing. The sympathetic activity was quantitated by counting the number of bursts in the mean voltage neurogram/min. Postural changes were analysed by considering the total activity to be a product of the number of bursts in relation to the number of heart beats (burst incidence) and the heart rate.2. In lying there were large interindividual differences in total activity, but for all subjects the activity increased when going from lying to sitting and from sitting to standing. With a few exceptions the increase between the lying and sitting postures was associated with an increase in both burst incidence and heart rate whereas between the sitting and standing postures there was an increase in heart rate but on the average no change in burst incidence.3. When going from lying to sitting or from sitting to standing the magnitude of the change in burst incidence was inversely related to the initial burst incidence so that subjects with low initial values usually showed greater increases in burst incidence than subjects with high initial values. Some subjects with high initial values decreased their burst incidence.4. With changes in postures there was an inverse linear relationship between the fraction of the change in MSA associated with a change in burst incidence and the fraction associated with a change in heart rate. An increase in total activity could be obtained by changing only burst incidence, by increasing heart rate without changing burst incidence, or by appropriate changes in both parameters. The slope of the regression line was -0.53 indicating that for adequate postural compensation fewer additional bursts were required when the compensatory response involved an increase in heart rate rather than an increase in only burst incidence.5. It is suggested that an impairment of the ability to regulate heart rate will make subjects with high burst incidence in the lying position orthostatically more vulnerable than those with low burst incidence.6. Shortly after standing up one subject developed bradycardia and subsequently fainted. The nerve recording was maintained until the subject collapsed. During the initial bradycardia no sympathetic bursts occurred suggesting that the syncope was associated with an interruption of normal baroreflex feedback between blood pressure and sympathetic outflow.     

What — if any — is the role of adrenergic mechanisms in histamine release from mast cells?

The effects of catecholamines on histamine release from rat peritoneal mast cells, was studied in an in vitro system. It was found that norepinephrine (10^–5–10^–3 M) exerts a significant, dose related, repressive effect on compound 48/80-induced histamine release. This effect is greatly potentiated by -antagonists and is noticeable throughout the concentration range 10^–11–10^–3 M norepinephrine. Phentolamine diminishes the repressive effect that norepinephrine shows at 10^–5 M.Norepinephrine (10^–5 M) totally inhibits the progressive histamine release induced by both compound 48/80 and strontium (10 M) in non-Ca²⁺-depleted cells. The release that is dependent on extracellular calcium is inhibited by norepinephrine.The repressive effect of norepinephrine at 10^–3 is counteracted by 5.6 mM d-glucose, 2-deoxyglucose abolishes this effect. The repression of histamine release by 10^–5 M norepinephrine is not influenced byd-glucose.These results suggest that the effects on histamine release, observed within a low concentration range of norepinephrine (<10^–3 M), may be due to -adrenoreceptor mechanisms and an interference in transmembrane calcium transport. Our data further suggest that norepinephrine at 10^–3 M may inhibit oxidative phosphorylation.Isoproterenol and epinephrine (10^–9–10^–5 M) show little effect on 48/80-induced histamine release in a normal medium. However, when calcium is excluded from the medium, histamine release is potentiated. These results seem to indicate that isoproterenol and epinephrine act by displacing intracellular calcium, making it available for the exocytosis process.     

APOE ε4 and late-life cognition: mediation by structural brain imaging markers

European Journal of Epidemiology - The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease....     

Value appropriation in hepatitis C

The European Journal of Health Economics - In 2015, the Swedish government in an unprecedented move decided to allocate 150 million € to provide funding for new drugs for hepatitis C. This...     

Fibrodysplasia ossificans progressiva: Still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who turned to wood, its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable clues from the fly reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.     

Interspecies differences in the kinetic properties of deoxycytidine kinase elucidate the poor utility of a phase I pharmacologically directed dose-escalation concept for 2-chloro-2′-deoxyadenosine

2-Chloro-2-deoxyadenosine (CdA, Cladribine), is a purine antimetabolite currently under investigation in phase II clinical trials for the treatment of lymphoid malignancies. Significant differences in CdA toxicity between mice and humans were observed during phase I clinical evaluation. For the elucidation of interspecies differences in drug toxicity the pharmacokinetics of CdA after subcutaneous injection and the kinetic properties of the CdA-phosphorylating enzyme, deoxycytidine kinase (dCK), were compared in mice and humans. The ratio of the dose lethal to 10% of mice (LD₁₀) to the maximum tolerated dose (MTD) in humans was 50 and the ratio of the area under the curve obtained at approximately one-half the LD₁₀ (AUC_{approx. one-half the LD 10})/AUC_MTD was 49. A significant interspecies difference was observed in the kinetic properties of dCK, the main CdA-activating enzyme. With CdA as a substrate, the Michaelis constant (K _m) of dCK in crude extracts of mouse thymus was 10 times higher than that in human thymus. An approximately 9-fold interspecies difference in maximum velocity (V_max)/K _m indicated a higher efficiency of dCK for CdA in humans than in mice. The peak plasma concentration was 210 times higher and exceeded theK _m in mice. Initial and terminal half-lives were approximately 7 times shorter in mice and trough levels were similar in mice and humans. Thus, the differences in AUCs at equitoxic doses are largely explained by differences in the target enzyme properties and the pharmacokinetic pattern. The observed lower tolerance for CdA in humans as compared with mice confirms the view that antimetabolites may not be good candidates for pharmacokinetically guided dose-escalation schemes unless detailed information on interspecies variability in drug bioactivation is available.     

Diagnostic outcome of repeated mammography screening

Mammographic screening for breast cancer within health service routines was evaluated for the years 1987–1992, with special focus on repeated screening during 1989–1992. The overall attendance rate by women aged 40 to 74 years was 82.8%. During 1989–1992 malignancy was found in 2.6/1000 screened women, giving a 87.4% positive predictive rate at surgery and 95.9% efficiency. Among women aged 45, the positive predictive rate was >94%. Fine-needle aspiration (FNA) biopsy showed invasive cancers in 84% and highly suspected cancer in another 15%; 60% of the lesions were nonpalpable. For first-time (prevalence) screening (1987–1988) the positive predictive rate was 86% and the malignancy yield 6.4/1000. In women aged 40–44 years there were few surgical referrals (1.6%), but the positive predictive rate at surgery was only 48.3%, indicating diagnostic difficulties in young women. The median size of all invasive cancers was 12 mm: 84% were classified as pT1, and 23% had lymph node involvement. Stage II disease was found in 27% of all malignancies. The use of FNA in the diagnostic workup for breast cancer screening is of crucial importance to the maintenance of high positive predictive rates at surgery. Moreover, regular analysis is important even when mammographic screening is incorporated into the routine work of health services.

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Resumen El tamizaje mamográfico para cáncer del seno como parte de las rutinas de los servicios de salud fue evaluado para los años 1987–1992, con especial énfasis en el tamizaje repetido en el período 1989–1992. La tasa de cumplimiento por parte de las pacientes en las edades 40–74 años fue de 82.8%. En 1989–92 se halló neoplasia maligna en 2.6/1000 mujeres tamizadas, lo cual significó un índice de predicción de positividad en la cirugía de 87.4% y de eficiencia de 95.9%. Entre las mujeres con edad 45 años el valor de predicción de positividad fue >94%. La biopsia por aspiración con aguja fina demostró cánceres invasores en 84% y alta sospecha de cáncer en un 15% adicional; 60% de las lesiones fueron no palpables. En el tamizaje de primera vez (prevalencia, 1987–1988) el valor de predicción de positividad fue de 86% y el rendimiento de 6.4/1000. En las mujeres con edades 40–44 años se hicieron menos referencias para cirugía (1.6%) pero el valor de predicción de positividad en la cirugía fue apenas de 48.3%, lo cual indica dificultades diagnósticas en las pacientes más jóvenes. El tamaño promedio de los cánceres invasores fue 12 mm; 84% fueron clasificados como pT1 y 25% presentaban invasión ganglionar; 27% de todos los tumores malignos fueron estado II. La aspiración con aguja fina en la evaluación diagnóstica del tamizaje para cáncer mamario es de importancia crucial para el mantenimiento de un alto valor de predicción de positividad en la cirugía y el análisis regular es importante aun cuando el tamizaje mamográfico quede incorporado en el trabajo rutinario de los servicios de salud.

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Résumé Le dépistage systématique des cancers du sein par mammographie effectuée par les services de santé a été évalué entre 1987–1992, en particulier le dépistage répété pratiqué entre 1989–1992. Le taux de participation des femmes âgées entre 40–74 ans a été de 82.8%. Dans la période 1989–1992, une tumeur maligne a été retrouvée chez 2.6/1000 femmes, la chirurgie permettant de calculer une valeur prédictive positive de 87.4% et une efficacité de 95.9%. Chez les femmes âgées de plus de 45 ans, la valeur prédictive positive a dépassé 94%. La ponction biopsie a fourni la preuve de cancer invasif dans 84% des cas et celle d'une forte suspicion dans 15% des cas, alors que 60% des lésions n'étaient pas palpables. Par comparaison, la valeur prédictive positive pendant la période de dépistage entre 1987–88 a été de 96% pour une prévalence de cancer de 6.4/1000. Chez la femme âgée entre 40–44 ans, très peu de femmes ont été opérées, avec une valeur prédictive positive de 48.3%, ce qui démontre les difficultés de diagnostic chez la femme jeune. La taille médiane de tous les cancers invasifs était de 12 mm: 84% étaient classés comme pT1 et 23% avaient un envahissement lymphatique. On a trouvé un stade II chez 27% des patientes tous cancers confondus. L'utilisation de ponction biopsie est capitale pour le diagnostic de cancer de sein pour maintenir une valeur prédictive positive élevée lors de la chirurgie et une analyse régulière est nécessaire même lorsque le dépistage systématique par mammographie est inclu dans le programme des service de santé.