Zur Frage eines ursächlichen Zusammenhanges zwischen der Hemmung der Glykolyse und der onkolytischen Wirksamkeit von Trenimon

Zusammenfassung Nach einmaliger i.p.-Injektion verschiedener Trenimondosen werden die NAD-Konzentration und die anaerobe Glykolyse im Tumor gemessen zu einem Zeitpunkt, zu dem nach früheren Versuchen ihre maximale Beeinträchtigung zu erwarten ist. Bei einem anderen Kollektiv Jensen-sarkomtragender Ratten werden nach denselben Trenimondosen die Tumorgewichte verfolgt.Es wurde festgestellt, daß bei einer Dosis von 0,075 mg/kg Körpergewicht Trenimon i.p. (=etwa DL_50/4) noch eine 40%ige Heilung des Jensen-Sarkoms eintritt, ohne daß es zu einer Erniedrigung der NAD-Konzentration und zu einer Hemmung der Milchsäurebildung kommt. Ein ursächlicher Zusammenhang zwischen diesen Meßgrößen und der Tumorregression ist daher unwahrscheinlich.

---

Summary Studies were made to see if healing of Jensen-Sarcoma after treatment with Trenimon depends on the depression of NAD-concentration (Coenzyme of Triosephosphate-dehydrogenation) followed by inhibition of glycolysis. After a single i. p. injection of Trenimon in varying dosage anaerobic glycolysis was estimated, when, according to former investigations, maximal impairment had to be expected.In another group of rats with Jensen-Sarcoma, tumor weights were measured after the same Trenimon doses. It was found that after single treatment with 0.075 mg/kg b.w. (approximately DL _50/4) the rate of cure was 40% without decrease of NAD-concentration and inhibition of lactate-production. Obviously there is no relation between these parameters and tumor regression.

---

Im Text verwendete Abkürzungen NAD Nicotinamid-adenin-dinucleotid - DNS Desoxyribonucleinsäure - RNS RibonucleinsäureDiese Arbeit wurde mit dankenswerter Unterstützung der Deutschen Forschungsgemeinschaft durchgeführt. Wir danken Fräulein Miessner für ihre gute technische Hilfe.     

Sensitization of human keratinocytes to killing by parvovirus H-1 takes place during their malignant transformation but does not require them to be tumorigenic

To investigate the antineoplastic activity of parvoviruses, proliferating normal human epidermal cells and a series of established keratinocyte cell lines derived from squamous cell carcinomas or transformed in vitro, were compared for the outcome of H-1 virus infection. All established keratinocyte cell lines were more sensitive to killing by H-1 virus than normal epidermal cells, although to varying extents. Using a step-wise procedure for malignant transformation in vitro, we found that sensitization of transformed epidermal cells to H-1 virus can be dissociated from the acquisition of a tumorigenic phenotype. Thus, spontaneously- or SV40-immortalized human keratinocytes were moderately and highly sensitive to H-1 virus, respectively, and could be made tumorigenic by Harvey-ras oncogene transfection without a major change in their susceptibility to the virus. The capacity of human keratinocytes for replicating and expressing H-1 virus DNA appears to be a revealer of cellular alterations that take place in at least some pathways to malignant transformation but that may be insufficient to confer a tumorigenic potential.     

Complications during pregnancy in women with epilepsy: population-based cohort study

Objective  To investigate whether women with epilepsy have an increased risk of complications during pregnancy and to explore the impact of antiepileptic drug (AED) use.
Design  Population-based cohort study.
Setting  Data from Medical Birth Registry of Norway based on all births in Norway 1999–2005.
Population  All births ( n  = 372 128) delivered in Norway, ensured through linkage with the National Population Registry run by Statistics Norway. All singleton births and the first child in multiple pregnancies were included, leaving 365 107 pregnancies for analyses.
Main outcome measures  Pre-eclampsia (mild and severe), gestational hypertension, eclampsia, vaginal bleeding (early and late) and preterm birth.
Results  We compared 2805 pregnancies in women with a current or past history of epilepsy (0.8%) and 362 302 pregnancies in women without a history of epilepsy. Women with epilepsy had an increased risk of mild pre-eclampsia, [odds ratio 1.3: 95% confidence interval (1.1–1.5)] and delivery before week 34 [1.2: (1.0–1.5)].
Antiepileptic drugs were used in 33.6% ( n  = 942) of the pregnant women with epilepsy. Compared to women without epilepsy, women with epilepsy and AED use had an increased risk of mild pre-eclampsia [1.8: (1.3–2.4)], gestational hypertension [1.5: (1.0–2.2)], vaginal bleeding late in pregnancy [1.9: (1.1–3.2)], and delivery before 34 weeks of gestation [1.5: (1.1–2.0)]. No significant increase in the risk of these complications was observed in women with epilepsy not using AED. These results remained unchanged after exclusion of multiple pregnancies.
Conclusion  Women with epilepsy have a low complication rate, but special attention should be paid to those using AED during pregnancy.     

Epidermal homeostasis in long-term scaffold-enforced skin equivalents

Epidermal homeostasis is understood as the maintenance of epidermal tissue structure and function by a fine tuned regulatory mechanism balancing proliferation and cell loss by desquamation and apoptosis. The lack of appropriate experimental models has largely prevented a better understanding of the regulatory mechanisms controlling epidermal tissue homeostasis in human skin. Keratinocyte culture studies had revealed a strict dependency of regular epidermal differentiation on dermal interactions only accomplishable in three-dimensional skin models. As major drawbacks, conventional models, employing collagen hydrogels as dermal equivalents (DEs) exhibit a rather poor stability and limited lifespan. Here, we present an improved stabilized in vitro-model for long-term growth and differentiation of keratinocytes providing the basis for tissue homeostasis. Keratinocytes were grown on DEs reinforced by modified hyaluronic acid fibers (Hyalograft-3D) and colonized with skin fibroblasts, producing genuine dermis-type matrix. These skin equivalents (SEs) develop superior epidermal architecture with regular differentiation and ultrastructure. Critical aspects of differentiation, still unbalanced in early stages, are renormalized, most strikingly the coexpression of keratins K1/K10, downregulation of regeneration-associated keratins (K16), and restriction of K15 to the basal layer. The strict localization of integrins to basal cells underlining restored tissue polarity, the drop of keratinocyte growth rates towards physiological levels and the rapid formation of a mature basement membrane with abundant anchoring fibrils are altogether features fulfilling the criteria of tissue homeostasis. Therefore, these scaffold-based SEs not only allow for studying homeostasis control but also for the first time provide proper experimental conditions for establishing a stem cell niche in vitro.