Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

[Grief, depression and anxiety after spontaneous abortion--a study of systematic evaluation and factors of influence]. / Trauer, Depressivität und Angst nach einem Spontanabort--Eine Studie über systematische Erfassung und Einflussfaktoren.

Recent studies demonstrate profound and long-lasting adverse psychological and family sequelae of a spontaneous abortion. However, decisive issues of quality, course and determinants cannot be answered sufficiently due to shortcomings of research (e.g. lack of representative samples and adequate measures, reliance on cross-sectional study designs). Grief reactions and their determinants are differentiated in relation to depressiveness and anxiety in 86 patients from a longitudinal study, employing the Perinatal Grief Scale (Thoedter et al. 1988) and standardized symptom checklists. For the majority of the women, around the 10th week of gestation, the embryo is psychologically represented in fantasies, dreams and concrete arrangements in reality. Immediately after the abortion, these women react with painful feelings of "active grief" and "despair". Additional stresses in the pregnancy and lack of social support predict "self-reproachful coping". Women with recurrent abortions who have no children show depressive reactions. Retrospectively, these also present more anxiety and depressive moods during pregnancy. Results support reliability and validity of the grief scale. Implications for counselling and psychotherapy of women after a spontaneous abortion are discussed with respect to these risk constellations.

Identification of the polypeptide encoded by the URF-1 gene of Neurospora crassa mtDNA.

Two peptides, potentially representing antigenic determinants of a proposed gene product, were synthesized. The peptide sequences were deduced from the nucleotide sequence of the unidentified reading frame (URF)1 of the Neurospora crassa mitochondrial genome. Specific antisera to the synthetic peptides were produced. The antibodies recognized a single polypeptide species with an apparent relative molecular mass of about 30 000. The mitochondrial origin of this polypeptide was verified by in vivo labelling experiments in the presence of cycloheximide, as well as by in vitro translation using isolated mitochondria. The chemical identification of the protein was performed by partial radiosequencing of the N-terminal portion of the immunoprecipitated URF-1 product. The amount of URF-1 polypeptide present in N. crassa mitochondria is in the range of 1-2%. The protein is a constituent of the inner envelope of the organelle and probably part of a more complex membrane unit.