Glial cells missing a (GCMa) belongs to a new transcription factor family. Syncytin was shown to be a target gene of GCMa. Here, we demonstrate that the protein kinase A (PKA) pathway acts upstream of GCMa. After transient transfection of BeWo cells with PKA, GCMa transcriptional activity and both GCMa and syncytin transcripts were upregulated. This increase was accompanied by further cellular differentiation. Using normoxic or hypoxic conditions to mimic pathophysiological settings known to diminish trophoblast differentiation, we found that gene repressive effects of oxygen deficiency were compensated by the induction of the PKA pathway. We propose that GCMa-driven syncytin expression is the key mechanism for syncytiotrophoblast formation.

Background/Aims: Pre-eclampsia, a major cause of perinatal morbidity, is characterized by alterations in placental oxygen availability and trophoblast differentiation. We investigated how different levels of hypoxia alter the expression of syncytin-1, glial cells missing a (GCMa) and syncytin-1 receptor ASCT2 and affect syncytialization in primary term human trophoblasts. Methods: Cells were incubated at 1, 3, 6 and 21% O₂ for 24, 48 and 72 h with or without cyclic adenosine monophosphate (cAMP). Gene expression was analyzed by real-time PCR. Syncytialization was assessed using β-human chorionic gonadotropin measurement and desmoplakin immunostaining. Results: Following incubation with cAMP at 21% O₂, peak gene expression of syncytin-1 and GCMa was found after 24 h along with syncytium formation at 72 h. Conversely, incubation at 1% O₂ led to a time-dependent reduction of GCMa and syncytin-1 at the transcriptional level. Cell fusion occurred at 21 and 6% O₂ and was suppressed at 1% O₂. ASCT2 mRNA levels were preserved at normoxia and downregulated at 1% O₂ after 48 h. Conclusion: Our data support the premise that the expression of GCMa and syncytin-1 precedes syncytialization of trophoblasts, e.g. at 6% O₂, which is assumed to resemble physiological conditions. Severe hypoxia is associated with reduced GCMa and syncytin-1 transcripts and altered fusion of primary trophoblasts.

In an unselected population with a high amount of younger adults, normal spirometry did not show a short-term benefit for primary prevention of chronic obstructive lung disease in terms of increasing motivation to quit smoking.

The overall survival for patients with advanced hepatocellular carcinoma (HCC) is still limited. Although the multi-kinase inhibitor sorafenib has recently been approved for this disease, response rates are still low and patients often face dose-limiting toxicities which lead to a reduction in prognosis and treatment success. We here report a patient with metastasized HCC who shows a sustained response for more than 30 mo to sorafenib therapy after failure of a first line therapy with gemcitabine, oxaliplatin and bevacizumab.

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