The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 μM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.     

Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation

The initial aim of this study was to generate a transplantable glial tumour model of low-intermediate grade by disaggregation of a spontaneous tumour mass from genetically engineered models (GEM). This should result in an increased tumour incidence in comparison to GEM animals. An anaplastic oligoastrocytoma (OA) tumour of World Health Organization (WHO) grade III was obtained from a female GEM mouse with the S100β-v-erbB/inK4a-Arf (+/?) genotype maintained in the C57BL/6 background. The tumour tissue was disaggregated; tumour cells from it were grown in aggregates and stereotactically injected into C57BL/6 mice. Tumour development was followed using Magnetic Resonance Imaging (MRI), while changes in the metabolomics pattern of the masses were evaluated by Magnetic Resonance Spectroscopy/Spectroscopic Imaging (MRS/MRSI). Final tumour grade was evaluated by histopathological analysis. The total number of tumours generated from GEM cells from disaggregated tumour (CDT) was 67 with up to 100?% penetrance, as compared to 16?% in the local GEM model, with an average survival time of 66?±?55 days, up to 4.3-fold significantly higher than the standard GL261 glioblastoma (GBM) tumour model. Tumours produced by transplantation of cells freshly obtained from disaggregated GEM tumour were diagnosed as WHO grade III anaplastic oligodendroglioma (ODG) and OA, while tumours produced from a previously frozen sample were diagnosed as WHO grade IV GBM. We successfully grew CDT and generated tumours from a grade III GEM glial tumour. Freezing and cell culture protocols produced progression to grade IV GBM, which makes the developed transplantable model qualify as potential secondary GBM model in mice.     

Medial malleolar osteotomy for the treatment of talar osteochondral lesions: anatomical and morbidity considerations

Purpose

Osteochondral lesions of the talus are often located posteromedially requiring open surgery to facilitate solid and complete osteochondral reconstruction. The aim of the study was to identify the optimal anatomical site for medial malleolar osteotomy based on the criteria of minimal cartilage damage (Study I) and to report on the morbidity in patients receiving osteotomy performed at the previously identified site (Study II).

Methods

For Study I, cartilage coverage of the tibiofibular ankle joint facet was measured in 40 cadaveric ankles (20 cadaver specimens). In Study II, we assessed clinical (VAS pain score, AOFAS score, range of motion) and radiological outcome measures (SPECT-CT) in 17 patients (mean age, 36.8 ± 10.8 years) undergoing medial malleolar osteotomy.

Results

The medial edge in the transition zone of the tibial plafond to the medial malleolus showed less than 75 % of cartilage coverage in 62.5 % of cadavers (Study I). Surgery resulted in lower pain levels (2.4 ± 2.6 compared with 6.3 ± 1.8 points; p < 0.001) and greater AOFAS scores (82.9 ± 14.1 compared with 43.5 ± 10.8 to points; p < 0.001) compared with baseline (Study II). No signs of intra-operative damage or mal- or non-union were found. Long-term morbidity was found in one patient. Implant removal was necessary in 12 of 17 patients (71 %).

Conclusion

Anatomically, there is an optimal location for the medial malleolar osteotomy at the medial ankle edge involving minimal cartilage damage. Clinical results using this location showed no short- or mid-term morbidity and little long-term morbidity. However, many patients required re-intervention for implant removal.

Level of evidence

IV.

     

Possible evidence for contribution of arbuscular mycorrhizal fungi (AMF) in phytoremediation of iron–cyanide (Fe–CN) complexes

Arbuscular mycorrhizal fungi (AMF) are integral functioning parts of plant root systems and are widely recognized for enhancing contaminants uptake and metabolism on severely disturbed sites. However, the patterns of their influence on the phytoremediation of iron–cyanide (Fe–CN) complexes are unknown. Fe–CN complexes are of great common interest, as iron is one of the most abundant element in soil and water. Effect of ryegrass (Lolium perenne L.) roots inoculation, using mycorrhizal fungi (Rhizophagus irregularis and a mixture of R. irregularis, Funneliformis mosseae, Rhizophagus aggregatus, and Claroideoglomus etunicatum), on iron–cyanide sorption was studied. Results indicated significantly higher colonization of R. irregularis than the mixture of AMF species on ryegrass roots. Series of batch experiments using potassium hexacyanoferrate (II) solutions, in varying concentrations revealed significantly higher reduction of total CN and free CN content in the mycorrhizal roots, indicating greater cyanide decrease in the treatment inoculated with R. irregularis. Our study is a first indication of the possible positive contribution of AM fungi on the phytoremediation of iron–cyanide complexes.