Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2

The alkyloid compound ellipticine derived from the berrywood tree is a topoisomerase II poison that is used in ovarian and breast cancer treatment. In this study, we report the identification of ellipticine derivatives and their tetracyclic angular benzopyridoindole analogues as novel ATP-competitive inhibitors of the protein kinase CK2. In vitro and in vivo assays showed that these compounds have a good pharmacologic profile, causing a marked inhibition of CK2 activity associated with cell cycle arrest and apoptosis in human cancer cells. Further, in vivo assays demonstrate antitumor activity in a mouse xenograft model of human glioblastoma. Finally, crystal structures of CK2-inhibitor complex provide structural insights on the molecular basis of CK2 inhibition. Our work lays the foundation for development of clinically useful CK2 inhibitors derived from a well-studied scaffold with suitable pharmacokinetics parameters.     

Biomechanical analysis of the splenic avulsion mechanism

The spleen is a frequently injured abdominal organ in road accidents, with an injury frequency close to 30 %. The splenic avulsion exhibit a significant ratio of morbidity. It is clinically described as the complete failure of the pancreatico-splenic ligament (PSL) which is composed of splenic vessels and connective tissues. What are the biomechanical mechanisms involved with spleen avulsion? Is it possible to quantify tolerance levels of PSL structure? The current work combines both experimental and finite element (FE) investigations to determine the splenic avulsion process. Tensile tests on 13 PSL samples were performed up to failure. The experimental results provide reference data for model validation and showed a failure process starting at a peak force of 70 ± 34 N combined with a peak strain of 105 ± 26 %. In an attempt to identify possible vessel ruptures within the PSL, a FE model of the PSL was developed including both vessels and connective tissues. The vessel wall behaviour up to failure was reproduced using an Ogden law and calibrated by inverse analysis according to literature data. The connective tissues function was modelled by a cohesion-loss interface. Once model correlation to experimental results was achieved, numerical simulation revealed that haemorrhage could occur even before the maximum peak is reached. Indeed, the first vessel ruptures were recorded at a strain of 92 % at the upper lobe vein.     

Combination of different molecular mechanisms leading to fluconazole resistance in a Candida lusitaniae clinical isolate

We report on the underlying molecular mechanisms likely responsible for the high-level fluconazole resistance in a Candida lusitaniae clinical isolate. Fluconazole resistance correlated with overexpression of ERG11 and of several efflux pump genes, in particular, the orthologs of the Candida albicans MDR1, PDR16, CDR1, CDR2, and YOR1.     

Robustness of intratumour 18F-FDG PET uptake heterogeneity quantification for therapy response prediction in oesophageal carcinoma

Purpose

Intratumour uptake heterogeneity in PET quantified in terms of textural features for response to therapy has been investigated in several studies, including assessment of their robustness for reconstruction and physiological reproducibility. However, there has been no thorough assessment of the potential impact of preprocessing steps on the resulting quantification and its predictive value. The goal of this work was to assess the robustness of PET heterogeneity in textural features for delineation of functional volumes and partial volume correction (PVC).

Methods

This retrospective analysis included 50 patients with oesophageal cancer. PVC of each PET image was performed. Tumour volumes were determined using fixed and adaptive thresholding, and the fuzzy locally adaptive Bayesian algorithm, and heterogeneity was quantified using local and regional textural features. Differences in the absolute values of the image-derived parameters considered were assessed using Bland-Altman analysis. The impact on their predictive value for the identification of patient nonresponders was assessed by comparing areas under the receiver operating characteristic curves.

Results

Heterogeneity parameters were more dependent on delineation than on PVC. The parameters most sensitive to delineation and PVC were regional ones (intensity variability and size zone variability), whereas local parameters such as entropy and homogeneity were the most robust. Despite the large differences in absolute values obtained from different delineation methods or after PVC, these differences did not necessarily translate into a significant impact on their predictive value.

Conclusion

Parameters such as entropy, homogeneity, dissimilarity (for local heterogeneity characterization) and zone percentage (for regional characterization) should be preferred. This selection is based on a demonstrated high differentiation power in terms of predicting response, as well as a significant robustness with respect to the delineation method used and the partial volume effects.     

Hypoparathyroidism in systemic lupus erythematosus

Hypoparathyroidism is a rare disease. The main cause of hypoparathyroidism is postsurgical hypoparathyroidism. However, cases of hypoparathyroidism in patients suffering from SLE exist although it is uncommon. Only three previous cases have been reported. We present the case of a woman suffering both from systemic lupus erythematosus and hypoparathyroidism. This reported association of hypoparathyroidism with lupus expands the spectrum of endocrine disorders seen in this disease. We suggest that there may be a common underlying pathophysiological process linking these diseases.