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Abstract Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.

Abstract Background Cholinergic hypothesis of Alzheimer’s disease (AD) is based on the findings that a reduced and/or perturbed cholinergic activity in the central nervous system correlates with cognitive decline in patients with Alzheimer’s disease. The hypothesis resulted in the development of centrally-acting agents potentiating cholinergic neurotransmission; these drugs, however, only slowed down the cognitive decline and could not prevent it. Consequently, the perturbation of the central cholinergic signalling has been accepted as a part of the Alzheimer’s aetiology but not necessarily the primary cause of the disease. In the present study we have focused on the rs3810950 polymorphism of ChAT (choline acetyltransferase) gene that has not been studied in Czech population before. Methods We carried out an association study to test for a relationship between the rs3810950 polymorphism and Alzheimer’s disease in a group of 1186 persons; 759 patients with Alzheimer’s disease and 427 control subjects. Furthermore, we performed molecular modelling of the terminal domain (1st-126th amino acid residue) of one of the ChAT isoforms (M) to visualise in silico whether the rs3810950 polymorphism (A120T) can change any features of the tertiary structure of the protein which would have a potential to alter its function. Results The AA genotype of CHAT was associated with a 1.25 times higher risk of AD (p

Introduction During 2008–2012, a total of 466 ticks Ixodes ricinus removed from humans were collected and tested for the presence of Borrelia burgdorferi sensu lato (Bbsl). Ticks were collected in all districts of the South Moravian region of the Czech Republic (CZ). Objective The aim of this study was to determine the infestation of Bbsl in ticks Ixodes ricinus and the identification of genospecies of Bbsl group by DNA sequencing. Material and Methods DNA isolation from homogenates was performed by UltraClean BloodSpin DNA kit (MoBio) and by automated instrument Prepito (Perkin-Elmer). Detection of spirochetes was carried out by RealTime PCR kit EliGene Borrelia LC (Elisabeth Pharmacon). Finally, all the positive samples were sequenced on an ABI 3130 Genetic Analyzer (Life Technologies) and identified in the BLAST (NCBI) database. Results A total positivity of the samples was 26%. For the first time in the Czech Republic, 5 of the isolated strains were genotyped as Borrelia spielmanii (7.1%). Other representatives of Bbsl were also observed: B. afzelii (70.0%), B. garinii (10.0%), B. valaisiana (8.6%), and B. burgdorferi s. s. (4.3%). Conclusions A general view of the spreading of Bbsl in the South Moravian region was demonstrated. The most interesting result of the study is the finding of B. spielmanii for the first time in this region.

Tooth agenesis is one of the most common craniofacial disorders in humans. More than 350 genes have been associated with teeth development. In this study, we enrolled 60 child patients (age 13 to 17) with various types of tooth agenesis. Whole gene sequences of PAX9, MSX1, AXIN2, EDA, EDAR and WNT10a genes were sequenced by next generation sequencing on the Illumina MiSeq platform. We found previously undescribed heterozygous nonsense mutation g.8177G>T (c.610G>T) in MSX1 gene in one child. Mutation was verified by Sanger sequencing. Sequencing analysis was performed in other family members of the affected child. All family members carrying g.8177G>T mutation suffered from oligodontia (missing more than 6 teeth excluding third molars). Mutation g.8177G>T leads to a stop codon (p.E204X) and premature termination of Msx1 protein translation. Based on previous in vitro experiments on mutation disrupting function of Msx1 homeodomain, we assume that the heterozygous g.8177G>T nonsense mutation affects the amount and function of Msx1 protein and leads to tooth agenesis.