In beta-lactam therapy, investigation of the pharmacokinetic-pharmacodynamic (PK-PD) relationship has provided surrogate makers to predict clinical outcome. This study was designed to verify the therapeutic efficacy and clinical utility of beta-lactam therapeutic drug monitoring (TDM) in critically ill patients using high-performance liquid chromatography (HPLC). This cohort study included 13 patients who were intravenously administered ceftazidime (n = 6), cefepime (n = 1), imipenem (n = 1), meropenem (n = 1), or piperacillin (n = 4). Blood samples were collected at 3 time points fitted to a 1-compartment model, and concentrations were determined using HPLC. The PK-PD target was the percentage of the dosing interval during which the antibiotic concentration exceeded the minimum inhibitory concentration for the pathogens (%T > MIC), which is 50% for penicillins (piperacillin), 60% for cephalosporins (ceftazidime and cefepime), and 40% for carbapenems (imipenem and meropenem). Our process using HPLC enables the analytical results of TDM to be available within half a day. The results revealed significant inter-patient pharmacokinetic variability. During the initial regimen, beta-lactam concentrations reached the target %T > MIC in all patients, and dosage reduction was required for 5 patients (38%). Of the 13 evaluable patients, clinical improvement was observed in 11 (85%), and microbiological success was observed in 10 (77%). In summary, beta-lactam TDM achieved the treatment goals and might also allow for the personalization to prevent overdosing for variable pharmacokinetic changes in critically ill patients. These findings indicate that beta-lactam TDM using HPLC can be used in the standard pharmacy clinical practice for critically ill patients.

The stress dependent tumour cells found to harbour Hsp90 and its inducible component Hsp90á in activated superchaperone complexes are highly sensitive to pharmacological Hsp90 inhibitors compared to normal cells where Hsp90 is present in an uncomplexed state. Downregulating Hsp90á can be achieved using chemical inhibitors and RNAi such as siRNA’s or shRNA’s. This study aimed at assessing the efficacy of siRNA (targeting hsp90á exon 5) and shRNA (targeting hsp90á exon 4 and 5 border) in three glioma cell lines (1321N1, GOS-3 and U87-MG). hsp90á expression at mRNA and protein levels was monitored using qRT-PCR and immunofluorescence, respectively. The downstream effect of silencing hsp90á was determined by measuring the Akt/PKB kinase activity level. While siRNA treatment decreased hsp90α mRNA copy numbers by ~35%, shRNA decreased it by ~63% (three glioma cell lines). Furthermore, hsp90α inhibition by siRNA resulted in downregulating Akt/PKB kinase by ~29%, whereas shRNA downregulated it to ~3% (three glioma cell lines). Considering the vital role of Akt kinase in cell signalling, anti-apoptotic and drug resistant pathways in tumours, the treatment induced sensitivity of Akt to degradation results in a novel therapeutic strategy emphasising a greater potential of shRNA as opposed to siRNA in silencing hsp90á and subsequently Akt in glioma cells.

There is increasing evidence that abnormal protein synthesis and modification are associated with a variety of human diseases. In the coming era of personalized/precision medicine, it will be required to utilize a rapid, highly sensitive and quantitative method to analyze the proteins and related post-translational modifications in clinical specimens in order to better define specific therapies for patients. However, the current gold standard in proteomic analysis is still the traditional Western blot, which requires many manual steps with lower sensitivity and provides a semi-quantitative read-out. Here, in this manuscript, we present the first report of a novel fully automated Capillary Electrophoresis (CE)-based immunodetection technology, called the Simple Western size assay, which is run on
the instrument, called the SimonTM. This technology is based on nanovolume size-based protein separation that can be used to quantify proteomic profiles of clinical specimens for both biomarker discovery and diagnostics. Our results demonstrated that the Simple Western has higher sensitivity of target protein detection, a greater linear dynamic range of different molecular weight proteins, high reproducibility and the capacity for the higherthroughput screening of samples using small sample input volumes compared to traditional Western blot analysis. In addition, the quantitativeness and accuracy, the exquisite sensitivity and reduced background noise, has made the Simon Western highly versatile. This technology can quantitative the level of protein and related post-translational modifications in translational medicine research, such as specific biomarkers for diabetes and cancer research. These results based on several broad applications in this study suggest the Simple Western size assay will be a novel potential protein detection accelerator in the personalized and translational medicine era.

In this study we tested gene-candidates, associated with the stress-resistance and personality traits, aggression in particular, in 16 world-class judo sportsmen, and 40 young men as a control sample from general Russian population (all men were of Caucasian origin). The polygenic profile with 9 candidate genes which included 10 polymorphisms (i.e., AR, DRD4, DRD2, DAT1, COMT, 5-HTTL, MAOA, HTR1A and HTR2A) connected to the functioning of serotonin, dopamine, and androgenic systems were determined. It was demonstrated that judo sportsmen significantly differed from the control group by higher frequencies of AR alleles with lower numbers of CAG repeats, V/V genotype of COMT gene, and G/G genotype of HTR1A gene, thus suggesting these polymorphisms as genetic markers of sportive success in wrestling.

In mammals, complex-I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain has 31
supernumerary subunits in addition to the 14 conserved from prokaryotes to humans. Multiplicity of structural protein components, as well as of biogenesis factors, make complex-I a sensible pace-maker of mitochondrial respiration. The work reviewed here shows that the Alternative Splicing and Nonsense Mediated Decay pathways regulate the transcription products of different nuclear genes encoding subunits of complex I. Complex-I dysfunction has been found to be associated with several human diseases. Involvement of altered pattern of transcription products of complex-I genes in pathogenetic mechanisms of these diseases is examined.