Olomouc, Czech Republic
Olomouc, Czech Republic

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Snasel J.,Czech Institute of Organic Chemistry And Biochemistry | Naus P.,Czech Institute of Organic Chemistry And Biochemistry | Dostal J.,Czech Institute of Organic Chemistry And Biochemistry | Hnizda A.,Czech Institute of Organic Chemistry And Biochemistry | And 16 more authors.
Journal of Medicinal Chemistry | Year: 2014

Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D 1H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of hADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites. © 2014 American Chemical Society.


Hruban L.,Masaryk University | Spilka J.,Czech Technical University | Chudacek V.,Czech Technical University | Janku P.,Masaryk University | And 11 more authors.
Journal of Evaluation in Clinical Practice | Year: 2015

Rationale, aims and objectives To evaluate obstetricians' inter- and intra-observer agreement on intrapartum cardiotocogram (CTG) recordings and to examine obstetricians' evaluations with respect to umbilical artery pH and base deficit. Methods Nine experienced obstetricians annotated 634 intrapartum CTG recordings. The evaluation of each recording was divided into four steps: evaluation of two 30-minute windows in the first stage of labour, evaluation of one window in the second stage of labour and labour outcome prediction. The complete set of evaluations used for this experiment is available online. The inter- and intra-observer agreement was evaluated using proportion of agreement and kappa coefficient. Clinicians' sensitivity and specificity was computed with respect to umbilical artery pH, base deficit and to Apgar score at the fifth minute. Results The overall proportion of agreement between clinicians reached 48% with 95% confidence intervals (CI) (CI: 47-50). Regarding the different classes, proportion of agreement ranged from 57% (CI: 54-60) for normal to 41% (CI: 36-46) for pathological class. The sensitivity of clinicians' majority vote to objective outcome was 39% (CI: 16-63) for the umbilical artery base deficit and 27% (CI: 16-42) for pH. The specificity was 89% (CI: 86-92) for both types of objective outcome. Conclusions The reported inter-/intra-observer variability is large and this holds irrespective of clinicians' experience or work place. The results support the need of modernized guidelines for CTG evaluation and/or objectivization and repeatability by introduction of a computerized approach that could standardize the process of CTG evaluation within the delivery ward. © 2015 John Wiley & Sons, Ltd.


Surinova S.,ETH Zurich | Surinova S.,University College London | Choi M.,Purdue University | Tao S.,German Cancer Research Center | And 18 more authors.
EMBO Molecular Medicine | Year: 2015

Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection. © 2015 EMBO.


PubMed | Prague Podoli, University of Hradec Kralove, Masaryk University, University Hospital in Olomouc and 4 more.
Type: Journal Article | Journal: Journal of evaluation in clinical practice | Year: 2015

To evaluate obstetricians inter- and intra-observer agreement on intrapartum cardiotocogram (CTG) recordings and to examine obstetricians evaluations with respect to umbilical artery pH and base deficit.Nine experienced obstetricians annotated 634 intrapartum CTG recordings. The evaluation of each recording was divided into four steps: evaluation of two 30-minute windows in the first stage of labour, evaluation of one window in the second stage of labour and labour outcome prediction. The complete set of evaluations used for this experiment is available online. The inter- and intra-observer agreement was evaluated using proportion of agreement and kappa coefficient. Clinicians sensitivity and specificity was computed with respect to umbilical artery pH, base deficit and to Apgar score at the fifth minute.The overall proportion of agreement between clinicians reached 48% with 95% confidence intervals (CI) (CI: 47-50). Regarding the different classes, proportion of agreement ranged from 57% (CI: 54-60) for normal to 41% (CI: 36-46) for pathological class. The sensitivity of clinicians majority vote to objective outcome was 39% (CI: 16-63) for the umbilical artery base deficit and 27% (CI: 16-42) for pH. The specificity was 89% (CI: 86-92) for both types of objective outcome.The reported inter-/intra-observer variability is large and this holds irrespective of clinicians experience or work place. The results support the need of modernized guidelines for CTG evaluation and/or objectivization and repeatability by introduction of a computerized approach that could standardize the process of CTG evaluation within the delivery ward.


PubMed | German Cancer Research Center, Palacky University, ETH Zurich, Purdue University and University Hospital in Olomouc
Type: Evaluation Studies | Journal: EMBO molecular medicine | Year: 2015

Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection.


Ociskova M.,University Hospital in Olomouc | Ociskova M.,Palacky University | Prasko J.,University Hospital in Olomouc | Kamaradova D.,University Hospital in Olomouc | And 2 more authors.
Neuropsychiatric Disease and Treatment | Year: 2015

Background: A number of psychiatric patients experience stigma connected to prejudices about mental disorders. It has been shown that stigma is most harmful when it is internalized. Most of the studies were performed on individuals either with psychoses or with mood disorders, and hence, there are almost no studies with other diagnostic categories. The goals of this research were to identify factors that are significantly related to self-stigma in patients with anxiety disorders and to suggest possible models of causality for these relationships. Methods: A total of 109 patients with anxiety disorders and possible comorbid depressive or personality disorders, who were admitted to the psychotherapeutic department participated in this study. All patients completed several psychodiagnostic methods, ie, the Internalized Stigma of Mental Illness Scale, Temperament and Character Inventory-Revised Version, Adult Dispositional Hope Scale, Dissociative Experiences Scale, Beck Anxiety Inventory, Beck Depression Inventory-Second Edition, and Clinical Global Impression (also completed by the senior psychiatrist). Results: The overall level of self-stigma was positively associated with a comorbid personality disorder, more severe symptomatology, more intense symptoms of anxiety and depression, and higher levels of dissociation and harm avoidance. Self-stigma was negatively related to hope, reward dependence, persistence, self-directedness, and cooperativeness. Multiple regression analysis showed that the most significant factors connected to self-stigma are harm avoidance, the intensity of depressive symptoms, and self-directedness. Two models of causality were proposed and validated. It seems that the tendency to dissociate in stress increases the probability of development of self-stigma, and this relationship is entirely mediated by avoidance of harm. Conversely, self-directedness lowers the probability of occurrence of self-stigma, and this effect is partly mediated by hope. Conclusion: Patients with anxiety disorders accompanied with or without comorbid depressive or personality disorders may suffer from self-stigma. Individuals with greater sensitivity to rejection and other socially aversive stimuli are prone to the development of self-stigma. Other personality factors, such as hopeful thinking and self-acceptance serve as factors promoting resilience concerning self-stigma. © 2015 Ociskova et al.


Vencalek O.,Palacky University | Facevicova K.,Palacky University | Furst T.,Palacky University | Grepl M.,University Hospital in Olomouc
Cancer Epidemiology | Year: 2013

Objectives: To present a new predictive model for repeated prostate biopsy outcomes. Several practical problems are described that arise when searching for a proper model among those that already exist. A new model is developed with only two explanatory variables and a simple graphical output. Methods: This is a retrospective cohort study based on data collected from December 2006 to June 2011 at the Clinic of Urology of the University Hospital in Olomouc, Czech Republic. The cohort consists of 221 patients who underwent the first repeated biopsy after an initial biopsy with a negative outcome. All patients had prostate-specific antigen (PSA) levels between 1.5 and 16.5. ng/mL and a prostate volume not greater than 100. mL. A logistic regression model was fitted. Results: Of the 221 patients, 29 (13%) were diagnosed with prostate cancer on the repeated biopsy. The final model includes the PSA level and the transitory zone volume as predictors. Its accuracy is 76.4%. The cut-off point of 0.0687 in the predicted positive repeated biopsy outcome assures 95% sensitivity and prevents 42% of unnecessary biopsies. Conclusions: The accuracy of the model is comparable to that of more complex models (with more than two predictors) published in the literature. The model includes only two routinely measured variables, and hence it is accessible for a wide range of practitioners. The simple graphical outcome makes the model even more attractive. © 2013 Elsevier Ltd.


Hrabakova R.,Academy of Sciences of the Czech Republic | Kollareddy M.,University Hospital in Olomouc | Tyleckova J.,Academy of Sciences of the Czech Republic | Halada P.,Academy of Sciences of the Czech Republic | And 3 more authors.
Journal of Proteome Research | Year: 2013

Drug resistance is the major obstacle to successful cancer therapy. Our study focuses on resistance to Aurora kinase inhibitors tested as anti-cancer drugs in clinical trials. We have used 2D electrophoresis in the pH ranges of 4-7 and 6-11 followed by protein identification using MALDITOF/TOF to compare the protein composition of HCT116 colon cancer cells either sensitive to CYC116 and ZM447439 inhibitors or resistant toward these drugs. The analysis also included p53+/+ and p53-/-phenotypes of HCT116 cells. Our findings demonstrate that platelet-activating factor acetylhydrolase and GTP-binding nuclear protein Ran contribute to the development of resistance to ZM447439 only where resistance is related to p53. On the other hand, serine hydroxymethyltransferase was found to promote the tumor growth in cells resistant to CYC116 without the influence of p53. Computer modeling of interaction networks highlighted a direct link of the p53-independent mechanism of resistance to CYC116 with autophagy. Importantly, serine hydroxymethyltransferase, serpin B5, and calretinin represent the target proteins that may help overcome resistance in combination therapies. In addition, serpin B5 and calretinin appear to be candidate biomarkers that may be accessible in patients for monitoring of cancer therapy with ease. © 2012 American Chemical Society.


PubMed | University Hospital in Olomouc and Palacky University
Type: | Journal: Neuropsychiatric disease and treatment | Year: 2015

A number of psychiatric patients experience stigma connected to prejudices about mental disorders. It has been shown that stigma is most harmful when it is internalized. Most of the studies were performed on individuals either with psychoses or with mood disorders, and hence, there are almost no studies with other diagnostic categories. The goals of this research were to identify factors that are significantly related to self-stigma in patients with anxiety disorders and to suggest possible models of causality for these relationships.A total of 109 patients with anxiety disorders and possible comorbid depressive or personality disorders, who were admitted to the psychotherapeutic department participated in this study. All patients completed several psychodiagnostic methods, ie, the Internalized Stigma of Mental Illness Scale, Temperament and Character Inventory-Revised Version, Adult Dispositional Hope Scale, Dissociative Experiences Scale, Beck Anxiety Inventory, Beck Depression Inventory-Second Edition, and Clinical Global Impression (also completed by the senior psychiatrist).The overall level of self-stigma was positively associated with a comorbid personality disorder, more severe symptomatology, more intense symptoms of anxiety and depression, and higher levels of dissociation and harm avoidance. Self-stigma was negatively related to hope, reward dependence, persistence, self-directedness, and cooperativeness. Multiple regression analysis showed that the most significant factors connected to self-stigma are harm avoidance, the intensity of depressive symptoms, and self-directedness. Two models of causality were proposed and validated. It seems that the tendency to dissociate in stress increases the probability of development of self-stigma, and this relationship is entirely mediated by avoidance of harm. Conversely, self-directedness lowers the probability of occurrence of self-stigma, and this effect is partly mediated by hope.Patients with anxiety disorders accompanied with or without comorbid depressive or personality disorders may suffer from self-stigma. Individuals with greater sensitivity to rejection and other socially aversive stimuli are prone to the development of self-stigma. Other personality factors, such as hopeful thinking and self-acceptance serve as factors promoting resilience concerning self-stigma.


Many compounds related to L-tryptophan (L-TRP) have interesting biological or pharmacological activity, and their abnormal neurotransmission seems to be linked to a wide range of neurodegenerative and psychiatric diseases. A high-throughput method based on ultra-high performance liquid chromatography connected to electrospray tandem mass spectrometry (UHPLC-ESI-MS/MS) was developed for the quantitative analysis of L-TRP and 16 of its metabolites in human serum and cerebrospinal fluid (CSF), representing both major and minor routes of L-TRP catabolism. The combination of a fast LC gradient with selective tandem mass spectrometry enabled accurate analysis of almost 100 samples in 24h. The standard isotope dilution method was used for quantitative determination. The methods lower limits of quantification for serum and cerebrospinal fluid ranged from 0.05 to 15nmol/L and 0.3 to 45nmol/L, respectively. Analytical recoveries ranged from 10.4 to 218.1% for serum and 22.1 to 370.0% for CSF. The methods accuracy ranged from 82.4 to 128.5% for serum matrix and 90.7 to 127.7% for CSF matrix. All intra- and inter-day coefficients of variation were below 15%. These results demonstrate that the new method is capable of quantifying endogenous serum and CSF levels of a heterogeneous group of compounds spanning a wide range of concentrations. The method was used to determine the physiological levels of target analytes in serum and CSF samples from 18 individuals, demonstrating its reliability and potential usefulness in large-scale epidemiological studies.

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