Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation.

Background: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept.

Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions.

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability.

Physicochemical and biopharmaceutical characterization of novel Matrix-Liposomes.

Matrix-Liposomes (MLs) are a very promising solid oral drug delivery system; however, data on their interaction with biological membranes are not available. Here, we describe the quality of MLs manufactured by dual centrifugation. MLs were prepared with a Z-average range of 139 to 160 nm and a PDI of 0.

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase II Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity.

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase II (Top2B) activity in chronic anthracycline cardiotoxicity.

Skin wipe test: A simple, inexpensive, and fast approach in the diagnosis of cystic fibrosis.

Objective: To assess the performance of a newly developed skin wipe test (SWT) for the diagnosis of cystic fibrosis (CF).

Study Design: Spontaneously formed sweat from the forearm was wiped by a cotton swab moistened with 100 µL of deionized (DI) water and extracted into 400 µL of DI water (SWT). The conventional Macroduct sweat test (ST) was performed simultaneously.

A product of immunoreactive trypsinogen and pancreatitis-associated protein as second-tier strategy in cystic fibrosis newborn screening.

Background: In cystic fibrosis newborn screening (CFNBS), immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) can be used as screening parameters. We evaluated the IRT×PAP product as second-tier parameter in CFNBS in newborns with elevated IRT.

Methods: Data on 410,111 screened newborns including 78 patients with classical cystic fibrosis (CF) from two European centers were retrospectively analyzed by discrimination analysis to identify a screening protocol with optimal cutoffs.

Cost-of-illness analysis and regression modeling in cystic fibrosis: a retrospective prevalence-based study.

Background: Economic data pertaining to cystic fibrosis (CF), is limited in Europe generally, and completely lacking in Central and Eastern Europe. We performed an analysis of all direct costs associated with CF relative to key disease features and laboratory examinations.

Methods: A retrospective prevalence-based cost-of-illness (COI) study was performed in a representative cohort of 242 CF patients in the Czech Republic, which represents about 65 % of all Czech CF patients.

Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations.

Background: In recent years different IRT/PAP protocols have been evaluated, but the individual performance remains unclear. To optimize the IRT/PAP strategy we compared protocols from three regional CF newborn screening centers (Heidelberg, Dresden, and Prague).

Methods: We evaluated the effect of elevating the IRT-cut-off from 50 to 65 μg/l (~97.

Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations.

Background: This two decade long study presents a comprehensive overview of the CFTR mutation distribution in a representative cohort of 600 Czech CF patients derived from all regions of the Czech Republic.

Methods: We examined the most common CF-causing mutations using the Elucigene CF-EU2v1™ assay, followed by MLPA, mutation scanning and/or sequencing of the entire CFTR coding region and splice site junctions.

Results: We identified 99.

PCR detection of Burkholderia cepacia complex as one of key factors to handle a long-term outbreak.

Background: Once the outbreak with Burkholderia cenocepacia ST32 was identified in the Prague cystic fibrosis (CF) centre, molecular tools were implemented into diagnostic routine in order to complement infection control measures with as accurate as possible microbiological service. In addition, genotyping techniques were applied as part of an infection surveillance program to assign species and strain status in samples positive for Burkholderia cepacia complex (Bcc). We sought to evaluate a usefulness of Bcc-specific PCR in infection control and to map evolution of the outbreak.

Prospective and parallel assessments of cystic fibrosis newborn screening protocols in the Czech Republic: IRT/DNA/IRT versus IRT/PAP and IRT/PAP/DNA.

Unlabelled: Cystic fibrosis (CF) is a life-threatening disease for which early diagnosis following newborn screening (NBS) improves the prognosis. We performed a prospective assessment of the immunoreactive trypsinogen (IRT)/DNA/IRT protocol currently in use nationwide, versus the IRT/pancreatitis-associated protein (PAP) and IRT/PAP/DNA CF NBS protocols. Dried blood spots (DBS) from 106,522 Czech newborns were examined for IRT concentrations.

Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport.

Rationale: The diagnosis of cystic fibrosis (CF) is based on a characteristic clinical picture in association with a sweat chloride (Cl(-)) concentration greater than 60 mmol/L or the identification of two CF-causing mutations. A challenging problem is the significant number of children for whom no definitive diagnosis is possible because they present with symptoms suggestive of CF, a sweat chloride level in the intermediate range between 30 and 60 mmol/L, and only one or no identified CF-causing mutation.

Objectives: To investigate the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways of children with intermediate sweat tests and inconclusive genetic findings in correlation with clinical phenotype and genotype.

Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.

We investigated whether mutations in the genes that code for the different subunits of the amiloride-sensitive epithelial sodium channel (ENaC) might result in cystic fibrosis (CF)-like disease. In a small fraction of the patients, the disease could be potentially explained by an ENaC mutation by a Mendelian mechanism, such as p.V114I and p.

Pilot newborn screening project for cystic fibrosis in the Czech Republic: defining role of the delay in its symptomatic diagnosis and influence of ultrasound-based prenatal diagnosis on the incidence of the disease.

The objective need for cystic fibrosis (CF) newborn screening (NBS) in the Czech Republic has recently been substantiated by a significant delay of its symptomatic diagnosis. This trend most likely resulted from the process of decentralisation of health care which led to the deterioration of care for patients who need specialised approaches. Applied newborn screening model (IRT/DNA/IRT) was efficacious enough to detect CF cases with median age at diagnosis of 37 days.