BACKGROUND: Extensive application of pyrethroids to control Varroa destructor, an invasive mite devastating bee colonies, has resulted in a global spread of resistant mite populations. In this study, we analyzed the spatio-temporal dynamics of resistant V. destructor populations in Czechia, stemming from the L925V mutation. Mites were collected during 2011-2018 directly or from winter beeswax debris, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and densitometry was used to detect the L925V mutation. RESULTS: Pooled samples of 10 mites were classified, based on their PCR-RFLP patterns, as tau-fluvalinate-sensitive (56%), resistant (9%), or mixed (35%), with the latter including sensitive and resistant homo- and heterozygotes. We identified two zones with higher frequencies of resistance, one in southern Moravia and the other in Bohemia. The mutant populations were evenly distributed throughout the monitored districts, with a few temporal and spatial local fluctuations. The greatest increase in resistance was observed in 2016, following massive losses of bee colonies in the winter of 2015. This event appeared to be closely associated with fluctuations in resistant mite populations and their dispersion. CONCLUSION: Two outbreaks of resistance were detected in Czechia; however, the amount of applied tau-fluvalinate was not correlated with the frequency of resistance in mites. There was no remarkable increase in mite resistance in 2011-2018, although the use of tau-fluvalinate increased 40-fold between 2011 and 2015. PCR-RFLP analysis, performed on mites present in beeswax debris, is a suitable method for monitoring the L925V mutation in V. destructor. © 2018 Society of Chemical Industry.

• Klíčová slova
• Apis mellifera, Varroa destructor, kdr, resistance, sodium channel, tau-fluvalinate,
• MeSH
• bodová mutace * MeSH
• časoprostorová analýza * MeSH
• léková rezistence genetika   MeSH
• nitrily chemie   MeSH
• pyrethriny chemie   MeSH
• sodíkové kanály genetika   MeSH
• stereoizomerie MeSH
• Varroidae genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• fluvalinate MeSH Prohlížeč
• nitrily MeSH
• pyrethriny MeSH
• sodíkové kanály MeSH

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.

• MeSH
• akutní lymfatická leukemie farmakoterapie   genetika   metabolismus   patologie   MeSH
• angiogenní proteiny genetika   MeSH
• chemorezistence genetika   MeSH
• fúzní onkogenní proteiny MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• předškolní dítě MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• recidiva MeSH
• růstový faktor odvozený z trombocytů - receptor beta genetika   MeSH
• sekvenování celého genomu MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• AGGF1 protein, human MeSH Prohlížeč
• angiogenní proteiny MeSH
• fúzní onkogenní proteiny MeSH
• inhibitory proteinkinas MeSH
• PDGFRB protein, human MeSH Prohlížeč
• protinádorové látky MeSH
• růstový faktor odvozený z trombocytů - receptor beta MeSH

According to previous reports in the literature, the T790M mutation indicates an acquired resistance to tyrosine kinase inhibitors. The initial positive effect of combination chemotherapy with erlotinib as the first line of treatment correlates with several positive predictors including the type of carcinoma, non-smoking status, occurrence of rash and the presence of exon 19 EGFR gene mutation. The case of a 32-year-old, non-smoker with non-contributory history patient, who was diagnosed with adenocarcinoma in the left lung T4N0M0 stage IIIB is reported. The patient underwent 6 cycles of chemotherapy with erlotinib, gemcitabine and cisplatin, followed by complete remission. Fifteen months after commencing therapy, disease recurred over subsequent therapy with erlotinib and then gefitinib. During that time, bone and cerebral metastases with pericardial effusion were detected. The patient died 7 months later. Genetic examination of tumour tissue collected at the beginning of therapy revealed activating exon 19 mutation in the EGFR gene. Later, during the relapse, the same mutation was still present and, in addition, a T790M mutation in exon 20 of EGFR was found. The subsequently acquired resistance against both erlotinib, as well as gefitinib was most likely a result of tumor cells acquiring the T790M mutations and escaping the drug effect. The authors recommend testing for T790M mutation presence in selected patients prior to targeted therapy with tyrosine kinase inhibitors.

• MeSH
• adenokarcinom farmakoterapie   genetika   MeSH
• chemorezistence genetika   MeSH
• chinazoliny aplikace a dávkování   MeSH
• cisplatina aplikace a dávkování   MeSH
• deoxycytidin aplikace a dávkování   analogy a deriváty   MeSH
• dospělí MeSH
• erbB receptory genetika   MeSH
• erlotinib MeSH
• gemcitabin MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• mutace MeSH
• nádory plic farmakoterapie   genetika   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• sekvence nukleotidů MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinazoliny MeSH
• cisplatina MeSH
• deoxycytidin MeSH
• erbB receptory MeSH
• erlotinib MeSH
• gemcitabin MeSH

Leukemias harboring the ETV6-ABL1 fusion represent a rare subset of hematological malignancies with unfavorable outcomes. The constitutively active chimeric Etv6-Abl1 tyrosine kinase can be specifically inhibited by tyrosine kinase inhibitors (TKIs). Although TKIs represent an important therapeutic tool, so far, the mechanism underlying the potential TKI resistance in ETV6-ABL1-positive malignancies has not been studied in detail. To address this issue, we established a TKI-resistant ETV6-ABL1-positive leukemic cell line through long-term exposure to imatinib. ETV6-ABL1-dependent mechanisms (including fusion gene/protein mutation, amplification, enhanced expression or phosphorylation) and increased TKI efflux were excluded as potential causes of resistance. We showed that TKI effectively inhibited the Etv6-Abl1 kinase activity in resistant cells, and using short hairpin RNA (shRNA)-mediated silencing, we confirmed that the resistant cells became independent from the ETV6-ABL1 oncogene. Through analysis of the genomic and proteomic profiles of resistant cells, we identified an acquired mutation in the GNB1 gene, K89M, as the most likely cause of the resistance. We showed that cells harboring mutated GNB1 were capable of restoring signaling through the phosphoinositide-3-kinase (PI3K)/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, whose activation is inhibited by TKI. This alternative GNB1K89M-mediated pro-survival signaling rendered ETV6-ABL1-positive leukemic cells resistant to TKI therapy. The mechanism of TKI resistance is independent of the targeted chimeric kinase and thus is potentially relevant not only to ETV6-ABL1-positive leukemias but also to a wider spectrum of malignancies treated by kinase inhibitors.

• MeSH
• chemorezistence účinky léků   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• leukemie farmakoterapie   genetika   patologie   MeSH
• lidé MeSH
• malá interferující RNA genetika   MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• proteiny vázající GTP - beta-podjednotky genetika   MeSH
• signální transdukce účinky léků   MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• GNB1 protein, human MeSH Prohlížeč
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• malá interferující RNA MeSH
• proteiny vázající GTP - beta-podjednotky MeSH
• TEL-ABL fusion protein, human MeSH Prohlížeč
• tyrosinkinasy MeSH

Despite the widespread use of anticoagulant rodenticides in baits for controlling commensal rodent pests, their application is problematic due to secondary intoxication and increasing resistance. In contrast to studies on Western European house mice (Mus musculus domesticus), few resistance studies have focused on Eastern European house mice (M. musculus musculus), which have a western distribution boundary in the Czech Republic. This study newly analysed the VKORC1 gene in M. m. musculus field populations from Czech farms and grain stores and identified a nonsynonymous mutation Tyr139Phe. This mutation was common throughout the Czech Republic and was present in 80.2% of the 86 individuals sampled. Additionally, all individuals exhibited a genotype with three synonymous mutations specific to the subspecies M. m. musculus. The functional (mortality-survival) response of the Tyr139Phe mutation was validated in a laboratory choice feeding test using bromadiolone-based bait, where all resistant homozygous individuals survived, while all susceptible mice died, with a mean survival of 6.9 days.

• Klíčová slova
• Mus musculus musculus, VKORC1, Anticoagulant rodenticides, Resistance, Rodent pests,
• MeSH
• 4-hydroxykumariny MeSH
• antikoagulancia * farmakologie   MeSH
• epoxidreduktasy vitaminu K * genetika   MeSH
• genotyp MeSH
• léková rezistence genetika   MeSH
• mutace * MeSH
• myši MeSH
• rodenticidy * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• 4-hydroxykumariny MeSH
• antikoagulancia * MeSH
• bromadiolone MeSH Prohlížeč
• epoxidreduktasy vitaminu K * MeSH
• rodenticidy * MeSH

High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.

• Klíčová slova
• TP53, biomarkers, ovarian carcinoma, platinum resistance, treatment response,
• MeSH
• chemorezistence * genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 * genetika   MeSH
• nádory vaječníků * genetika   farmakoterapie   patologie   MeSH
• platina terapeutické užití   farmakologie   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenování exomu metody   MeSH
• senioři MeSH
• serózní cystadenokarcinom * genetika   farmakoterapie   patologie   MeSH
• zárodečné mutace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorový supresorový protein p53 * MeSH
• platina MeSH
• TP53 protein, human MeSH Prohlížeč

Therapeutic efficacy of sulfadoxine-pyrimethamine (SP), which is commonly used to treat falciparum malaria, was assessed in isolates of Plasmodium falciparum (Welch, 1897) and Plasmodium vivax (Grassi et Feletti, 1890) ofAligarh, Uttar Pradesh, North India and Taif, Saudi Arabia during 2011-2012. Both the species showed mutations in dihydrofolate reductase (DHFR) enzyme as they have common biochemical drug targets. Mutation rate for pfdhfr was higher compared to pvdhfr because the drug was mainly given to treat falciparum malaria. Since both the species coexist, P. vivax was also exposed to SP due to faulty species diagnosis or medication without specific diagnosis. Low level of mutations against SP in P. falciparum of Saudi isolates indicates that the SP combination is still effective for the treatment of falciparum malaria. Since SP is used as first-line of treatment because of high level of resistance against chloroquine (CQ), it may result in spread of higher level of mutations resulting in drug resistance and treatment failure in near future. Therefore, to avoid further higher mutations in the parasite, use of better treatment regimens such as artesunate combination therapy must be introduced against SP combination.

• MeSH
• fixní kombinace léků MeSH
• léková rezistence * MeSH
• mutace MeSH
• Plasmodium falciparum účinky léků   genetika   MeSH
• Plasmodium vivax účinky léků   genetika   MeSH
• pyrimethamin farmakologie   MeSH
• regulace genové exprese MeSH
• sulfadoxin farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fanasil, pyrimethamine drug combination MeSH Prohlížeč
• fixní kombinace léků MeSH
• pyrimethamin MeSH
• sulfadoxin MeSH

INTRODUCTION: Tuberculosis is considered one of the most fatal diseases worldwide, with an estimation of 10.1 million cases. In this study, whole-genome sequencing was used to determine the genomic characterisation of 40 Mycobacterium tuberculosis isolates from patients with different nationalities hospitalised in the Czech Republic. MATERIALS AND METHODS: Susceptibility testing for first-line drugs was performed. DNA was sequenced using the Illumina MiSeq platform. Spoligotype single-nucleotide polymorphisms and mutations in antibiotic-resistant genes were detected, and phylogenetic analysis was performed. RESULTS: Samples showing phenotypic resistance to at least one drug were 12 to streptomycin, 11 to isoniazid, 7 to rifampicin, 6 to ethambutol and 5 to pyrazinamide. Phenotypic and genotypic profiles did not match in all cases, suggesting the presence of a novel mutation in some cases and a low expression of resistant genes in others. The presented phylogeny enables the correct assignation of M. tuberculosis lineages and sublineages. Our results suggest that the most dominant lineage in our samples was lineage 4 (33/40). CONCLUSION: To our knowledge, this is the first study using this approach to be done in the Czech Republic. Lineage 4 was the predominant lineage identified among our samples. Nevertheless, the dominance of Lineage 4 along with other lineages suggests that infections can originate from different sources.

• Klíčová slova
• Extensively drug-resistant, Multidrug resistant, Mycobacterium tuberculosis, Spoligotype, Whole-genome sequencing,
• MeSH
• antituberkulotika * farmakologie   MeSH
• fylogeneze MeSH
• lidé MeSH
• mnohočetná bakteriální léková rezistence * genetika   MeSH
• multirezistentní tuberkulóza * MeSH
• mutace MeSH
• Mycobacterium tuberculosis * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• antituberkulotika * MeSH

We investigated the genetic basis of glycopeptide resistance in laboratory-derived strains of S. haemolyticus with emphasis on differences between vancomycin and teicoplanin. The genomes of two stable teicoplanin-resistant laboratory mutants selected on vancomycin or teicoplanin were sequenced and compared to parental S. haemolyticus strain W2/124. Only the two non-synonymous mutations, VraS Q289K and WalK V550L were identified. No other mutations or genome rearrangements were detected. Increased cell wall thickness, resistance to lysostaphin-induced lysis and adaptation of cell growth rates specifically to teicoplanin were phenotypes observed in a sequenced strain with the VraS Q289K mutation. Neither of the VraS Q289K and WalK V550L mutations was present in the genomes of 121S. haemolyticus clinical isolates. However, all but two of the teicoplanin resistant strains carried non-synonymous SNPs in vraSRTU and walKR-YycHIJ operons pointing to their importance for the glycopeptide resistance.

• Klíčová slova
• Mutation, Resistance, Staphylococcus haemolyticus, Teicoplanin, Vancomycin,
• MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální léková rezistence genetika   MeSH
• DNA bakterií genetika   MeSH
• fenotyp MeSH
• genom bakteriální genetika   MeSH
• histidinkinasa genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• rezistence na vankomycin genetika   MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• stafylokokové infekce mikrobiologie   MeSH
• Staphylococcus haemolyticus účinky léků   genetika   izolace a purifikace   MeSH
• teikoplanin farmakologie   MeSH
• vankomycin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Polsko MeSH
• Názvy látek
• antibakteriální látky MeSH
• DNA bakterií MeSH
• histidinkinasa MeSH
• teikoplanin MeSH
• vankomycin MeSH

Mutations occurring in viral polymerase gene of hepatitis B virus (HBV) due to the use of nucleos(t)id analogs reduce the activity of the drugs by causing antiviral resistance. In this study, it was aimed to evaluate mutations responsible for drug resistance and drug resistance mutation rates in patients followed up by the diagnosis of chronic hepatitis B (CHB). A total of 318 CHB patients were included in the study. HBV mutations were detected using the INNO-LiPA commercial kit based on the reverse hybridization principle. Drug resistance mutation was detected in 46.86% (149/318) of the patients. The rates of drug resistance were found 36.79% (117/318) for lamivudine resistance, 12.58% (40/318) for entecavir (ETV), and 7.86% (25/318) for adefovir. In 10 patients, the possible tenofovir (TDF) resistance (3.14%) was found. Single-drug and double-drug resistances were detected in 34.59% and in 11.01% of the patients, respectively. Triple drug resistance was detected in only 1.26% of the patients. Unlike various studies in Turkey and in other countries, remarkable resistance to ETV and TDF were found in this study. The high rate of the probable TDF resistance was striking, with 3.14%.

• MeSH
• antivirové látky farmakologie   terapeutické užití   MeSH
• chronická hepatitida B farmakoterapie   mikrobiologie   MeSH
• dítě MeSH
• DNA virů genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mnohočetná virová léková rezistence genetika   MeSH
• mutace MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• reverzní transkriptasa genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• virová léková rezistence genetika   MeSH
• virus hepatitidy B účinky léků   genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Turecko MeSH
• Názvy látek
• antivirové látky MeSH
• DNA virů MeSH
• reverzní transkriptasa MeSH