Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome.

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

Positive matrix factorization of seasonally resolved organic aerosol at three different central European background sites based on nuclear magnetic resonance Aerosolomics data.

Concentration data derived from 1H NMR analysis of the water-soluble organic compounds from fine aerosol (PM2.5) at three Central European background stations, Kosetice, Frýdlant (both in the Czech Republic), and Melpitz (Germany), were used for detailed source apportionment analysis. Two winter and two summer episodes (year 2021) with higher organic concentrations and similar wind directions were selected for NMR analyses. The concentration profiles of 61 water-soluble organic compounds were determined by NMR Aerosolomics and a principal component analysis (PCA) was performed on this dataset. Based on the PCA results, 23 compounds were selected for positive matrix factorization (PMF) analysis in order to identify dominant aerosol sources at rural background sites in Central Europe. Both the PCA and the subsequent PMF analyses clearly distinguished the characteristics of winter and summer aerosol particles. In summer, four factors were identified from PMF and were associated with biogenic aerosol (61-78 %), background aerosol (9-15 %), industrial biomass combustion (7-13 %), and residential heating (5-13 %). In winter, only 3 factors were identified - industrial biomass combustion (33-49 %), residential heating (37-45 %) and a background aerosol (8-30 %). The main difference was observed in the winter season with a stronger contribution of emissions from industrial biomass burning at the Czech stations Kosetice and Frýdlant (47-49 %) compared to the Melpitz station (33 %). However, in general, there were negligible differences in identified sources between stations in the given seasons, indicating a certain homogeneity in PM2.5 composition within Central Europe at least during the sampling periods.

PredictONCO: a web tool supporting decision-making in precision oncology by extending the bioinformatics predictions with advanced computing and machine learning.

PredictONCO 1.0 is a unique web server that analyzes effects of mutations on proteins frequently altered in various cancer types. The server can assess the impact of mutations on the protein sequential and structural properties and apply a virtual screening to identify potential inhibitors that could be used as a highly individualized therapeutic approach, possibly based on the drug repurposing. PredictONCO integrates predictive algorithms and state-of-the-art computational tools combined with information from established databases. The user interface was carefully designed for the target specialists in precision oncology, molecular pathology, clinical genetics and clinical sciences. The tool summarizes the effect of the mutation on protein stability and function and currently covers 44 common oncological targets. The binding affinities of Food and Drug Administration/ European Medicines Agency -approved drugs with the wild-type and mutant proteins are calculated to facilitate treatment decisions. The reliability of predictions was confirmed against 108 clinically validated mutations. The server provides a fast and compact output, ideal for the often time-sensitive decision-making process in oncology. Three use cases of missense mutations, (i) K22A in cyclin-dependent kinase 4 identified in melanoma, (ii) E1197K mutation in anaplastic lymphoma kinase 4 identified in lung carcinoma and (iii) V765A mutation in epidermal growth factor receptor in a patient with congenital mismatch repair deficiency highlight how the tool can increase levels of confidence regarding the pathogenicity of the variants and identify the most effective inhibitors. The server is available at https://loschmidt.chemi.muni.cz/predictonco.

Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors.

Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.

Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity.

This was a prospective cohort study of eighteen patients with large and debilitating vascular malformations with one or more major systemic complications. In all patients, we discovered activating alterations in either TEK or PIK3CA. Based on these findings, targeted treatment using the PI3K inhibitor alpelisib was started with regular check-ups, therapy duration varied from 6 to 31 months. In all patients, marked improvement in quality of life was observed. We observed radiological improvement in fourteen patients (two of them being on combination with either propranolol or sirolimus), stable disease in 2 patients. For 2 patients, an MRI scan was not available as they were shortly on treatment, however, a clinically visible response in size reduction or structure regression, together with pain relief was observed. In patients with elevated D-dimer levels before alpelisib administration, a major improvement was noted, suggesting its biomarker role. We observed overall very good tolerance of the treatment, documenting a single patient with grade 3 hyperglycemia. Patients with size reduction were offered local therapies wherever possible. Our report presents a promising approach for the treatment of VMs harboring different targetable TEK and PIK3CA gene mutations with a low toxicity profile and high efficacy.

Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

BACKGROUND: Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. CASE PRESENTATION: We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. CONCLUSIONS: To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location.

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.

Long-term trends of ultrafine and fine particle number concentrations in New York State: Apportioning between emissions and dispersion.

In the past several decades, a variety of efforts have been made in the United States to improve air quality, and ambient particulate matter (PM) concentrations have been used as a metric to evaluate the efficacy of environmental policies. However, ambient PM concentrations result from a combination of source emission rates and meteorological conditions, which also change over time. Dispersion normalization was recently developed to reduce the influence of atmospheric dispersion and proved an effective approach that enhanced diel/seasonal patterns and thus provides improved source apportionment results for speciated PM mass and particle number concentration (PNC) measurements. In this work, dispersion normalization was incorporated in long-term trend analysis of 11-500 nm PNCs derived from particle number size distributions (PNSDs) measured in Rochester, NY from 2005 to 2019. Before dispersion normalization, a consistent reduction was observed across the measured size range during 2005-2012, while after 2012, the decreasing trends slowed down for accumulation mode PNCs (100-500 nm) and reversed for ultrafine particles (UFPs, 11-100 nm). Through dispersion normalization, we showed that these changes were driven by both emission rates and dispersion. Thus, it is important for future studies to assess the effects of the changing meteorological conditions when evaluating policy effectiveness on controlling PM concentrations. Before and after dispersion normalization, an evident increase in nucleation mode particles was observed during 2015-2019. This increase was possibly enabled by a cleaner atmosphere and will pose new challenges for future source apportionment and accountability studies.

European aerosol phenomenology - 8: Harmonised source apportionment of organic aerosol using 22 Year-long ACSM/AMS datasets.

Organic aerosol (OA) is a key component of total submicron particulate matter (PM1), and comprehensive knowledge of OA sources across Europe is crucial to mitigate PM1 levels. Europe has a well-established air quality research infrastructure from which yearlong datasets using 21 aerosol chemical speciation monitors (ACSMs) and 1 aerosol mass spectrometer (AMS) were gathered during 2013-2019. It includes 9 non-urban and 13 urban sites. This study developed a state-of-the-art source apportionment protocol to analyse long-term OA mass spectrum data by applying the most advanced source apportionment strategies (i.e., rolling PMF, ME-2, and bootstrap). This harmonised protocol was followed strictly for all 22 datasets, making the source apportionment results more comparable. In addition, it enables quantification of the most common OA components such as hydrocarbon-like OA (HOA), biomass burning OA (BBOA), cooking-like OA (COA), more oxidised-oxygenated OA (MO-OOA), and less oxidised-oxygenated OA (LO-OOA). Other components such as coal combustion OA (CCOA), solid fuel OA (SFOA: mainly mixture of coal and peat combustion), cigarette smoke OA (CSOA), sea salt (mostly inorganic but part of the OA mass spectrum), coffee OA, and ship industry OA could also be separated at a few specific sites. Oxygenated OA (OOA) components make up most of the submicron OA mass (average = 71.1%, range from 43.7 to 100%). Solid fuel combustion-related OA components (i.e., BBOA, CCOA, and SFOA) are still considerable with in total 16.0% yearly contribution to the OA, yet mainly during winter months (21.4%). Overall, this comprehensive protocol works effectively across all sites governed by different sources and generates robust and consistent source apportionment results. Our work presents a comprehensive overview of OA sources in Europe with a unique combination of high time resolution (30-240 min) and long-term data coverage (9-36 months), providing essential information to improve/validate air quality, health impact, and climate models.

Assessing the impact of antiemetic guideline compliance on prevention of chemotherapy-induced nausea and vomiting: Results of the nausea/emesis registry in oncology (NERO).

BACKGROUND: Evidence-based antiemetic guidelines offer predominantly consistent recommendations for chemotherapy-induced nausea and vomiting (CINV) prophylaxis. However, studies suggest that adherence to these recommendations is suboptimal. We explored inconsistencies between clinical practice and guideline-recommended treatment with a registry evaluating the effect of guideline-consistent CINV prophylaxis (GCCP) on patient outcomes. PATIENTS AND METHODS: This was a prospective, non-interventional, multicentre study. The primary objective was to assess the overall (Days 1-5) complete response (CR: no emesis/no rescue use) rates in patients who received GCCP or guideline-inconsistent CINV prophylaxis (GICP) using diaries for 5 days following chemotherapy. Cycle 1 results are presented in patients who received either (1) anthracycline/cyclophosphamide (AC) highly emetogenic chemotherapy (HEC), non-AC HEC or carboplatin, with GCCP for all these groups consisting of prophylaxis with an NK1 receptor antagonist (RA), 5-HT3RA and dexamethasone prior to chemotherapy or (2) moderately emetogenic chemotherapy (MEC), with GCCP consisting of a 5-HT3RA and dexamethasone prior to chemotherapy as per MASCC/ESMO 2016 guidelines, in place at the time of the study. RESULTS: 1,089 patients were part of the cycle 1 efficacy evaluation. Overall GCCP was 23%. CR rates were significantly higher (P < 0.05) in patients receiving GCCP (62.2%) versus GICP (52.6%) in the overall population, as well as in the subsets of patients receiving AC/non-AC HEC (60.2% versus 47.8%), MEC (73.8% versus 57.8%) and in those non-naïve to the chemotherapy received (65.9% versus 53.8%). No impact on daily living due to CINV (FLIE assessment) was observed in 43.4% patients receiving GCCP versus 28.5% GICP (P < 0.001). CONCLUSION: Consistent with prior studies, GCCP was very low; a significant benefit of almost 10% improved prevention of CINV was observed with GCCP. As per MASCC/ESMO guidelines, such an absolute difference should be practice changing. Comprehensive multifaceted strategies are needed to achieve better adherence to antiemetic guidelines.

Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma.

Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses.

Spatial-temporal variability of aerosol sources based on chemical composition and particle number size distributions in an urban settlement influenced by metallurgical industry.

The Moravian-Silesian region of the Czech Republic with its capital city Ostrava is a European air pollution hot spot for airborne particulate matter (PM). Therefore, the spatiotemporal variability assessment of source contributions to aerosol particles is essential for the successful abatement strategies implementation. Positive Matrix Factorization (PMF) was applied to highly-time resolved PM0.15-1.15 chemical composition (1 h resolution) and particle number size distribution (PNSD, 14 nm - 10 µm) data measured at the suburban (Ostrava-Plesná) and urban (Ostrava-Radvanice) residential receptor sites in parallel during an intensive winter campaign. Diel patterns, meteorological variables, inorganic and organic markers, and associations between the chemical composition factors and PNSD factors were used to identify the pollution sources and their origins (local, urban agglomeration and regional). The source apportionment analysis resolved six and four PM0.15-1.15 sources in Plesná and Radvanice, respectively. In Plesná, local residential combustion sources (coal and biomass combustion) followed by regional combustion sources (residential heating, metallurgical industry) were the main contributors to PM0.15-1.15. In Radvanice, local residential combustion and the metallurgical industry were the most important PM0.15-1.15 sources. Aitken and accumulation mode particles emitted by local residential combustion sources along with common urban sources (residential heating, industry and traffic) were the main contributors to the particle number concentration (PNC) in Plesná. Additionally, accumulation mode particles from local residential combustion sources and regional pollution dominated the particle volume concentration (PVC). In Radvanice, local industrial sources were the major contributors to PNC and local coal combustion was the main contributor to PVC. The source apportionment results from the complementary datasets elucidated the relevance of highly time-resolved parallel measurements at both receptor sites given the specific meteorological conditions produced by the regional orography. These results are in agreement with our previous studies conducted at this site. Graphical abstract.

Assessment of air pollution origin based on year-long parallel measurement of PM2.5 and PM10 at two suburban sites in Prague, Czech Republic.

From 2nd April 2008 to 28th March 2009, a total 248 daily samples of the PM2.5 and PM10 were collected every sixth day parallel at two suburban sites (Libus and Suchdol) located at the two opposite sides (south and north, respectively) of Prague, Czech Republic. The PM2.5 samples were analyzed for ions by ion chromatography (IC), organic and elemental carbon (OC and EC) by OC/EC analyzer and PM10 samples also for 56 elements by inductively coupled plasma-mass spectrometry (ICP-MS). The average annual PM2.5 and PM10 was 24.4 ±â€¯13.0 µg m-3 and 26.7 ±â€¯15.1 µg m-3, respectively, in Prague-Libus, and 25.1 ±â€¯22.1 µg m-3 and 27.1 ±â€¯23.2 µg m-3, respectively, in Prague-Suchdol. Since the species forming large part of the aerosol mass were strongly correlated (Spearman's rank correlation coefficient rs > 0.80), the variability of PM2.5 and PM10 concentration was mainly driven by the local meteorology or regional and/or long range transport. PM10 mass closure was calculated based on analytical results with the average percentage of recalculated mass of 77 ±â€¯19% in Prague-Libus and 86 ±â€¯16% in Prague-Suchdol. The most abundant groups in PM10 at both sites during the four seasons were OM (Prague-Libus 34% and Prague-Suchdol 37%) and SIA (Prague-Libus 30% and Prague-Suchdol 34%). The Positive Matrix Factorization (PMF) was applied to the chemical composition of PM10 from both sites (124 samples) together to determine its sources. The nine factors were assigned as: mixed factor secondary sulphate and biomass burning, secondary sulphate, traffic, secondary nitrate, road dust, residential heating, aged sea salt, industry and mixed factor road salt along with aged sea salt. According to the polar plots and ventilation index (VI) east/west classification analysis the sources were separated based on origin to four categories local, urban agglomeration, regional and long range transport (LRT). The mixed source secondary sulphate and biomass burning, residential heating and industry were common sources of local origin at both sites. Prague-Suchdol was influenced by traffic related pollution from the urban agglomeration more than Prague-Libus where the traffic and road dust/salt were of local origin. The regional pollution by secondary sulphates and nitrate was also relevant at both sites along with long range transport of sea salt from North Atlantic Ocean, Norwegian Sea and North Sea. The contribution of the local sources to PM10 was significant mainly at Prague-Libus site. However, the sources of regional origin were also important and influence of urban agglomeration pollution to PM10 is not negligible as well.

The influence of local emissions and regional air pollution transport on a European air pollution hot spot.

The EU air quality standards have been frequently exceeded in one of the European air pollution hot spots: Ostrava. The aim of this study was to perform an air quality comparison between an urban site (Radvanice), which has a nearby metallurgical complex, and a suburban site (Plesná) to estimate air pollution sources and determine their local and/or regional origins. Twenty-four hour PM1 and PM10 (particular matter) concentrations, detailed mass size distributions (MSDs) to distinguish the sources of the fine and coarse PM, and their chemical compositions were investigated in parallel at both sites during the winter of 2014. Positive matrix factorization (PMF) was applied to the PM1 and PM10 chemical compositions to investigate their sources. During the measurement campaign, prevailing northeastern-southwestern (NE-SW) wind directions (WDs) were recorded. Higher average PM10 concentration was measured in Radvanice than in Plesná, whereas PM1 concentrations were similar at both sites. A source apportionment analysis revealed six and five sources for PM10 and PM1, respectively. In Radvanice, the amount of PM and the most chemical species were similar under SW and NE WD conditions. The dominant sources were industrial (43% for PM10 and 27% for PM1), which were caused by a large metallurgical complex located to the SW, and biomass burning (25% for PM10 and 36% for PM1). In Plesná, the concentrations of PM and all species significantly increased under NE WD conditions. Secondary inorganic aerosols were dominant, with the highest contributions deriving from the NE WD. Therefore, regional pollution transport from the industrial sector in Silesian Province (Poland) was evident. Biomass burning contributed 22% and 24% to PM10 and PM1, respectively. The air quality in Ostrava was influenced by local sources and regional pollution transport. The issue of poor air quality in this region is complex. Therefore, international cooperation from both states (the Czech Republic and Poland) is needed to achieve a reduction in air pollution levels.

New comprehensive approach for airborne asbestos characterisation and monitoring.

High concentrations of airborne asbestos in the ambient air are still a serious problem of air quality in numerous localities around the world. Since 2002, elevated concentrations of asbestos minerals of unknown origin have been detected in the ambient air of Pilsen, Czech Republic. To determine the asbestos fibre sources in this urban air, a systematic study was conducted. First, 14 bulk dust samples were collected in Pilsen at nine localities, and 6 bulk samples of construction aggregates for gravel production were collected in a quarry in the Pilsen-Litice district. The quarry is the largest quarry in the Pilsen region and the closest quarry to the built-up urban area. X-ray diffraction of the asbestos minerals revealed that monoclinic amphibole (MA, namely actinolite based on subsequent SEM-EDX analysis) in the bulk samples accounted for < 1-33% of the mass and that the highest values were found in the bulk dust samples from the railway platform of the Pilsen main railway station. Simultaneously, 24-h samples of airborne particulate matter (PM) at three localities in Pilsen were collected. Actinolite was identified in 40% of the PM samples. The relationship between the meteorology and presence of actinolite in the 24 PM10 samples was not proven, probably due to the long sampling integration time. Therefore, highly time-and-size-resolved PM sampling was performed. Second, sampling of size-segregated aerosols and measurements of the wind speed (WS), wind direction (WD), precipitation (P) and hourly PM10, PM2.5 and PM1 were conducted in a suburban locality near the quarry in two monthly highly time-resolved periods (30, 60, 120 min). Three/eight PM size fractions were sampled by a Davis Rotating-drum Uniform-size-cut Monitor (3/8DRUM) and analysed for the presences of asbestos fibres by scanning electron microscopy with energy dispersive x-ray spectroscopy (SEM-EDX). Asbestos fibre detection in highly time-resolved PM samples and current WD and WS determination allows the apportionment directionality of asbestos fibre sources. The number of critical actinolite asbestos fibres (length ≥ 5 µm and width < 3 µm, 3:1) increased with the PM1-10/PM10 and PM2.5-10/PM10 ratios, WS > 2 m s-1 and precipitation < 1 mm. Additionally, the number of critical actinolite asbestos fibres was not related to a specific WD. Therefore, we conclude that the sources of airborne critical actinolite asbestos fibres in Pilsen's urban area are omnipresent. Frequent use of construction aggregates and gravel from the metamorphic spilite quarries in the Pilsen region and in many localities around the urban area is a plausible explanation for the omnipresence of the critical actinolite asbestos fibres concentration in Pilsen's ambient air. Mitigation strategies to reduce the concentrations of critical actinolite asbestos fibres must be developed. Continuous monitoring and performing SEM-EDX analysis of highly time-and-size-resolved PM samples, correlated with fast changing WS and WD, seems to be a strong tool for efficiently controlling the mitigation strategies of critical actinolite asbestos fibres.

Comparison of PM2.5 chemical composition and sources at a rural background site in Central Europe between 1993/1994/1995 and 2009/2010: Effect of legislative regulations and economic transformation on the air quality.

From December 1993 to January 1995 and from October 2009 to October 2010, a total of 320 and 365 daily samples of the PM2.5 were collected at a rural background site (National Atmospheric Observatory Kosetice) in Central Europe. The PM2.5 samples were analyzed for 29 and 26 elements respectively by Particle-Induced X-ray Emission (PIXE) and water-soluble inorganic ions by Ion Chromatography (IC) in 2009/2010. The Positive Matrix Factorization (PMF) was applied to the chemical composition of PM2.5 to determine its sources. The decreasing trends of almost all elements concentrations, especially the metals regulated by the EU Directive (2004/107/EC) are evident. The annual median ratios indicate a decrease in concentrations of the PM2.5 elements. The slight increase of K concentrations and Spearman's rank correlation coefficient rs 0.09 K/Se points to a rise in residential wood combustion. The S concentrations are nearly comparable (higher mean in 2009/2010, while the annual median ratio is under 1). The five major source types in the mid-1990s were ascribed to brown coal combustion, oil combustion, sea salt and dust - long-range transport, re-suspended dust and black coal combustion. The industrial combustion of brown and/or black coal (rs 0.75 Se/As, rs 0.57 Ga/Ge and rs 0.20 As/Zn) and oil (rs 0.72 V/Ni) of the regional origin dominated. In the 1990s, the potential source regions were the border area of Czech Republic, German and Poland (brown coal), the Moravia-Silesia region at the Czech-Polish border (black coal), and Slovakia, Austria, Hungary, and the Balkans (oil). In 2009/2010, the apportioned sources were sulfate, residential heating, nitrate, industry, re-suspended dust, and sea salt and dust - long-range transport. The secondary sulfate from coal combustion and residential biomass burning (rs 0.96, K/K+) of local origin dominated. The declining trend of the elemental concentrations and change in the source pattern of the regional background PM2.5 in Central Europe between the mid-1990s and 2009/10 reflects the economic transformation and impact of stricter legislation in Central Europe.

An insight into the complex roles of metallothioneins in malignant diseases with emphasis on (sub)isoforms/isoforms and epigenetics phenomena.

Metallothioneins (MTs) belong to a group of small cysteine-rich proteins that are ubiquitous throughout all kingdoms. The main function of MTs is scavenging of free radicals and detoxification and homeostating of heavy metals. In humans, 16 genes localized on chromosome 16 have been identified to encode four MT isoforms labelled by numbers (MT-1-MT-4). MT-2, MT-3 and MT-4 proteins are encoded by a single gene. MT-1 comprises many (sub)isoforms. The known active MT-1 genes are MT-1A, -1B, -1E, -1F, -1G, -1H, -1M and -1X. The rest of the MT-1 genes (MT-1C, -1D, -1I, -1J and -1L) are pseudogenes. The expression and localization of individual MT (sub)isoforms and pseudogenes vary at intra-cellular level and in individual tissues. Changes in MT expression are associated with the process of carcinogenesis of various types of human malignancies, or with a more aggressive phenotype and therapeutic resistance. Hence, MT (sub)isoform profiling status could be utilized for diagnostics and therapy of tumour diseases. This review aims on a comprehensive summary of methods for analysis of MTs at (sub)isoforms levels, their expression in single tumour diseases and strategies how this knowledge can be utilized in anticancer therapy.

Source apportionment of aerosol particles at a European air pollution hot spot using particle number size distributions and chemical composition.

Ostrava in the Moravian-Silesian region (Czech Republic) is a European air pollution hot spot for airborne particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), and ultrafine particles (UFPs). Air pollution source apportionment is essential for implementation of successful abatement strategies. UFPs or nanoparticles of diameter <100 nm exhibit the highest deposition efficiency in human lungs. To permit apportionment of PM sources at the hot-spot including nanoparticles, Positive Matrix Factorization (PMF) was applied to highly time resolved particle number size distributions (NSD, 14 nm-10 µm) and PM0.09-1.15 chemical composition. Diurnal patterns, meteorological variables, gaseous pollutants, organic markers, and associations between the NSD factors and chemical composition factors were used to identify the pollution sources. The PMF on the NSD reveals two factors in the ultrafine size range: industrial UFPs (28%, number mode diameter - NMD 45 nm), industrial/fresh road traffic nanoparticles (26%, NMD 26 nm); three factors in the accumulation size range: urban background (24%, NMD 93 nm), coal burning (14%, volume mode diameter - VMD 0.5 µm), regional pollution (3%, VMD 0.8 µm) and one factor in the coarse size range: industrial coarse particles/road dust (2%, VMD 5 µm). The PMF analysis of PM0.09-1.15 revealed four factors: SIA/CC/BB (52%), road dust (18%), sinter/steel (16%), iron production (16%). The factors in the ultrafine size range resolved with NSD have a positive correlation with sinter/steel production and iron production factors resolved with chemical composition. Coal combustion factor resolved with NSD has moderate correlation with SIA/CC/BB factor. The organic markers homohopanes correlate with coal combustion and the levoglucosan correlates with urban background. The PMF applications to NSD and chemical composition datasets are complementary. PAHs in PM1 were found to be associated with coal combustion factor.

Regorafenib in the Real-Life Clinical Practice: Data from the Czech Registry.

OBJECTIVE: To describe the use of regorafenib for the treatment of metastatic colorectal cancer (mCRC) in clinical practice in the Czech Republic, and to describe the clinical outcomes of patients in terms of safety and survival. PATIENTS AND METHODS: The data of patients treated with regorafenib were extracted from the national CORECT registry. The CORECT registry is a non-interventional post-marketing database, gathering information about patients with CRC and treated with targeted agents. Twenty oncology centres in the Czech Republic contributed to this registry. Collected data included patients' characteristics, disease history, cancer treatments, response to treatments and safety. RESULTS: A total of 148 patients treated with regorafenib in clinical practice were analysed. At regorafenib initiation, almost all patients were fully active or slightly restricted in physical activity. Regorafenib was not administered as first-line treatment in any patient. Median progression-free survival was 3.5 months and median overall survival was 9.3 months. One-year survival rate was 44.6 %. Four partial responses were observed and 51 stable diseases. Progression was observed in 66 patients (44.6 %). The main reported adverse events were skin toxicity (5.4 %) and fatigue (2.0 %). CONCLUSIONS: Regorafenib is a well-established treatment for pretreated patients with mCRC, however real-life data are scarce. Our results demonstrated slightly better efficacy of regorafenib and better safety profile in patients with mCRC compared to the randomised trials.