Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p, and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.

• Klíčová slova
• breast cancer, integrative analysis, interaction network, multiomics, oxysterols, survival,
• MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádory prsu * patologie   MeSH
• oxysteroly * MeSH
• transkriptom genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• messenger RNA MeSH
• mikro RNA * MeSH
• oxysteroly * MeSH

INTRODUCTION: Human kinesin 14 (KIF14) is one of the 70 prognostic marker genes (so-called Amsterdam profile) previously identified by the microarray of breast carcinomas, and its high transcript expression in tumor specimens indicates a poor prognosis for patients. We performed a pilot study to explore the prognostic and predictive meaning of KIF14 germline genetic variability in breast cancer patients. METHODS: KIF14 coding sequence, including 5' and 3' untranslated regions and overlaps to introns for identification of splicing sites, was analyzed using next-generation sequencing in the testing set of blood DNA samples from 105 breast cancer patients with clinical follow-up. After rigorous evaluation of major allele frequency, haplotype blocks, in silico predicted functional aspects, expression quantitative trait loci, and clinical associations, eight single nucleotide variants were subsequently validated in the evaluation set of 808 patients. RESULTS: Carriers of minor alleles G (rs17448931) or T (rs3806362) had significantly shorter overall survival than wild type homozygotes (p = 0.010 and p = 0.023, respectively) thus successfully replicating the results of the testing set. Both associations remained significant in the multivariate Cox regression analysis, including molecular subtype and stage as covariates (hazard ratio, HR = 1.7, 95% confidence interval (CI) = 1.1-2.8 for rs17448931 and HR = 1.9, CI 1.2-3.0 for rs3806362). DISCUSSION: In conclusion, our preliminary data suggest that minor alleles in rs17448931 and rs3806362 of KIF14 represent candidate biomarkers of poor prognosis of breast cancer patients. After pending validation in independent populations and eventual functional characterization, these candidates might become useful biomarkers in the clinics.

• MeSH
• kineziny * MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory prsu * patologie   MeSH
• nukleotidy MeSH
• onkogenní proteiny genetika   metabolismus   MeSH
• pilotní projekty MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• KIF14 protein, human MeSH Prohlížeč
• kineziny * MeSH
• nádorové biomarkery MeSH
• nukleotidy MeSH
• onkogenní proteiny MeSH

Early detection of cancer is one of the unmet needs in clinical medicine. Peripheral blood analysis is a preferred method for efficient population screening, because blood collection is well embedded in clinical practice and minimally invasive for patients. Lipids are important biomolecules, and variations in lipid concentrations can reflect pathological disorders. Lipidomic profiling of human plasma by the coupling of ultrahigh-performance supercritical fluid chromatography and mass spectrometry is investigated with the aim to distinguish patients with breast, kidney, and prostate cancers from healthy controls. The mean sensitivity, specificity, and accuracy of the lipid profiling approach were 85%, 95%, and 92% for kidney cancer; 91%, 97%, and 94% for breast cancer; and 87%, 95%, and 92% for prostate cancer. No association of statistical models with tumor stage is observed. The statistically most significant lipid species for the differentiation of cancer types studied are CE 16:0, Cer 42:1, LPC 18:2, PC 36:2, PC 36:3, SM 32:1, and SM 41:1 These seven lipids represent a potential biomarker panel for kidney, breast, and prostate cancer screening, but a further verification step in a prospective study has to be performed to verify clinical utility.

• MeSH
• časná detekce nádoru MeSH
• dospělí MeSH
• heparin chemie   MeSH
• hmotnostní spektrometrie MeSH
• ledviny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipidomika * MeSH
• lipidy chemie   MeSH
• mladý dospělý MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory prostaty metabolismus   MeSH
• nádory prsu metabolismus   MeSH
• plocha pod křivkou MeSH
• prospektivní studie MeSH
• prostata metabolismus   MeSH
• prsy metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• reprodukovatelnost výsledků MeSH
• retrospektivní studie MeSH
• ROC křivka MeSH
• senioři MeSH
• statistické modely MeSH
• studie případů a kontrol MeSH
• superkritická fluidní chromatografie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• heparin MeSH
• lipidy MeSH
• nádorové biomarkery MeSH

INTRODUCTION: The authors report long-term outcomes in patients who received neoadjuvant chemoradiotherapy and consequently underwent hybrid oesophagectomy for oesophageal cancer (OC). AIM: To evaluate long-term outcomes in patients suffering from OC, who underwent hybrid oesophagectomy. MATERIAL AND METHODS: Our cohort consisted of patients suffering from OC, who received neoadjuvant chemoradiotherapy. Hybrid esophagectomy was performed 8-10 weeks after oncological treatment. RESULTS: Ninety-four patients underwent surgery for OC from 2011 to 2015. Histology revealed adenocarcinoma in 60.6%, squamous cell carcinoma (SCC) in 36.2%, and other type of cancer in 3.2%. Seventy-three (77.7%) patients with advanced stage (T3-4, N0-2, M0) were indicated to receive neoadjuvant chemoradiotherapy (nCRT). Trans-hiatal hybrid oesophagectomy was performed in 83 (88.3%) patients. Transthoracic hybrid oesophagectomy was performed in 11 (11.7%) patients. Histology of the resected specimens of 18 (24.7%) patients did not reveal OC, i.e. pathological complete response (pCR). In our cohort, we proved an association between occurrence of pCR and age as well as disease-free survival (DFS). The patients who presented with pCR were significantly younger - below 60 years of age (p = 0.017). They also showed significantly higher mean DFS (p = 0.004). CONCLUSIONS: Combined oesophagectomy with neoadjuvant chemoradiotherapy results in a better long-term outcome in patients suffering from oesophageal cancer. In our set of patients who underwent hybrid esophagectomy, satisfactory short-term and especially long-term results of surgical treatment for oesophageal cancer were observed.

• Klíčová slova
• hybrid oesophagectomy, long-term outcome, oesophageal cancer, pathological complete response,
• Publikační typ
• časopisecké články MeSH

Breast cancer is the most frequent cancer in the female population worldwide. The role of germline genetic variability in cytochromes P450 (CYP) in breast cancer prognosis and individualized therapy awaits detailed elucidation. In the present study, we used the next-generation sequencing to assess associations of germline variants in the coding and regulatory sequences of all human CYP genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 22 prioritized variants associating with a response or survival in the above evaluation phase were then analyzed by allelic discrimination in the large confirmation set (n = 802). Associations of variants in CYP1B1, CYP4F12, CYP4X1, and TBXAS1 with the response to the neoadjuvant cytotoxic chemotherapy were replicated by the confirmation phase. However, just association of variant rs17102977 in CYP4X1 passed the correction for multiple testing and can be considered clinically and statistically validated. Replicated associations for variants in CYP4X1, CYP24A1, and CYP26B1 with disease-free survival of all patients or patients stratified to subgroups according to therapy type have not passed a false discovery rate test. Although statistically not confirmed by the present study, the role of CYP genes in breast cancer prognosis should not be ruled out. In conclusion, the present study brings replicated association of variant rs17102977 in CYP4X1 with the response of patients to the neoadjuvant cytotoxic chemotherapy and warrants further research of genetic variation CYPs in breast cancer.

• Klíčová slova
• breast cancer, cytochrome P450, next-generation sequencing, prognosis, response, survival, therapy,
• MeSH
• genetická variace * MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádorové proteiny * genetika   metabolismus   MeSH
• nádory prsu * farmakoterapie   enzymologie   genetika   mortalita   MeSH
• neoadjuvantní terapie * MeSH
• přežití po terapii bez příznaků nemoci MeSH
• systém (enzymů) cytochromů P-450 * genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• Názvy látek
• nádorové proteiny * MeSH
• systém (enzymů) cytochromů P-450 * MeSH

BACKGROUND AND OBJECTIVE: Membrane solute carrier transporters play an important role in the transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess the prognostic relevance of gene expression and genetic variability of selected solute carrier transporters in breast cancer. METHODS: Gene expression was determined by quantitative real-time polymerase chain reaction. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in DNA extracted from the blood of patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology. Common variants (minor allele frequency ≥ 5%) with in silico-predicted functional relevance were further analyzed in a large cohort of patients with breast cancer (n = 815) and their prognostic and predictive potential was estimated (validation phase). RESULTS: A gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in the prognosis of patients with breast cancer. In total, 135 genetic variants (20 novel) were identified in both genes in the exploratory phase. Of these variants, 130 were non-coding, three missense, and two synonymous. One common variant in SLCO1A2 and four variants in SLC46A1 were predicted to be pathogenic by in silico programs and subsequently validated. A SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients. CONCLUSIONS: This study revealed the prognostic value of a SLC46A1 haplotype block for breast cancer that should be further studied.

• MeSH
• analýza přežití MeSH
• folátový přenašeč spřažený s transportem protonů genetika   MeSH
• genetická variace * MeSH
• haplotypy MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory prsu genetika   MeSH
• přenašeče organických aniontů genetika   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza DNA MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• folátový přenašeč spřažený s transportem protonů MeSH
• nádorové biomarkery MeSH
• přenašeče organických aniontů MeSH
• SLC46A1 protein, human MeSH Prohlížeč
• SLCO1A2 protein, human MeSH Prohlížeč

Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations.

• Klíčová slova
• ABC transporter, breast cancer, competitive allele-specific PCR, disease-free survival, next-generation sequencing, therapy response,
• MeSH
• ABC transportéry genetika   MeSH
• alely MeSH
• frekvence genu MeSH
• genetická variace * MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• Kaplanův-Meierův odhad MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• nádorové biomarkery * MeSH
• nádory prsu diagnóza   genetika   mortalita   terapie   MeSH
• neoadjuvantní terapie MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• výsledek terapie MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• nádorové biomarkery * MeSH

AIM: The aim of this study was to reduce the severe respiratory complications of esophageal cancer surgery often leading to death. METHODS: Two groups of patients operated on for esophageal cancer were evaluated in this retrospective analysis. The first group was operated between 2006-2011, prior to the implementation of preoperative microbiological examination while the second group had surgery between 2012-2017 after implementation of this examination. RESULTS: In total, 260 patients, 220 males and 40 females underwent esophagectomy. Between 2006-2011, 113 (87.6%) males and 16 (12.4%) females and between 2012-2017, esophagectomy was performed in 107 (81.7%) males and 24 (18.3%) females. In the first cohort, 10 patients died due to respiratory complications. The 30-day mortality was 6.9% and 90-day was 9.3%. In the second cohort, 4 patients died from respiratory complications. The 30-day mortality was 1.5% and 90-day mortality was 3.1%. With regard to the incidence of respiratory complications (P=0.014), these occurred more frequently in patients with sputum collection, however, severe respiratory complications were more often observed in patients without sputum collection. Significantly fewer patients died (P=0.036) in the group with sputum collection. The incidence of respiratory complications was very significantly higher in the patients who died (P<0.0001). CONCLUSION: The incidence of severe respiratory complications (causing death) may be reduced by identifying clinically silent respiratory tract infections.

• Klíčová slova
• esophageal cancer, morbidity, mortality, preoperative examination, respiratory complications,
• MeSH
• dospělí MeSH
• dýchací soustava mikrobiologie   MeSH
• ezofagektomie škodlivé účinky   MeSH
• incidence MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory jícnu mortalita   chirurgie   MeSH
• pooperační komplikace etiologie   MeSH
• poruchy dýchání etiologie   mikrobiologie   mortalita   MeSH
• předoperační péče metody   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Ultrahigh-performance supercritical fluid chromatography - mass spectrometry (UHPSFC/MS), ultrahigh-performance liquid chromatography - mass spectrometry (UHPLC/MS), and matrix-assisted laser desorption/ionization (MALDI) - MS techniques were used for the lipidomic characterization of exosomes isolated from human plasma. The high-throughput methods UHPSFC/MS and UHPLC/MS using a silica-based column containing sub-2 μm particles enabled the lipid class separation and the quantitation based on exogenous class internal standards in <7 minute run time. MALDI provided the complementary information on anionic lipid classes, such as sulfatides. The nontargeted analysis of 12 healthy volunteers was performed, and absolute molar concentration of 244 lipids in exosomes and 191 lipids in plasma belonging to 10 lipid classes were quantified. The statistical evaluation of data included principal component analysis, orthogonal partial least square discriminant analysis, S-plots, p-values, T-values, fold changes, false discovery rate, box plots, and correlation plots, which resulted in the information on lipid changes in exosomes in comparison to plasma. The major changes were detected in the composition of triacylglycerols, diacylglycerols, phosphatidylcholines, and lysophosphatidylcholines, whereby sphingomyelins, phosphatidylinositols, and sulfatides showed rather similar profiles in both biological matrices.

• Klíčová slova
• Exosomes, Lipidomics, Lipids, Liquid chromatography, Mass spectrometry, Plasma, Supercritical fluid chromatography,
• MeSH
• diglyceridy krev   izolace a purifikace   metabolismus   MeSH
• dospělí MeSH
• exozómy chemie   metabolismus   MeSH
• fosfatidylcholiny krev   izolace a purifikace   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipidomika metody   MeSH
• lysofosfatidylcholiny krev   izolace a purifikace   metabolismus   MeSH
• metabolismus lipidů * MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• superkritická fluidní chromatografie metody   MeSH
• triglyceridy krev   izolace a purifikace   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• diglyceridy MeSH
• fosfatidylcholiny MeSH
• lysofosfatidylcholiny MeSH
• triglyceridy MeSH

The ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC/MS) method was optimized and validated for the determination of oxylipins in human plasma using the targeted approach with selected reaction monitoring (SRM) in the negative-ion electrospray ionization (ESI) mode. Reversed phase UHPLC separation on an octadecylsilica column enabled the analysis of 63 oxylipins including numerous isomeric species within 12-min run time. The method was validated (calibration curve, linearity, limit of detection, limit of quantification, carry-over, precision, accuracy, recovery rate, and matrix effect) and applied to 40 human female plasma samples from breast cancer patients and age-matched healthy volunteers (control). Thirty-six oxylipins were detected in human plasma with concentrations above the limit of detection, and 21 of them were quantified with concentrations above the limit of quantitation. The concentrations determined in healthy controls are in a good agreement with previously reported data on human plasma. Quantitative data were statistically evaluated by multivariate data analysis (MDA) methods including principal component analysis (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA). S-plot and box plots showed that 13-HODE, 9-HODE, 13-HOTrE, 9-HOTrE, and 12-HHTrE were the most upregulated oxylipin species in plasma of breast cancer patients.

• Klíčová slova
• Breast cancer, Eicosanoids, Human plasma, Oxylipins, Statistical analysis, UHPLC/MS,
• MeSH
• analýza hlavních komponent MeSH
• chromatografie s reverzní fází metody   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací metody   MeSH
• lidé MeSH
• limita detekce MeSH
• multivariační analýza MeSH
• nádory prsu krev   MeSH
• oxylipiny krev   MeSH
• reprodukovatelnost výsledků MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• validační studie MeSH
• Názvy látek
• oxylipiny MeSH