BACKGROUND: The study aimed to evaluate the impact of integrating molecular classification with imaging-based preoperative staging on risk stratification prediction in endometrial cancer patients in accordance with ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology) 2021 guidelines. METHODS: A retrospective cohort of 143 endometrial cancer patients was analyzed to assess changes in preoperative risk stratification after incorporating molecular classification into clinical evaluation. Preoperative clinical staging was primarily based on transvaginal ultrasound imaging. The overall agreement between preoperative risk group estimates (with/without molecular classification) and final postoperative outcomes was assessed using weighted Cohen's Kappa, with bootstrap 95% confidence intervals and quadratic weights. RESULTS: The addition of molecular classification significantly improved preoperative risk stratification accuracy (from 59.4 to 73.4%), particularly for patients post-operatively classified as high-risk. Kappa values indicated an improvement in overall agreement between preoperative and postoperative risk stratification following the addition of molecular classification, from 0.551 (95% CI: 0.430-0.671) to 0.767 (95% CI: 0.675-0.849). The non-overlapping confidence intervals indicated statistical significance. Preoperative assessment without molecular input tended to underestimate risk stratification. However, 26.6% of patients remained misclassified due to other factors, mostly within the intermediate and high-intermediate risk groups. CONCLUSIONS: Incorporating molecular classification enhances preoperative risk stratification and has the potential to tailor surgical treatment. Further validation through prospective multicentric studies is needed to support our findings.

• Klíčová slova
• ESGO/ESTRO/ESP 2021 guidelines, Endometrial cancer, Molecular classification, Next-generation sequencing, Risk stratification, Sentinel node biopsy, Ultrasonography,
• MeSH
• dospělí MeSH
• hodnocení rizik metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory endometria * chirurgie   patologie   klasifikace   diagnostické zobrazování   genetika   diagnóza   MeSH
• předoperační období MeSH
• předoperační péče MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Adrenergic activation of protein kinase A (PKA) in cardiac muscle targets the sarcolemma, sarcoplasmic reticulum, and contractile apparatus to increase contractile force and heart rate. In the thin filaments of the contractile apparatus, cardiac troponin I (cTnI) Ser22 and Ser23 in the cardiac-specific N-terminal peptide (NcTnI: residues 1 to 32) are the targets for PKA phosphorylation. Phosphorylation causes a 2-3 fold decrease of affinity of cTn for Ca2+ associated with a higher rate of Ca2+ dissociation from cTnC leading to a faster relaxation rate of the cardiac muscle (lusitropy). Cardiomyopathy-linked mutations primarily affect Ca2+ regulation or the PKA-dependent modulatory system, such that Ca2+-sensitivity becomes independent of phosphorylation level (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of Ca2+-sensitivity could have potential for treatment of these pathologies. We have found that a number of small molecules, including silybin B, resveratrol and EGCG, can restore coupling in single filament assays. METHODS: We did molecular dynamics simulations (5x1500ns for each condition) of the unphosphorylated and phosphorylated cardiac troponin core with the G159D DCM mutation in the presence of the 5 ligands and analysed the effects on several dynamic parameters. We also studied the effect of the ligands on the contractility of cardiac muscle myocytes with ACTC E99K and TNNT2 R92Q mutations in response to dobutamine. RESULTS: Silybin B, EGCG and resveratrol restored the phosphorylation-induced change in molecular dynamics to wild-type values, whilst silybin A, an inactive isomer of silybin B, and Epicatechin gallate, an EGCG analogue that does not recouple, did not. We analysed the atomic-level changes induced by ligand binding to explain recoupling. Mutations ACTC E99K and TNNT2 R92Q blunt the increased relaxation speed response to β1 adrenergic stimulation of cardiac myocytes and we found that resveratrol, EGCG and silybin B could restore the β1 adrenergic response, whereas silybin A did not. DISCUSSION: The uncoupling phenomenon caused by cardiomyopathy-related mutations and the ability of small molecules to restore coupling in vitro and lusitropy in myocytes is observed at the cellular, molecular and atomistic levels therefore, restoring lusitropy is a suitable target for treatment. Further research on compounds that restore lusitropy is thus indicated as treatments for genetic cardiomyopathies. Further molecular dynamics simulations could define the specific properties needed for recoupling and allow for the prediction and design of potential new drugs.

• Klíčová slova
• EGCG, PKA phosphorylation, cardiomyopathy, lusitropy, molecular dynamics simulation, myocyte contraction, silybin, troponin (cTnI),
• Publikační typ
• časopisecké články MeSH

Cardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the activation of cardiac fibroblasts (cFbs) to myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictive in vitro models of heart fibrosis has so far hampered the search for innovative treatments, as most of the cellular-based in vitro reductionist models do not take into account the leading role of ECM cues in driving the progression of the pathology. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (α-SMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblasts in vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere assembly, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis.

• Klíčová slova
• Cardiac fibrosis modelling, Decellularized extracellular matrix, Induced pluripotent stem cells, iPSC-derived-cardiac fibroblasts, iPSC-derived-cardiomyocytes,
• MeSH
• buněčná diferenciace MeSH
• extracelulární matrix * metabolismus   MeSH
• fenotyp * MeSH
• fibróza * MeSH
• indukované pluripotentní kmenové buňky * metabolismus   MeSH
• kardiomyocyty * metabolismus   patologie   MeSH
• lidé MeSH
• myofibroblasty patologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Glioblastoma is the commonest primary malignant brain tumor, with a very poor prognosis and short overall survival. It is characterized by its high intra- and intertumoral heterogeneity, in terms of both the level of single-nucleotide variants, copy number alterations, and aneuploidy. Therefore, routine diagnosis can be challenging in some cases. We present a complicated case of glioblastoma, which was characterized with five cytogenomic methods: interphase fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, comparative genomic hybridization array and single-nucleotide polymorphism, targeted gene panel, and whole-genome sequencing. These cytogenomic methods revealed classical findings associated with glioblastoma, such as a lack of IDH and TERT mutations, gain of chromosome 7, and loss of chromosome 10. At least three pathological clones were identified, including one with whole-genome duplication, and one with loss of 1p and suspected loss of 19q. Deletion and mutation of the TP53 gene were detected with numerous breakends on 17p and 20q. Based on these findings, we recommend a combined approach to the diagnosis of glioblastoma involving the detection of copy number alterations, mutations, and aneuploidy. The choice of the best combination of methods is based on cost, time required, staff expertise, and laboratory equipment. This integrated strategy could contribute directly to tangible improvements in the diagnosis, prognosis, and prediction of the therapeutic responses of patients with brain tumors.

• Klíčová slova
• I-FISH, MLPA, WGS, aCGH/SNP, cytogenomics, diagnostics, gene panel,
• MeSH
• glioblastom * genetika   patologie   diagnóza   MeSH
• hybridizace in situ fluorescenční metody   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku * genetika   patologie   diagnóza   MeSH
• prognóza MeSH
• srovnávací genomová hybridizace metody   MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• nádorové biomarkery MeSH

OBJECTIVE: This study aims to evaluate the efficacy of the Uniform Data Set (UDS) 2 battery in distinguishing between individuals with mild cognitive impairment (MCI) attributable to Alzheimer's disease (MCI-AD) and those with MCI due to other causes (MCI-nonAD), based on contemporary AT(N) biomarker criteria. Despite the implementation of the novel UDS 3 battery, the UDS 2 battery is still used in several non-English-speaking countries. METHODS: We employed a cross-sectional design. A total of 113 Czech participants with MCI underwent a comprehensive diagnostic assessment, including cerebrospinal fluid biomarker evaluation, resulting in two groups: 45 individuals with prodromal AD (A+T+) and 68 participants with non-Alzheimer's pathological changes or normal AD biomarkers (A-). Multivariable logistic regression analyses were employed with neuropsychological test scores and demographic variables as predictors and AD status as an outcome. Model 1 included UDS 2 scores that differed between AD and non-AD groups (Logical Memory delayed recall), Model 2 employed also Letter Fluency and Rey's Auditory Verbal Learning Test (RAVLT). The two models were compared using area under the receiver operating characteristic curves. We also created separate logistic regression models for each of the UDS 2 scores. RESULTS: Worse performance in delayed recall of Logical Memory significantly predicted the presence of positive AD biomarkers. In addition, the inclusion of Letter Fluency RAVLT into the model significantly enhanced its discriminative capacity. CONCLUSION: Our findings demonstrate that using Letter Fluency and RAVLT alongside the UDS 2 battery can enhance its potential for differential diagnostics.

• Klíčová slova
• Alzheimer’s disease, Assessment, Mild cognitive impairment,
• MeSH
• Alzheimerova nemoc * diagnóza   mozkomíšní mok   MeSH
• amyloidní beta-protein mozkomíšní mok   MeSH
• biologické markery * mozkomíšní mok   MeSH
• diferenciální diagnóza MeSH
• kognitivní dysfunkce * diagnóza   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neuropsychologické testy * normy   statistika a číselné údaje   MeSH
• proteiny tau mozkomíšní mok   MeSH
• průřezové studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• biologické markery * MeSH
• proteiny tau MeSH

The curvature of the lumbar spine plays a critical role in maintaining spinal function, stability, weight distribution, and load transfer. We have developed a mathematical model of the lumbar spine curve by introducing a novel mechanism: minimization of the elastic bending energy of the spine with respect to two biomechanical parameters: dimensionless lumbosacral spinal curvature c LS and dimensionless curvature increment along the spine CI. While most of the biomechanical studies focus on a particular segment of the spine, the distinction of the presented model is that it describes the shape of the thoracolumbar spine by considering it as a whole (non-locally) and thus includes interactions between the different spinal levels in a holistic approach. From radiographs, we have assessed standard geometrical parameters: lumbar lordosis LL, pelvic incidence PI, pelvic tilt PT, sacral slope ψ0 and sagittal balance parameter SB = sagittal vertical axis (SVA)/sacrum-bicoxofemoral distance (SFD) of 42 patients with lumbar spinal stenosis (SS) or degenerative spondylolisthesis (SL) and 21 radiologically normal subjects. SB statistically significantly correlated with model parameters c L5 (r = -0.34, p = 0.009) and -CI (r = 0.33, p = 0.012) but not with standard geometrical parameters. A statistically significant difference with sufficient statistical power between the patients and the normal groups was obtained for c LS, CI, and SB but not for standard geometrical parameters. The model provides a possibility to predict changes in the thoracolumbar spine shape in surgery planning and in assessment of different spine pathologies.

• Klíčová slova
• Elastic energy, Lumbar lordosis, Sagittal balance, Spine curvature, Thoracolumbar spine,
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The aim of this study was to retrospectively analyse the ultrasound findings in the axillary lymph nodes in breast cancer patients with morphological changes that required biopsy. In most cases the morphological changes were minimal. MATERIALS AND METHODS: Between January 2014 and September 2019 examination of axillary lymph nodes with subsequent core-biopsy was performed in 185 breast cancer patients at the Department of Radiology. Lymph node metastases were detected in 145 cases, while in the remaining 40 cases benign changes or normal lymph node (LN) histology was observed. Ultrasound morphological characteristics and the sensitivity and specificity were evaluated retrospectively. Seven ultrasound characteristics were evaluated - diffuse cortical thickening, focal cortical thickening, absence of the hilum, cortical non-homogeneities, L/T ratio (longitudinal to transverse axis), type of vascularization and perinodal oedema. RESULTS AND CONCLUSION: It is a diagnostic challenge to recognize metastases in the lymph nodes with minimal morphological changes. The most specific signs are non-homogeneities in the cortex of the lymph node as well as the absence of fat hilum and perinodal oedema. Metastases are significantly more frequent in LNs with a lower L/T ratio, in LNs with perinodal oedema and with a peripheral type of vascularization. Biopsy of these lymph nodes is necessary to confirm or exclude metastases, especially if it affects the type of treatment.

• Klíčová slova
• breast cancer, lymph node, metastases, ultrasound,
• MeSH
• axila MeSH
• lidé MeSH
• lymfatické metastázy * diagnostické zobrazování   patologie   MeSH
• lymfatické uzliny * krevní zásobení   diagnostické zobrazování   patologie   MeSH
• nádory prsu * diagnostické zobrazování   patologie   MeSH
• patologická angiogeneze diagnostické zobrazování   patologie   MeSH
• prediktivní hodnota testů MeSH
• retrospektivní studie MeSH
• senzitivita a specificita MeSH
• ultrasonografie * metody   statistika a číselné údaje   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH

Epithelial-mesenchymal transition (EMT) is a crucial and fundamental mechanism in many cellular processes, beginning with embryogenesis via tissue remodulation and wound healing, and plays a vital role in tumorigenesis and metastasis formation. EMT is a complex process that involves many transcription factors and genes that enable the tumor cell to leave the primary location, invade the basement membrane, and send metastasis to other tissues. Moreover, it may help the tumor avoid the immune system and establish radioresistance and chemoresistance. It may also change the normal microenvironment, thus promoting other key factors for tumor survival, such as hypoxia-induced factor-1 (HIF-1) and promoting neoangiogenesis. In this review, we will focus mainly on the role of EMT in benign prostate disease and especially in the process of establishment of malignant prostate tumors, their invasiveness, and aggressive behavior. We will discuss relevant study methods for EMT evaluation and possible clinical implications. We will also introduce clinical trials conducted according to CONSORT 2010 that try to harness EMT properties in the form of circulating tumor cells to predict aggressive patterns of prostate cancer. This review will provide the most up-to-date information to establish a keen understanding of the cellular and microenvironmental processes for developing novel treatment lines by modifying or blocking the pathways.

• Klíčová slova
• BPH, EMT, epithelial-mesenchymal transition, prostate cancer, transcription factors,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Although clinical applications represent the next challenge in single-cell genomics and digital pathology, we still lack computational methods to analyze single-cell or pathomics data to find sample-level trajectories or clusters associated with diseases. This remains challenging as single-cell/pathomics data are multi-scale, i.e., a sample is represented by clusters of cells/structures, and samples cannot be easily compared with each other. Here we propose PatIent Level analysis with Optimal Transport (PILOT). PILOT uses optimal transport to compute the Wasserstein distance between two individual single-cell samples. This allows us to perform unsupervised analysis at the sample level and uncover trajectories or cellular clusters associated with disease progression. We evaluate PILOT and competing approaches in single-cell genomics or pathomics studies involving various human diseases with up to 600 samples/patients and millions of cells or tissue structures. Our results demonstrate that PILOT detects disease-associated samples from large and complex single-cell or pathomics data. Moreover, PILOT provides a statistical approach to find changes in cell populations, gene expression, and tissue structures related to the trajectories or clusters supporting interpretation of predictions.

• Klíčová slova
• Clustering, Disease Progression, Multi-scale Analysis, Optimal Transport, Wasserstein Distance,
• MeSH
• algoritmy * MeSH
• genomika * metody   MeSH
• lidé MeSH
• shluková analýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: To investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer. METHODS: Patients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated. RESULTS: Thirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31-66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS. CONCLUSION: Mid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

• Klíčová slova
• Chemotherapy response, Diffusion weighted MRI, Dynamic 18F-FDG PET, Dynamic contrast enhanced MRI, Recurrence,
• MeSH
• dospělí MeSH
• fluorodeoxyglukosa F18 terapeutické užití   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• nádory prsu * diagnostické zobrazování   farmakoterapie   MeSH
• neoadjuvantní terapie metody   MeSH
• pozitronová emisní tomografie metody   MeSH
• prospektivní studie MeSH
• radiofarmaka terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• fluorodeoxyglukosa F18 MeSH
• radiofarmaka MeSH