The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT1 and AT2) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT1, AT2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases.

• MeSH
• angiotensin I * metabolismus   MeSH
• angiotensin II * MeSH
• kardiovaskulární nemoci metabolismus   genetika   MeSH
• krevní tlak fyziologie   MeSH
• krysa rodu rattus MeSH
• ledviny metabolismus   MeSH
• nemoci ledvin metabolismus   genetika   MeSH
• peptidové fragmenty * metabolismus   MeSH
• potkani Sprague-Dawley * MeSH
• potkani transgenní * MeSH
• protoonkogen Mas MeSH
• receptor angiotensinu typ 1 genetika   metabolismus   MeSH
• receptory spřažené s G-proteiny genetika   metabolismus   MeSH
• rekombinantní fúzní proteiny metabolismus   MeSH
• renin-angiotensin systém * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: The purpose of this study is to report novel and unusual USP6 fusion partners in aneurysmal bone cysts (ABCs). These findings may be useful in routine diagnostics as well as in studying the biology of USP6-related disorders. METHODS: A cohort of seven patients diagnosed with ABC examined between 2014 and 2023 at Motol University Hospital in Prague was included into this retrospective non-randomised study. All cases were analysed using histopathological evaluation, immunohistochemistry and Anchored multiplex RNA methods. Demographic characteristics and clinical data were also analysed. RESULTS: We identified two novel (ZFX and IP6K2), three unusual (MEF2A, EIF1 and COL1A2) and two common (CDH11) fusion partners with USP6 gene among all seven cases of ABC. CONCLUSIONS: Cases in our study were diagnosed as ABCs due to characteristic clinical and morphological presentation. However, not all cases are as self-evident, and molecular testing is necessary. The identification of these gene alterations can be useful in distinction between true ABC and ABC-like changes among many benign and malignant bone tumours.

• MeSH
• aneurysmatické kostní cysty * genetika   patologie   MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• kolagen typu I MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• retrospektivní studie MeSH
• thiolesterasa ubikvitinu * genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Myoepithelial neoplasms of the skin and soft tissue still represent a confusing and somewhat controversial field in pathology as it appears that this category includes several different entities. However, recent studies have suggested that both apocrine mixed tumors (AMT) and cutaneous myoepitheliomas (CM) harbor identical chromosomal rearrangements involving the PLAG1 gene and hence may represent a morphological spectrum. The aim of the present study was to share our institutional experience with these tumors and specifically focus on studying their immunohistochemical and molecular features to further assess their relatedness. Eleven cases of AMT and 7 cases of CM were collected and analyzed using immunohistochemistry (IHC), PLAG1 FISH, and Archer FusionPlex assay. There were 14 male and 4 female patients with ages ranging from 26 to 85 years (median 55.8 years, mean 58.5 years). AMTs were mainly located in the head and neck (n = 10), while CMs were mainly located in the acral sites (n = 5). PLAG1 IHC was diffusely strongly positive in 14/17 (82%) cases, whereas a single case of AMT diffusely expressed HMGA2. Both tumor groups showed PLAG1 gene fusions which were detected in 6/13 analyzable samples (AMT, n = 4 and CM, n = 2), and included TRPS1::PLAG1 (n = 3), NDRG1::PLAG1 (n = 1), CTNNB1::PLAG1 (n = 1) and a novel PXDNL::PLAG1 fusion (n = 1). The remaining 5 cases were negative, 5 were not analyzable and the single case positive for HMGA2 by IHC revealed a potential HMGA2 gene rearrangement. The cases were further studied by FISH, with 12/17 cases showing PLAG1 gene rearrangement (AMT, n = 8 and CM, n = 4). Altogether, 14/18 cases showed PLAG1 gene rearrangement by at least one of the methods. PLAG1 immunohistochemistry had a 92% specificity and sensitivity. Our study provided additional data to suggest that AMT and CM share overlapping morphological and immunohistochemical features as well as molecular background characterized by PLAG1 gene fusions and thus represent a morphological spectrum. In addition, we identified a novel PXDNL::PLAG1 fusion and suggested that rare cases may harbor HMGA2 gene alterations which seem to be mutually exclusive with PLAG1 gene fusions. The relatedness of these tumors to salivary gland myoepithelial neoplasms and distinctness from eccrine mixed tumors and other skin and soft tissue myoepithelial neoplasms with EWSR1/FUS fusions is discussed.

• MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• genová přestavba * MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myoepiteliální nádor * genetika   patologie   MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory komplexní a smíšené genetika   patologie   chemie   MeSH
• nádory kůže * genetika   patologie   MeSH
• nádory potních žláz genetika   patologie   MeSH
• protein HMGA2 * genetika   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
• srovnávací studie MeSH

Achieving a reliable and accurate biomedical image segmentation is a long-standing problem. In order to train or adapt the segmentation methods or measure their performance, reference segmentation masks are required. Usually gold-standard annotations, i.e. human-origin reference annotations, are used as reference although they are very hard to obtain. The increasing size of the acquired image data, large dimensionality such as 3D or 3D + time, limited human expert time, and annotator variability, typically result in sparsely annotated gold-standard datasets. Reliable silver-standard annotations, i.e. computer-origin reference annotations, are needed to provide dense segmentation annotations by fusing multiple computer-origin segmentation results. The produced dense silver-standard annotations can then be either used as reference annotations directly, or converted into gold-standard ones with much lighter manual curation, which saves experts' time significantly. We propose a novel full-resolution multi-rater fusion convolutional neural network (CNN) architecture for biomedical image segmentation masks, called DeepFuse, which lacks any down-sampling layers. Staying everywhere at the full resolution enables DeepFuse to fully benefit from the enormous feature extraction capabilities of CNNs. DeepFuse outperforms the popular and commonly used fusion methods, STAPLE, SIMPLE and other majority-voting-based approaches with statistical significance on a wide range of benchmark datasets as demonstrated on examples of a challenging task of 2D and 3D cell and cell nuclei instance segmentation for a wide range of microscopy modalities, magnifications, cell shapes and densities. A remarkable feature of the proposed method is that it can apply specialized post-processing to the segmentation masks of each rater separately and recover under-segmented object parts during the refinement phase even if the majority of inputs vote otherwise. Thus, DeepFuse takes a big step towards obtaining fast and reliable computer-origin segmentation annotations for biomedical images.

• MeSH
• lidé MeSH
• neuronové sítě * MeSH
• počítačové zpracování obrazu * metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Assessing the biological behavior of uterine inflammatory myofibroblastic tumors (IMTs) remains challenging. This study evaluated previously proposed risk schemes and features in 9 IMTs (6 indolent, 3 aggressive) by integrating clinicopathological features, immunohistochemistry, and next-generation sequencing (NGS). High-risk features (necrosis, infiltrative growth, nuclear atypia) were present in both groups, with LVSI in 1/3 of aggressive IMTs. Aberrant p16 expression and CDKN2A/2B deletions were noted in 2/3 aggressive cases. All cases harbored ALK fusions, wild-type p53, and lacked pathogenic gene mutations. Aggressive cases harbored arm-level and segmental copy number gains/losses at chr 1, 2, X, and had significantly reduced AR expression. The clinicopathological risk stratification score (CRSS) predicted the biological behavior correctly in cases with complete clinicopathological data (size, mitoses, age, infiltrative growth). Two morcellated cases (one indolent and one aggressive) would have been predicted as low risk based solely on the absence of pathogenic mutations. Hereby, the reliability of the proposed CRSS was confirmed. Aberrant p16 expression predicted malignant behavior in 2/3 aggressive cases. Absence of pathogenic mutations or presence of large scale CNVs does not seem to be a predictor of clinical behavior. Additional studies and NGS analyses of more cases may improve risk stratification for patients with incomplete clinicopathological information and may reveal additional risk stratifiers (such as the suggested large-scale CNVs or AR downregulation) for IMTs.

• MeSH
• dospělí MeSH
• imunohistochemie MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory dělohy * patologie   genetika   MeSH
• nádory ze svalové tkáně * patologie   genetika   MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Pacienti se vzácnými nádory, jako jsou nádory štítné žlázy se specifickými mutacemi, donedávna neměli mnoho léčebných perspektiv. Díky precizní medicíně, která nám umožní nalézt konkrétní léčebné cíle, můžeme těmto nemocným nabídnout moderní přípravky a zlepšit tak jejich perspektivu i prodloužit život. Článek se zabývá zvláštní skupinou pacientů s nádory štítné žlázy s fúzí RET a shrnuje možnosti léčby na základě dat z klinických studií. Okrajově jsou zmíněny též tumory štítnice s mutací RET, u nichž jsou používány stejné přípravky.

Until recently, patients with rare tumors, such as thyroid tumors with specific mutations, did not have many treatment alternatives. Thanks to precision medicine, which allows us to find specific treatment goals, we can offer these patients modern preparations and thus improve their perspective and prolong their lives. The article deals with a special group of patients with thyroid tumors with RET fusion and summarizes treatment options based on data from clinical trials. Thyroid tumors with RET mutation are also marginally mentioned, for which the same preparations are used.

• MeSH
• doba přežití bez progrese choroby MeSH
• inhibitory tyrosinkinasy farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• nádory štítné žlázy * farmakoterapie   MeSH
• protokoly protinádorové léčby MeSH
• Check Tag
• lidé MeSH

Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes.

• MeSH
• anaplastická lymfomová kináza * metabolismus   genetika   MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   patologie   genetika   metabolismus   MeSH
• benzamidy farmakologie   MeSH
• histondeacetylasa 1 * genetika   antagonisté a inhibitory   fyziologie   metabolismus   MeSH
• histondeacetylasa 2 genetika   MeSH
• inhibitory histondeacetylas * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• pyridiny farmakologie   MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The cross-section measurement of Antimony (Sb) is pivotal to modify or stagnate the rate of neutron flux in nuclear reactors. Neutron induced reaction cross-section data for isotopes of Sb is meagre as per reported in EXFOR. A comprehensive attempt has been made to analyse the reaction cross-section of 121Sb and 123Sb at monoenergetic neutron energy of 14.96 ± 0.03 MeV. The experiment was performed at the Neutron and Ion Irradiation Facility, Institute for Plasma Research (IPR), Gujarat (India). The 27Al(n,α)24Na reaction is used to monitor the flux and to estimate the cross-section of (n,2n), (n,p) reactions using neutron activation technique. Monoenergetic neutrons generated by D-T fusion reaction were bombarded on the natural sample of Sb to induce radioactivity. A High Purity Germanium detector (HPGe) with a resolution of 2.1 keV at 1.33 MeV γ-ray energy of 60Co based on GENIE software was used for the counting of emitted gamma photo peaks. Calculated results are compared with the existing studies from EXFOR. The cross-section values are estimated using TALYS-2.0 statistical code by employing different input parameters, along with the latest Evaluated Nuclear data libraries (ENDF/B-VIII.0, JEFF-3.3). To obtain more precise data, uncertainties from various parameters are propagated using the correlation coefficients among all the parameters. This systematic detailed covariance analysis helps to reduce the present discrepancies and to refine the nuclear data.

• Publikační typ
• časopisecké články MeSH

PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

• MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• gliom * genetika   patologie   mortalita   terapie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému * genetika   terapie   mortalita   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• pyrazoly terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• receptor trkA * genetika   antagonisté a inhibitory   MeSH
• receptor trkB genetika   antagonisté a inhibitory   MeSH
• receptor trkC genetika   antagonisté a inhibitory   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

CONTEXT.—: Non-smooth muscle uterine sarcomas are mostly represented by low-grade endometrial stromal sarcoma. However, several other rare, distinct types of uterine sarcoma are recognized, including high-grade endometrial stromal sarcoma, tumors with kinase fusions, uterine tumors resembling ovarian sex cord tumors, soft tissue-type sarcoma, and emerging entities such as KAT6A/B-rearranged tumors. The landscape of uterine sarcomas has changed, mostly because of the increasing knowledge concerning their molecular aberrations. OBJECTIVE.—: To offer a comprehensive review of the literature focusing on fusions occurring in tumors other than smooth muscle mesenchymal uterine tumors with respect to their type, frequency, and overlap between diagnostic categories and entities. DATA SOURCES.—: The data were mined from the PubMed/MEDLINE database covering the time period from January 1988 to June 2023. In total, 156 studies focusing on the problematics of fusions occurring in non-smooth muscle mesenchymal uterine tumors were selected, and thus became the basis for this review. CONCLUSIONS.—: One hundred ten fusions were identified in 703 tumors. The diagnostic significance of the molecular aberrations occurring in these tumors can be unclear in some cases. This can be related to the rare aberrations with a limited number of reported cases. Additionally, even well-known aberrations considered as specific for a certain distinct entity can occur in other lesions, the biological behavior and clinical significance of which can differ substantially.

• MeSH
• endometriální stromální nádory genetika   patologie   diagnóza   MeSH
• endometriální stromální sarkom genetika   patologie   MeSH
• fúze genů MeSH
• lidé MeSH
• nádory dělohy * genetika   patologie   diagnóza   MeSH
• sarkom genetika   patologie   diagnóza   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH