The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

• MeSH
• dlaždicobuněčné karcinomy hlavy a krku virologie   patologie   genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• fúzní onkogenní proteiny genetika   MeSH
• infekce papilomavirem * patologie   komplikace   genetika   virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory hlavy a krku * patologie   virologie   genetika   MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• receptor fibroblastových růstových faktorů, typ 3 * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom patologie   genetika   virologie   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

Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.

• MeSH
• aneuploidie * MeSH
• B-lymfocyty metabolismus   MeSH
• chromozomální nestabilita * genetika   MeSH
• difúzní velkobuněčný B-lymfom * genetika   patologie   metabolismus   MeSH
• kolagen farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• receptor DDR1 * genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The use of microfluidic sperm sorting (MFSS) systems in infertility treatment is increasing due to their practicality and ease of use. While often presented as highly effective, their efficacy in patients with varying sperm analysis results remains uncertain. In this study, we evaluated the effectiveness of MFSS compared with the swim-up (SU) technique in terms of oxygen radical levels and spermiogram parameters. Samples from each patient were processed using both methods, followed by assessments of sperm concentration, motility, morphology, DNA integrity, acrosomal status, and mitochondrial membrane potential. Participants were selected based on sperm analysis and categorized as normozoospermic (n = 40) or non-normozoospermic (n = 28). An analysis of separation techniques revealed no significant differences, except for a lower percentage of DNA-fragmented sperm in the MFSS group compared with SU within the non-normozoospermic cohort (SU: 10.0% vs. MFSS: 5.69%, p = 0.027). No differences were observed between SU and MFSS in normozoospermic men. The MFSS method is a simple technique, frequently used in laboratories, that yields good results but does not offer a substantial advantage over SU. The primary benefit of MFSS appears to be a significant reduction in the proportion of sperm with DNA fragmentation compared with SU in patients with abnormal sperm analysis results.

• MeSH
• analýza spermatu metody   MeSH
• dospělí MeSH
• fragmentace DNA MeSH
• intracytoplazmatické injekce spermie * metody   MeSH
• lidé MeSH
• membránový potenciál mitochondrií MeSH
• mikrofluidika * metody   MeSH
• motilita spermií * MeSH
• mužská infertilita terapie   MeSH
• separace buněk * metody   MeSH
• spermie * cytologie   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Cíl: Těhotenství se nepovažuje za stav zvyšující náchylnost organismu k infekci SARS-CoV-2 (severe-acute-respiratory-syndrome-related coronavirus 2), avšak v případě nákazy v graviditě se zvyšuje riziko závažnějšího průběhu nemoci covid-19. Ve většině případů ovšem bývá průběh infekce v graviditě mírný nebo bezpříznakový. Hlavním cílem studie u těhotných žen s covidem-19 (coronavirové onemocnění) bylo dokázat, že způsob porodu se nemění a závažné komplikace jak porodnické, tak neonatologické se kvůli tomuto onemocnění nevyskytují častěji. Metody: Do retrospektivní, observační, multicentrické studie byly zařazeny pacientky s pozitivním testem na covid-19, které byly přijaty a následně porodily v období od 15. března 2020 do 15. března 2021. Data z porodnických oddělení pěti center v České republice během pandemie covidu-19 byla analyzována ve vztahu k metodě a době porodu, symptomům covidu-19 a potenciálním komplikacím s ohledem na demografii a komorbidity těhotných žen. Infekce koronavirem byla u pacientek potvrzena pomocí PCR (polymerázové řetězové reakce). Statistická analýza byla hodnocena pomocí programu Excel. Výsledky: Během sledovaného období bylo ve studijních centrech detekováno 236 těhotných žen s covidem-19. Většina pacientek byla asymptomatická (59,7 %). U symptomatických pacientek byly nejčastějšími příznaky kašel (52,6 %), nachlazení (43,2 %) a horečka (37,9 %) a covidová pneumonie byla diagnostikována u 8 pacientek. Porod byl proveden vaginálně u 52,5 % pacientek, těhotenství bylo ukončeno císařským řezem v 44,5 %, per VEX (vakuumextrakce) v 2,1 % a per forcipem v 0,8 % případů. Průměrný týden gravidity v době porodu byl 38 a předčasný porod byl proveden u 19,1 % pacientek. Výsledky tyto studie u těhotných žen s covidem-19 prokázaly, že způsob porodu se nezměnil a výskyt větších komplikací jak porodnických, tak neonatologických nebyl ve většině případů zaznamenán. Dva prezentované závažné průběhy covidu-19 u těhotných žen však vedly k předčasnému ukončení těhotenství. Jediným přidruženým rizikovým faktorem byla obezita pacientky. Závěry: Ačkoli je covid-19 onemocnění, které je u těhotných žen většinou asymptomatické nebo má pouze mírné příznaky podobné chřipce, je spojeno se zvýšenou nemocností a úmrtností ve srovnání s těhotnými ženami bez covidu-19. Výzvou do budoucna je možnost segregace pacientek do nízko a vysoce rizikových skupin na základě prokázaných rizikových faktorů a důsledné očkování těhotných žen nebo žen plánujících početí. V kritických případech je nutné správné načasování předčasného ukončení těhotenství a včasná indikace počátku zrání plic plodu.

Objective: Pregnancy is not considered a condition that increases the body‘s susceptibility to SARS-CoV-2 (severe-acute-respiratory-syndrome-related coronavirus-2) infection, but in the case of infection in pregnancy, there is an increased risk of a more severe course of COVID-19 (coronavirus disease-19). However, the course of infection in pregnancy is mild or asymptomatic in most cases. The main objective of the study in pregnant women with COVID-19 was to prove that the delivery method is not changed, and serious complications do not occur more frequently due to this disease. Methods: In a retrospective, observational, multicentric study, the pregnant women positively tested to COVID-19 were admitted and subsequently gave birth in the period from 15 March 2020 to 15 March 2021. Data from the delivery departments of five centers in the Czech Republic during COVID-19 pandemic were analyzed in relation to the delivery method and time, COVID-19 symptoms and potential complications with respect to demographics and comorbidities of pregnant women. COVID-19 positivity was confirmed with PCR (polymerase-chain reaction). The Excel program was used during statistical analysis. Results: During the observed study period, 236 pregnant women with COVID-19 were detected at study centers. Most of the patients were asymptomatic (59.7%). In symptomatic patients, most common symptoms were cough (52.6 %), cold (43.2%) and fever (37.9%), and COVID-19 pneumonia was diagnosed in 8 patients. The delivery was performed vaginally in 52.5% patients, the pregnancy was terminated by C-section (cesarean section) in 44.5%, per VEX (vacuum extractor) in 2.1% and per forcipem in 0.8% cases. The average week of pregnancy at the time of delivery was 38 (29–41) and preterm delivery was performed in 19.1% patients. The study results in pregnant women with COVID-19 demonstrated that the method of delivery was not changed and major delivery and neonatological complications did not develop in most cases. However, two presented serious courses of COVID-19 in pregnant women led to premature terminations of pregnancies. The only associated risk factor was the patient‘s obesity. Conclusions: Although COVID-19 is a disease that is mostly asymptomatic in pregnant women or with only mild flu-like symptoms, it is associated with increased morbidity and mortality compared to pregnant women without COVID-19. The challenge for the future is the possibility of segregating patients into lowand high-risk groups based on proven risk factors, and consistent vaccination of pregnant women or women planning conception. In critical cases, the correct timing of premature termination of pregnancy and early indication of the beginning of fetal lung maturation is necessary.

• MeSH
• COVID-19 * komplikace   mortalita   MeSH
• diagnostické zobrazování metody   MeSH
• komplikace porodu * mikrobiologie   MeSH
• komplikace těhotenství * mikrobiologie   MeSH
• lidé MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Only a limited number of biomarkers guide personalized management of pancreatic neuroendocrine tumors (PanNETs). Transcriptome profiling of microRNA (miRs) and mRNA has shown value in segregating PanNETs and identifying patients more likely to respond to treatment. Because miRs are key regulators of mRNA expression, we sought to integrate expression data from both RNA species into miR-mRNA interaction networks to advance our understanding of PanNET biology. METHODS: We used deep miR/mRNA sequencing on six low-grade/high-risk, well-differentiated PanNETs compared with seven non-diseased tissues to identify differentially expressed miRs/mRNAs. Then we crossed a list of differentially expressed mRNAs with a list of in silico predicted mRNA targets of the most and least abundant miRs to generate high probability miR-mRNA interaction networks. RESULTS: Gene ontology and pathway analyses revealed several miR-mRNA pairs implicated in cellular processes and pathways suggesting perturbed neuroendocrine function (miR-7 and Reg family genes), cell adhesion (miR-216 family and NLGN1, NCAM1, and CNTN1; miR-670 and the claudins, CLDN1 and CLDN2), and metabolic processes (miR-670 and BCAT1/MPST; miR-129 and CTH). CONCLUSION: These novel miR-mRNA interaction networks identified dysregulated pathways not observed when assessing mRNA alone and provide a foundation for further investigation of their utility as diagnostic and predictive biomarkers.

• MeSH
• genové regulační sítě MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA * genetika   MeSH
• mikro RNA * genetika   MeSH
• nádorové biomarkery genetika   MeSH
• nádory slinivky břišní * genetika   patologie   diagnóza   MeSH
• neuroendokrinní nádory * genetika   patologie   diagnóza   MeSH
• pankreas * metabolismus   patologie   MeSH
• regulace genové exprese u nádorů MeSH
• stanovení celkové genové exprese MeSH
• transkriptom MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This qualitative study examines the implementation of an empowerment approach in marginalised Roma communities from the perspective of social workers. Data from 11 semi-structured interviews were analyzed using selected analytical procedures of grounded theory, identifying the main categories: the socioeconomic background of clients (context), community needs and long-term goals (causal conditions), social support and external influences (intervening conditions), and educational projects and participation (strategic actions). The empowerment process leads to independence, sustainability, and improvement of the community environment (consequences). While social work at the micro and meso levels is crucial for the inclusion of the poorest residents of segregated Roma enclaves, significant achievements have not been made at the macro level, particularly in terms of political involvement and the fight against anti-Roma racism. The study also highlights systemic reliance on European structural funds and the lack of state support. Future research could map the perspectives and empowerment of emerging helping professionals.

• MeSH
• empowerment MeSH
• komunitní participační výzkum MeSH
• kvalitativní výzkum MeSH
• lidé MeSH
• Romové * psychologie   MeSH
• sociální pracovníci * MeSH
• zdraví menšin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Geografické názvy
• Slovenská republika MeSH

To identify the neurocognitive mechanisms underpinning the social difficulties that characterize autism, we performed functional magnetic resonance imaging on pairs of autistic and non-autistic adults simultaneously whilst they interacted with one another on the iterated Ultimatum Game (iUG)-an interactive task that emulates the reciprocal characteristic of naturalistic interpersonal exchanges. Two age-matched sets of male-male dyads were investigated: 16 comprised an autistic Responder and a non-autistic Proposer, and 19 comprised non-autistic pairs of Responder and Proposer. Players' round-by-round behavior on the iUG was modeled as reciprocal choices, and dynamic functional connectivity (dFC) was measured to identify the neural mechanisms underpinning reciprocal behaviors. Behavioral expressions of reciprocity were significantly reduced in autistic compared with non-autistic Responders, yet no such differences were observed between the non-autistic Proposers in either set of dyads. Furthermore, we identified latent dFC states with temporal properties associated with reciprocity. Autistic interactants spent less time in brain states characterized by dynamic inter-network integration and segregation among the Default Mode Network and cognitive control networks, suggesting that their reduced expressions of social-emotional reciprocity reflect less efficient reconfigurations among brain networks supporting flexible cognition and behavior. These findings advance our mechanistic understanding of the social difficulties characterizing autism.

• MeSH
• autistická porucha * patofyziologie   psychologie   diagnostické zobrazování   MeSH
• dospělí MeSH
• emoce * fyziologie   MeSH
• interpersonální vztahy * MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• mozek * patofyziologie   diagnostické zobrazování   MeSH
• sociální chování * MeSH
• sociální interakce * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Replication stress, particularly in hard-to-replicate regions such as telomeres and centromeres, leads to the accumulation of replication intermediates that must be processed to ensure proper chromosome segregation. In this study, we identify a critical role for the interaction between RECQ4 and MUS81 in managing such stress. We show that RECQ4 physically interacts with MUS81, targeting it to specific DNA substrates and enhancing its endonuclease activity. Loss of this interaction, results in significant chromosomal segregation defects, including the accumulation of micronuclei, anaphase bridges, and ultrafine bridges (UFBs). Our data further demonstrate that the RECQ4-MUS81 interaction plays an important role in ALT-positive cells, where MUS81 foci primarily colocalise with telomeres, highlighting its role in telomere maintenance. We also observe that a mutation associated with Rothmund-Thomson syndrome, which produces a truncated RECQ4 unable to interact with MUS81, recapitulates these chromosome instability phenotypes. This underscores the importance of RECQ4-MUS81 in safeguarding genome integrity and suggests potential implications for human disease. Our findings demonstrate the RECQ4-MUS81 interaction as a key mechanism in alleviating replication stress at hard-to-replicate regions and highlight its relevance in pathological conditions such as RTS.

• MeSH
• chromozomální nestabilita MeSH
• DNA vazebné proteiny * metabolismus   genetika   MeSH
• endonukleasy * metabolismus   genetika   MeSH
• helikasy RecQ * metabolismus   genetika   MeSH
• homeostáza telomer MeSH
• lidé MeSH
• mutace MeSH
• replikace DNA * MeSH
• Rothmundův-Thomsonův syndrom * genetika   metabolismus   MeSH
• segregace chromozomů MeSH
• telomery * metabolismus   genetika   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Epigenetic DNA modifications are pivotal in eukaryotic gene expression, but their regulatory significance in bacteria is less understood. In Synechocystis 6803, the DNA methyltransferase M.Ssp6803II modifies the first cytosine in the GGCC motif, forming N4-methylcytosine (GGm4CC). Deletion of the sll0729 gene encoding M.Ssp6803II (∆sll0729) caused a bluish phenotype due to reduced chlorophyll levels, which was reversed by suppressor mutations. Re-sequencing of 7 suppressor clones revealed a common GGCC to GGTC mutation in the slr1790 promoter's discriminator sequence, encoding protoporphyrinogen IX oxidase, HemJ, crucial for tetrapyrrole biosynthesis. Transcriptomic and qPCR analyses indicated aberrant slr1790 expression in ∆sll0729 mutants. This aberration led to the accumulation of coproporphyrin III and protoporphyrin IX, indicative of impaired HemJ activity. To confirm the importance of DNA methylation in hemJ expression, hemJ promoter variants with varying discriminator sequences were introduced into the wild type, followed by sll0729 deletion. The sll0729 deletion segregated in strains with the GGTC discriminator motif, resulting in wild-type-like pigmentation, whereas freshly prepared ∆sll0729 mutants with the native hemJ promoter exhibited the bluish phenotype. These findings demonstrate that hemJ is tightly regulated in Synechocystis and that N4-methylcytosine is essential for proper hemJ expression. Thus, cytosine N4-methylation is a relevant epigenetic marker in Synechocystis and likely other cyanobacteria.

• MeSH
• bakteriální proteiny metabolismus   genetika   MeSH
• epigeneze genetická * MeSH
• metylace DNA * MeSH
• mutace MeSH
• promotorové oblasti (genetika) * MeSH
• regulace genové exprese u bakterií MeSH
• Synechocystis * genetika   metabolismus   MeSH
• tetrapyrroly * metabolismus   biosyntéza   MeSH
• Publikační typ
• časopisecké články MeSH

Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor, even in the era of novel immunotherapies. Here, we applied spatial transcriptomics (RNA tomography for spatially resolved transcriptomics [tomo-seq] [n = 2] and 10x Visium [n = 12]) and single-cell RNA sequencing (n = 3) to a set of 14 EMD biopsies to dissect the 3-dimensional architecture of tumor cells and their microenvironment. Overall, infiltrating immune and stromal cells showed both intrapatient and interpatient variations, with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, which is consistent with genomic instability. We further identified the spatial expression differences between GPRC5D and TNFRSF17, 2 important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T cells. Notably, exhausted TIM3+/PD-1+ T cells diffusely colocalized with MM cells, whereas functional and activated CD8+ T cells showed a focal infiltration pattern along with M1 macrophages in tumor-free regions. This segregation of fit and exhausted T cells was resolved in the case of response to T-cell-engaging bispecific antibodies. MM and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.

• MeSH
• lidé MeSH
• mnohočetný myelom * genetika   patologie   imunologie   MeSH
• nádorové mikroprostředí * imunologie   genetika   MeSH
• stanovení celkové genové exprese MeSH
• T-lymfocyty imunologie   patologie   metabolismus   MeSH
• transkriptom * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH