Alzheimer's disease (AD) is the most debilitating form of dementia, characterized by amyloid-β (Aβ)-related toxic mechanisms such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. The development of AD is influenced by environmental factors linked to lifestyle, including physical and mental inactivity, diet, and smoking, all of which have been associated with the severity of the disease and Aβ-related pathology. In this study, we used differentiated SH-SY5Y neuroblastoma and C6 glioma cells to investigate the neuroprotective and anti-inflammatory effects of daidzein, a naturally occurring isoflavone, in the context of Aβ oligomer-related toxicity. We observed that pre-treatment with daidzein prevented Aβ-induced cell viability loss, increased oxidative stress, and mitochondrial membrane potential decline in both SH-SY5Y and C6 cells. Furthermore, daidzein application reduced elevated levels of MAPK pathway proteins, pro-inflammatory molecules (cyclooxygenase-2 and IL-1β), and pyroptosis markers, including caspase-1 and gasdermin D, all of which were increased by Aβ exposure. These findings strongly suggest that daidzein alleviates inflammation and toxicity caused by Aβ oligomers. Our results indicate that daidzein could be a potential therapeutic agent for AD and other Aβ-related neurodegenerative diseases.

• MeSH
• amyloidní beta-protein * toxicita   MeSH
• antiflogistika * farmakologie   MeSH
• gliom * patologie   metabolismus   farmakoterapie   MeSH
• isoflavony * farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• nádorové buněčné linie MeSH
• neuroblastom * patologie   metabolismus   farmakoterapie   MeSH
• neuroprotektivní látky * farmakologie   MeSH
• oxidační stres účinky léků   MeSH
• pyroptóza účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Cerebellar Mutism Syndrome (CMS) is a neurological complication of posterior fossa (PF) tumour surgery in children, and postoperative speech impairment (POSI) is the cardinal symptom of CMS. The role of tumour volume on the risk of POSI remains unexplored. This study investigates the association between tumour volume and the risk of POSI. METHODS: We included 360 patients from the European CMS study with available preoperative T1-weighted contrast-enhanced brain MRI. Speech status was assessed within two weeks postoperatively and categorised into three levels: habitual speech, severely reduced speech, and mutism. Tumour volumes were calculated using the BrainLab Elements SmartBrushTM, a semi-automated segmentation tool. We used proportional odds models to estimate the odds ratio (OR) with adjustments for tumour location, pathology, and age. Based on the primary analysis, a risk stratification model for medulloblastoma patients was constructed, and the optimal volume cut-off was determined with Youden's Index. RESULTS: We found no effect of the overall tumour volume on the risk of POSI. This result did not change when adjusted for tumour location, pathology, and age. We found an association between tumour volume of medulloblastoma and the risk of POSI (unadjusted OR of 1.04 per increase in cm3 (95% CI 1.01;1.07, p = 0.01)), which did not change when adjusting for tumour location and age. The risk stratification cut-off for the tumour volume of medulloblastoma was calculated to be 16,5 cm3. Patients with medulloblastoma and preoperative tumour volumes below 16,5 cm3 had an absolute risk of 13% for POSI (low-risk group), whereas patients with preoperative tumour volumes above 16,5 cm3 had an absolute risk of 50% for POSI (high-risk group). CONCLUSION: Our data showed an association between preoperative tumour volume and the risk of POSI in children with medulloblastoma, while no association was found for the volume of other tumour types. We suggest a straightforward cut-off risk model for assessing the risk of POSI in children with medulloblastoma based on preoperative tumour volume. This approach can aid clinicians in informing patients and parents about the complications related to CMS following PF tumour surgery in children. CLINICAL TRIALS: ID NCT02300766 (October 2014).

• MeSH
• dítě MeSH
• infratentoriální nádory * chirurgie   patologie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• meduloblastom * chirurgie   patologie   MeSH
• mladiství MeSH
• mutismus * etiologie   MeSH
• nádory mozečku * chirurgie   patologie   MeSH
• pooperační komplikace * etiologie   MeSH
• poruchy řeči * etiologie   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• tumor burden * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

• MeSH
• adenom diagnóza   terapie   MeSH
• anastomóza chirurgická MeSH
• dospělí MeSH
• familiární adenomatózní polypóza * chirurgie   diagnostické zobrazování   komplikace   MeSH
• kolektomie MeSH
• lidé MeSH
• meduloblastom * chirurgie   diagnóza   terapie   MeSH
• peritonitida diagnóza   terapie   MeSH
• pouch MeSH
• tlusté střevo chirurgie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Neuropatologická diagnostika nádorů centrální nervové soustavy se v posledních letech výrazně posunula díky molekulárně biologickým poznatkům i novým metodám, jako je metylační profilování. V současné WHO klasifikaci se na jejich podkladě změnil jednak obecný přístup ke gradingu a reportování nádorů. Také byly vytvořeny nové skupiny nádorů a nové jednotky, zdůrazňující rozdíly mezi morfologicky obdobnými nádory s rozdílným molekulárně patologickým pozadím. Tento edukativní článek předkládá aktuální pohled na členění nejčastějších dětských nádorů CNS a jeho vliv na současné diagnostické postupy.

Neuropathological diagnostics of central nervous system tumours has advanced significantly in recent years thanks to molecular biological insights and new methods such as methylation profiling. In the current WHO classification, the general approach to grading and reporting of tumours has changed as a result. New tumour groups and new units have also been created, highlighting the differences between morphologically similar tumours with different molecular pathological backgrounds. This educative article gives actual view on groups of the most frequent pediatric CNS tumours and its impact on diagnostic approaches.

• MeSH
• diagnostické techniky molekulární MeSH
• ependymom diagnóza   patologie   MeSH
• gliom diagnóza   genetika   patologie   MeSH
• lidé MeSH
• meduloblastom diagnóza   patologie   MeSH
• metylace DNA MeSH
• nádory centrálního nervového systému * diagnóza   genetika   klasifikace   MeSH
• nádory mozku diagnóza   genetika   klasifikace   MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé MeSH

AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 μM on neuroblastoma cells.

• MeSH
• histondeacetylasy * metabolismus   MeSH
• inhibitory histondeacetylas * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• neuroblastom * farmakoterapie   patologie   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• umělá inteligence MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

• MeSH
• anaplastická lymfomová kináza * genetika   metabolismus   antagonisté a inhibitory   MeSH
• apoptóza účinky léků   genetika   MeSH
• chemorezistence genetika   účinky léků   MeSH
• dibenzocyklohepteny * MeSH
• farnesyltranstransferasa * antagonisté a inhibitory   metabolismus   MeSH
• GTP-fosfohydrolasy * genetika   metabolismus   MeSH
• inhibitory proteinkinas * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• membránové proteiny metabolismus   genetika   MeSH
• mikro RNA * genetika   metabolismus   MeSH
• mutace MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• neuroblastom * farmakoterapie   genetika   patologie   metabolismus   MeSH
• piperidiny * farmakologie   terapeutické užití   MeSH
• pyridiny * farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• synergismus léků MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

• MeSH
• chronická nemoc MeSH
• dítě MeSH
• kohortové studie MeSH
• kojenec MeSH
• kraniospinální iradiace * škodlivé účinky   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• meduloblastom * radioterapie   MeSH
• nádory mozečku * radioterapie   MeSH
• nádory mozku * terapie   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• proteiny hedgehog MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• akutní lymfatická leukemie diagnóza   farmakoterapie   MeSH
• diferenciální diagnóza MeSH
• dítě * MeSH
• germinální a embryonální nádory diagnóza   terapie   MeSH
• hepatoblastom chirurgie   diagnóza   terapie   MeSH
• lidé MeSH
• lymfom diagnóza   farmakoterapie   terapie   MeSH
• nádory centrálního nervového systému chirurgie   diagnóza   terapie   MeSH
• nádory * chirurgie   diagnóza   terapie   MeSH
• neuroblastom diagnóza   terapie   MeSH
• sarkom chirurgie   diagnóza   terapie   MeSH
• Wilmsův nádor diagnóza   terapie   MeSH
• Check Tag
• dítě * MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory centrálního nervového systému * genetika   MeSH
• předškolní dítě MeSH
• primitivní neuroektodermové nádory * genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• proteiny vázající RNA genetika   MeSH
• signální dráha Wnt genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mitochondria are central for cancer responses to therapy-induced stress signals. Refractory tumors often show attenuated sensitivity to apoptotic signaling, yet clinically relevant molecular actors to target mitochondria-mediated resistance remain elusive. Here, we show that MYC-driven neuroblastoma cells rely on intact mitochondrial ribosome (mitoribosome) processivity and undergo cell death following pharmacological inhibition of mitochondrial translation, regardless of their multidrug/mitochondrial resistance and stem-like phenotypes. Mechanistically, inhibiting mitoribosomes induced the mitochondrial stress-activated integrated stress response (ISR), leading to downregulation of c-MYC/N-MYC proteins prior to neuroblastoma cell death, which could be both rescued by the ISR inhibitor ISRIB. The ISR blocks global protein synthesis and shifted the c-MYC/N-MYC turnover toward proteasomal degradation. Comparing models of various neuroectodermal tumors and normal fibroblasts revealed overexpression of MYC proteins phosphorylated at the degradation-promoting site T58 as a factor that predetermines vulnerability of MYC-driven neuroblastoma to mitoribosome inhibition. Reducing N-MYC levels in a neuroblastoma model with tunable MYCN expression mitigated cell death induction upon inhibition of mitochondrial translation and functionally validated the propensity of neuroblastoma cells for MYC-dependent cell death in response to the mitochondrial ISR. Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors.

• MeSH
• apoptóza MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• neuroblastom * farmakoterapie   genetika   metabolismus   MeSH
• protoonkogen n-myc genetika   metabolismus   MeSH
• protoonkogenní proteiny c-myc genetika   metabolismus   MeSH
• signální transdukce MeSH
• umělé letální mutace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH