The overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1-108, 69-108 and 98-108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100-108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69-103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220-10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target.
- MeSH
- aktivace transkripce MeSH
- lidé MeSH
- proteinové domény MeSH
- protoonkogenní proteiny c-myc * metabolismus genetika MeSH
- sekvence aminokyselin MeSH
- vazba proteinů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Multiformní glioblastom (GBM) je běžný maligní nádor mozku u dospělých a navzdory agresivní léčbě zůstává prakticky nevyléčitelný se špatnou prognózou a mediánem přežití 12 měsíců po resekci, radioterapii a chemoterapii. Terapeutické přístupy k imunoterapii GBM mají omezenou úspěšnost, zejména v důsledku chráněné bariéry mozku a imunosupresivního mikroprostředí nádoru. Nový výzkum naznačuje možnost použití imunitních efektorových buněk, které účinně zničí maligní GBM buňky. Naše předchozí studie ukázala, že vrozené gamma-delta (gd) T buňky byly vysoce reaktivní na nádor GBM. Cílem navrhovaného projektu je buněčná a molekulární analýza gd T buněk u pacientů před a během léčby včetně podrobné charakterizace jejich interakcí s GBM buňkami a identifikace významných markerů v mikroprostředí nádorů, které jsou odpovědné za rezistenci na terapii a relapsu onemocnění. Současné výzkumné záměry zaměřené na odstranění reziduálních nádorových buněk pomocí gd T buněk poskytují platformu pro imunoterapii GBM.; Glioblastoma multiforme (GBM) is the common malignant brain tumour in adults and despite aggressive treatment it remains virtually incurable with a poor prognosis and median survival of 12 months following resection, radiotherapy and chemotherapy. Therapeutic approaches to GBM immunotherapy have had limited success, principally due to the protected brain barrier and the immunosuppressive tumour microenvironment. New research indicates the possibility of using immune effector cells that effectively destroy malignant GBM cells. Our previous study showed innate gamma-delta (gd) T cells were highly reactive to GBM tumour. The aim of the proposed project is cellular and molecular analyses of gd T cells in patients before and during treatment, including the detailed characterization of their interactions with GBM cells and identification of significant markers within the tumour microenvironment responsible for therapy resistance and relapse of the disease. The current research interests aiming to eliminate residual tumour cells by gd T cells provide a platform for GBM immunotherapy.
- Klíčová slova
- tumour microenvironment, nádorové mikroprostředí, glioblastoma, glioblastom, Gammadelta T buňky, Gammadelta T cells,
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
BACKGROUND AND OBJECTIVES: Endovascular treatment of cerebral aneurysms has tremendously advanced over the past decades. Nevertheless, aneurysm residual and recurrence remain challenges after embolization. The objective of this study was to elucidate the portion of embolized aneurysms requiring open surgery and evaluate whether newer endovascular treatments have changed the need for open surgery after failed embolization. METHODS: All 15 cerebrovascular centers in Austria and the Czech Republic provided overall aneurysm treatment frequency data and retrospectively reviewed consecutive cerebral aneurysms treated with open surgical treatment after failure of embolization from 2000 to 2022. All endovascular modalities were included. RESULTS: On average, 1362 aneurysms were treated annually in the 2 countries. The incidence increased from 0.006% in 2005 to 0.008% in 2020 in the overall population. Open surgery after failed endovascular intervention was necessary in 128 aneurysms (0.8%), a proportion that remained constant over time. Subarachnoid hemorrhage was the initial presentation in 70.3% of aneurysms. The most common location was the anterior communicating artery region (40.6%), followed by the middle cerebral artery (25.0%). The median diameter was 6 mm (2-32). Initial endovascular treatment included coiling (107 aneurysms), balloon-assist (10), stent-assist (4), intrasaccular device (3), flow diversion (2), and others (2). Complete occlusion after initial embolization was recorded in 40.6%. Seventy-one percent of aneurysms were operated within 3 years after embolization. In 7%, the indication for surgery was (re-)rupture and, in 88.3%, reperfusion. Device removal was performed in 16.4%. Symptomatic intraoperative and postoperative complications occurred in 10.2%. Complete aneurysm occlusion after open surgery was achieved in 94%. CONCLUSION: Open surgery remains a rare indication for cerebral aneurysms after failed endovascular embolization even in the age of novel endovascular technology, such as flow diverters and intrasaccular devices. Regardless, it is mostly performed for ruptured aneurysms initially treated with primary coiling that are in the anterior circulation.
- MeSH
- dospělí MeSH
- endovaskulární výkony * metody MeSH
- intrakraniální aneurysma * chirurgie epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrochirurgie metody MeSH
- neurochirurgické výkony metody MeSH
- neúspěšná terapie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- terapeutická embolizace * metody 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
- multicentrická studie MeSH
- Geografické názvy
- Česká republika MeSH
- Rakousko MeSH
BACKGROUND: The aim of this retrospective study is to analyze a consecutive cohort of brain metastasis (BM) patients treated off clinical trials through combination of surgery and radiotherapy over the last 15 years in a tertiary neurooncology center. MATERIALS AND METHODS: All BM patients operated between 2007-2019 received adjuvant linac-based radiotherapy categorized to whole brain radiotherapy (WBRT) and tumor bed stereotactic radiotherapy. Survival outcomes and local control was analyzed. RESULTS: In total, 118 patients were enrolled, those with stereotactic radiotherapy (41%) had better baseline characteristics mirrored in longer overall survival (OS) [18 vs. 7.1 months, p < 0.001; hazard ratio (HR) 0.47, p = 0.004] with median follow-up of 58 months. Cumulative incidence for local, distant, and extracranial control was not significantly different between groups, with 12-month cumulative control of 22% vs. 18%, 44% vs. 29%, and 35% vs. 32% for stereotactic and WBRT group, respectively. WBRT was an independent factor for better distal brain control. CONCLUSIONS: Real world data demonstrating significantly better overall survival in patients treated with postoperative targeted radiotherapy compared with postoperative WBRT is presented, with no significant difference in cumulative incidence for local or distant brain control. The majority of patients with targeted radiotherapy had a fractionated dose schedule with outcomes comparable to single-dose radiation trials of postoperative targeted radiotherapy.
- Publikační typ
- časopisecké články MeSH
- MeSH
- artróza páteře * chirurgie diagnostické zobrazování patologie MeSH
- lidé MeSH
- ortopedické výkony * klasifikace metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Brain injuries are the most common cause of death in productive age. Besides the extent of the injury, other systemic factors can also affect the outcome. Patients suffering from severe brain injury often experience extracranial inflammatory complications during the early period of treatment. Here, we investigate the changes in immunity in patients with brain injury. METHODS: 121 patients and 92 healthy controls were included in the research. Blood samples were collected on admission and analyzed by flow cytometry and biochemical methods. Multiple clusters of differentiation (CD) and antibody levels were investigated. The results were compared between patients and controls. In addition, results of two classes of severity (Glasgow Coma Scale, GCS, of 3-5 vs. 6-8) were also compared. RESULTS: Parameters of humoral immunity in patients immediately after admission were significantly lower than those from healthy donors, with the exception of IgE elevated as much as to resemble allergic reaction (p < 0.01). Of cellular parameters, only natural killer (NK) cluster CD56 + was elevated (p < 0.01). Extracranial infectious complications were more common in patients with GCS 3-5. CONCLUSIONS: Strong immune system disorders were observed in patients after severe brain injury, which may contribute to the worse outcome in such patients.
- MeSH
- biologické markery MeSH
- Glasgowská stupnice kómat MeSH
- lidé MeSH
- nemoci imunitního systému * komplikace MeSH
- poranění mozku * komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Úvod: Cílem naší studie je prezentovat výsledky léčby u pacientů s prodělaným aneuryzmatickým subarachnoidálním krvácením (SAK) po 3 měsících od ataky, kteří byli ošetřeni clippingem (NCH) nebo coilingem (EV). Materiál a metodika: Studie byla provedena na základě retrospektivní analýzy databáze pacientů s mozkovými aneuryzmaty, kteří byli léčeni mezi lety 2009 a 2019 ve FN Brno. Do studie bylo zařazeno 499 pacientů. Z těchto pacientů bylo 345 (69 %) ošetřeno NCH a 154 (31 %) bylo ošetřeno EV. Pacienty jsme rozdělili do 4 skupin: dle věku na skupiny 0–64 let a 65+ let a dále dle modality ošetření výduti NCH nebo EV. Hodnotili jsme vliv vstupního Hunt-Hessova skóre (HH) na výsledek ošetření dle věku a dané modality a také vztah mezi aktuálním věkem pacienta a výsledkem léčby po 3 měsících od ataky SAK, hodnoceným pomocí modifikované Rankinovy škály (modified Rankin scale; mRS), kde úspěšný výsledek léčby byl mRS 0–2 (soběstačný pacient). Výsledky: Z celkového počtu 499 pacientů bylo 345 (69 %) ošetřeno NCH a 154 (31 %) EV, přičemž průměrný věk NCH a EV ošetřených pacientů nebyl statisticky signifikantně rozdílný (p = 0,2216). U chirurgicky i endovaskulárně léčených pacientů ve všech věkových kategoriích jsme nezaznamenali statisticky signifikantní rozdíl ve skóre HH (p = 0,1664) ani v grafické závažnosti SAK dle Fischerova skóre (p = 0,5041). Uspokojivý výsledek léčby (mRS 0–2) po 3 měsících od ataky mělo ve skupině 65+ let po NCH 49 pacientů (52,88 %), u 65+ po EV 23 (60,61 %). Špatný výsledek léčby (mRS 3–6) po 3 měsících mělo 43 pacientů (47,12 %) ošetřených NCH a 15 (39,39 %) ošetřených EV, což je statisticky významné (p = 0,0002). Uspokojivý výsledek léčby (mRS 0–2) po 3 měsících s dobrým klinickým stavem při přijetí (HH 1–2) mělo ve skupině 0–64 let po NCH 136 pacientů (55 %) a u 65+ po NCH 28 (33 %). Špatný výsledek léčby (mRS 3–6) po 3 měsících při špatném počátečním klinickém stavu (HH 3–5) mělo 50 pacientů (20 %) ošetřených NCH ve skupině 0 -64 let a 39 (44 %) ošetřených NCH ve skupině 65+, což je statisticky významné (p = 0,0001). Závěr: Senioři (65+ let) na rozdíl od mladších pacientů po SAK trpí zvýšeným rizikem špatného neurologického stavu po 3 měsících od ataky, obzvláště jsou-li v těžkém klinickém stavu při přijetí. Nezanedbatelná část těchto pacientů však po ošetření výduti zůstává v dobrém klinickém stavu, proto je potřeba metodu ošetření a rozsah léčby posuzovat individuálně. U seniorů ošetřených endovaskulárně jsme pozorovali lepší výsledek léčby po 3 měsících ve srovnání s pacienty ošetřenými otevřenou operací.
Introduction: The aim of our study is to present the treatment outcomes of patients with aneurysmal subarachnoid hemorrhage (SAH) 3 months after the attack who were treated with clipping (MS) or coiling (EV). Materials and methods: The study was based on a retrospective analysis of a database of patients with cerebral aneurysms who were treated at the University Hospital Brno between 2009 and 2019. A total of 499 patients were included in the study. Of these patients, 345 (69%) were treated with surgical MS and 154 (31%) were treated with EV. Patients were divided into 4 groups: according to the age into 0–64 years and 65+ years group, and according to the modality of treatment of aneurysm by MS or EV. We evaluated the effect of the initial Hunt-Hess (HH) score on the treatment outcome according to age and modality and also the relationship between the current age of the patient and the treatment outcome at 3 months after the SAH attack, as assessed by a modified Rankin scale (mRS), where the successful treatment outcome was mRS 0–2 (self-sufficient patient), and the effect of the initial Hunt-Hess score (HH) on the treatment outcome was based on age and modality. Results: Of the 499 patients, 345 (69%) were treated with MS and 154 (31%) with EV, and the average age of MS and EV treated patients was not statistically significantly different (P = 0.2216). In both surgically and endovascularly treated patients in all age categories; we did not observe a statistically significant difference in HH score (P = 0.1664) or in graphical severity of SAH according to the Fischer score (P = 0.5041). Satisfactory treatment outcome (mRS 0–2) at 3 months after the attack was found in 49 (52.88%) in the 65+ years group after MS and 23 (60.61%) in the 65+ years group after EV. Poor treatment outcome (mRS 3–6) at 3 months was found in 43 (47.12%) in MS treated and 15 (39.39%) in EV treated patients, which was statistically significant (P = 0.0002). Satisfactory treatment outcome (mRS 0–2) at 3 months with good clinical status on admission (HH 1–2) was seen in 136 (55%) patients in the 0–64 years group after MS and 28 (33%) in the 65+ years group after MS. Poor treatment outcome (mRS 3–6) after 3 months with poor initial clinical condition (HH 3–5) had 50 (20%) patients treated with MS in the 0 -64 years group and 39 (44%) treated with MS in the 65+ years group, which is statistically significant (P = 0.0001). Conclusion: Elderly (65+ years) after SAH are at a higher risk of poor neurological status 3 months after the attack compared to younger patients, especially if they are in a severe clinical condition on admission. However, a significant proportion of these patients remain in a good clinical condition after treatment of an aneurysm, so the method of treatment and extent of treatment needs to be assessed individually. In elderly patients treated endovascularly, we observed a better treatment outcome at 3 months compared with patients treated by open surgery.
- MeSH
- lidé MeSH
- senioři MeSH
- statistika jako téma MeSH
- subarachnoidální krvácení * chirurgie MeSH
- výsledek terapie * MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- klinická studie MeSH
- práce podpořená grantem MeSH
Paliativní péče (PP) je aktivní multidisciplinární péče, která primárně není zaměřena na prodloužení života nebo léčby u onkologických pacientů, ale na zmírnění symptomů základního onemocnění a tím i zlepšení kvality jejich života. PP by měla být poskytována již v průběhu komplexní onkologické péče a být její nedílnou součástí. Tento trend se týká rovněž neuroonkologických pacientů s primárním nádorem mozku. Pacienti s primárním nádorem mozku nepatří v rámci onkologických pacientů ke skupině nejpočetnější, ale vzhledem k tomu, že vedle celkových příznaků onkologického onemocnění se u nich projevuje i postižení progresivním neurologickým onemocněním, jedná se o specifickou skupinu pacientů. PP se v průběhu onemocnění snaží řešit a pozitivně ovlivnit nejen symptomy související s onkologickým onemocněním, nýbrž zahrnuje i péči psychologickou, sociální a spirituální. V případě, že jsou možnosti onkologické protinádorové léčby vyčerpány, nebo je léčba z různých důvodů ukončena, stává se PP hlavním léčebným postupem. Pro pacienty s HGG (high grade glioma) - s ohledem na progresivní průběh tohoto onemocnění - by měla být PP zahájena ihned po operaci současně se zahájením začátkem jejich onkologické terapie. U pacientů s LGG (low grade glioma), kdy je průběh jejich nemoci mnohem pozvolnější - nejsou jednoznačná doporučení pro zahájení multidisciplinární PP. Ta by měla být indikována a zahájena či započata v závislosti na jejich aktuálním zdravotním a psychickém stavu, s cílem co nejdéle udržet dobrou kvalitu jejich života v průběhu onemocnění. Cílem tohoto sdělení je přinést přehled nejčastějších symptomů u pacientů s primárním nádorem mozku s možností ovlivnění těchto symptomů v rámci PP.
Palliative care (PP) is active multidisciplinary care, which is not primarily aimed at prolonging life or treatment of cancer patients, but at alleviating the symptoms of the underlying disease and thereby improving their quality of life. PP should already be provided during complex oncological care and be an integral part of it. This trend also applies to neuro-oncology patients with a primary brain tumour. Patients with a primary brain tumour do not belong to the most numerous group of oncology patients, but given that, in addition to general symptoms of oncological disease, they are also affected by a progressive neurological disease, they are a specific group of patients. During the care of these patients, PP tries to solve and positively influence not only the symptoms related to the oncological disease, but also includes psychological, social and spiritual care. In the event that the possibilities of oncological antitumor treatment are exhausted, or the treatment is terminated for various reasons, PP becomes the main treatment procedure. For patients with HGG (high grade glioma) - considering the progressive course of this disease - PP should be started immediately after surgery at the same time as the start of their oncological therapy. In patients with LGG (low grade glioma) - when the course of their disease is much more gradual - there are no clear recommendations for the initiation of multidisciplinary PP. This should be indicated and started depending on their current health and psychological state, with the aim of maintaining their good quality of life as long as possible during the course of the disease. The aim of this review article is to provide an overview of the most common symptoms in patients with a primary brain tumour with the possibility of influencing these symptoms within the framework of PP.
Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th-April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017-2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017-2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community ́s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.
- MeSH
- chronický subdurální hematom * MeSH
- COVID-19 * MeSH
- lidé MeSH
- neurochirurgické výkony MeSH
- pandemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
