- Publikační typ
- abstrakt z konference MeSH
Proteins are biopolymers composed of amino acids. Proteins play a role almost in all processes in living organisms. In cells, proteins are synthesized on ribosomes in a process called translation, where amino acids are connected one at a time by a chemical bond according to a pre-defined scenario stored as the genetic information. Relative to their lifetime, proteins spend non-negligible time attached to the ribosome. This review focuses on phenomena that involve a nascent protein before it is released from the ribosome, i.e., in the first moments of their own synthesis, co-translationally. The text partly covers a lecture given by the author at the Summer School for High School Teachers and Students organized by UCT Prague in August 2021.
- MeSH
- proteosyntéza * MeSH
- ribozomy chemie MeSH
- translační modifikace proteinu * fyziologie MeSH
- Publikační typ
- práce podpořená grantem MeSH
Úvod: Tofacitinib je léčivo ze skupiny inhibitorů Janusovy kinázy v perorální formě, které je určeno pro léčbu ulcerózní kolitidy (UC – ulcerative colitis). Účinnost přípravku byla prokázána v registračních studiích, avšak data o účinnosti a bezpečnosti z klinické praxe jsou dosud zřídkavá. Cílem této práce bylo posoudit klinickou odpověď na 8týdenní indukční léčbu tofacitinibem u pacientů s UC. Metodika: Do hodnocení byli zařazeni konsekutivní pacienti, u kterých byla zahájena léčba tofacitinibem v dávce 2 × 10 mg denně. Aktivita onemocnění byla posuzována indexem aktivity Mayo vč. endoskopického subskóre na počátku léčby a v týdnu 8, spolu s hodnocením zánětlivých parametrů v podobě C-reaktivního proteinu (CRP) a fekálního kalprotektinu (FC – fecal calprotectin). Jako odpovídající na léčbu byli v týdnu 8 hodnoceni pacienti s celkovým indexem Mayo 0–5 spolu s endoskopickým subskóre 0–1. Při každé návštěvě byly hodnoceny nežádoucí účinky léčby. Výsledky: Hodnocení proběhlo u 24 pacientů (41,7 % muži, 58,3 % ženy) o průměrném stáří 35,3 ± 11,8 let. Průměrná doba trvání choroby byla 8,3 ± 5,2 let. Průměrný pacient souboru byl v minulosti léčen dvěma biologiky, nicméně 25 % bylo zcela naivních k biologické léčbě. V týdnu 0 byla souběžná léčba kortikoidy přítomna u 41,7 % pacientů, jiná imunosupresvní nebo biologická léčba podávána nebyla. Po 8 týdnech odpovědělo na léčbu 52,9 % pacientů. Celkové Mayo skóre pokleslo u respondérů z hodnoty 5,9 ± 3,5 na 1,1 ± 1,3 (p = 0,01), zatímco u nonrespondérů došlo k nesignifikantní změně z 8,0 ± 2,5 na 8,9 ± 2,1 (p = 0,86). Zlepšení endoskopického skóre z 2,0 ± 1,0 na 0,6 ± 0,7 (p = 0,02) u respondérů kontrastuje se zcela nezměněnou hodnotou u pacientů bez odpovědi (2,9). Významný pokles hodnot CRP (6,7 ± 6,2 vs. 2,0 ± 2,2 mg/l; p = 0,04 a FC (1 195 ± 1 189 vs. 578 ± 654 μg/g; p = 0,05) byl zaznamenán rovněž pouze v kohortě s klinickou odpovědí. Všechny hodnocené parametry v týdnu 0 byly v obou kohortách srovnatelné, s výjimkou triacylglycerolů, jejichž vstupní hodnota byla u nonrespondérů vyšší. Léčba byla do 8 týdnů ukončena u 23,5 % pacientů, u všech z důvodu nedostatečné odpovědi. Byly zaznamenány dvě stížnosti na bolesti hlavy po zahájení léčby a po jednom výskytu cytomegalovirové kolitidy, klostridiové kolitidy a orální kandidózy. Závěr: Účinnost indukční fáze léčby tofacitinibem byla pozorována přibližně u poloviny pacientů s UC. S ohledem na omezený vzorek pacientů a délku terapie nutno získat dlouhodobá data o účinnosti a bezpečnosti léku.
Introduction: Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). Its efficiency was proven in registration trials, however data from real clinical practice are still sparse. Our aim was to evaluate efficacy and safety of tofacitinib in UC patients within 8-week induction period. Methods: Data from consecutive UC patients who started tofacitinib 10 mg twice a day were evaluated. Disease activity was assessed by Mayo score including endoscopic Mayo at baseline and week 8 together with C-reactive protein (CRP) and fecal calprotectin (FC). At week 8, patients with total Mayo ≤ 5 with endoscopic subscore ≤ 1 were considered responders. Adverse events were registered at each visit. Results: A total of 24 patients (41.7% males), mean age 35.3 ±11.8 years were included. The mean disease duration was 8.3 ± 5.2 years. In median, the patients were previously treated with two biologic agents, however 25% of the patients were naïve to any biologic therapy. Systemic corticosteroids were present in 41.7% of patients at baseline and no patient had concomitant biologic or immunosuppressive therapy. At week 8, 52.9% of patients responded to treatment. The mean total Mayo decreased in responders from 5.9 ± 3.5 to 1.1 ± 1.3 (p = 0.01), while non-responders it changed from 8.0 ± 2.5 to 8.9 ± 2.1 (p = 0.86). Endoscopic subscore decreased from 2.0 ± 1.0 to 0.6 ± 0.7 (p = 0.02) in responders, however remained stable in non-responders (2.9). CRP and FC dropped significantly in responders (6.7 ± 6.2 vs. 2.0 ± 2.2 mg/L, p = 0.04; 1,195 ± 1,189 vs. 578 ± 654 μg/g, p = 0.05), but not in non-responders. Non-responders had significantly higher baseline triglycerides compared to responders. Tofacitinib was stopped in 23.5% of patients until week 8 due to insufficient response. Two patients reported headaches after treatment initiation and single events of Cytomegalovirus colitis, Clostridium difficile colitis and oral candidiasis occurred. Conclusion: Tofacitinib was efficient in inducing clinical response with mucosal healing in about half of UC patients after 8 weeks of therapy. A need for long-term outcomes and for safety data with emphasis on infectious complications warrant further investigation.
- Klíčová slova
- tofacitinib citrát,
- MeSH
- dospělí MeSH
- hodnocení léčiv MeSH
- Janus kinasa 3 antagonisté a inhibitory farmakologie terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé středního věku MeSH
- lidé MeSH
- ulcerózní kolitida * farmakoterapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Brain perfusion is reduced early after subarachnoid hemorrhage (SAH) due to intracranial hypertension and early vasospasm. The contribution of these two mechanisms is unknown. By performing a prophylactic decompressive craniectomy (DC) in a rat model of SAH we aimed to study brain perfusion after the component of intracranial hypertension has been eliminated. We used 2x2 factorial design, where rats received either decompressive craniectomy or sham operation followed by injection of 250 microl of blood or normal saline into prechiasmatic cistern. The cortical perfusion has been continually measured by laser speckle-contrast analysis for 30 min. Injection of blood caused a sudden increase of intracranial pressure (ICP) and drop of cerebral perfusion, which returned to baseline within 6 min. DC effectively prevented the rise of ICP, but brain perfusion after SAH was significantly lower and took longer to normalize compared to non-DC animals due to increased cerebral vascular resistance, which lasted throughout 30 min experimental period. Our findings suggest that intracranial hypertension plays dominant role in the very early hypoperfusion after SAH whilst the role of early vasospasm is only minor. Prophylactic DC effectively maintained cerebral perfusion pressure, but worsened cerebral perfusion by increased vascular resistance.
- MeSH
- intrakraniální hypertenze komplikace patofyziologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech * MeSH
- mozková kůra krevní zásobení patofyziologie MeSH
- mozkový krevní oběh fyziologie MeSH
- potkani Wistar MeSH
- subarachnoidální krvácení komplikace patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Causes of early hypoperfusion after subarachnoid hemorrhage (SAH) include intracranial hypertension as well as vasoconstriction. The aim of the study was to assess the effect of intracerebroventricular (ICV) administration of sodium nitroprusside (SNP) on early hypoperfusion after SAH. Male Wistar rats (220-240 g) were used, SAH group received 250 microl of fresh autologous arterial blood into the prechiasmatic cistern; sham-operated animals received 250 microl of isotonic solution. Therapeutic intervention: ICV administration of 10 microg SNP; 5 microl 5 % glucose (SNP vehicle) and untreated control. Brain perfusion and invasive blood pressure were monitored for 30 min during and after induction of SAH. Despite SNP caused increase of perfusion in sham-operated animals, no response was observed in half of SAH animals. The other half developed hypotension accompanied by brain hypoperfusion. There was no difference between brain perfusion in SNP-treated, glucose-treated and untreated SAH animals during the monitored period. We did not observe expected beneficial effect of ICV administration of SNP after SAH. Moreover, half of the SNP-treated animals developed serious hypotension which led to brain hypoperfusion. This is the important finding showing that this is not the option for early management in patient after SAH.
- MeSH
- antihypertenziva aplikace a dávkování škodlivé účinky MeSH
- intrakraniální hypotenze chemicky indukované patofyziologie MeSH
- intraventrikulární infuze MeSH
- krysa rodu rattus MeSH
- mozek krevní zásobení účinky léků patofyziologie MeSH
- mozkový krevní oběh účinky léků fyziologie MeSH
- nitroprusid aplikace a dávkování škodlivé účinky MeSH
- potkani Wistar MeSH
- subarachnoidální krvácení farmakoterapie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- DNA * fyziologie MeSH
- hydrofobní a hydrofilní interakce MeSH
- lidé MeSH
- sekvence nukleotidů genetika MeSH
- Check Tag
- lidé MeSH
BACKGROUND INFORMATION: Considering an analogy between wound healing and tumour progression, we studied chemokine and cytokine transcription and expression in normal fibroblasts by co-culture and in situ. RESULTS: Whole-genome transcriptome profiling revealed strong upregulation for the interleukin (IL)-6, IL-8 and the chemokine CXCL-1 in in vitro co-cultures of normal fibroblasts with either normal or malignant epithelial cells compared to fibroblast cultures. The same ILs/chemokines were distinctly upregulated in clinical samples of squamous cell carcinoma when compared with paired normal mucosae. Analysis of culture supernatants showed that during the course of co-culture of the fibroblasts with the epithelial cells, IL-6, IL-8 and CXCL-1 were secreted to the culture medium. Experiments with addition of any of the proteins to the culture medium supported the notion that these ILs/chemokines strongly contributed to maintenance of a low-differentiation phenotype of epithelial cells, evaluated by the detection of keratin-8. Simultaneous addition of all factors increased the extent of the effect. These studies were extended by experiments with epithelial cells, either cultured in medium conditioned by preceding use for malignant keratinocytes without and in the presence of normal or cancer-associated fibroblasts or medium containing antibodies against IL-6, IL-8 and CXCL-1. CONCLUSIONS: Our results indicate an analogy between wound healing and tumour growth, support the importance of epithelial-mesenchymal interaction in this model system and establish a potential bio-inspired anticancer therapy.
- MeSH
- chemokin CXCL1 biosyntéza genetika MeSH
- epitelo-mezenchymální tranzice genetika MeSH
- epitelové buňky metabolismus patologie MeSH
- fibroblasty metabolismus patologie MeSH
- imunohistochemie MeSH
- interleukin-6 biosyntéza genetika MeSH
- interleukin-8 biosyntéza genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny biosyntéza genetika MeSH
- nádory glandulární a epitelové metabolismus patologie MeSH
- regulace genové exprese u nádorů * MeSH
- škára metabolismus patologie MeSH
- stanovení celkové genové exprese MeSH
- transkriptom genetika MeSH
- upregulace genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
