Wyniki wyszukiwania

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mTOR inhibitors in epilepsy management: from bench to bedside

100%

Kotulska K.

Acta Neurobiologiae Experimentalis

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2017

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tom 77

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nr Suppl.1

Substantial and growing body of evidence now supports the role of mTOR pathway activation in epilepsy both in preclinical and clinical settings. In humans, mTOR activation has been showed to play an important role in seizures and epileptogenesis in numerous acquired and genetic epilepsies. Moreover, several studies indicate that mTOR signaling pathway is implicated in multidrug resistance resulting from P-gp expression in chronic epilepsy. Thus, the use of mTOR inhibitors is widely considered as an emerging potential therapy in many epilepsies. Tuberous sclerosis complex (TSC) is a genetic disorder characterized the development of hamartomas in various organs and tissues. The molecular hallmark of the disease is the overactivation of mTOR pathway resulting from inactivating mutations in either TSC1 or TSC2 genes. Epilepsy is present in 80–90% of TSC patients and usually appears in the first year of life. In the majority of affected patients, epilepsy is associated with developmental delay. Preclinical studies showed that mTOR inhibition with sirolimus might alleviate or prevent seizures in animal models of TSC. In recent years, many case reports showed beneficial effect of mTOR inhibitors in TSC patients with drug-resistant epilepsy. EXIST-3 trial was the first clinical study to show efficacy of everolimus in drug-resistant epilepsy associated with TSC. There are few other trials of mTOR inhibitors in epilepsy associated with TSC, focal cortical dysplasias, and Sturge-Weber ongoing. Given the data from basic research and the results of first clinical studies, mTOR inhibitors should be considered as promising therapeutic option in drug-resistant epilepsies.

2

Systemy dynamicznego oświetlenia ulic - przykład rozwiązań Smart City

63%

Kotulski L., Kotulska K.

Aura

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2018

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nr 04

3

Cell size and proliferation of subependymal giant cell astrocytomas are regulation by mTOR ans Ras-ERK signaling pathway

51%

Tyburczy M., Kotulska K., Jozwiak S., Kaminska B.

Acta Neurobiologiae Experimentalis

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2009

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tom 69

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nr 3

Tuberous sclerosis complex (TSC) is characterized by cortical developmental malformations that are associated with epilepsy and appearance of benign brain tumors – subependymal giant cell astrocytomas (SEGAs) which are composed of distinct cell types, including giant cells and dysplastic neurons. TSC results from mutations in TSC1 and TSC2, which lead to the mTOR pathway activation, and p70S6 kinase and ribosomal S6 protein phosphorylation. ERK pathway is also aberrantly activated in SEGAs. Clinical trials with the mTOR inhibitor – rapamycin have demonstrated reduction in size of SEGAs, but the molecular mechanisms are unknown. In the present study, we evaluated the effects of rapamycin and the ERK pathway inhibitor – UO126 on cell size, proliferation and viability of cell cultures derived from SEGA. Rapamycin or UO126 alone did not affect viability and proliferation of SEGA cells. However, treatment with both drugs reduced proliferation of SEGA cells. Staining of F-actin revealed decrease of cell size in SEGA cultures exposed to rapamycin alone or in combination with UO126, but treatment with UO126 alone did not infl uence cell size nor morphology. Our studies demonstrate that simultaneous inhibition of both mTOR and ERK signaling pathways reduces proliferation of SEGA cells. Moreover, inhibition of mTOR signaling with rapamycin diminishes a volume of giant SEGA cells. It implicates that inhibitors of mTOR and ERK pathways should be considered for clinical trials of SEGAs.

4

Does restruction of jugular venous outflow induce multiple sclerosis-like signs in rat brains?p.S66-S67

39%

Jedrzejowska-Szypulka H., Kotulska K., Kapustka B., Laczynski M., Larysz-Brysz M., Lewin-Kowalik J.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

BACKGROUND AND AIMS: Hypothesis that multiple sclerosis (MS) may be caused by chronic cerebrospinal venous insufficiency (CCVI) has gained public interest from both patients and physicians. However, there’s still lack of evidence for it. We have investigated presence of neuronal demyelination and degeneration, similar to these found in MS, in rat model of CCVI created by occlusion of jugular veins (JVs). METHODS: Twenty-five young female Wistar C rats were used. Complete ligation of both JVs (BO group), left JV (UO), or partial ligation (stenosis resulting in ~70% reduction of blood flow) of both JVs were performed. Blood flow in JVs was measured with Laser Doppler Flow Assessment. Neurological assessment using Neurologic Deficit Scale (NDS), 5-point EAE staging protocol, and gait analysis with CatWalk was performed. After 12 weeks, MRI for detecting demyelinating plaques as well as signs of bloodbrain barrier (BBB) disruption was performed. Histologic analysis of brain specimens was focused on markers of inflammation and demyelination. RESULTS: No neurologic deficits were found in all experimental animals. Both NDS, EAE and gait analysis did not differ from normal. MRI T2- and T1- weighted imaging as well as FLAIR sequence did not reveal any abnormalities in the brains of experimental rats. Histological analysis did not show any signs of inflammation or demyelination. CONCLUSIONS: Twelve-week CCVI in rats, both complete and partial, did not induce any changes resembling pathologies observed in MS. Therefore, linking CCVI with origin of MS remains controversial.

5

Cu/Zn-SOD overexpression impairs regeneration and aggravates neuropathic pain after sciatic nerve injury

39%

Lewin-Kowalik J., Kotulska K., London J., LePecheur M., Paly E., Golka B., Larysz-Brysz M.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

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nr 3

6

Functional impairment of nerve regeneration in trkBplus/minus mice

39%

Lewin-Kowalik J., Kotulska K., Marcol W., Larysz-Brysz M., Malinowska-Kolodziej L., Golka B.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

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nr 3

7

MRI-monitored cord blood-derived cell transplantation to the ventricular system of child with global cerebral ischemia-a case report

27%

Janowski M., Kmiec T., Jurkiewicz E., Kropiwnicki T., Habich A., Kotulska K., Jelonek E., Sarnowska A., Litwin M., Boruczkowski D., Lukomska B., Walecki J., Roszkowski M., Jozwiak S., Domanska-Janik K.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

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nr 1

Introduction: Neurological disorders are the most common cause of serious disability and have a major impact on financial healthrelated burden to society. Most of them are definitely associated with cell death: sudden or chronic. Conventional treatment methods yield disappointing results. Thus the discoveries in stem cell biology have fueled the interest in cell-based therapeutical approach. Based on experimental data cord blood has been proposed as a novel, autologous cell source for pediatric population. Non-invasive monitoring of cell fate following transplantation has been recently recommended as a basis for rational stem cell therapy. Subject: One year old child experienced devastating, cardiac arrest-induced cerebral ischemia. Despite a broad rehabilitation program diagnose of vegetative state has been established three months later. After next three months of continued rehabilitation no noticeable improvement has also been found and the child has been included into study. The protocol has been approved by the ethical commission of The Children’s Memorial Health Institute in Warsaw, Poland. Then the child’s own cord blood cells have been neurally-converted over 10 days in culture within GMP facility. Prior to transplantation cells were labeled with iron oxide (SPIO) for MR imaging. For scaling sensitivity of MR signal different concentrations of SPIO-labeled cells were scanned in the phantom. Then patient received monthly 3 subsequent cell infusions (1.2 x 107 cells each) to lateral ventricles. The follow up continued up to 6 months and included both clinical assessment and MR examinations. Results: High efficiency of neural cell conversion and SPIO labeling as well as no cytotoxicity were observed. The employed method of cell transplantation was found to be efficient to deliver cells to CNS as confirmed by MR imaging. Gradual decrease of SPIO signal intensity was observed over the period of follow up. No adverse events or abnormal reaction to cell implantation was detected. The follow up revealed mild functional improvement - decreased nystagmus, spasticity and the number of epileptic seizures. Moreover, the features of the child contact with parents has appeared, thus vegetative state can not be diagnosed any more. Conclusions: This report indicates that transplantation of autologous, neurally-committed cord blood-derived cells to the ventricular system of child is safe, feasible and able to result with mild functional improvement. Additionally cell-related MRI signal can be monitored for more than 4 months in transplanted brain hemisphere. Supported by MSHE grants no 0141/B/P01/2008/35 and 0142/B/ P01/2008/35.

Ograniczanie wyników

mTOR inhibitors in epilepsy management: from bench to bedside

Systemy dynamicznego oświetlenia ulic - przykład rozwiązań Smart City

Cell size and proliferation of subependymal giant cell astrocytomas are regulation by mTOR ans Ras-ERK signaling pathway

Does restruction of jugular venous outflow induce multiple sclerosis-like signs in rat brains?p.S66-S67

Cu/Zn-SOD overexpression impairs regeneration and aggravates neuropathic pain after sciatic nerve injury

Functional impairment of nerve regeneration in trkBplus/minus mice

MRI-monitored cord blood-derived cell transplantation to the ventricular system of child with global cerebral ischemia-a case report