146 research outputs found
Oculocerebrorenal syndrome of Lowe protein controls cytoskeletal reorganisation during human platelet spreading
No full textLowe syndrome (LS) is a rare, X-linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5-phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-4-monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL-inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co-localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL-inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS
Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation
No full textRisks and benefits in a personalized application of allogeneic transplantation in patients with AML in first CR
No full textAllogeneic Hematopoietic Stem Cell Transplantation in patients with Acute Myeloid Leukemia : a personalized approach
Full text linkThe majority of patients with newly diagnosed acute myeloid leukemia (AML) obtain complete hematological remission (CR) after induction chemotherapy, but the incidence of relapse is considerable despite chemotherapeutic consolidation therapy. Currently, post-remission treatment (PRT) for the prevention of relapse may include continued chemotherapy, autologous hematopoietic stem cell transplantation (HSCT), or allogeneic HSCT (alloHSCT). Although alloHSCT is associated with the lowest incidence of relapse, counterbalancing non-relapse mortality (NRM) may compromise overall outcome. The decision to perform an alloHSCT for patients with AML in first CR depends on the assessment of risks and benefits (ie, mortality and relapse risk reduction), which is based on disease features, but also factors related to patient characteristics, transplantation procedures and type of donor. Such a risk versus benefit evaluation of alloHSCT has evolved into a personalized approach for patients with AML in first CR. The studies described in this thesis address the benefits of alloHSCT identifying different AML patient subgroups with improved outcome following alloHSCT. Secondly, the studies in this thesis addressed morbidity and mortality following alloHSCT. Lastly, this thesis discussed the value of alloHSCT as PRT in specific AML subgroups, potential challenges with respect to alloHSCT-related NRM, and statistical considerations analyzing PRT for AML. A personalized transplant decision approach for patients with AML in first CR was presented, which may be applied in daily clinical practice
Validation of the transplant conditioning intensity (TCI) index for allogeneic hematopoietic cell transplantation
No full textAbstract The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018–2021) and were one decade older (55–75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1–2], [2.5–3.5], [4–6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy satisfactorily and across other established prognostic factors
Teorie a aplikace postupu DoE (planovani experimentu) ve farmaceuticke technologii
Full text linkUniverzita Karlova, Farmaceutická fakulta v Hradci Králové Katedra: Katedra farmaceutické technologie Katedra biofyziky a fyzikální chemie Kandidát: Mgr. Julie Maruška Školitel: doc. Dipl.-Math. Erik Jurjen Duintjer Tebbens, Ph.D. Konzultant: doc. PharmDr. Zdeňka Šklubalová, Ph.D. Název disertační práce: Teorie a aplikace postupu DoE (plánovaní experimentů) ve farmaceutické technologii Tradiční proces vývoje nových přípravků zahrnuje výběr kombinací různých typů faktorů ovlivňujících řadu vlastností konečné lékové formy. Tato situace je vhodná pro použití metod z oblasti statistického plánovaní experimentů (DoE). V současné době začínají nejnovější publikace v oblasti farmaceutické technologie týkající se vývoje nových lékových forem stále více začleňovat techniky plánovaní experimentů, které jsou předmětem studia v této práci. Tato interdisciplinární disertační práce je anotovaným shrnutím publikací a výzkumných aktivit autora a klade si za cíl zkoumat postupy DoE zaměřené na jejich praktické využití v oblasti farmaceutické technologie; aplikovat vybrané techniky na reálné postupy farmaceutické technologie; a představit přehled nejúčinnějších DoE technik pro implementaci ve výzkumu v oblasti farmaceutické technologie. V prvním publikovaném článku jsme provedli retrospektivní analýzu získaných dat...Charles University, Faculty of pharmacy in Hradec Králové Department: Department of Pharmaceutical Technology Department of Biophysics and Physical Chemistry Candidate: Mgr. Julie Maruška Supervisor: Assoc. Prof. Dipl.-Math. Erik Jurjen Duintjer Tebbens, Ph.D. Consultant: Assoc. Prof. PharmDr. Zdeňka Šklubalová, Ph.D. Title of dissertation: Theory and applications of DoE (design of experiments) in pharmaceutical technology The conventional process for developing new medicines involves selecting combinations of various types of factors that impact numerous properties of the final dosage form. This scenario is well-suited for using methods from the statistical field of design of experiments (DoE). Currently, the latest publications on pharmaceutical technology related to the development of new dosage forms are increasingly beginning to incorporate experimental design techniques, which are the subject of study in this work. This interdisciplinary dissertation thesis is an annotated summary of the publication and research activities of the author and aims to explore the DoE approaches focusing on their practical applications within the realm of pharmaceutical technology; to apply the selected techniques in actual processes of pharmaceutical technology; and to present a review of the most useful...Department of Biophysics and Physical ChemistryKatedra biofyziky a fyzikální chemieFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov
Teorie a aplikace postupu DoE (planovani experimentu) ve farmaceuticke technologii
Full text linkUniverzita Karlova, Farmaceutická fakulta v Hradci Králové Katedra: Katedra farmaceutické technologie Katedra biofyziky a fyzikální chemie Kandidát: Mgr. Julie Maruška Školitel: doc. Dipl.-Math. Erik Jurjen Duintjer Tebbens, Ph.D. Konzultant: doc. PharmDr. Zdeňka Šklubalová, Ph.D. Název disertační práce: Teorie a aplikace postupu DoE (plánovaní experimentů) ve farmaceutické technologii Tradiční proces vývoje nových přípravků zahrnuje výběr kombinací různých typů faktorů ovlivňujících řadu vlastností konečné lékové formy. Tato situace je vhodná pro použití metod z oblasti statistického plánovaní experimentů (DoE). V současné době začínají nejnovější publikace v oblasti farmaceutické technologie týkající se vývoje nových lékových forem stále více začleňovat techniky plánovaní experimentů, které jsou předmětem studia v této práci. Tato interdisciplinární disertační práce je anotovaným shrnutím publikací a výzkumných aktivit autora a klade si za cíl zkoumat postupy DoE zaměřené na jejich praktické využití v oblasti farmaceutické technologie; aplikovat vybrané techniky na reálné postupy farmaceutické technologie; a představit přehled nejúčinnějších DoE technik pro implementaci ve výzkumu v oblasti farmaceutické technologie. V prvním publikovaném článku jsme provedli retrospektivní analýzu získaných dat...Charles University, Faculty of pharmacy in Hradec Králové Department: Department of Pharmaceutical Technology Department of Biophysics and Physical Chemistry Candidate: Mgr. Julie Maruška Supervisor: Assoc. Prof. Dipl.-Math. Erik Jurjen Duintjer Tebbens, Ph.D. Consultant: Assoc. Prof. PharmDr. Zdeňka Šklubalová, Ph.D. Title of dissertation: Theory and applications of DoE (design of experiments) in pharmaceutical technology The conventional process for developing new medicines involves selecting combinations of various types of factors that impact numerous properties of the final dosage form. This scenario is well-suited for using methods from the statistical field of design of experiments (DoE). Currently, the latest publications on pharmaceutical technology related to the development of new dosage forms are increasingly beginning to incorporate experimental design techniques, which are the subject of study in this work. This interdisciplinary dissertation thesis is an annotated summary of the publication and research activities of the author and aims to explore the DoE approaches focusing on their practical applications within the realm of pharmaceutical technology; to apply the selected techniques in actual processes of pharmaceutical technology; and to present a review of the most useful...Department of Biophysics and Physical ChemistryKatedra biofyziky a fyzikální chemieFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov
Theory and applications of DoE (design of experiments) in pharmaceutical technology
No full textCharles University, Faculty of pharmacy in Hradec Králové Department: Department of Pharmaceutical Technology Department of Biophysics and Physical Chemistry Candidate: Mgr. Julie Maruška Supervisor: Assoc. Prof. Dipl.-Math. Erik Jurjen Duintjer Tebbens, Ph.D. Consultant: Assoc. Prof. PharmDr. Zdeňka Šklubalová, Ph.D. Title of dissertation: Theory and applications of DoE (design of experiments) in pharmaceutical technology The conventional process for developing new medicines involves selecting combinations of various types of factors that impact numerous properties of the final dosage form. This scenario is well-suited for using methods from the statistical field of design of experiments (DoE). Currently, the latest publications on pharmaceutical technology related to the development of new dosage forms are increasingly beginning to incorporate experimental design techniques, which are the subject of study in this work. This interdisciplinary dissertation thesis is an annotated summary of the publication and research activities of the author and aims to explore the DoE approaches focusing on their practical applications within the realm of pharmaceutical technology; to apply the selected techniques in actual processes of pharmaceutical technology; and to present a review of the most useful..
Allogeneic stem cell transplantation in de novo core-binding factor acute myeloid leukemia in first complete remission: data from the EBMT.
Full text linkCore-binding factor acute myeloid leukemia (CBF-AML) represents 12-15% of all AML cases. Although CBF positivity infers a survival advantage, overall survival (OS) remains dismal. Treatment is with cytarabine/anthracycline-based chemotherapy induction followed by high-dose cytarabine (HiDAC) consolidation. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is reserved for relapse or for patients having not achieved MRD-negativity at high risk for relapse. The role of SCT in first complete remission (CR1) remains controversial and is considered in high risk conditions. In this retrospective, multi-national, European Society for Blood and Marrow Transplantation (EBMT)-based study, we identified 1901 patients with de novo CBF-AML who received an allo-SCT or autologous transplantation (ASCT) in CR1. 65.5% harbored t(8;21) and 34.4% inv(16). In this group, the majority (77%) were treated with allo-SCT in CR1. In multivariate analysis, treatment with allo-SCT was an independent and significant, negative predictor of NRM and OS (HR 4.26, p < 0.0001 and HR 1.67, p = 0.003) and among patients treated with allo-SCT, those treated with MSD had the best outcomes, comparable to those treated with ASCT. There was no interaction between the type of transplant and MRD status at time of SCT. In both, MRD-negative and MRD-positive groups, NRM was worse in the allo-SCT group (MRD-: 12.9% vs 5.2%, p = 0.007; MRD+: 10.6% vs 0%, p = 0.004). We therefore demonstrated that consolidation in CR1 with allo-SCT results in worse outcomes than ASCT. Whether consolidation with ASCT yields better outcomes than chemotherapy alone or chemotherapy in combination with Gemtuzumab Ozogamicin is yet to be investigated
Theory and applications of DoE (design of experiments) in pharmaceutical technology
No full textCharles University, Faculty of pharmacy in Hradec Králové Department: Department of Pharmaceutical Technology Department of Biophysics and Physical Chemistry Candidate: Mgr. Julie Maruška Supervisor: Assoc. Prof. Dipl.-Math. Erik Jurjen Duintjer Tebbens, Ph.D. Consultant: Assoc. Prof. PharmDr. Zdeňka Šklubalová, Ph.D. Title of dissertation: Theory and applications of DoE (design of experiments) in pharmaceutical technology The conventional process for developing new medicines involves selecting combinations of various types of factors that impact numerous properties of the final dosage form. This scenario is well-suited for using methods from the statistical field of design of experiments (DoE). Currently, the latest publications on pharmaceutical technology related to the development of new dosage forms are increasingly beginning to incorporate experimental design techniques, which are the subject of study in this work. This interdisciplinary dissertation thesis is an annotated summary of the publication and research activities of the author and aims to explore the DoE approaches focusing on their practical applications within the realm of pharmaceutical technology; to apply the selected techniques in actual processes of pharmaceutical technology; and to present a review of the most useful..
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