Új szintézismódszerek kidolgozása és alkalmazása célzott hatásterületen aktív heterociklusos molekulák szintézisére = Elaboration and application of new synthetic methodologies for the synthesis of heterocyclic molecules of aimed biological activity

Pályázati kutatásunk alapvető célja az volt, hogy néhány, a legutóbbi időkben felismert új szintézis-lehetőséget laboratóriumunkban meghonosítsunk, saját magunk új módszereket dolgozzunk ki, és mindezek segítségével felfedező kutatásokat végezzünk kiemelten fontos területen ható biológiailag aktív molekulák megtalálására és szintézisére. Beszámolhatunk arról, hogy palládium-katalizált C-C és C-N keresztkapcsolások segítségével új gyűrűvázakhoz jutottunk, és alapvető új átalakulásokat kezdeményeztünk az organokatalízis és fluoros technika területén. Módszereink segítségével főként a multidrog-rezisztenciát gátló vegyületek családjában értünk el figyelemre méltó eredményt. Kimutattuk, hogy néhány újszerűen szubsztituált fenotiazin-származék hatása meghaladja a kontrollként vizsgált verapamil hatását. A rezisztencia gátlása különösen a mikróbás fertőzések és tumoros betegségek leküzdésében kiemelt jelentőségű. A leghatékonyabb származékokat egy jövőbeli gyógyszerfejlesztés lead-molekulájaként tekintjük. Munkánk elvégzésébe nagy számban vontunk be graduális és posztgraduális hallgatókat. A kutatási eredményekből 7 PhD értekezés született, ezek közül 4 már sikeres védésre került, emellett két egyetemi záródolgozat is elkészült. Munkánk tudományos értékét a megjelent 18 közlemény fémjelzi, összesített hatástényezőjük 57.5. | The basic aim of the present project activity was to establish recently recognized new synthetic methodologies in our laboratory, to elaborate new procedures, and to apply these novel approaches for identification and synthesis of compounds exhibiting biological activity in important areas of drug research. It is to be emphasized that application of palladium-catalyzed C-C and C-N cross coupling reactions allowed the synthesis of new ring systems, whereas basically new transformations have been initiated in the areas of organocatalysis and fluorous techniques.. The new methods provided the most outstanding reaults in the area of multidrug resistance inhibition. Results of some phenothiazines with unusual substitution pattern exceeded the effect of verapamil used as a reference compound. Resistance inhibition is of primary importance in treatment of microbial infections and tumor diseases. Those synthesized compounds exhibiting the highest effectivity can be regarded as lead compounds for the future drug development. Great number of MSc and PhD students were involved into accomplishment of the project. Seven PhD dissertations were born, four of these have already been successfully defended and, furthermore, two master theses have also been finalized. The scientific value of the research activity is coined by the 18 scientific publications with a cumulative impact factor of 57.5

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start

(Table S1) Stable carbon and oxygen isotopes and Mg/Ca ratios of planktonic foraminifera from ODP Hole 198-1209B

The Paleocene-Eocene Thermal Maximum (PETM) has been attributed to a rapid rise in greenhouse gas levels. If so, warming should have occurred at all latitudes, although amplified toward the poles. Existing records reveal an increase in high-latitude sea surface temperatures (SSTs) (8° to 10°C) and in bottom water temperatures (4° to 5°C). To date, however, the character of the tropical SST response during this event remains unconstrained. Here we address this deficiency by using paired oxygen isotope and minor element (magnesium/calcium) ratios of planktonic foraminifera from a tropical Pacific core to estimate changes in SST. Using mixed-layer foraminifera, we found that the combined proxies imply a 4° to 5°C rise in Pacific SST during the PETM. These results would necessitate a rise in atmospheric pCO2 to levels three to four times as high as those estimated for the late Paleocene

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start

Key factors for national spread and scale-up of an eConsult innovation.

BackgroundExpanding healthcare innovations from the local to national level is a complex pursuit requiring careful assessment of all relevant factors. In this study (a component of a larger eConsult programme of research), we aimed to identify the key factors involved in the spread and scale-up of a successful regional eConsult model across Canada.MethodsWe conducted a constant comparative thematic analysis of stakeholder discussions captured during a full-day National eConsult Forum meeting held in Ottawa, Canada, on 11 December 2017. Sixty-four participants attended, representing provincial and territorial governments, national organisations, healthcare providers, researchers and patients. Proceedings were recorded, transcribed and underwent qualitative analysis using the Framework for Applied Policy Research.ResultsThis study identified four main themes that were critical to support the intentional efforts to spread and scale-up eConsult across Canada, namely (1) identifying population care needs and access problems, (2) engaging stakeholders who were willing to roll up their sleeves and take action, (3) building on current strategies and policies, and (4) measuring and communicating outcomes.ConclusionsEfforts to promote innovation in healthcare are more likely to succeed if they are based on an understanding of the forces that drive the spread and scale-up of innovation. Further research is needed to develop and strengthen the conceptual and applied foundations of the spread and scale-up of healthcare innovations, especially in the context of emergent learning health systems across Canada and beyond

Key factors for national spread and scale-up of an eConsult innovation.

BackgroundExpanding healthcare innovations from the local to national level is a complex pursuit requiring careful assessment of all relevant factors. In this study (a component of a larger eConsult programme of research), we aimed to identify the key factors involved in the spread and scale-up of a successful regional eConsult model across Canada.MethodsWe conducted a constant comparative thematic analysis of stakeholder discussions captured during a full-day National eConsult Forum meeting held in Ottawa, Canada, on 11 December 2017. Sixty-four participants attended, representing provincial and territorial governments, national organisations, healthcare providers, researchers and patients. Proceedings were recorded, transcribed and underwent qualitative analysis using the Framework for Applied Policy Research.ResultsThis study identified four main themes that were critical to support the intentional efforts to spread and scale-up eConsult across Canada, namely (1) identifying population care needs and access problems, (2) engaging stakeholders who were willing to roll up their sleeves and take action, (3) building on current strategies and policies, and (4) measuring and communicating outcomes.ConclusionsEfforts to promote innovation in healthcare are more likely to succeed if they are based on an understanding of the forces that drive the spread and scale-up of innovation. Further research is needed to develop and strengthen the conceptual and applied foundations of the spread and scale-up of healthcare innovations, especially in the context of emergent learning health systems across Canada and beyond

Automated manufacture of ΔNPM1 TCR-engineered T cells for AML therapy

Acute myeloid leukemia (AML) is a heterogeneous malignancy that requires further therapeutic improvement, especially for the elderly and for subgroups with poor prognosis. A recently discovered T cell receptor (TCR) targeting mutant nucleophosmin 1 (ΔNPM1) presents an attractive option for the development of a cancer antigen-targeted cellular therapy. Manufacturing of TCR-modified T cells, however, is still limited by a complex, time-consuming, and laborious procedure. Therefore, this study specifically addressed the requirements for a scaled manufacture of ΔNPM1-specific T cells in an automated, closed, and good manufacturing practice-compliant process. Starting from cryopreserved leukapheresis, 2E8 CD8-positive T cells were enriched, activated, lentivirally transduced, expanded, and finally formulated. By adjusting and optimizing culture conditions, we additionally reduced the manufacturing time from 12 to 8 days while still achieving a clinically relevant yield of up to 5.5E9 ΔNPM1 TCR-engineered T cells. The cellular product mainly consisted of highly viable CD8-positive T cells with an early memory phenotype. ΔNPM1 TCR CD8 T cells manufactured with the optimized process showed specific killing of AML in vitro and in vivo. The process has been implemented in an upcoming phase 1/2 clinical trial for the treatment of NPM1-mutated AML

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants : Post-hoc Analysis of Its Effect on Brain Injury

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II–III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start