Molecular modelling of thymidylate synthase and rational design of its inhibitors as novel anticancer drugs

In search of novel anticancer drugs, putative inhibitors of the enzyme thymidylate synthase were investigated. The dissertation presents several steps of computationally aided drug design. Two targets are described: active site of the enzyme, for competitive inhibitors, and an allosteric pocket at the dimer interface. The potential hits were selected by computational high-throughput screening (molecular docking calculations) of available drug and prodrug databases. The selected compounds were then modified and scored further to indicate potential leads. Molecular dynamics simulations were performed for selected putative inhibitors of thymidylate synthase, both competitive and allosteric, in order to assess their dynamical behaviour, binding properties and arrangement of the ligands, and to select lead compounds for further tests in vitro. Moreover, a library of peptoids is described, created with the aim to design novel compounds with the desired peptide-like properties. Furthermore, quantum mechanics calculations were conducted to aid the synthesis and investigation of novel enzyme inhibitors, including boron containing compounds.W poszukiwaniu leków przeciwnowotworowych nowej generacji badano potencjalne inhibitory enzymu syntazy tymidylanowej. Opisano szereg etapów komputerowo wspomaganego projektowania leków. Wybrano dwa miejsca docelowe dla poszukiwanych inhibitorów: kieszeń aktywną enzymu oraz kieszeń allosteryczną między podjednostkami białka. Potencjalnie obiecujące związki wybrano w drodze wysokowydajnej procedury przesiewania (przy zastosowaniu metod dokowania molekularnego) dostępnych baz danych leków i proleków, a następnie modyfikację i dalszą selekcję wyników dokowania. Dla wybranych potencjalnych inhibitorów syntazy tymidylanowej, zarówno kompetycyjnych, jak i allosterycznych, przeprowadzono symulacje metodą dynamiki molekularnej w celu oceny dynamiki układu, parametrów wiązania i ułożenia ligandów, jak również wskazania wiodących związków do dalszych badań in vitro. Ponadto opisano bibliotekę peptoidów, stworzoną w celu projektowania nowej generacji związków o pożądanych właściwościach peptydomimetycznych. Wykonano również obliczenia metodami mechaniki kwantowej mające na celu wspomaganie badań i syntezy nowych inhibitorów enzymów, w tym związków zawierających bor

Effective inhibition of lytic development of bacteriophages λ, P1 and T4 by starvation of their host, Escherichia coli

BACKGROUND: Bacteriophage infections of bacterial cultures cause serious problems in genetic engineering and biotechnology. They are dangerous not only because of direct effects on the currently infected cultures, i.e. their devastation, but also due to a high probability of spreading the phage progeny throughout a whole laboratory or plant, which causes a real danger for further cultivations. Therefore, a simple method for quick inhibition of phage development after detection of bacterial culture infection should be very useful. RESULTS: Here, we demonstrate that depletion of a carbon source from the culture medium, which provokes starvation of bacterial cells, results in rapid inhibition of lytic development of three Escherichia coli phages, λ, P1 and T4. Since the effect was similar for three different phages, it seems that it may be a general phenomenon. Moreover, similar effects were observed in flask cultures and in chemostats. CONCLUSION: Bacteriophage lytic development can be inhibited efficiently by carbon source limitation in bacterial cultures. Thus, if bacteriophage contamination is detected, starvation procedures may be recommended to alleviate deleterious effects of phage infection on the culture. We believe that this strategy, in combination with the use of automated and sensitive bacteriophage biosensors, may be employed in the fermentation laboratory practice to control phage outbreaks in bioprocesses more effectively

The effects of 3-year growth hormone treatment and body composition in Polish patients with Silver-Russell syndrome

Introduction: Silver-Russell syndrome (SRS) is characterized by clinical and genetic heterogeneity. SRS is the only disease entity associated with (epi)genetic abnormalities of 2 different chromosomes: 7 and 11. In SRS, the 2 most frequent molecular abnormalities are hypomethylation (loss of methylation) of region H19/IGF2:IG-DMR on chromosome 11p15.5 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). Therapy with recombinant human growth hormone (rhGH) is implemented to increase body height in children with SRS. The effect of the administered rhGH on height, weight, body mass index (BMI), body composition, and height velocity in patients with SRS during 3 years of rhGH therapy was analysed. Material and methods: 31 SRS patients (23 with 11p15 LOM, 8 with upd(7)mat) and 16 patients small for gestational age (SGA) as a control group were diagnosed and followed up in The Children’s Memorial Health Institute. Patients were eligible for the 2 Polish rhGH treatment programmes [for patients with SGA or with growth hormone deficiency (GHD)]. Anthropometric parameters were collected in all patients. Body composition using bioelectrical impedance was measured in 13 SRS and 14 SGA patients. Results: Height, weight, and weight for height (SDS) at baseline of rhGH therapy were lower in SRS patients than in the SGA control group: –3.3 ± 1.2 vs. -2.6 ± 06 (p = 0.012), –2.5 vs. -1.9 (p = 0.037), –1.7 vs. –1.1 (p = 0.038), respectively. Height SDS was increased from –3.3 ± 1.2 to –1.8 ± 1.0 and from –2.6 ± 0.6 to –1.3 ± 0.7 in the SRS and SGA groups, respectively. Patients with 11p15 LOM and upd(7)mat achieved similar height, 127.0 ± 15.7 vs. 128.9 ± 21.6 cm, and –2.0 ± 1.3 vs. –1.7 ± 1.0 SDS, respectively. Fat mass percentage decreased in SRS patients from 4.2% to 3.0% (p < 0.05) and in SGA patients from 7.6% to 6.6% (p < 0.05). Conclusions: Growth hormone therapy has a positive influence on the growth of SRS patients. Regardless of molecular abnormality type (11p15 LOM vs. upd(7)mat), height velocity was similar in SRS patients during 3 years of rhGH therapy

Projekt utworzenia sieci ośrodków diabetologicznych w województwie pomorskim

Wstęp. Cukrzyca stanowi ważny problem zdrowotny i ekonomiczny w Polsce. W województwie pomorskim choruje na nią około 110 tysięcy osób powyżej 18. roku życia. Co czwarty pacjent spośród nich jest nieświadomy posiadania choroby. Szacuje się, że liczba osób chorych na cukrzycę w Polsce i na Pomorzu będzie szybko wzrastać ze względu na coraz większą zapadalność oraz starzenie się społeczeństwa. Głównym celem niniejszego artykułu jest przedstawienie optymalnego dla województwa pomorskiego modelu sieci ośrodków diabetologicznych. Jego głównym założeniem ma być redukcja liczby hospitalizacji chorych z cukrzycą oraz zdecydowana poprawa opieki ambulatoryjnej. Materiał i metody. Oceniono dane dotyczące hospitalizacji osób z rozpoznaną cukrzycą w całym województwie pomorskim, uzyskane z bazy Pomorskiego Oddziału NFZ oraz dane osób hospitalizowanych z powodu cukrzycy w Uniwersyteckim Centrum Klinicznym w Gdańsku (szpitalu dysponującym jedynym oddziałem diabetologicznym w województwie). Następnie odniesiono się do aktualnych zaleceń towarzystw naukowych i wskazano wady obecnego systemu leczenia osób chorujących na cukrzycę. Ostatecznie zapro­ponowano model sieci ośrodków diabetologicznych dla województwa pomorskiego. Wyniki. Wyniki przedstawiono osobno dla opieki szpitalnej i ambulatoryjnej. Zaproponowano sieć 4 szpitali dla opieki całodobowej, zwracając uwagę na potrzeby finansowe, sprzętowe oraz wymagany personel. W opiece ambulatoryjnej zaproponowano szereg rozwiązań, zwłaszcza dotyczących opieki nad osobami młodymi z cukrzycą typu 1, kobietami ciężarnymi oraz pacjentami z zespołem stopy cukrzycowej.Introduction. Diabetes is an important health and economical problem in Poland. Pomorskie Region has a population of about 110.000 adult diabetics. Every fourth of them is unaware of having the disease. It is estimated that the number of people with diabetes in Poland will rapidly increase due to population aging. Aim. The aim of this article is to describe the optimal model of diabetes centers network in Pomorskie to reduce the number of hospitalizations of patients with diabetes and to improve outpatient care. Material and methods. Data of hospital care of diabetics in Pomorskie from National Health Service and from the University Clinical Centre in Gdansk was evaluated and compared to the current guidelines. Then defects of current healthcare on diabetics was indicated. Finally, the model of diabetes centers network in Pomorskie was proposed. Results. Results are presented separately for hospital and outpatient care. The network of four hospitals was proposed depending of the financial needs, required equipment and staff. In outpatient care several solutions was suggested, e.g. healthcare for young people with type 1 diabetes, pregnant women and patients with diabetic foot syndrome

Alder pollen season in poland in 2018

Alder pollen grains constitute the important allergen sources in this respect in the Northern Hemisphere. The aim of the study was to investigate the concentration of alder (Alnus spp.) in Bialystok, Bydgoszcz, Cracow, Drawsko Pomorskie, Lublin, Olsztyn, Opole, Piotrkow Trybunalski, Sosnowiec, Szczecin, Warsaw, Wroclaw and Zielona Gora in 2018. Measurements were performed by the volumetric method (Burkard and Lanzoni pollen samplers). Seasonal Pollen Index (SPI) was estimated as the annual sum of daily average pollen concentrations. The pollen season of alder in all Polish stations began on the 11th and 13th March and the high concentration persisted until the first days of April. The highest, record airborne concentration of 1068 pollen grains/m3 was noted in Lublin on the 13th March. The peak values of seasonal pollen count occurred between of 11th March and 4th April in all cities. In 2018 pollen concentration of alder was one of the lowest in all analysed cities

Analysis of the plantain pollen season in selected Polish cities in 2018

The paper presents the course of pollen season of plantain in Bialystok, Bydgoszcz, Drawsko Pomorskie, Cracow, Lublin, Olsztyn, Opole, Piotrkow Trybunalski, Sosnowiec, Szczecin, Warsaw, Wroclaw and Zielona Gora in 2018. Measurements were performed by the volumetric method (Burkard and Lanzoni pollen samplers). Pollen season was defined as the period in which 98% of the annual total catch occurred. The plantain pollen season started in the first decade of May and lasted until the end of September. Despite such a long pollen season in Poland, only in some cities there are days with an average concentration exceeding 10 P/m3. Significant differences were observed in annual sum values. The highest values were recorded in Lublin (400 grains) and Zielona Gora (308 grains), and the lowest in Drawsko Pomorskie (160 grains) and Olsztyn (184 grains). The value of annual average in 2018 was usually lower than in the previous years

Analysis of mugwort (Artemisia) pollen seasons in selected cities in Poland in 2018

The aim of the present study was to compare the mugwort pollen season in 2018 in Bialystok, Bydgoszcz, Cracow, Drawsko-Pomorskie, Lublin, Olsztyn, Opole, Sosnowiec, Szczecin, Warsaw, Wroclaw, and Zielona Gora. Pollen concentration measurements were made by the volumetric method using Burkard or Lanzoni pollen samplers. The pollen season was considered as the period during which 98% of the total annual pollen count occurred. The Seasonal Pollen Index (SPI) was calculated as the sum of the average daily pollen concentrations throughout the season determined for the individual cities. The mugwort pollen season started earliest in Bialystok (June 21st) and Bydgoszcz (June 25th), while in the other cities its onset occurred in the first 10 days of July. Significant differences were found in season duration (68–110 days), SPI, and peak value. The longest season occurred in Zielona Gora and Bydgoszcz, while the shortest one in Wroclaw. The highest SPI and maximum concentration values were observed in Lublin and Zielona Gora. In most of the cities, the peak value was recorded in the first 10 days of August. The highest risk of allergy in people sensitive to the pollen of this taxon was found in Zielona Gora, Lublin, and Warsaw

The oak pollen concentration in the air of selected cities in Poland in 2018

This paper contains an analysis of oak pollen seasons in selected cities of Poland in 2018. Sampling sites were located in the following cities: Bialystok, Bydgoszcz, Cracow, Drawsko Pomorskie, Lublin, Olsztyn, Opole, Piotrkow Trybunalski, Sosnowiec, Szczecin, Warsaw, Wroclaw and Zielona Gora. The volumetric method was applied using the Burkard or Lanzoni trap. The pollen season was determined by the 98% method. The season started earliest in Sosnowiec (April 14th). The mean duration of the pollen season was 33 days. The highest pollen concentration (713 P/m3) was observed in Wroclaw (April 19th). The peak values were recorded between April 19th and May 1st in the different cities

Ambrosia pollen season in selected cities in Poland in 2018

Ambrosia causes most pollen allergies in North America. After several Ambrosia species were introduced to Europe, an increase in the incidence of allergy to pollen of these plants has been observed in many countries. The aim of this study was to compare Ambrosia pollen seasons in 2018 in 13 cities located in different regions of Poland: Bialystok, Bydgoszcz, Cracow, Drawsko Pomorskie, Lublin, Olsztyn, Opole, Piotrkow Trybunalski, Sosnowiec, Szczecin, Warsaw, Wroclaw and Zielona Gora. The study was conducted by the volumetric method using Burkard or Lanzoni pollen samplers. The pollen season was determined by the 98% method. The earliest pollen season start dates (the end of July) were recorded in Zielona Gora, Bydgoszcz, Opole and Szczecin, while the latest ones in Drawsko Pomorskie and Bialystok. The longest pollen seasons occurred in Opole, Szczecin and Zielona Gora (79 days). The highest average daily concentrations of Ambrosia pollen were recorded in Bialystok (129 P/m3) and Lublin (99 P/m3), while the lowest ones in Drawsko Pomorskie and Szczecin (4 and 10 P/m3, respectively). The annual pollen sum reached the highest value in Opole (567 pollen grains) and Zielona Gora (555 pollen grains). It can be concluded from the pattern of Ambrosia pollen seasons at the monitoring sites studied that pollen of this taxon originates not only from Ambrosia locations in Poland but also from long-distance transport

The analysis of mugwort pollen count in selected Polish cities in 2014

Celem pracy było porównanie sezonu pyłkowego bylicy w 2014 r. w Bydgoszczy, Krakowie, Lublinie, Piotrkowie Trybunalskim, Poznaniu, Sosnowcu, Szczecinie i Warszawie. Pomiary stężenia pyłku prowadzono metodą objętościową z zastosowaniem aparatów Burkard oraz Lanzoni. Sezon pyłkowy wyznaczono jako okres, w którym w powietrzu występuje 98% rocznej sumy ziaren pyłku. Indeks SPI obliczono jako sumę średnich dobowych stężeń pyłku w danym sezonie. Sezon pyłkowy bylicy najwcześniej (13 czerwca) rozpoczął się w Szczecinie, a najpóźniej (15 lipca) – w Lublinie i Warszawie. Zanotowano znaczne różnice w czasie trwania sezonu. Najwyższe wartości stężeń zaobserwowano w Poznaniu, maksymalne stężenie wynoszące 172 z/m3 zarejestrowano 19 sierpnia. Maksymalne wartości sezonowe koncentracji pyłku we wszystkich miastach wystąpiły między 27 lipca a 19 sierpnia.The aim of the study was to compare the pollen season of mugwort in the cities of Bydgoszcz, Cracow, Lublin, Piotrków Trybunalski, Poznań, Sosnowiec, Szczecin and Warsaw in 2014. Measurements were performed by the volumetric method (Burkard and Lanzoni pollen sampler). Pollen season was defined as the period in which 98% of the annual total catch occurred. Seasonal Pollen Index (SPI) was estimated as the annual sum of daily average pollen concentrations. The pollen season of mugwort started first in Szczecin, on the 13th of June, and at the latest – on the 15th of July – in Lublin and Warsaw. The differences of pollen seasons duration were considerables. The highest record airborne concentration of 172 pollen grains/m3 was noted in Poznań on the 19th of August. The maximum values of seasonal pollen count occurred between 27th of July and 19th of August in all cities