Molecular mechanisms of antitumor activity of PAMAM dendrimer conjugates with anticancer drugs and a monoclonal antibody

Taxanes are considered fundamental drugs in the treatment of breast cancer, but despite the similarities, docetaxel (doc) and paclitaxel (ptx) work differently. For this reason, it is interesting to identify mechanisms of antitumor activity of PAMAM dendrimer conjugates that carry docetaxel or paclitaxel and monoclonal antibody trastuzumab, specifically targeted to cells which overexpressed HER-2. For this purpose, the impact on the level of reactive oxygen species, the mitochondrial membrane potential, cell cycle distribution and the activity of caspases-3/7, -8 and -9 of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined and compared with free docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. Moreover, apoptosis and necrosis were studied using flow cytometry and confocal microscopy, respectively. Our studies show the complexity of the potential mechanism of cytotoxic action of PAMAM-drug-trastuzumab conjugates that should be sought as a resultant of oxidative stress, mitochondrial activation of the caspase cascade and the HER-2 receptor blockade

Zatorowość płucna — przegląd metod diagnostyki obrazowej

Zatorowość płucna (ZP) określana jest jako jedna z częstszych kardiologicznych przyczyn bezpośredniego zagrożenia życia. O zatorowości płucnej mówimy w przypadku mechanicznego zamknięcia światła łożyska naczyniowego, najczęściej przez płynącą z prądem krwi skrzeplinę. Podejrzenie zatorowości płucnej postawić można na podstawie określonych, choć nieswoistych objawów podmiotowych i przedmiotowych, w tym badań laboratoryjnych oraz wywiadu chorobowego pacjenta. Zalecane do oceny klinicznego prawdopodobieństwa zatorowości płucnej są skale punktowe – Wellsa i Zmodyfikowana Skala Genewska. Do badań obrazowych pozwalających potwierdzić lub wykluczyć ZP należą metody z zastosowaniem promieniowania jonizującego, jak radiogram klatki piersiowej, scyntygrafia płuc, tomografia emisyjna pojedynczych fotonów (SPECT), angiotomografia tętnic płucnych czy klasyczna arteriografia tętnic płucnych; badania bez użycia promieniowania jonizującego, jak ultrasonografia - ultrasonograficzna próba uciskowa i echokardiografia czy, metoda obiecująca, lecz nie gotowa jeszcze do powszechnego stosowania – angiografia metodą rezonansu magnetycznego. Wybór metody obrazowania zależy od dostępności określonych badań oraz stanu klinicznego pacjenta.Zatorowość płucna (ZP) określana jest jako jedna z częstszych kardiologicznych przyczyn bezpośredniego zagrożenia życia. O zatorowości płucnej mówimy w przypadku mechanicznego zamknięcia światła łożyska naczyniowego, najczęściej przez płynącą z prądem krwi skrzeplinę. Podejrzenie zatorowości płucnej postawić można na podstawie określonych, choć nieswoistych objawów podmiotowych i przedmiotowych, w tym badań laboratoryjnych oraz wywiadu chorobowego pacjenta. Zalecane do oceny klinicznego prawdopodobieństwa zatorowości płucnej są skale punktowe – Wellsa i Zmodyfikowana Skala Genewska. Do badań obrazowych pozwalających potwierdzić lub wykluczyć ZP należą metody z zastosowaniem promieniowania jonizującego, jak radiogram klatki piersiowej, scyntygrafia płuc, tomografia emisyjna pojedynczych fotonów (SPECT), angiotomografia tętnic płucnych czy klasyczna arteriografia tętnic płucnych; badania bez użycia promieniowania jonizującego, jak ultrasonografia - ultrasonograficzna próba uciskowa i echokardiografia czy, metoda obiecująca, lecz nie gotowa jeszcze do powszechnego stosowania – angiografia metodą rezonansu magnetycznego. Wybór metody obrazowania zależy od dostępności określonych badań oraz stanu klinicznego pacjenta

Underground tourist routes as an element of Poland’s cultural heritage

Underground tourist routes respond to current trends in museum development. They can be treated as interactive exhibitions focused primarily on the visitor. Former underground mines are also important elements of cultural heritage. They preserve mining equipment and traces of mining techniques. Through interactivity they can perform an educational function, presenting mining memorabilia and customs. Underground routes are also tourist destinations, attracting a significant number of visitors. The present study covered eight routes located in different regions of Poland. Their tourist value was assessed and tourists were asked to complete a survey regarding the routes. The significance of the mining heritage was described and evaluated. On this basis, the strengths and weaknesses of the underground mine routes as places of presentation of cultural heritage were identified. The sites surveyed are characterised by their high potential but the level of awareness and tourist use is not high. The underground routes with the highest cultural heritage value are also those with high tourist potential

Effects of process parameters on structure and properties of melt-blown poly(lactic acid) nonwovens for skin regeneration

Skin regeneration requires a three-dimensional (3D) scaffold for cell adhesion, growth and proliferation. A type of the scaffold offering a 3D structure is a nonwoven material produced via a melt-blown technique. Process parameters of this technique can be adapted to improve the cellular response. Polylactic acid (PLA) was used to produce a nonwoven scaffold by a melt-blown technique. The key process parameters, i.e., the head and air temperature, were changed in the range from 180–270 °C to obtain eight different materials (MB1–MB8). The relationships between the process parameters, morphology, porosity, thermal properties and the cellular response were explored in this study. The mean fiber diameters ranged from 3 to 120 µm. The average material roughness values were between 47 and 160 µm, whereas the pore diameters ranged from 5 to 400 µm. The calorimetry thermograms revealed a correlation between the temperature parameters and crystallization. The response of keratinocytes and macrophages exhibited a higher cell viability on thicker fibers. The cell-scaffold interaction was observed via SEM after 7 days. This result proved that the features of melt-blown nonwoven scaffolds depended on the processing parameters, such as head temperature and air temperature. Thanks to examinations, the most suitable scaffolds for skin tissue regeneration were selected

Application of new lysine-based peptide dendrimers D3K2 and D3G2 for gene delivery: Specific cytotoxicity to cancer cells and transfection in vitro

In order to enhance intracellular uptake and accumulation of therapeutic nucleic acids for improved gene therapy methods, numerous delivery vectors have been elaborated. Based on their origin, gene carriers are generally classified as viral or non-viral vectors. Due to their significantly reduced immunogenicity and highly optimized methods of synthesis, nanoparticles (especially those imitating natural biomolecules) constitute a promising alternative for virus-based delivery devices. Thus, we set out to develop innovative peptide dendrimers for clinical application as transfection agents and gene carriers. In the present work we describe the synthesis of two novel lysine-based dendritic macromolecules (D3K2 and D3G2) and their initial characterization for cytotoxicity/genotoxicity and transfection potential in two human cell line models: cervix adenocarcinoma (HeLa) and microvascular endothelial (HMEC-1). This approach allowed us to identify more cationic D3K2 as potent delivery agent, being able to increase intracellular accumulation of large nucleic acid molecules such as plasmids. Moreover, the dendrimers exhibited specific cytotoxicity towards cancer cell line without showing significant toxic effects on normal cells. These observations are promising prognosis for future clinical application of this type of nanoparticles. © 2019 The Author

Association of low ficolin-2 concentration in cord serum with respiratory distress syndrome in preterm newborns

IntroductionFicolin-2 is a serum pattern recognition molecule, involved in complement activation via the lectin pathway. This study aimed to investigate the association of ficolin-2 concentration in cord blood serum with complications related to premature birth.Methods546 premature neonates were included. The concentration of ficolin-2 in cord blood serum was determined by a sandwich TRIFMA method. FCN2 genetic variants were analysed with RFLP-PCR, allele-specific PCR, Sanger sequencing or allelic discrimination using TaqMan probes method.FindingsCord blood serum ficolin-2 concentration correlated positively with Apgar score and inversely with the length of hospitalisation and stay at Neonatal Intensive Care Unit (NICU). Multivariate logistic regression analysis indicated that low ficolin-2 increased the possibility of respiratory distress syndrome (RDS) diagnosis [OR=2.05, 95% CI (1.24-3.37), p=0.005]. Median ficolin-2 concentration was significantly lower in neonates with RDS than in premature babies without this complication, irrespective of FCN2 gene polymorphisms localised to promoter and 3’untranslated regions: for patients born <33 GA: 1471 ng/ml vs. 2115 ng/ml (p=0.0003), and for patients born ≥33 GA 1610 ng/ml vs. 2081 ng/ml (p=0.012). Ficolin-2 level was also significantly lower in neonates requiring intubation in the delivery room (1461 ng/ml vs. 1938 ng/ml, p=0.023) and inversely correlated weakly with the duration of respiratory support (R=-0.154, p<0.001). Interestingly, in the neonates born at GA <33, ficolin-2 concentration permitted differentiation of those with/without RDS [AUC=0.712, 95% CI (0.612-0.817), p<0.001] and effective separation of babies with mild RDS from those with moderate/severe form of the disease [AUC=0.807, 95% CI (0.644-0.97), p=0.0002].ConclusionLow cord serum ficolin-2 concentration (especially in neonates born at GA <33 weeks) is associated with a higher risk of developing moderate/severe RDS, requiring respiratory support and intensive care

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Funkcjonowanie pacjentów po zabiegu TURP

Wstęp: Łagodny przerost gruczołu krokowego to jedno z najczęściej występujących schorzeń w męskiej populacji. Za złoty standard chirurgicznego leczenia łagodnego przerostu gruczołu krokowego uznaje się przezcewkową elektroresekcję prostaty (TURP). Szacuje się, że 70 – 90 % pacjentów ze wskazaniami do leczenia chirurgicznego poddawana jest zabiegowi TURP.Cel pracy: Celem pracy była ocena funkcjonowania pacjentów cierpiących na łagodny przerost stercza poddanych zabiegowi przezcewkowej elektroresekcji gruczołu krokowego przed i po wykonanym zabiegu.Materiał i metody: Badania przeprowadzono w grupie 40 mężczyzn – pacjentów Niepublicznego Zakładu Opieki Zdrowotnej Szpitala Specjalistycznego im. E. Leszczyńskiego w Katowicach. Do oceny funkcjonowania pacjentów przed i po zabiegu TURP wykorzystano autorski kwestionariusz ankiety.Wyniki: W badaniu udział wzięło 40 mężczyzn cierpiących na łagodny przerost gruczołu krokowego. Badani znajdowali się w przedziale wieku od 50 do 81 lat a średnia ich wieku wyniosła 66,03 roku. Badania wykazały, że 57,7 % badanych mężczyzn przed zabiegiem wskazało na znaczne utrudnienia w życiu codziennym a 27,5 % mężczyzn mówiło o nieznacznych utrudnieniach. Po zabiegu znaczne utrudnienia w codziennym funkcjonowaniu, spowodowane dolegliwościami ze strony układu moczowego zgłosiło tylko 7,5 % ankietowanych, nieznaczne utrudnienia 32,5 % . Aż 60,0 % badanych mężczyzn deklarowało, że po zabiegu odczuwane dolegliwości w żaden sposób nie utrudniają im codziennego funkcjonowania. Przeprowadzone badania wykazały, że zabieg TURP powoduje redukcję nasilenia objawów choroby i tym samym powoduje poprawę funkcjonowania pacjentów.Wnioski: Badanie wykazało znaczną poprawę w funkcjonowaniu pacjentów w okresie miesiąca po zabiegu TURP w stosunku do okresu bezpośrednio poprzedzającego zabieg.Introduction: Benign prostatic hyperplasia (BPH) is one of the most common diseases of men's population. What is considered to be a gold standard of the Benign prostatic hyperplasia's surgical treatment is Transurethral resection of the prostate, also known as TURP. Estimated 70% - 90% of patients with indications for a treatment goes under the TURP procedure. Purpose of the thesis: The purpose of the research was to evaluate the overall functioning of patients suffering from Benign prostatic hyperplasia before and after going under the of Transurethral resection of the prostate. Material and methods: the research was conducted on a group of 40 men – patients of a NZOZ (Non-Public Health Care Institution) of E. Leszczyński Specialist Hospital in Katowice. The functioning assessment before and after the TURP procedure has been measured basing on the author's survey form. Results: The survey was conducted on a group of 40 men diagnosed with Benign prostatic hyperplasia. Respondents were all in an age range between 50 and 81 and their calculated average age was 66,03 years old. Research showed, that 57,% of surveyed patients had indicated significant difficulties in everyday functioning before the TURP procedure, and 25,5% of men had pointed out inconsiderable difficulties. After the Transurethral resection of the prostate the percentage of patients complaining on significant difficulties in everyday functioning caused by urinary track issues was only 7,5% and those indicating inconsiderable difficulties – 32,5%. Even 60% of examined men admitted, that after the procedure the ailments they have been experiencing have not influenced or complicated their everyday functioning nohow. Performed research showed, that the technique of Transurethral resection of the prostate causes reduction of diseases symptoms increase and the same improves patients comfort of living. Conclusions: The research proved noticeable improvement of men functioning after approximately one month from the Transurethral resection of the prostate, comparing to the period from just before the surgical treatment