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STRESZCZENIE CEL NAUKOWY: Celem artykułu jest przybliżenie jednego z narzędzi demokracji bezpośredniej, tj. referendum, którego skuteczność uzależniona jest m.in. od regulacji prawnych oraz sposobu i umiejętności jego wykorzystywania przez mieszkańców. PROBLEM I METODY BADAWCZE: Autorka zamierza potwierdzić, względnie zakwestionować hipotezę, według której referendum nie jest skutecznym narzędziem społecznej kontroli władz lokalnych. W tym celu wykorzystała metody opisową, analizy i syntezy. PROCES WYWODU: Podstawę wywodu będzie stanowiło polskie referendum odwoławcze, ponieważ jest to najpopularniejsza i najczęściej wykorzystywana w naszym kraju forma referendum. Analizie poddane zostaną najważniejsze zmiany w zakresie prawa referendalnego oraz wybrane przykłady z praktyki wyborczej. W tym ostatnim przypadku istotne będzie wskazanie czynników i przykładów, które ograniczają skuteczność tej formy demokracji bezpośredniej. WYNIKI ANALIZY NAUKOWEJ: W wyniku przeprowadzonej analizy udało się pokazać, że referendum jest narzędziem służącym mieszkańcom do kontroli władzy. Częstotliwość jego wykorzystywania oraz skuteczność pozostawiają jednak wiele do życzenia. Wpływ na to mają zarówno przepisy referendalne, brak umiejętności wykorzystywania przez społeczność lokalną dostępnych form demokracji bezpośredniej (m.in. niewystarczająca edukacja obywatelska) czy brak zainteresowania sprawami społeczności lokalnych. WNIOSKI, INNOWACJE, REKOMENDACJE: Skuteczność referendum jest w największym stopniu uzależniona od regulacji prawnych, ale także od umiejętności korzystania z narzędzi demokracji bezpośredniej. Nawet najlepsze rozwiązania i przepisy nie pomogą, jeżeli obywatele nie będą wiedzieli, jak korzystać z dostępnych instrumentów. W związku z tym jednym ze sposobów na wzrost skuteczności referendum powinna być edukacja obywatelska.

The aim of this paper is two-fold. It focuses on the identification of crucial elements of the business model for the development of start-ups and for their potential to create innovation, as well as the influence of network cooperation on the components of their business model. The canvas model is used to illustrate the research outputs. Additionally, the research aimed at identifying what start-ups expect from the networks in which they exist (e.g., technological parks) in terms of creating appropriate conditions supporting innovations. The study was done using three expert panels in which 28 start-ups participated. The research and its results are qualitative and are presented as a case study. The research was conducted by the authors in 2019 and concerns start-ups participating in cooperation networks, but its results could be interesting not only for start-ups, but also for everyone interested in the issues of cooperation between various entities and its potential to stimulate innovation.

Lit jest lekiem normotymicznym, stosowanym z wyboru w leczeniu profilaktycznym choroby afektywnej dwubiegunowej (ChAD). Skuteczność profilaktyczna litu może być uwarukowana czynnikami genetycznymi, związanymi częściowo z predyspozycją do choroby afektywnej dwubiegunowej. W dziedzinie genetyki w psychiatrii pierwsza dekada XXI wieku została zdominowana przez badania „genów kandydujących”. W niniejszym artykule przedstawiono badania genów kandydujących związanych z profilaktyką litem, prowadzone na Uniwersytecie Medycznym w Poznaniu w latach 2005-2018. W tym czasie badane były polimorfizmy wielu genów, z których część jest również związana z predyspozycją do choroby afektywnej dwubiegunowej. Związek ze skutecznością profilaktyczną litu stwierdzono w przypadku polimorfizmów genów 5HTT, ACP1, ARNTL, BDNF, COMT, DRD1, FKBP5, FYN, GLCC, NR3C1 i TIM. Nie stwierdzono takiego związku w odniesieniu do genów 5HT2A, 5HT2C, DRD2, DRD3, DRD3, GRIN2B, GSK-3β, MMP-9 i NTRK2. Wykazano natomiast asocjację polimorfizmu genu GSK-3β z nerkowymi działaniami niepożądanymi w przebiegu stosowania litem. Omówiona została możliwa rola tych genów zarówno w mechanizmie profilaktycznej skuteczności litu, jak i w patogenezie choroby afektywnej dwubiegunowej.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ruxolitinib (RUX), an oral JAK1 and JAK2 inhibitor, has recently been approved for patients with SR-aGVHD. The aim of this study was to evaluate RUX efficacy and toxicity in a real-world setting. Eighteen patients received RUX at 5 mg or 10 mg twice a day after a median 3 lines of prior unsuccessful immunosuppressive therapy. Median time on RUX therapy was 28 days (range 7–129). Five patients (28%) responded to RUX, including 4 complete responses and 1 partial response. Response to RUX was irrespective of aGVHD grade and the number of involved organs. One-year overall survival (OS) was 60% for RUX-responders versus 31% for non-responders (p = ns). Treatment duration greater than 29.5 days was found to have a positive impact on OS (p

Background Revealing molecular mechanisms linked to androgen receptor activity can help to improve diagnosis and treatment of prostate cancer. Retinoic acid-induced 2 (RAI2) protein is thought to act as a transcriptional coregulator involved in hormonal responses and epithelial differentiation. We evaluated the clinical relevance and biological function of the RAI2 protein in prostate cancer. Methods We assessed RAI2 gene expression in the Cancer Genome Atlas prostate adenocarcinoma PanCancer cohort and protein expression in primary tumors (n = 199) by immunohistochemistry. We studied RAI2 gene expression as part of a multimarker panel in an enriched circulating tumor cell population isolated from blood samples (n = 38) of patients with metastatic prostate cancer. In prostate cancer cell lines, we analyzed the consequences of androgen receptor inhibition on RAI2 protein expression and the consequences of RAI2 depletion on the expression of the androgen receptor and selected target genes. Results Abundance of the RAI2 protein in adenocarcinomas correlated with the androgen receptor; keratins 8, 18, and 19; and E-cadherin as well as with an early biochemical recurrence. In circulating tumor cells, detection of RAI2 mRNA significantly correlated with gene expression of FOLH1, KLK3, RAI2, AR, and AR-V7. In VCaP and LNCaP cell lines, sustained inhibition of hormone receptor activity induced the RAI2 protein, whereas RAI2 depletion augmented the expression of MME, STEAP4, and WIPI1. Conclusions The RAI2 protein functions as a transcriptional coregulator of the androgen response in prostate cancer cells. Detection of RAI2 gene expression in blood samples from patients with metastatic prostate cancer indicated the presence of circulating tumor cells.

W artykule opracowano koncepcję ochrony przeciwpożarowej statku towarowego Regalica. W części teoretycznej omówiono zagadnienia dotyczące regulacji prawnych ochrony przeciwpożarowej statków morskich oraz zaprezentowano charakterystykę statku Regalica. W części praktycznej dokonano opracowania projektu systemu sygnalizacji pożarowej na opisywanym masowcu w oparciu o przepisy morskie. Na etapie opracowywania projektu wykonano następujące założenia projektowe: opis techniczny przyjętej instalacji wykrywania pożaru, dobór elementów liniowych, prowadzenie linii dozorowych i dobór przewodów, lokalizacja centrali sygnalizacji pożarowej oraz warunki zasilania. Ponadto w tej części przedstawiono kompleksową koncepcję ochrony przeciwpożarowej. Na końcu sformułowano wnioski mające wpływ na proces projektowania systemów sygnalizacji pożarowej.

Jednym z państw-sygnatariuszy Europejskiej Karty Samorządu Lokalnego jest Republika Malty, w której samorząd terytorialny wprowadzono na mocy ustawy z dnia 30 czerwca 1993 roku o radach lokalnych. W raporcie pokontrolnym Komitetu Monitorującego podniesiono, że samorząd maltański narusza postanowienia Karty, ponieważ jednostki samorządowe nie są w pełni niezależne finansowo. Komitet postulował także przekazanie radom lokalnych dodatkowych zadań, a także możliwości pozyskiwania środków finansowych z podatków i opłat lokalnych.

Introduction: This study attempts to assess the concentration of intracellular matrix metalloproteinase (MMP-9) before and after the treatment of depressive episodes with ECT therapy and also to correlate the concentration of this enzyme with the use of commonly used general anaesthetics. Materials and methods: The study group comprised of 37 patients hospitalized in the Department of Adult Psychiatry in Poznan, with a diagnosis of episodes of drug-resistant depression during the course of bipolar and unipolar affective disorders, and who were being treated using electroconvulsive therapy. For the purpose of inducing anaesthesia during the procedure propofol was used in 10 cases, thiopental in 9 cases. Propofol was alternated with ketamine in a further 10 cases and thiopental was alternated with ketamine in another 9 cases. In order to assess the intensity of depression symptoms, the 17 point Hamilton depression scale was used, immediately before commencing ECT therapy, and one day after its completion. The serum concentration of MMP-9 was determined before and after the series of ECT treatments. In order to assess the serum concentration of MMP-9, an ELISA immunoenzymatic method was applied. Results: In this study, a significant reduction of MMP-9 concentration was noted after therapy, relative to the starting concentration, in the serum of patients suffering from depressive episodes resulting from either unipolar or bipolar affective disorders. These results correlated with improved psychiatric state, as assessed by the Hamilton scale. A significantly lower MMP-9 concentration was noted in the serum of patients given alternating thiopental and ketamine anaesthesia. Conclusions: This study suggests the importance of the enzyme as a biological marker for the effective treatment of depression. Furthermore, the choice of general anaesthetic applied during ECT also plays a role.

As early as the first half of the 19th century, attempts were made to describe the inhabitants of the Carpathians (Carpathian Highlander Region – Goralszczyzna), taking into account the existing divisions into groups (“clans”) or ethnographic regions. In accordance with the modernist (Enlightenment-positivist) paradigm of scientific cognition, these groups / regions were presented in a “substantial” manner, following the principles of the objective and methodological naturalism. The first researcher who divided the population living in the northern slopes of the Carpathians – analogically to how these mountains are divided – into three “ethnographic groups” and in then into “clans” was Wincenty Pol. He did not present this quite detailed ethnographic delimitation in a graphic form due to the lack of a map suitable for this purpose. A detailed map, presenting the divisions and ranges of the Polish Highlander Region and its ethnographic groups proposed by Pol and several other researchers, was made only almost 120 years later by Jozef Babicz. The differences between the boundaries of the Highlander region and the ranges of the groups / regions it contains indicate that the substantial approach to these issues is inadequate to the depicted social and cultural reality. Certain views of Pol may inspire the creation of an alternative concept of ethnographic diversity in general, and of the Polish Highlander Region in particular.

BACKGROUND Systemic intravenous thrombolysis and mechanical thrombectomy (MT) are guideline-recommended reperfusion therapies in large-vessel-occlusion ischemic stroke. However, for acute ischemic stroke of extracranial carotid artery origin (AIS-CA) there have been no specific trials, resulting in a data gap. MATERIAL AND METHODS We evaluated referral/treatment pathways, serial imaging, and neurologic 90-day outcomes in consecutive patients, presenting in a real-life series in 2 stroke centers over a period of 6 months, with AIS-CA eligible for emergency mechanical reperfusion (EMR) on top of thrombolysis as per guideline criteria. RESULTS Of 30 EMR-eligible patients (33.3% in-window for thrombolysis and thrombolysed, 73.3% male, age 39-87 years, median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 10, pre-stroke mRS 0-1 in all, tandem lesions 26.7%), 20 (66.7%) were EMR-referred (60% - endovascular, 6.7% - surgery referrals). Only 40% received EMR, nearly exclusively in stroke centers with carotid artery stenting (CAS) expertise (100% eligible patient acceptance rate, 100% treatment delivery involving CAS±MT with culprit lesion sequestration using micronet-covered stents). The emergency surgery rate was 0%. Baseline clinical and imaging characteristics did not differ between EMR-treated and EMR-untreated patients. Ninety-day neurologic status was profoundly better in EMR-treated patients: mRS 0-2 (91.7% vs 0%; P0.001); mRS 3-5 (8.3% vs 88.9%; P0.001), mRS 6 (0% vs 11.1%; P0.001). CONCLUSIONS In a real-life AIS-CA setting, the referral rate of EMR-eligible patients for EMR was low, and the treatment rate was even lower. AIS-CA revascularization was delivered predominantly in stroke thrombectomy-capable cardioangiology centers, resulting in overwhelmingly superior patient outcome. Large vessel occlusion stroke referral and management pathways should involve centers with proximal-protected CAS expertise. AIS-CA, irrespective of any thrombolysis administration, is a hyperacute cerebral emergency and EMR-eligible patients should be immediately referred for mechanical reperfusion.

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Przedmiotem artykułu jest analiza Uchwały Naczelnego Sądu Administracyjnego z dnia 2 grudnia 2019 r. (II OPS 1/19), stwierdzającej niedopuszczalność transkrypcji zagranicznego aktu urodzenia dziecka rodziców tej samej płci. Artykuł prezentuje zasadnicze motywy rozstrzygnięcia, charakteryzując jednocześnie podstawowe instytucje prawne, które znalazły zastosowanie w ramach przedmiotowego rozstrzygnięcia. Są to więc instrumenty normatywne wyrażone w ustawie z dnia 28 listopada 2014 r. Prawo o aktach stanu cywilnego (Dz. U. z 2020 r. poz. 463, 695) zobowiązujące kierownika urzędu stanu cywilnego do odmowy dokonania transkrypcji w przypadku sprzeczności tejże z podstawowymi zasadami prządku prawnego RP. Następnie związana z powyższym, występująca na gruncie prawa prywatnego międzynarodowego instytucja klauzuli porządku publicznego. Tłem (które nie ogranicza się jednak do li tylko akcesoryjnej roli), dla niniejszych rozważań są owe podstawowe zasady porządku prawnego RP, w szczególności zaś kluczowy dla wskazanego rozstrzygnięcia art. 18 Konstytucji RP, stanowiący o istocie małżeństwa i jego ochronie w świetle polskiej aksjologii konstytucyjnej. Artykuł prezentuje zasadnicze stanowiska doktryny i orzecznictwa w kluczowych dla niniejszej problematyki kwestiach. Systematyka pracy jest następująca: najpierw przedmiotem analizy jest uchwała Naczelnego Sądu Administracyjnego, następnie charakteryzowane w oparciu o naukę prawa i judykaturę, wskazane instytucje prywatnoprawne, następnie zaś odniesienie tychże i ich rola w świetle aksjologii Konstytucji RP.

The local government in the Republic of Malta is a young institution which was established in 1993. Until2019, Malta’s local government comprised one tier and its basis was the municipality. Since 2019, it hasa two-tier structure and the units of territorial division are the region and the municipality. Even thoughsuccessive local government reforms increased the powers of the local authorities, the scope of their tasksis not very extensive. A major problem is also the local government’s financial dependence on centralauthorities. Nonetheless, an analysis of changes introduced to date through successive amendments andreforms allows a conclusion that the actions which are undertaken mean changes in a good direction whichwill be continued.

Patients with relapsed/refractory acute myeloid leukemia (r/r AML) are characterized as having a poor prognosis. The only viable option of treatment for these patients is allogenic stem cell transplantation (allo-HSCT). Therefore, we have attempted to analyse factors related to both the disease itself and the transplantation procedure that could have an influence on the improvement of outcomes in this group of patients.Sixty-four patients with r/r AML underwent allo-HSCT at our center in 2012 to 2021. Fifty-two had active disease at the beginning of theallo-HSCT procedure, with amedian number of blasts in bone marrow (BM) of 18, and 12 had therapeutic aplasia after the last reinduction (blasts5% in BM).The probability of overall survival (OS) at 2 years was 25%. The median follow-up for survivors was 21.5 months. Progression-free survival (PFS) estimates were above 46%. The main cause of death was disease progression (49%). A statistically significant effect on premature death was reported for the diagnosis of secondary AML (sAML) and cytomelovirus (CMV) reactivation post allo-HSCT. On the other hand, chronic graft versus host disease (cGVHD) decreased the risk of disease progression. sAML and CMV reactivation were found to have opposite effects.

The object of this work is to determine the correlation on the Nusselt number on the individual rows of a four-row tubular finned heat exchanger with continuous fins with a staggered tube arrangement using CFD modelling. Correlations for calculating Darcy-Weisbach friction factors on individual tube rows were also determined. Relationships for the Nusselt number and friction factor derived for the entire exchanger based on CFD modelling were compared with those available in the literature determined using experimental data. The maximum relative differences between the Nusselt number for a four-row exchanger determined experimentally and by CFD modelling are in the range from 22% for a Reynolds number based on a tube's outside diameter of 1,000 to 30% for a Reynolds number of 13,000. The maximum relative differences between the friction factor for a four-row exchanger determined experimentally and by CFD modelling are in the range of 50% for a Reynolds number based on a tube outer diameter of 1,000 to 10% for a Reynolds number of 13,000. The CFD modeling performed shows that in the range of Reynolds numbers based on hydraulic diameters from 150 to 1,400, the Nusselt number for the first row in a four-row finned heat exchanger is about 22% to 15% higher than the average Nusselt number for the entire exchanger. In the range of Reynolds number changes based on hydraulic diameter from 2,800 to 6,000, the Nusselt numbers on the first and second rows of tubes are close to each other. Correlations on Nusselt numbers and friction factors derived for individual tube rows can be used in the design of plate-fin and tube heat exchangers used in equipment such as air-source heat pumps, automotive radiators, air-conditioning systems and in air hot-liquid coolers. In particular, the correlations can be used to select the optimum number of tube rows in the exchanger.

Cryptogenic stroke may be associated with a patent foramen ovale (PFO). Both cardiovascular risk factors and transcatheter closure of PFO may have an impact on the risk of recurrent cerebrovascular events.The aim of the study was to assess the occurrence and risk factors of recurrent cerebrovascular events (rCVE) in patients with a history of cryptogenic stroke or transient ischemic attack (TIA) and PFO.Overall, 392 patients (median [interquartile range, IQR] age 39.5 [30-49] years, 64.3% women, 35.7% men) with a history of cryptogenic stroke / TIA and confirmed PFO underwent a long‑term follow‑up with a median (IQR) of 51.5 (35-65) months. The primary end point was defined as rCVE including stroke and TIA.During the follow‑up, 17 patients with a history of cryptogenic stroke / TIA and confirmed PFO (4.3%, 11 women, 6 men) developed rCVE. In a multivariable analysis, the Risk of Paradoxical Embolism (RoPE) score was associated with a lower risk of rCVE (odds ratio [OR], 0.61 per 1 point; 95% CI, 0.45-0.84; P = 0.002). The transcatheter closure of PFO did not have a significant impact on rCVE in the study population (P = 0.19).The occurrence of rCVE in the patients with cryptogenic stroke / TIA and PFO reached 4.3% regardless of a high percentage of patients who underwent the PFO closure. RoPE score was associated with a lower risk of rCVE in the study population.

Emotional Dysregulations (ED) represent a major health risk present in about 5% of children and are associated with diverse forms of childhood psychiatric disorders and symptoms such as Attention-Deficit/Hyperactivity Disorder (ADHD) [...]

EnglishMozambique is a multilingual and multicultural country in which Portuguese, the post-colonial language adopted as the official language, is in contact with many native languages of the Bantu branch that for most Mozambicans constitute the mother tongue and are used in daily communication. As a result of state policy, in which Portuguese is also the only language of instruction, the number of Mozambicans who have Portuguese as their mother tongue has grown. Under the above conditions, a variety of Portuguese has been formed that is distinct from the European variety of Portuguese, which results from the linguistic and cultural diversity of its users. The present study intends to consider some lexical transferences that occur in Mozambican sociolinguistic context, called “mozambicanisms”, namely the loans from Bantu languages that interfere in communication, marking the identity of its speakers. portuguesMocambique e um pais multilingue e multicultural em que a lingua portuguesa, lingua pos-colonial adotada como lingua oficial, encontra-se em situacao de contacto com muitas linguas autoctones do ramo bantu que para a maior parte dos Mocambianos constituem a lingua materna, sendo utilizadas na comunicacao diaria. Como resultado da politica do Estado, em que o portugues e tambem a unica lingua de ensino, cresceu o numero de Mocambicanos que tem portugues como lingua materna. Nas condicoes acima formou-se uma variedade de portugues distinta da variedade do portugues europeu que resulta da diversidade linguistica e cultural dos seus usuarios. O presente estudo pretende considerar algumas transferencias lexicais que ocorrem em contexto sociolinguistico mocambicano, chamadas de mocambicanismos, nomeadamente os emprestimos das linguas bantu que interferem na comunicacao, marcando a identidade dos seus falantes.

Introduction: Gait is the basic physical activity of a person to which s/he is much better adapted than to running or maintaining a sitting position. Proper gait pattern has beneficial effects on locomotor and respiratory system efficacy, while asymmetrical, abnormal gait may cause musculoskeletal dysfunctions. The purpose of the study is to compare symmetry and range of pelvic movement in gait among boys playing football and their non-playing peers. Material and methods: A total of 121 boys were surveyed, including 33 soccer players aged 10-14 and 82 of their non-playing peers, using a portable system for functional movement analysis - BTS G-WALK. Symmetry and range of motion of the right and left pelvis in the sagittal, frontal and horizontal planes were analysed while walking on a straight section. Basic anthropometric measurements were also taken. Results: There was no difference in the value of the pelvic symmetry coefficient between the football- and non-players. However, a significantly greater range of pelvic rotation and movement in the sagittal plane was found among the boys playing football. Attention is drawn to the greater range of pelvic movement towards posterior tilt among young soccer players. Conclusions: Further studies should be conducted to assess whether excessive movement of the pelvis in gait towards posterior tilt among young soccer players is related to body posture quality, and whether the excessive range of pelvic movement in the sagittal and horizontal planes correlates with the incidence of locomotor injuries or lower spine pain.

The aim of our study was to develop a novel method for nanocarriers’ preparation as a fluorine magnetic resonance imaging (19F MRI)-detectable drug delivery system. The novelty of the proposed approach is based on the application of fluorinated polyelectrolyte Nafion as a contrast agent since typical MRI contrast agents are based on paramagnetic gadolinium or ferro/superparamagnetic iron oxide compounds. An advantage of using an 19F-based tracer comes from the fact that the 19F image is detected at a different resonance frequency than the 1H image. In addition, the close to zero natural concentration of 19F nuclei in the human body makes fluorine atoms a promising MRI marker without any natural background signal. That creates the opportunity to localize and identify only exogenous fluorinated compounds with 100% specificity. The nanocarriers were formed by the deposition of polyelectrolytes on nanoemulsion droplets via the layer-by-layer technique with the saturation approach. The polyelectrolyte multilayer shell was composed of Nafion, the fluorinated ionic polymer used for labeling by 19F nuclei, and poly-l-lysine (PLL). The surface of such prepared nanocarriers was further pegylated by adsorption of pegylated polyanion, poly-l-glutamic acid (PGA). The 19F MRI-detectable hydrophobic nanocarriers with an average size of 170 nm and a sufficient signal-to-noise ratio have been developed and optimized to be used for passive tumor targeting and drug delivery.

Previously, we found that increased Retinoic acid-induced 2 (RAI2) protein concentration in primary tumors predicts early biochemical relapse of prostate cancer patients and described a co-repressor function of RAI2 related to androgen receptor activity (1). The presence of a non-canonical tandem ALDLS motif on RAI2 protein prompted the present investigation on a possible role of a dual interaction of RAI2 with C-terminal binding proteins (CtBPs) in relation to prostate cancer progression. We analyzed RAI2 gene expression as well as CtBP1 protein localization and constitution in circulating tumors cells (CTCs) isolated from metastatic prostate cancer patients by semi-quantitative PCR analysis and immune-fluorescence staining. We employed an integrated structural biology approach combining biophysical techniques like isothermal calorimetry, circular dichroism, size exclusion chromatography with high-resolution structural biology techniques including X-ray crystallography and single particle cryo-electron microscopy. We established RAI2-depleted VCaP cells and used this model for validation of the obtained results. RAI2 gene expression is significantly increased in CTCs isolated from patients with castration-resistant disease in comparison to CTCs isolated from patients with hormone-sensitive, aggressive or neuroendocrine variant prostate cancer. We detected CtBP1 protein foci in the nuclei of individual CTCs. We show that RAI2 induces CtBP polymerization. Using single particle cryo-electron microscopy, we obtained crucial insights into the structural organization of this filament. RAI2 inactivation in VCaP cells caused a significant reduction of both CtBP proteins, which is accompanied by the disappearance of CtBP protein aggregates in nuclei. In addition, we observed the induction of neuroendocrine features, marked by the induction of Synaptophysin and Chromogranin A, a higher nucleus to cytoplasm ratio and smaller cell size of RAI2-depleted cells. In summary, we report tandem motifs-induced polymerization of CtBP’s for the first time. We found that elevated RAI2 gene expression is a characteristic of castration-resistant prostate cancer. Because RAI2 depletion resulted in loss of CtBP aggregates and the induction of neuroendocrine traits, we conclude that RAI2-driven CtBP polymerization sustains epithelial differentiation in castration-resistant prostate cancer. These findings holds potential for the diagnosis of castration-resistant disease and inhibiting the progression from castration-resistant to neuroendocrine prostate cancer. 1. Besler K, Weglarz A, Keller L, von Amsberg G, Bednarz-Knoll N, Offermann A, et al. Expression Patterns and Corepressor Function of Retinoic Acid-induced 2 in Prostate Cancer. Clin Chem 2022;68:973-83 Citation Format: Stefan Werner, Nishit Goradia, Edukondalu Mullapudi, Lina Merkens, Sarah Greimeier, Aleksandra Węglarz, Gunhild von Amsberg, Harriet Wikman, Klaus Pantel, Matthias Wilmanns. Retinoic acid-induced 2 driven polymerization of c-terminal binding proteins sustains epithelial differentiation in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1447.

Hydrazone-based molecular switches serve as efficient ratiometric pH-sensitive agents that can be tracked with

The purpose of the work was to determine the intraspecific variability of the stinging nettle, in respect of the mass of leaves and their chemical composition, including the content of phenolic compounds and assimilative pigments. The objects of the study were 10 populations of nettle, originating from the eastern and southern part of Poland. The results obtained indicate a high level of variability between and within the populations investigated but not strictly related to their geographical locations. The mass of the leaves ranged from 0.19 to 0.28 kg dry weight (DW)/plant (Coefficient of variation (CV) = 16.33%). Using HPLC–DAD, four phenolic acids were detected, i.e., caffeoylmalic (570.97–1367.40 mg/100 g DW), chlorogenic (352.79–1070.83 mg/100 g DW), neochlorogenic (114.56–284.77 mg/100 g DW) and cichoric (58.31–189.52 mg/100 g DW) acids, with the last one differentiating populations to the highest degree (CV = 48.83%). All of the analyzed populations met the requirements of the European Pharmacopoeia (Ph Eur 10th) concerning the minimum content of caffeoylmalic and chlorogenic acids in nettle leaves (not less than 0.3%). Within the flavonoid fraction, two compounds were identified, namely rutoside (917.05–1937.43 mg/100 g DW, CV = 21.32%) and hyperoside (42.01–289.45 mg/100 g DW; CV = 55.26%). The level of chlorophyll a ranged from 3.82 to 4.49 mg/g DW, chlorophyll b from 1.59 to 2.19 mg/g DW, while the content of carotenoids varied from 2.34 to 2.60 mg/100 g DW. Given all the traits investigated, the level of a population’s polymorphism (CV) was visibly higher within a population than between populations. Population no. 4 was distinguished by the highest mass of leaves, and the highest content of rutoside, while population no. 2 was distinguished by the highest content of hyperoside, caffeoylmalic and chlorogenic acid.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3′-5′—guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

BackgroundOverweight and obesity in children have a negative impact not only on the physical development but also on the mental health of children. That is why researchers are constantly looking for possible causes of such high frequency of this phenomenon. One of the environmental factors contributing to abnormal weight changes in children may be maternal exposure to adverse environmental factors during pregnancy, which in previous studies led to inconclusive results showing both overweight and obesity and underweight in children. The aim of the study was to examine the relationship between prenatal stress and body weight status. MethodsThe cohort study included 254 girls and 276 boys. Information on prenatal stress was collected with a questionnaire completed by a parent/guardian of a 6–12-year-old child. We assessed the body mass status on the basis of BMI according to the IOTF criterion and on the basis of body fat according to McCarthy criterion. ResultsThe results of our study show that the prenatal stress was related to increased risk of overweight (OR 2.14, 95%CI: 1.25-3.65) diagnosed on the basis of body fat cut-off points, but not when the BMI was a diagnostic criterion (OR 1.03, 95%CI:0.58-1.83). ConclusionThe method of diagnosis based on the fat content appears to be an indicator of the occurrence of abnormalities in body composition due to prenatal stress more sensitive than that based on the BMI. Level of evidence: Evidence obtained from well-designed cohort or case-control analytic studies

Fracture toughness, bending strength, Young's modulus, hardness and subcritical crack growth were determined for six different alumina/zirconia composites. The bending strength was modelled using Weibull distribution. The fracture toughness, bending strength and resistance to subcritical crack growth increase as a function of ZrO2 content (stabilized with 3 mol% Y2O3). The authors claim that a threshold stress in a three-parameter Weibull distribution may correspond to a threshold stress intensity factor in which the subcritical crack growth is negligible.

Introduction Observational studies have shown that migraine has been associated with patent foramen ovale (PFO). Whilst studies investigating PFO closure for the treatment of migraine have been neutral, there is some evidence that symptoms of migraine may improve if the PFO was closed after ischemic stroke. Aim To establish whether closure of PFO in patients with stroke or transient ischemic attack (TIA) is associated with reduction in the severity of co-existent migraine headaches. Material and methods Patients with ischemic stroke or TIA, PFO suitable for percutaneous closure and migraine, were given migraine severity questionnaires prior to PFO closure. These were followed up at 6 and 12 months after closure with the same questionnaire. The primary endpoint was change in migraine severity using the Migraine Severity Scale (MIGSEV). Migraine episode frequency, disability (using the MIDAS scale), and pain intensity were also assessed. Results Sixty-two patients were included in the analysis. MIGSEV scores reduced from 7 (7–8) at baseline to 4 (3.25–6) at 6-month follow-up, and 3 (0–4) at 12-month follow-up (p < 0.001). Other measures of migraine headache were also improved at both 6- and 12-month follow-up. Twenty-four (38%) patients were rendered migraine free at 12 months. Conclusions PFO closure for stroke or TIA prevention in patients with migraine was associated with a reduction in markers of migraine headache severity.

Novel functionalized (biofunctionalization followed by cisplatin immobilization) Fe3O4@SiO2@Au nanoparticles (NPs) were designed. The encapsulation of Fe3O4 cores inside continuous SiO2 shells preserves their initial structure and strong magnetic properties, while the shell surface can be decorated by small Au NPs, and then cisplatin (cPt) can be successfully immobilized on their surface. The fabricated NPs exhibit very strong T2 contrasting properties for magnetic resonance imaging (MRI). The functionalized Fe3O4@SiO2@Au NPs are tested for a potential application in photothermal cancer therapy, which is simulated by irradiation of two colon cancer cell lines (SW480 and SW620) with a laser (λ = 808 nm, W = 100 mW cm−2). It is found that the functionalized NPs possess low toxicity towards cancer cells (∼10–15%), which however could be drastically increased by laser irradiation, leading to a mortality of the cells of ∼43–50%. This increase of the cytotoxic properties of the Fe3O4@SiO2@Au NPs, due to the synergic effect between the presence of cPt plus Au NPs and laser irradiation, makes these NPs perspective agents for potential (MRI)-guided stimulated chemo-photothermal treatment of cancer.

There are huge demands on multifunctional nanocarriers to be used in nanomedicine. Herein, we present a simple and efficient method for the preparation of multifunctional magnetically responsive polymeric-based nanocarriers optimized for biomedical applications. The hybrid delivery system is composed of drug-loaded polymer nanoparticles (poly(caprolactone), PCL) coated with a multilayer shell of polyglutamic acid (PGA) and superparamagnetic iron oxide nanoparticles (SPIONs), which are known as bio-acceptable components. The PCL nanocarriers with a model anticancer drug (Paclitaxel, PTX) were formed by the spontaneous emulsification solvent evaporation (SESE) method, while the magnetically responsive multilayer shell was formed via the layer-by-layer (LbL) method. As a result, we obtained magnetically responsive polycaprolactone nanocarriers (MN-PCL NCs) with an average size of about 120 nm. Using the 9.4 T preclinical magnetic resonance imaging (MRI) scanner we confirmed, that obtained MN-PCL NCs can be successfully used as a MRI-detectable drug delivery system. The magnetic hyperthermia effect of the MN-PCL NCs was demonstrated by applying a 25 mT radio-frequency (f = 429 kHz) alternating magnetic field. We found a Specific Absorption Rate (SAR) of 55 W g−1. The conducted research fulfills the first step of investigation for biomedical application, which is mandatory for the planning of any in vitro and in vivo studies.