5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells

Multidrug resistance (MDR) is considered one of the major mechanisms responsible for the failure of numerous anticancer and antiviral chemotherapies. Various strategies to overcome the MDR phenomenon have been developed, and one of the most attractive research directions is focused on the inhibition of MDR transporters, membrane proteins that extrude cytotoxic drugs from living cells. Here, we report the results of our studies on a series newly synthesized of 5-arylidenerhodanines and their ability to inhibit the ABCB1 efflux pump in mouse T-lymphoma cancer cells. In the series, compounds possessing a triphenylamine moiety and the carboxyl group in their structure were of particular interest. These amphiphilic compounds showed over 17-fold stronger efflux pump inhibitory effects than verapamil. The cytotoxic and antiproliferative effects of target rhodanines on T-lymphoma cells were also investigated. A putative binding mode for 11, one of the most potent P-gp inhibitors tested here, was predicted by molecular docking studies and discussed with regard to the binding mode of verapamil

Wrodzony hiperinsulinizm — próba optymalizacji diagnostyki i leczenia u polskich pacjentów

  Introduction: Congenital hyperinsulinism of Infancy (CHI) comprises heterogenic defects of insulin secretion with diverse molecular aetiology, histological features, severity of symptoms, and response to pharmacotherapy. The study aimed to establish the first clinical characteristics of Polish patients with CHI and to propose a novel clinical algorithm allowing the prioritisation of genetic and radiology studies, based on patient’s characteristics and response to pharmacotherapy. Material and methods: Thirty-one patients with CHI were recruited from five reference centres in Poland. Clinical and biochemical parameters were statistically evaluated and compared to those of a control group (n = 30). Results: CHI predisposes to increased birth weight (p = 0.004), lower Apgar score (p = 0.004), perinatal complications (74%), and neurological implications (48%). Diagnostic process and therapy were inconsistent. A trial of pharmacotherapy was applied in 21 patients (68%), and diagnostic imaging with 18F-L-DOPA PET was performed in only 3. Eighteen patients (58%) were surgically treated, including 8 infants (44%) aged less than 2 months. Depending on the type of resection, further hypoglycaemia was observed postoperatively in 50% (n = 9) and hyperglycaemia in 39% (n = 7) of cases. Based on foregoing results, a clinical algorithm was proposed. Conclusions: Standardisation of clinical management with the use of pharmacotherapy, genetic screening, and diagnostic imaging will allow the optimisation of therapy and minimisation of treatment complications. (Endokrynol Pol 2015; 66 (4): 322–328)    Wstęp: Wrodzony hiperinsulinizm (CHI) obejmuje heterogenną grupę zaburzeń sekrecji insuliny przez komórki β trzustki i charakteryzuje się zróżnicowaną etiologią molekularną, obrazem histopatologicznym, nasileniem objawów oraz odpowiedzią na leczenie farmakologiczne. Celem pracy było stworzenie charakterystyki klinicznej polskich pacjentów z wrodzonym hiperinsulinizmem oraz podjęcie próby stworzenia algorytmu diagnostyczno-terapeutycznego, umożliwiającego priorytetyzację badań genetycznych i obrazowych w zależności od obrazu klinicznego, wyników badań laboratoryjnych oraz odpowiedzi na leczenie farmakologiczne. Materiał i metody: Do badania włączono 31 pacjentów z rozpoznaną hipoglikemią w przebiegu hiperinsulinizmu z 5 ośrodków w Polsce. Analizę danych klinicznych oraz parametrów biochemicznych pacjentów hipoglikemią odniesiono do 30-osobowej grupy kontrolnej. Wyniki: Pacjenci z CHI charakteryzowali się znacznie wyższą masą urodzeniową (p = 0,004), niższą oceną uzyskaną w okołoporodowej skali Apgar (p = 0,004), częstszymi komplikacjami okołoporodowymi (74%) oraz powikłaniami neurologicznymi (48%). Przeprowadzona w badanej grupie diagnostyka była niespójna. U 21 pacjentów (68%) włączono leczenie za pomocą Diazoksydu, a u 3 pacjentów (9,7%) wykonano diagnostykę obrazową przy użyciu 18F-L-DOPA PET. Wśród 18 (58%) pacjentów leczonych chirurgicznie u 8 (44%) resekcję wykonano w wieku poniżej 2. miesiąca życia. Pooperacyjnie w zależności od typu wykonanej operacji obserwowano hipoglikemię u 50% (n = 9), a hiperglikemię u 39% (n = 7). Na podstawie uzyskanych wyników zaproponowano pierwszy w Polsce algorytm diagnostyczno- terapeutyczny. Wnioski: Ujednolicenie schematu postępowania diagnostycznego-terapeutycznego z wykorzystaniem wszystkich dostępnych metod umożliwi zapobieganie kolejnym epizodom choroby, oraz zminimalizuje komplikacje wynikające z leczenia. (Endokrynol Pol 2015; 66 (4): 322–328)

We Do Not Like It: A Likert-Type Scale Survey on the Attitudes of a Young Population towards the Transhumanistic Theory of Education

Transhumanists assume that future education may be purely based on technological stimulation. The question is: Do potential clients of education “like” such vision? In order to check this, we asked over one thousand two hundred young Poles to evaluate their identification with the transhumanistic theory of education. The results are quite surprising: its show that they disagree with the assumptions of this theory, while they rather agree with the postulates of more traditional (and no technology-based) concepts of education

DH and JH usage in murine fetal liver mirrors that of human fetal liver

In mouse and human, the regulated development of antibody repertoire diversity during ontogeny proceeds in parallel with the development of the ability to generate antibodies to an array of specific antigens. Compared to adult, the human fetal antibody repertoire limits N addition and uses specifically positioned VDJ gene segments more frequently, including V6-1 the most DH-proximal VH, DQ52, the most JH-proximal DH, and JH2, which is DH-proximal. The murine fetal antibody repertoire also limits the incorporation of N nucleotides and uses its most DH proximal VH, VH81X, more frequently. To test whether DH and JH also follow the pattern observed in human, we used the scheme of Hardy to sort B lineage cells from BALB/c fetal and neonatal liver, RT-PCR cloned and sequenced VH7183-containing VDJCμ transcripts, and then assessed VH7183-DH-JH and complementary determining region 3 of the immunoglobulin heavy chain (CDR-H3) content in comparison to the previously studied adult BALB/c mouse repertoire. Due to the deficiency in N nucleotide addition, perinatal CDR-H3s manifested a distinct pattern of amino acid usage and predicted loop structures. As in the case of adult bone marrow, we observed a focusing of CDR-H3 length and CDR-H3 loop hydrophobicity, especially in the transition from the early to late pre-B cell stage, a developmental checkpoint associated with expression of the pre-B cell receptor. However, fetal liver usage of JH-proximal DHQ52 and DH-proximal JH2 was markedly greater than that of adult bone marrow. Thus, the early pattern of DH and JH usage in mouse feta liver mirrors that of human

Retaliation versus vigilantism: Why do we choose to punish?

Victims retaliating against aggressors tend to gain the benefit of a deterrent effect against future exploitation through second-party punishment. However, research has not adequately explained the benefits behind vigilantism where unaffiliated third-parties risk personal costs to administer punishment for an act that had no impact on their economic well-being. Differences in costs and benefits of second-party punishment (2PP) and third party punishment (3PP) suggest that the two punitive behaviors may originate from dissimilar contextual cues, and serve different adaptive functions. However, differences between 2PP and 3PP are often blurred in the literature, with researchers taking the findings on 2PP to draw conclusions about 3PP, and vice versa. This dissertation outlines the functionally distinct roles second- and third-parties assume in conflict (Chapter 1), and empirically tests predictions of the proposed model (Chapter 2–3). In Chapter 1, I evaluate experimental paradigms eliciting different types of punitive responses, and examine both animal and human behavioral data on inputs and outputs characteristic of 2PP and 3PP. I propose that 2PP functions to deter, while 3PP serves as a coordination and conflict resolution device. I predict that second-parties are more sensitive to inputs relevant to achieving the goal of discouraging future violations than third-parties. In Study 1 and 2 (Chapter 2), I use fictional crime scenarios to test the effect of probability of crime detection on punitive judgment. I find that second-parties are more likely to take probabilities into account than third-parties when assigning punishment. In Study 1 through 4 (Chapter 3), I use behavioral economic games to explore conditions under which second- and third-parties seek out—or avoid—information about norm violations. I find that in case of more serious violations, second-parties show interest in details of Dictator\u27s decision, but only when provided with an option to punish. In contrast, presence or absence of an opportunity to punish has no effect on third-parties. Taken together, these findings demonstrate that second- and third-parties respond differently to relevant contextual cues, further supporting the claim that punishment administered by avengers and vigilantes follow different behavioral rules