Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

This work is licensed under a Creative Commons Attribution 4.0 International License.Purpose Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers. Methods PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice. Results Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors. Conclusions Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.Intramural Research Program (IRP) of the NIHNational Cancer InstituteCenter for Cancer Research (ZIA BC 011267

Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C

PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors

Assessment of organizational culture in Kaunas city tourism agencies

The bachelor thesis aggregated and analyzed various Lithuanian and foreign authors, the concept of organizational culture and the concept of organizational culture levels, types and functions, its impact on the companyʼs business development. In order to assess the organizational culture Kaunas tourism agencies were used K. S. Cameron and R. E. Quinn competing values frame construction (Organizational Culture Assessment Instrument). In the practical section summarizes the three Kaunas tourism agency managers and staff survey results. The conclusions formed about organizational culture studied tourism agencies. The research problem – what type of organizational culture dominated by different Kaunas tourism agencies? The aim – to assess organizational culture Kaunas tourism agencies. The object of research – the organizational culture assessment Kaunas tourism agencies. Objectives of the research: 1. Define the concept of organizational culture. 2. To analyze the levels of organizational culture, types and functions. 3. To reveal the influence of organizational culture and tourism agencies. 4. Figure out how to Kaunas tourism agency workers the prevailing organizational culture. Working methods: • The scientific literature; • A questionnaire-based survey; • Descriptive statistical analysis of the data. Conclusions: Analyzed Kaunas city tourism agencies, managers and employees think highly dominant clan type of organizational culture is also characterized by the type hierarchy culture. All organizations are intended to reduce the hierarchy culture type of influence. The clan culture is intended to increase. Market and adhocracy remain the same or will also attempt to increase

Does not legalization of Civil Union Institute in Lithuania infringes the principle of quality?

Šiame magistriniame darbe analizuojama partnerystės instituto neįteisinimo Lietuvos Respublikoje problema, kada visuomenėje susiformuoja skirtingos lyties asmenų grupė, kuri negali pasinaudoti partnerystės instituto teikiamomis teisėmis. Dėl to yra keliamas klausimas: ar partnerystės instituto neįteisinimas Lietuvos Respublikoje pažeidžia lygiateisiškumo principą? Siekiant atsakyti į iškeltą klausimą, darbe tiriami šie problemos aspektai: ar partnerystės ir santuokos institutai yra tapatūs, partnerystės instituto sukeliamos pasekmės, įstatymo leidėjo kompetencija dėl partnerystės ir kitų šeimos formų reglamentavimo. Darbą sudaro trys dalys, kuriose problema nagrinėjama teoriniu ir praktiniu atžvilgiu. Pirmoje darbo dalyje, siekiant nustatyti ar partnerystė ir santuoka savo turiniu yra tapatūs institutai, analizuojama santuokos ir partnerystės institutų samprata ir genezė, lyginami šių institutų tikslai. Antroje darbo dalyje aptariamos partnerystės instituto sukeliamos pasekmės, kada institutas nėra įteisintas. Tai atliekama nustatant asmenų, kurie nėra sudarę santuokos teisines pasekmes turtiniuose ir neturtiniuose santykiuose bei nustatant ar Lietuvoje įteisinti šeimos teisės institutai pilnai saugo visų subjektų teises. Trečiojoje darbo dalyje, siekiant nustatyti įstatymo leidėjo kompetenciją dėl partnerystės ir kitų šeimos formų reglamentavimo, atliekama Europos Žmogaus Teisių Teismo ir užsienio šalių praktikos analizė susijusi su bylomis dėl partnerystės ar kitų šeimos formų bei plačiau išanalizuojamas partnerystės instituto reglamentavimas, sąlygos, sukeltos pasekmės kitoje valstybėje, kurioje šis institutas jau įteisintas. Atlikus tyrimą nustatyta, kad santuokos ir partnerystės institutų normos turinio prasme yra vienodos, t.y. saugo tas pačias vertybes bei sukuria tuos pačius lūkesčius - saugoti silpnesnę santykių šalį. Taip pat nustatyta, kad nesant partnerystės institutui ir asmenims nesudarius santuokos, tokių asmenų turtiniai ir neturtiniai santykiai – reguliuojami žymiai siauriau. Be to nustatyta, kad partnerystės institutas negarantuoja šių santykių subjektams visapusiškų teisių ir pareigų. Dėl to gali būti skirtas tos pačios lyties asmenų santykių reglamentavimui, bet ne kaip alternatyva santuokai. Būtent Europos Žmogaus Teisių Teismas išskiria, kad partnerystės institutas yra įvardijamas kaip vienas iš apsaugos būdų, bet ne kaip vienintelis ir privalomas. Taigi, vadovaujantis tuo, kas išdėstyta, nustatyta, kad partnerystės instituto neįteisinimas Lietuvos Respublikoje, nepažeidžia lygiateisiškumo principo.The current master's thesis analyses the problem of not legalizing partnership institute in the Republic of Lithuania when the society forms groups of different genders which cannot benefit from the competence provided by the partnership institute. Consequently, a question rises: does not legalization of civil union institute in Lithuania infringes the principle of equality? In order to answer this question, the work analyses these aspects of the problem: are institutes of partnership and marriage the same; consequences raised by partnership institute; the legislator's competence regarding regulation of partnership and other family forms. The work consists of three parts which consider the issue from a theoretical and a practical perspective. In the first part, in order to determine whether partnership and marriage institutes are the same concerning their content, the concept and genesis of marriage and partnership institutes are analysed and their objectives are compared. The second part of this work discusses consequences caused by partnership institute when the institute is not legalized. This is done by determining the legal consequences of people who have not married in property and non-property relations as well as determining whether family law institutes legalized in Lithuania fully protect the rights of all subjects. The third part of the work, in order to determine the competence of the legislator on partnership and regulation of other family forms, an analysis of European Court of Human Rights and foreign practice. This analysis is related to proceedings concerning partnership or other family forms. This part also wider analyses regulation of partnership institute as well as conditions, caused consequences in another country where this institute is already legalized. The investigation showed that not only in the case of marriage but also partnership, individuals seek legal family relationship on their free will, both institutes require registration under mandatory rules in order to establish a legal fact of the emergence of rights and duties, as the state is obliged to protect such relations. Moreover, the standards of marriage and partnership institutes are the same in terms of their content i.e. they protect the same values and create the same expectations to protect the weaker party of the relationship. As a result it can be concluded that marriage and partnership are identical and the presence of identical institutes is unnecessary. It was also found that in the absence of partnership institute and having not concluded a marriage, the property and non-property relations of such individuals are regulated much narrower. Under legislation which establishes the rights of these individuals to the property for individuals who have not concluded a marriage, the total joint property regime cannot be applied. This means the assets will be subject to common ownership regime which will be determined only under certain conditions and only for specific property. Meanwhile regarding moral rights, people who do not choose marriage and not having an opportunity to conclude partnership are granted fewer rights. One of the examples would be absence of right to a surname or limited adoption rights and similar. Thus, it can be argued that in the absence of partnership institute and individuals having not concluded a marriage, the property and non-property relations of such individuals are regulated much narrower. It was also determined that legislation currently existing in Lithuania as well as institutes regulating relationships between individuals do not provide the right to acquire the status of family for one of the law subjects (individuals of the same sex). It was further found that there is no specific list of family forms in the practice of European Court of Human Rights relating to other forms of family relationship which would be created at the basis of marriage but would be protected by the Article 8 of European Convention on Human Rights. Certainly, it should be noted that the concept of family relations is perceived not only as a formal legal relationship which requires a certain degree of formality (registration), but also as a de facto relationship. Therefore, it must be noted that in determining whether people's interests and rights are protected under the Convention, the Court in each case must assess a number of factors: whether the individuals' interpersonal relations are close, whether the state has not breached the framework of interference into the private life. This shows that the partnership institute is not directly protected by the Convention. Based on the analysis of countries where partnership is regulated, it was found that usually partnership institute does not provide subjects of the relationship full protection of rights and interests in contrast to marriage. it can be stated that partnership institute covers only part of the rights and responsibilities and thus is designed for regulating same-sex relations but not as an alternative to marriage. Of course, European Court of Human Rights distinguishes that partnership institute is named as one of the ways of protection but not as the only and mandatory. Thus, in accordance with the stated above, it was found that non-legalization of civil union institute in the Republic of Lithuania does not infringes the principle of equality

Genes regulating ceh-22 and pharyngeal development of Caenorhabditis elegans.

Genes regulating ceh-22 and pharyngeal development of Caenorhabditis elegans

Notch1 promotes survival of E2A-deficient T cell lymphomas through pre–T cell receptor–dependent and –independent mechanisms

Loss of E2A transcription factor activity or activation of the intracellular form of Notch1 (ICN) leads to the development of leukemia or lymphoma in humans or mice, respectively. Current models propose that ICN functions by suppressing E2A through a pre–T cell receptor (TCR)–dependent mechanism. Here we show that lymphomas arising in E2A–/– mice require the activation of Notch1 for their survival and have accumulated mutations in, or near, the Notch1 PEST domain, resulting in increased stability and signaling. In contrast, lymphomas arising in p53–/– mice show the activation of Notch1, but no mutations were identified in ICN. The requirement for Notch1 signaling in E2A–/– lymphomas cannot be overcome by ectopic expression of pTα; however, pTα is required for optimal survival and expansion of these cells. Our findings indicate that the activation of Notch1 is an important “second hit” for the transformation of E2A–/– T cell lymphomas and that Notch1 promotes survival through pre–TCR-dependent and -independent mechanisms