In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.

Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21- Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT- 61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer

Дифференциальная диагностика двусторонних изменений легких на опыте стационара по приему внебольничных пневмоний – не только COVID-19

Due to the current epidemiological situation caused by the spread of the new SARS-CoV-2 coronavirus, in March 2020 several Moscow hospitals were completely or partially redesigned to receive patients with community- acquired pneumonia.Purpose. The aim of the survey is to analyze clinical, laboratory and radiological data in patients with coronavirus infection at the early stages of its spread in Russia, and to clarify diseases for differential diagnosis mainly based on CT evidence.Materials and methods. We studied data from 21 patients with verified coronavirus infection admitted to the hospital for community-acquired pneumonia. Clinical symptoms, laboratory and physical indicators, as well as typical lung changes on the CT were evaluated.Results. Major clinical symptoms in coronavirus patients are fever (100%), cough (90.5%), shortness of breath (76.1%). Laboratory indicators showed increases in CRP (85.7%), leukocytosis (66.6%), and LDG (84.6%). According to CT, 95.2% of lung changes involved both sides, and 66.7% occurred in all lung fields. The sign of “ground glass” was observed in a 100% of the cases, its combination with the “paving stone” – in 61,9%, “ground glass” coupled with small areas of consolidations were detected in 33,3% of the cases. Changes such as nodules, cavities and massive areas of consolidation were not identified.Conclusion. On the basis of our own data we confirmed the main trends of diagnostics and clinical features, which were identified by authors from Asia and Europe, who faced this infection earlier, and also considered important CT characteristics useful for differential diagnosis of coronavirus lung damage and other lung diseases.В связи со сложившейся напряженной эпидемиологической ситуацией, обусловленной распространением нового коронавируса SARS-CoV-2, в марте 2020 г. несколько московских стационаров были полностью или частично перепрофилированы для приема пациентов с внебольничными пневмониями.Цель исследования: проанализировать клинические, лабораторные и лучевые данные у больных с коронавирусной инфекцией на начальных этапах ее распространения в России, а также выделить основные заболевания для дифференциальной диагностики с акцентом на данные КТ.Материал и методы. Для рассмотрения взяты данные 21 пациента с верифицированной коронавирусной инфекцией, которые поступали в ГКБ имени В.П. Демихова в стационар по приему внебольничных пневмоний. Оценивались клинические симптомы, лабораторные и физикальные показатели, а также характерные изменения в легких по данным КТ.Результаты. Основные клинические симптомы, выявленные у больных коронавирусной инфекцией: гипертермия (100%), кашель (90,5%), одышка (76,1%). Со стороны лабораторных показателей отмечались повышение уровня C-реактивного белка (85,7%), лейкоцитоз (66,6%), повышение лактатдегидрогеназы (84,6%). По данным КТ в 95,2% изменения в легких имелись с обеих сторон и в 66,7% занимали все легочные поля. В 100% поражение проявлялось участками уплотнения по типу “матового стекла”, в 61,9% это сочеталось с ретикулярной исчерченностью за счет внутридолькового интерстиция, в 33,3% – с уплотнениями в виде консолидаций. Такие изменения, как очаги, полости и массивные консолидации, выявлены не были.Заключение. На собственных данных мы подтвердили основные тренды, касающиеся клинической картины и различных аспектов диагностики, которые обозначили авторы из стран Азии и Европы, столкнувшиеся с инфекцией раньше, а также рассмотрели важные дифференциальные позиции с другими заболеваниями легких по данным КТ

Род Dinophysis Ehrenb. (Dinophyta) в украинских прибрежных водах Черного моря: видовой состав, распределение, динамика

Обобщены результаты многолетних оригинальных исследований и литературных данных по видовому составу рода Dinophysis в украинских прибрежных водах Черного моря.Results of long-term original researches and the literary data of a species biodiversity of the genus Dinophysis of the Ukrainian coast of Black Sea are generalize

Sulfurous Gases As Biological Messengers and Toxins: Comparative Genetics of Their Metabolism in Model Organisms

Gasotransmitters are biologically produced gaseous signalling molecules. As gases with potent biological activities, they are toxic as air pollutants, and the sulfurous compounds are used as fumigants. Most investigations focus on medical aspects of gasotransmitter biology rather than toxicity toward invertebrate pests of agriculture. In fact, the pathways for the metabolism of sulfur containing gases in lower organisms have not yet been described. To address this deficit, we use protein sequences from Homo sapiens to query Genbank for homologous proteins in Caenorhabditis elegans, Drosophila melanogaster, and Saccharomyces cerevisiae. In C. elegans, we find genes for all mammalian pathways for synthesis and catabolism of the three sulfur containing gasotransmitters, H2S, SO2 and COS. The genes for H2S synthesis have actually increased in number in C. elegans. Interestingly, D. melanogaster and Arthropoda in general, lack a gene for 3-mercaptopyruvate sulfurtransferase, an enzym for H2S synthesis under reducing conditions

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling

Sovereignty and Salvation in the Vernacular, 1050-1150: Das Ezzolied, Das Annolied, Die Kaiserchronik, vv. 247-667, Das Lob Salomons, Historia Judith

These texts will be of interest because they represent a kind of writing - at the intersection of ecclesiastical and secular power, drawing on the whole range of medieval Latin learning, yet written in vernacular verse - that is not found elsewhere in the European Middle Ages. In addition, they may be of use in teaching since, although relatively short, they illustrate a great number of characteristic medieval ways of writing and can be linked to a number of quite remarkable historical figures.https://scholarworks.wmich.edu/mip_teamsmgt/1000/thumbnail.jp