Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarinoma invasion and tumor growth

The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation. AT13148, Y27632, and H1152 induced morphological changes and reduced cellular contractile force generation, motility on pliable discontinuous substrates, and three-dimensional collagen matrix invasion. AT13148 treatment reduced subcutaneous tumor growth and blocked invasion of healthy pancreatic tissue by KPC tumor cells in vivo without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has anti-tumor properties that may be beneficial in combination therapies or in the adjuvant setting to reduce pancreatic cancer cell invasion and slow primary tumor growth. AT13148 might also have the additional benefit of enabling tumor resection by maintaining separation between tumor and healthy tissue boundaries

The effect of climate change on avian offspring production: A global meta-analysis

Climate change affects timing of reproduction in many bird species, but few studies have investigated its influence on annual reproductive output. Here, we assess changes in the annual production of young by female breeders in 201 populations of 104 bird species (N = 745,962 clutches) covering all continents between 1970 and 2019. Overall, average offspring production has declined in recent decades, but considerable differences were found among species and populations. A total of 56.7% of populations showed a declining trend in offspring production (significant in 17.4%), whereas 43.3% exhibited an increase (significant in 10.4%). The results show that climatic changes affect offspring production through compounded effects on ecological and life history traits of species. Migratory and larger-bodied species experienced reduced offspring production with increasing temperatures during the chick-rearing period, whereas smaller-bodied, sedentary species tended to produce more offspring. Likewise, multi-brooded species showed increased breeding success with increasing temperatures, whereas rising temperatures were unrelated to repro- ductive success in single-brooded species. Our study suggests that rapid declines in size of bird populations reported by many studies from different parts of the world are driven only to a small degree by changes in the production of young

Dormant conflict. 20 years of independence in Bosnia and Herzegovina

W kwietniu 1992 jugosłowiańska republika Bośnia i Hercegowina ogłasza niepodległość. Wkrótce na obszarze całego państwa dochodzi do konfliktów etnicznych, których efektem jest trzyletnia wojna domowa zakończona wymuszonym porozumieniem w Dayton i obecność międzynarodowych sił pokojowo-stabilizacyjnych. Mimo obecności militarnej międzynarodowych sił zbrojnych i cywilnej działalności Biura Wysokiego Przedstawiciela w Bośni i Hercegowinie nie udało się stworzyć jednolitego państwa, jak również doprowadzić do wygaśnięcia konfliktów etnicznych.In April 1992 the Yugoslav republic of Bosnia and Herzegovina declared independence. Soon ethnic conflicts erupted across the country, leading to a three-year civil war ended by the peace treaty in Dayton and the presence of the international implementation and stabilization forces. Despite the operations of the international military forces and the civilian activities of the Office of the High Representative (OHR) in Bosnia and Herzegovina, the Bosnian nations have failed to create a unified state, as well as to terminate the ethnic conflicts

Characterization, properties, prospects and difficulties in the use of blue natural dyes for food colouring

Wskutek zmian na rynku barwników spożywczych, w ostatnim czasie wzrasta zainteresowanie barwnikami pochodzącymi z naturalnych źródeł. Barwniki syntetyczne koloru żółtego, pomarańczowego, czy czerwonego łatwo jest zastąpić barwnikami naturalnymi o wystarczającej trwałości. Natomiast zamiana barwników syntetycznych w kolorze niebieskim na barwniki naturalne staje się już większym wyzwaniem dla producentów żywności. W przyrodzie występuje kilka niebieskich barwników naturalnych, jednak nie jest to barwa występująca powszechnie. Niniejszy artykuł zawiera charakterystykę kilku niebieskich barwników naturalnych, z uwzględnieniem ich właściwości tj. rozpuszczalności, odporności na działanie światła, temperaturę, czy pH środowiska. Wszystkie te czynniki jak również istniejące uregulowania prawne mogą determinować ich użycie jako barwników spożywczych.Interest of natural dyes have been increasing for the few years. Synthetic colors like yellow, orange or red is easy to replace by natural dyes of sufficient stability. By replacing synthetic colors in blue on natural dyes it is becoming a greater challenge for food producers. In nature, there are several natural-blue dyes but this is not a commonly occurs colour. This article contains characteristics of several blue natural dyes, with their properties, ie. solubility, lightfastness, temperature or pH of the environment. All these factors as well as existing legislation may determine their use as food colorants