Cancer cells that are resistant to Bax/Bak-dependent intrinsic apoptosis can be eliminated by proteasome inhibition. Here, we show that proteasome inhibition induces the formation of high molecular ...weight platforms in the cytosol that serve to activate caspase-8. The activation complexes contain Fas-associated death domain (FADD) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Furthermore, the complexes contain TRAIL-receptor 2 (TRAIL-R2) but not TRAIL-receptor 1 (TRAIL-R1). While RIPK1 inhibition or depletion did not affect proteasome inhibitor-induced cell death, TRAIL-R2 was found essential for efficient caspase-8 activation, since the loss of TRAIL-R2 expression abrogated caspase processing, significantly reduced cell death, and promoted cell re-growth after drug washout. Overall, our study provides novel insight into the mechanisms by which proteasome inhibition eliminates otherwise apoptosis-resistant cells, and highlights the crucial role of a ligand-independent but TRAIL-R2-dependent activation mechanism for caspase-8 in this scenario.
The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately ...one‐third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling‐centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.
The current article reviews the most up‐to‐date literature on Endoplasmic Reticulum (ER) biology and articulates this information from a signalling perspective. Not only do we cover the basic cell biology aspects of adaptive ER signalling but also provide information about the latest discoveries on ER stress targeting drugs and their potential use in the clinic.
Dasatinib (Sprycel) was developed as a tyrosine kinase inhibitor targeting Bcr-Abl and the family of Src kinases. Dasatinib is commonly used for the treatment of acute lymphoblastic and chronic ...myelogenous leukemia. Previous clinical studies in melanoma returned inconclusive results and suggested that patients respond highly heterogeneously to dasatinib as single agent or in combination with standard-of-care chemotherapeutic dacarbazine. Reliable biomarkers to predict dasatinib responsiveness in melanoma have not yet been developed.
Here, we collected comprehensive in vitro data from experimentally well-controlled conditions to study the effect of dasatinib, alone and in combination with dacarbazine, on cell proliferation and cell survival. Sixteen treatment conditions, covering therapeutically relevant concentrations ranges of both drugs, were tested in 12 melanoma cell lines with diverse mutational backgrounds. Melanoma cell lines responded heterogeneously and, importantly, dasatinib and dacarbazine did not synergize in suppressing proliferation or inducing cell death. Since dasatinib is a promiscuous kinase inhibitor, possibly affecting multiple disease-relevant pathways, we also determined if basal phospho-protein amounts and treatment-induced changes in phospho-protein levels are indicative of dasatinib responsiveness. We found that treatment-induced de-phosphorylation of p53 correlates with dasatinib responsiveness in malignant melanoma.
Loss of p53 phosphorylation might be an interesting candidate for a kinetic marker of dasatinib responsiveness in melanoma, pending more comprehensive validation in future studies.
Summary
Crosstalk between Wnt and p53 signalling pathways in cancer has long been suggested. Therefore in this study we have investigated the involvement of these pathways in meningiomas by analysing ...their main effector molecules, beta‐catenin and p53. Cellular expression of p53 and beta‐catenin proteins and genetic changes in TP53 were analysed by immunohistochemistry, PCR/RFLP and direct sequencing of TP53 exon 4. All the findings were analysed statistically. Our analysis showed that 47.5% of the 59 meningiomas demonstrated loss of expression of p53 protein. Moderate and strong p53 expression in the nuclei was observed in 8.5% and 6.8% of meningiomas respectively. Gross deletion of TP53 gene was observed in one meningioma, but nucleotide alterations were observed in 35.7% of meningiomas. In contrast, beta‐catenin, the main Wnt signalling molecule, was upregulated in 71.2%, while strong expression was observed in 28.8% of meningiomas. The concomitant expressions of p53 and beta‐catenin were investigated in the same patients. In the analysed meningiomas, the levels of the two proteins were significantly negatively correlated (P = 0.002). This indicates that meningiomas with lost p53 upregulate beta‐catenin and activate Wnt signalling. Besides showing the reciprocal relationship between proteins, we also showed that the expression of p53 was significantly (P = 0.021) associated with higher meningioma grades (II and III), while beta‐catenin upregulation was not associated with malignancy grades. Additionally, women exhibited significantly higher values of p53 loss when compared to males (P = 0.005). Our findings provide novel information about p53 involvement in meningeal brain tumours and reveal the complex relationship between Wnt and p53 signalling, they suggest an important role for beta‐catenin in these tumours.
Port baseline surveys (PBS) provide species inventories in and around ports, with a focus on non-indigenous species that may have been introduced by vessels, primarily via ballast water. PBS are an ...essential tool to support effective management strategies for non-indigenous as well as native harmful aquatic organisms and pathogens (HAOP). This paper describes the methodology of PBS that were conducted in 12 Adriatic ports. The PBS employed existing protocols that were adapted to meet the characteristics of the Adriatic sites. Their results are reported in several papers included in this special issue, each of which is devoted to a specific community. An overview of existing surveys protocols – which provide valuable support to decision-making and to design effective monitoring of non-indigenous species – is also supplied.
•Existing port baseline surveys protocols and their pros and cons are discussed.•The port baseline survey protocol for the Adriatic is described.•Recommendations based on the Adriatic PBS experience are provided.
The influence of different boron precursor powders on the critical current density of MgB2 superconductor with added Ni-Co-B nanoparticles is investigated. Different types of boron have different ...morphologies, particle sizes and impurity content, all of which have a strong impact on the critical current density (J c). The boron samples investigated in this study include three different boron powders: semicrystalline boron (denoted as SC), with nanosized particles and high purity (99%) supplied from Specialty Materials, Inc. (USA); amorphous boron (denoted as AB), with nanosized particles and high purity (99%) supplied from Russia; and finally pure crystalline boron (denoted as CB), with micron-sized particles and 96% purity supplied from Tangshan WeiHao (China). The MgB2 samples made from AB showed the best improvement of critical current with 2.5wt.% Ni-Co-B doping; J c was above 100,000Acm-2 at 4T and 5K. Under the same conditions, J c for MgB2 made from SC was slightly worse than for the MgB2 made from AB, 100,000Acm-2. On the other hand, MgB2 made from CB presented sharply reduced J c with Ni-Co-B doping at both measured temperatures, 5K and 20K.
A new procedure for the preparation of amorphous Ni–Co–B nanoparticles is reported, with a detailed investigation of their morphology by X-ray diffraction and transmission electron microscopy, as ...well as their magnetic properties. Many factors, such as chemical composition, anisotropy, size and shape of the particles, were controlled through chemical synthesis, resulting in the control of morphological and magnetic properties of the nanoparticles. Controlling pH values with ethylenediamine and using sodium dodecyl sulfate surfactant lowered the size of the nanoparticles to below 10nm. Such a small structure and chemical disorder in nanocrystalline materials lead to magnetic properties that are different from those in their bulk-sized counterparts. The obtained nanoparticles can be used for different purposes, from pharmaceutical applications to implementations in different materials technology. The focus of this research is the synthesis of Ni–Co–B nanoparticles in a new way and studying the reaction of Ni–Co–B nanoparticles with Mg and B precursors and their effect on MgB2 properties. New nanostructures are formed in the reaction of Ni–Co–B nanoparticles with Mg: Mg2Ni, Co2Mg and possibly Mg2Co.
Aim:
Ivo Andrić (1892–1975) was awarded the Nobel Prize in Literature in 1961. He was born and lived in Bosnia-Herzegovina, and forged particularly deep connections with the Franciscans, addressed by ...the people of Bosnia as “uncles”. This article presents all mentions of Franciscans in Andrić’s publications and his characterization of them.
Methods:
We studied all available literary works of Ivo Andrić.
Results:
Andrić was born in small town of Travnik in today’s Bosnia-Herzegovina, a Catholic surrounding in which Franciscan monks provided the religious needs of the parish. Therefore, Andrić developed friendships with Franciscans and cherished it all until his life. His first close Franciscan friend, Fra Alojzije Perčinlić, was the Pastor of Ovčarevo; the last Franciscan friend he made was Fra Ljubo Hrgić, a writer from Zenica. Andrić regularly referred to the Franciscans in his works, from his first book – Ex ponto – published in 1918, to his Omer Pasha Latas, a novel published posthumously in 1976. He used fifteen Franciscan works and monastic annals as major sources for his doctoral dissertation entitled The Development of Spiritual Life in Bosnia under the Influence of Turkish Rule, which he defended in 1924 at the University of Graz. The dissertation described how the Franciscans lived, the role they played in people’s life, and the work they did in Bosnia and Herzegovina over a period of six hundred years. In gb his dissertation he named more than thirty Franciscans, and a total of 44 in his works.
Conclusion:
Andrić was well acquainted with the lives, virtues, accomplishments, and human flaws of the Bosnian Franciscans. Few writers presented the Franciscans as favorably as Ivo Andrić did in his doctoral dissertation and other works. Human flaws that he found in “uncles” were mere “a drop in the ocean” of his favorable accounts about the order.
Croatia has a low-level HIV epidemic; 553 persons were diagnosed with HIV infection in the period 1985-2005. The principal mode of transmission was sex between men (40% of cases) and heterosexual ...contact (40%). Only about 10% of cases were injecting drug users. Testing data also suggest a low prevalence of HIV infection in Croatia, even in vulnerable groups. Behavioral data indicate risky sexual behaviors, with the clear need for interventions. National policy towards HIVIAIDS is operated through the National Committee on HIV/AIDS, a multisectorial advisory body to the Government of Croatia. Croatia applied to the Global Fund to fight AIDS, tuberculosis and malaria in 2002 which resulted in a 4,9 million USD grant for scaling up prevention interventions. Croatia has a centralized system of treatment and care which is provided at the University Hospital for Infectious Diseases in Zagreb. Highly active antiretroviral treatment is provided free of charge from April 1998.
Rad se bavi percepcijom i imidžom Hrvatske iz perspektive hrvatskih iseljenika i njihovih potomaka u Europi, Australiji te Sjevernoj i Južnoj Americi. Autori polaze od važnosti imidža zemlje u ...suvremenim međunarodnim odnosima, te uloge iseljenika u promociji Hrvatske, angažmanu za hrvatske interese u svijetu, kao i mogućnostima povratka, useljavanja i ulaganja. Kako bi taj angažman bio uspješan nužno je poznavanje Hrvatske i njezina suvremenoga identiteta, odnosno praćenje života u njihovoj domovini. Stoga rad donosi rezultate anketnoga istraživanja na uzorku odabranih hrvatskih zajednica na četiri kontinenta, koji se bave razinom informiranosti, načinom informiranja, percepcijom i imidžom Hrvatske, te načinima oblikovanja toga imidža u svijetu. Rad također pokušava odgovoriti na pitanja koliko se imidž Hrvatske razlikuje s obzirom na države i kontinente življenja, dob ispitanika te duljinu življenja izvan domovine.
PDF
