Prijenosnici natrija i glukoze: nove mete ciljanih terapija u liječenju raka?

Glucose, the key source of metabolic energy, is imported into cells by two categories of transporters: 1) facilitative glucose transporters (GLUTs) and 2) secondary active sodium-glucose cotransporters (SGLTs). Cancer cells have an increased demand for glucose uptake and utilisation compared to normal cells. Previous studies have demonstrated the overexpression of GLUTs, mainly GLUT1, in many cancer types. As the current standard positron emission tomography (PET) tracer 2-deoxy-2-(18F)fluoro-D-glucose (2-FDG) for imaging tumour cells via GLUT1 lacks in sensitivity and specificity, it may soon be replaced by the newly designed, highly sensitive and specific SGLT tracer α-methyl-4-(F-18)fluoro-4-deoxy-Dglucopyranoside (Me-4FDG) in clinical detection and tumour staging. This tracer has recently demonstrated the functional activity of SGLT in pancreatic, prostate, and brain cancers. The mRNA and protein expression of SGLTs have also been reported in colon/colorectal, lung, ovarian, head, neck, and oral squamous carcinomas. So far, SGLTs have been poorly investigated in cancer, and their protein expression and localisation are often controversial due to a lack of specific SGLT antibodies. In this review, we describe current knowledge concerning SGLT1 and SGLT2 (over)expression in various cancer types. The findings of SGLTs in malignant cells may help in developing novel cancer therapies with SGLT2 or SGLT1/SGLT2 inhibitors already used in diabetes mellitus treatment.Glukoza, glavni izvor metaboličke energije, ulazi u stanicu na dva načina: 1) olakšanom difuzijom pomoću prijenosnika glukoze GLUT i 2) sekundarno aktivnim prijenosom pomoću prijenosnika natrija i glukoze SGLT. Stanice raka imaju povećani unos glukoze u usporedbi s normalnim stanicama. Prethodna istraživanja pokazala su povećanu ekspresiju prijenosnika GLUT, uglavnom GLUT1, u mnogim tipovima raka. Radiofarmaceutik (engl. tracer) 2-deoksi-2-(18F) fluoro-D-glukoza (2-FDG), koji se koristi za detekciju tumorskih stanica putem GLUT1, nije dovoljno osjetljiv i specifičan. Uskoro bi mogao biti zamijenjen α-metil-4-(F-18) fluoro-4-deoksi-D-glukopiranozidom (Me-4FDG), novim i visoko osjetljivim, i specifičnim SGLT-radiofarmaceutikom u kliničkoj detekciji i određivanju stadija tumora. Tim je radiofarmaceutikom nedavno dokazana funkcionalna aktivnost prijenosnika SGLT u raku gušterače, prostate i mozga. Ekspresija mRNA i proteina SGLT također je pronađena u raku debelog crijeva, pluća, jajnika, glave, vrata i pločastih stanica usne šupljine. Prijenosnici SGLT nedovoljno su istraženi u raku, a njihova ekspresija i lokalizacija često su oprečne zbog nedostatka specifičnih SGLT-protutijela. U ovom preglednom radu opisujemo trenutačna znanja o povećanoj ekspresiji prijenosnika SGLT1 i SGLT2 u različitim tipovima raka. Spoznaje o ekspresiji i/ili lokalizaciji prijenosnika SGLT u malignim stanicama pomoći će u razvoju novih terapija u liječenju raka korištenjem već poznatih antidijabetika, SGLT2 ili SGLT1/SGLT2 inhibitora

Venice and Dubrovnik During the Great Earthquake of 1667

The article examines the Venetian-Ragusan relations during one of the most dramatic moments in Dubrovnik’s history―the first few weeks after the Great Earthquake of 1667. This large-scale crisis which not only destroyed the city physically, but also its socio-political order, had a profound impact on the relations between the two Adriatic republics. Starting from the assumption that the situations of crisis allow a privileged insight into the nature of historical phenomena, this text centres on the microfactography of this dramatic period. On the one hand, it reconstructs various diplomatic contacts, speculations and plans in Venice itself, among which the most intriguing was the initiative for the union between the two republics and their patriciates. On the other hand, the article traces the situation in the surroundings of Dubrovnik, where general governor Cornaro made recurrent attempts at pressuring the remaining nobility into aggregation with the Most Serene Republic

Unraveling mucin type o-glycosylation signatures of colorectal cancer

The surface of eukaryotic cells contains a very dense layer of oligosaccharides called glycans that are linked to protein and lipid carriers and play an important role in cell-cell and cell-extracellular matrix interactions. Cancer-induced changes in glycosylation have an impact on the function of major glycoproteins in the human colon, therefore studies focused on colorectal cancer (CRC)-specific glycosylation signatures can provide novel insights into onset and progression of this disease. The major focus of this thesis was to investigate mucin type O-glycosylation signatures of CRC. For this purpose, a protocol for in-depth analysis of N- and O-glycans obtained from cell lines was developed (Chapter 2) using nanoscale porous graphitized carbon liquid chromatography coupled to mass spectrometry (PGC-nano-LC-MS). In Chapter 3 additional conditions were optimized in the MS methodology by using polar protic dopant (methanol and isopropanol) enriched nitrogen gas to increase sensitivity on the MS and tandem MS level. In Chapter 4 we applied the methodology developed in Chapter 2 to the analysis of O-glycosylation signatures of 26 different CRC cell lines. This analysis resulted in the characterization of more than 150 O-glycan structures and increased our understanding of glycan expression in the analyzed cell lines. To gain further understanding in the mechanisms underlying glycomic changes with colon cell differentiation, we explored changes in the cell line glycome and proteome upon spontaneous and butyrate-stimulated differentiation in in vitro cell culture (Chapter 5). By performing an integrative approach, we generated hypotheses about glycosylation signatures of specific cell adhesion proteins, which may play an important role in cancer progression. The localization of glycans on the cell surface and their role in biological processes are important in cancer pathogenesis, making them potential candidates for glycan targeting immunotherapy. Therefore, we further optimized the methodology to enable comprehensive analysis of N- and O-glycans from specific regions of formalin-fixed, paraffin-embedded tissues using laser capture microdissections and applied it for the analysis of selected regions of CRC tissues and their patient-matched colon mucosa controls (Chapter 6). We identified specific tumor-associated carbohydrate antigens (TACAs) that show expression only in the tumor samples, with no or limited expression in the normal colon mucosa. Since TACAs are present in high abundance on the surface of cancer cells which are linked to many different proteins, these are very promising targets for the development of tumor-specific immunotherapy. LUMC / Geneeskund

PRINCIP RADA OTTO MOTORA

U radu će se navesti i opisati konstrukcijski dijelovi motora s unutrašnjim izgaranjem, te će se navesti njihova namjena i karakteristike. Obradit će se princip rada četverotaktnog i dvotaktnog Otto motora, te će se navesti razlika između njih. Obradit će priprema gorive smjese kod Otto motora, objasniti uloga i važnost rasplinjača. Motori s unutarnjim izgaranjem su strojevi u kojima gorivo izgara neposredno unutar radnog prostora, a toplinska energija koja nastaje, pretvara se u mehanički rad tj. kretanje automobila.The paper will list and describe the structural parts of the internal combustion engine and will indicate their purpose and characteristics. The principle of operation of the four-stroke and two-stroke Otto engines will be discussed and the differences between them will be stated. The preparation of the fuel mixture with the Otto engine will be elaborated, as well as the role and importance of the carburetor. Internal combustion engines are machines in which fuel is burned directly inside the workspace, and the resulting heat energy is converted into mechanical work, ie. the movement of cars