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Тумул III е најголем во групата од десет тумули во археолошкиот локалитет Орлова Чука. Ископувањата од 1994 година доведоа до откритие на десет гробници, радијално наредени околу едена поголема гробница. Гробниците се наредени во круг во должина од 18 метри во дијаметар. Во овие гробници се пронајдени огромен број археолошки предмети.

Во 1988 година Институтот за конзервација на културни споменици и Музејот на град Штип извршија археолошко истражување на срдновековната некропола во близина на црквата Св. Ѓорѓи, на археолошкиот локалитет Баргала. Археолошките истражувања од 1966 година открија ранохристијански град Баргала, кој бил ранохристијански центар во источна Македонија. Градот опстојувал во текот на четвртиот, петиот и шестиот век се до неговото уништување од страна на словенските и аварските племиња, во текот на последните години на VI век. Тогаш уништениот град бил населен со словенски племиња. Црквата Св. Ѓорѓија и некрополата која е изградена близу црквата се доказ за тоа.

Археолошкиот локалитет "Долна Бежанија" се наоѓа на 1,5 км јужно од селото Криви Дол. Се наоѓа на два рида со неправилна форма и зафаќа површина од 1200м2. Врз основа на нашето контролно истражување можеме да претпоставиме дека локалитетот Долна Бежанија е оштетена некропола со пронајдени остатоци од погребани луѓе. Ова мислење е поткрепено со фактот дека не е пронајдена населба, туку само некропола. Базирано на пронајдените наоди можеме да заклучиме дека локалитетот датира од XIII до XI век п.н.е. што одговара на периодот од Бронзеното или почетокот на Железното време во Македонија.

Meandering beams, crenellated surfaces, and zigzag-shaped electrodes are employed as compliant elements in microscale applications ranging from springs attached to proof masses in microelectromechanical systems (MEMS) to stretchable electrodes in flexible electronics and dielectric elastomer actuators. An understanding of how the meander shape affects the stiffness of these structures would permit preliminary design without the necessity of fabricating or running simulations on each case. In this paper, we present general guidelines for designing meandering cantilevers, showing how the amplitude, angle, length, and thickness affect both the axial and bending stiffnesses. Simple analytical expressions are derived, and the results are compared with those from numerical simulations and experimental measurements. The more complex case of a stiff thin film overlying a crenellated elastomer is also simulated.

Itraconazole is a widely used antifungal drug that has been recently shown to inhibit angiogenesis in vivo and to block non-small cell lung cancer growth in animal models. Based on these and other results, itraconazole is currently being evaluated in four clinical trials as a cancer therapeutic. Angiogenesis, one of the hallmarks of cancer, is required for tumor growth and is driven by tumor-secreted growth factors including vascular endothelial growth factor (VEGF). We now report that in endothelial cells, itraconazole inhibits signaling of VEGF through the VEGF receptor 2 (VEGFR2) (80% inhibition; p < 0.05) and subsequently through a downstream substrate, PLCϒ1 (60% inhibition; p < 0.05). Mechanistically, we show that this was due to a nearly complete loss of VEGF binding to VEGR2 that was secondary to a loss of cell surface expression of the receptor. After itraconazole treatment, VEGFR2 was retained in a perinuclear aggregate which partially overlapped with the cis-Golgi marker GM130. Correlated with this loss of VEGFR2 signaling and trafficking, was a dramatic change in VEGFR2 mobility on SDS-PAGE which resulted from incomplete N-glycosylation. Itraconazole globally reduced poly-LacNAc and tetra-antennary glycans in endothelial cells and induced hypoglycosylation of EGFR in a renal cell carcinoma line, suggesting that the effects of itraconazole apply to multiple cell types and receptors. Importantly, small molecule inducers of lysosomal accumulation and mTOR inhibition, two previously known itraconazole-induced effects, did not interfere with VEGFR2 glycosylation. Similarly, glycosylation inhibitors did not affect cholesterol trafficking or inhibit mTOR. However, increasing cellular cholesterol levels, which was known to rescue the effects of itraconazole on mTOR and cholesterol trafficking, restored VEGFR2 glycosylation and signaling. Thus, the newly described properties of itraconazole occur in parallel to inhibition of cholesterol trafficking and mTOR but appear downstream of a single target. Taking these findings together, we propose a model in which itraconazole inhibits intracellular trafficking. This model could explain the loss of VEGFR2 signaling, incomplete VEGFR2 glycosylation, as well as disruption of cholesterol trafficking and mTOR signaling. Importantly, the effects of itraconazole we report here may significantly contribute to the in vivo efficacy of itraconazole and are relevant to ongoing clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2316. doi:1538-7445.AM2012-2316

Itraconazole is an antifungal drug that was recently found to potently inhibit the Hedgehog (Hh) signaling pathway. The mechanism of inhibition of Hh signaling is distinct from that of cyclopamine-competitive inhibitors currently in late-stage clinical development. Itraconazole has also been described as a potent inhibitor of activation of vascular endothelial growth factor receptor-2 (VEGFR-2) and tumor associated angiogenesis. The unexpected activities associated with this FDA-approved agent offer a unique opportunity for expansion of its use to the oncology arena. As such, itraconazole is currently being evaluated in several clinical trials targeting proliferative disease, including basal cell carcinoma and recurrent metastatic non-small cell lung cancer. To date, the target(s) of itraconazole responsible for these activities remain to be determined. In these studies we expand the characterization of the activity profile for itraconazole by examining potency in the context of a Smoothened receptor point-mutation associated with clinical resistance to vismodegib (GDC-0449). Additionally, in the interest of understanding the structure-activity relationship (SAR) guiding Hh pathway targeting and working towards the identification and development of inhibitors demonstrating greater potency and specificity; twenty-five itraconazole side chain analogs were synthesized and assayed for inhibition of Hh pathway activation. Furthermore, the SAR associated with the inhibition of phospho-activatable forms of VEGFR2 is also described. Through these analyses we report that itraconazole maintains potency against the Hh pathway in the context of the D477G Smoothened mutation (mouse homologue to human D473H). We also conclude that SAR trends for targeting of the Hh pathway are divergent from those associated with inhibition of VEGFR2 signaling. Taken together, these results suggest that modification of the sec-butyl side chain of itraconazole can enhance compound activity and differentially affects inhibition of the Hh pathway and VEGFR2 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C147.

Alek Nacev1, Skye H Kim2, Jaime Rodriguez-Canales2, Michael A Tangrea2, Benjamin Shapiro1, Michael R Emmert-Buck21Fischell Department of Bioengineering, University of Maryland, College Park, MD; 2Pathogenetics Unit, Laboratory of Pathology, Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, MD, USAAbstract: A nanoparticle delivery system termed dynamic magnetic shift (DMS) has the potential to more effectively treat metastatic cancer by equilibrating therapeutic magnetic nanoparticles throughout tumors. To evaluate the feasibility of DMS, histological liver sections from autopsy cases of women who died from breast neoplasms were studied to measure vessel number, size, and spatial distribution in both metastatic tumors and normal tissue. Consistent with prior studies, normal tissue had a higher vascular density with a vessel-to-nuclei ratio of 0.48 ± 0.14 (n = 1000), whereas tumor tissue had a ratio of 0.13 ± 0.07 (n = 1000). For tumors, distances from cells to their nearest blood vessel were larger (average 43.8 µm, maximum 287 µm, n ≈ 5500) than normal cells (average 5.3 µm, maximum 67.8 µm, n ≈ 5500), implying that systemically delivered nanoparticles diffusing from vessels into surrounding tissue would preferentially dose healthy instead of cancerous cells. Numerical simulations of magnetically driven particle transport based on the autopsy data indicate that DMS would correct the problem by increasing nanoparticle levels in hypovascular regions of metastases to that of normal tissue, elevating the time-averaged concentration delivered to the tumor for magnetic actuation versus diffusion alone by 1.86-fold, and increasing the maximum concentration over time by 1.89-fold. Thus, DMS may prove useful in facilitating therapeutic nanoparticles to reach poorly vascularized regions of metastatic tumors that are not accessed by diffusion alone.Keywords: cancer, metastases, vasculature, drug delivery, magnetic, nanoparticles

Во трудот се прикажани фабули и игли пронајдени во археолошките локалитети во Штипско кои датираат од железниот период во Македонија. Иако некои до наодите веќе се објавени, во трудот се поместени сите наоди од овој период на едно место. Наодите се од локалитетите "Баби" и "Орлови Чуки", селата Криви Дол и Радање, месноста Горно поле, с. Стар Караорман

The present study had three principal purposes: (1) to collect, on one sample, information concerning lifetime usage of major drugs, overall frequency of usage, places and situations of initial usage, and exposure to drug usage through social group contacts; (2) to assure subjects of absolute anonymity in order to avoid biases introduced by identification of subjects; and (3) to obtain high questionnaire return rates in order to assure reduction of sample biases. A drug survey questionnaire dealing with marijuana, amphetamines, heroine, hallucinogens, tranquilizers, and antidepressants was administered in classroom settings to a total of 332 college students. Subjects did not record their names and thus were assured of complete anonymity. The return rate for questionnaires was 99.4%. Data were subgrouped for analysis to differentiate freshmen and upperclassmen and to differentiate males and females. For various subgroups, lifetime usage of marijuana and LSD ranged from 55 to 80.6% and from 14 to 30%, respectively. Current use ranged from 30.1 to 62.5% for marijuana and from 2.5 to 9.1% for hallucinogens. Sex differences were minimal, and usage levels were generally higher in upperclassmen than in freshmen.