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A dicarboxylato-diamide-type compound 2,2'-[(1,2-dioxoethane-1,2- -diyl)diimino]dibenzoic acid (H4obbz) (1) was synthesized and characterized. The crystal structure of K2H2obbz?2H2O (2) was determined by X-ray diffracttion analysis. The cytotoxic activities of the compounds were tested against four different cancer cell lines MCF-7, A549, HT-29, HeLa and a human normal cell line MRC-5. The results indicate reasonable dose-dependent cytotoxicity of the ligands that show selectivity against the tested carcinoma and healthy cell lines. Flow cytometric analysis and fluorescence microscopy showed that the most active compound, H4obbz, induced apoptosis and G0/G1 cell cycle arrest, indicating blockage of DNA synthesis as a possible mechanism that triggers apoptosis. Docking and molecular dynamics simulations gave similar responses regarding interactions (binding) between their ligands and chaperon Grp78. The MMGBSA determined ?G binding energies were in the range from ?104 to ?140 kJ mol-1.

After the modern Serbian state was restored under the leadership of Prince Milos, who chose Kragujevac to be the capital, doctors came from abroad, working mainly on military-medical affairs. The first graduate physician who stayed in Kragujevac was Constantinos Alexandridi, MD, and at the time Vito Romita, MD, and Bartolomeo Cunibert, MD, were active as well. The first Serbian doctor, a Serb from abroad who came to Serbia (1826), was Jovan Stejic, MD, and the first Serbian doctor who was born in Serbia, was Stevan Milosavljevic, MD. The organizers of military and civilian medical services at the time were Karel Pacek, MD, and Emmerich Lindenmayer, MD. The first institutions that had characteristics of hospitals ('spitalji') were established in Kragujevac and Pozarevac (1832), but due to the lack of personnel and resources, these institutions as well as others like them had unstable organization. The first military hospital was formed in 1836 on the left bank of Lepenica River, at the edge of the Prince's Palace complex. The first health and medical authorities were established in the structure of government and administration in 1838, and one of the first leaders of these institutions were Jovan Stejic, MD, and Carlo Beloni, MD. Nine district physicians were appointed on August 7th, 1839 and they served for a long time as the highest organs of preventive and curative medicine. Josif Pancic, MD, Ljubomir Radivojevic, MD, Mladen Jankovic, MD, and Filip Tajsic, MD, were among the most deserving for the foundation of the District Hospital in Kragujevac on November 20th, 1860, after many delays. The work of a doctor of that time was not particularly appreciated, their private work provided their primary source of income and medical progress in Kragujevac was mainly related to military health care until the ninth decade of the 19th century.

Uterine leiomyomas (fibroids) are the most common benign tumors in women of reproductive age. Although the local application of low doses of methotrexate (MTX) is used as an effective treatment of the myomas, myotrexate could be a promising new drug. This study investigated the cytotoxic and apoptotic effects of both MTX and myotrexate in human fibroblasts derived from the uterine fibroids (T hES cell line). The myotrexate adduct is an aqueous solution of MTX and L-arginine. Cells were treated with a graded concentrations of both MTX and myothrexate (0.1-16 µM) for 24 h. The cytotoxicity was assayed by MTT test, apoptosis was evaluated by Annexin V-FITC assay and their possible role in apoptosis was determined by immnu- flourescence. Both MTX and myotrexate induced apoptosis in T hES cells in a dose dependent manner (p0.001). Myotrexate significantly increased the percentage of AnnexinV positive cells, BAX/Bcl-2 ratio and subsequent caspase-3 activation compared to the MTX treated cells (p0.05). Both MTX or myotrexate treatment showed a diffuse staining of cytochrome c indicating its release from mitochondria to the cytosol, suggesting that their mechanisms of action most likely involves the mitochondrial apoptotic pathway.