Aim: Here, we explored the role of NCAM/FGFR1 signaling and pro-fibrotic gene expression signatures as initiating or driving forces of EMT program in cultured human proximal tubular epithelial cells. Introduction: Epithelial-to-mesenchymal transition (EMT) contributes to maladaptive repair and parenchymal damage during renal fibrosis. Based on previous reports, neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor 1 (FGFR1) are both considered to be mechanistically involved in the EMT process. Material and Methods: By using an established in vitro model of EMT of the human proximal tubular epithelial cells (HK-2 cells) in response to TGF-β1 (10ng/mL) exposure, NCAM/FGFR1 signaling responses were analyzed by light microscopy, immune-labelling, qRT-PCR and scratch assays. Modulation of FGFR1 was induced using PD173074 (100nM). Distribution of TGF-β1 downstream effectors was assessed in HK-2 cells of the EMT program as well as in 50 biopsies of different human kidney diseases to explore their in vivo correlation. Results: EMT associated with morphological changes started 48h after TGF-ß1 treatment of the HK-2 cells and was clearly apparent after 72 hours, associated with loss of CDH1 (encoding E-Cadherin) and transcriptional induction of SNAI1 (encoding SNAIL), SNAI2 (encoding SLUG), TWIST1, MMP2, MMP9, CDH2 (encoding N-Cadherin), ITGA5 (encoding integrin-α5), ITGB1 (encoding integrin-β1), ACTA2 (encoding α-SMA) and S100A4 (encoding FSP1). After 24 hours of TGF-β1 exposure at the early stage of SPECIJALNA SESIJA: SESIJA SPECIJALIZANATA 7 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. EMT program, transcriptional induction of several NCAM isoforms along with FGFR1 was observed, implicating a mechanistic link between NCAM/FGFR1 signaling and induction of EMT. These assumptions were further supported by the inhibition of the EMT program after specific blocking of FGFR1 signaling responses by PD173074. Moreover, there was evidence for an in vivo TGF-β1 pathway activation with EMT response signal signatures in diseased human kidneys in correlation to impaired renal excretory functions. Conclusion: Modulation of NCAM/FGFR1 signaling blocks the EMT program in cultured human proximal tubular epithelial cells. NCAM/FGFR1 signaling appears to be involved in initial phases of TGF-ß1 initiated EMT of tubular cells and thus could contribute to maladaptive repair and parenchymal damage during renal fibrosis.

Aim: The aim of the study is to investigate the effect of prenatal treatment of metronidazole on the process of cerebellar foliation in the guinea pig. Introduction: The use of metronidazole in pregnancy still occupies very different attitudes among doctors who prescribe them. Neurotoxicity is a common side effect in the use of metronidazole, but there is still no clear animal study. Materials and Method: We studied 42 guinea pig fetuses obtain from 12 pregnant guinea pig dams.  Dams were separated in experimental (6) and control6) group(K). Experimental group(E) received from 42-49 day of gestation at every PLENARY ORAL PRESENTATION 22 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. 12 hour (at 8 a.m. and 8 p.m.) subcutaneous injection od saline solution of metronidazole in concentration of 28 mg/kg.  Control group received using same time protocol just saline solution. At 50th day of gestation all dams were sacrified and fetuses were used for further analysis. In each  fetuses (22 in E, and 20 K group). Firstly we make gross picture of the brain and secondary we separated vermis region for further histological and immunohistochemical analysis. Results: An analysis of macroscopic images of the dorsal side of the cerebellum in the experimental group of individuals revealed malformations in 15 out of 22 fetuses (68.2%). The most affected folia was VII and characterized with aberrant diagonal positioning along the entire dorsal side of the vermis. Other folia were partial presence, with micro, and agyria changes. Conclusion: Prenatal use of metronidazole in guinea pigs during the 42-49th day of gestation cause disturbance in cerebellar foliation.

Aim: To determine the degree of correlation between TTF-1 (+) expression and EGFR mutation status in lung adenocarcinoma. Introduction: Adenocarcinoma of the lung is mainly diagnosed based on standard morphological criteria. The thyroid gland transcription factor (TTF-1) is currently the most commonly used immunohistochemical marker in the differentiation of invasive adenocarcinoma of the lung from another primary and metastatic carcinoma, has a prognostic significance and is a predictor of the EGFR mutation status. Material and Methods: This retrospective study enrolled 60 patients with histologically confirmed primary lung adenocarcinoma who underwent lung cancer surgery at Institute for lung disease Vojvodina between 2010 and 2015. Tumor specimens of these patients were investigated for TTF-1 expression and mutations in EGFR using immunohistochemistry and PCR analysis. Statistical analysis is in statistic software Statistica 12. Results: The study included 35 men and 25 women, with an average age of 61.8 ą 8.08 years. Of the 60 cases, TTF-1 ( ) expression was recorded in 52 (87%) (p <0.001), the statistical difference is not significant when comparing smoking habitsby gender, and tumor size among them. EGFR ( ) mutation status was found in 3/60 (5%) cases [egzon 21 (2) and exon 20 (1)], of which TTF-1 (+) expression was in two cases. Conclusion: There is a statistically significant difference between the TTF-1 (-) and TTF-1 (+) adenocarcinoma and a high degree of correlation between EGFR mutation status and TTF-1 (+) expression.

Aim: Reporting of autopsy case of fatal accidental poisoning by colchicine from meadow saffron. Introduction: Meadow saffron (Colchicum autumnale) is a perennial herbaceous plant similar to the edible wild garlic (Allium ursinum). Toxic substance in meadow saffron is alcaloid colchicine. Colchicine poisoning is a very dangerous condition, which can lead to fatal outcome. Case report: A 50-years-old male was admitted to the hospital complaining of weakness, abdominal pain, nausea, vomiting and diarrhea without blood. Day before he ate two plants thinking they’re wild garlic and seven hours after ingestion he felt first symptoms. During the course of the hospital stay, he had gastroenterocolitis, acute renal failure, hepatic lesion and cardiorespiratory insufficiency with fatal outcome. Post-mortem examination reveled:brain oedema, lung oedema and congestion, heart weighing 700 grams, ventricular hypertrophy, myocardial fibrosis, liver congestion and steatosis, spleen congestion, pancreatic fibrosis. Organs sections were taken for pathohistological analysis. Body fluids and parts of organs were toxicologically analyzed. Pathohistological findings:brain oedema, diffuse perivascular and interstitial myocardial fibrosis, myocardial haemorrhage, lungs congestion and edema, micro- and macrovesicular liver steatosis, centrilobular liver necrosis, lymphocytic inflammatory infiltrate in liver portions, spleen’s red pulp congestion, kidney congestion and interstitial bleeding, coagulation necrosis of the proximal tubules of the kidney. Toxicological analysis showed colchicine in blood-0.011 mg/L, urine-0.051 mg/L, liver with gallbladder-0.007 mg/ kg, kidney-0.008 mg/kg. Conclusion: Ingestion of the meadow saffron can lead to poisoning with fatal outcome due to colchicine. Colchicine intoxication should be suspected in patients with gastrointestinal symptoms after consuming wild plants.

Sarcomatoid differentiation in renal cell carcinoma (sarcomatoid renal cell carcinoma – sRCC) represents a dedifferentiated high grade neoplasm of the kidney that contains carcinomatous and sarcomatous component. sRCC is an uncommon tumor, with the incidence of 5-8% of renal carcinoma. Sarcomatoid differentiation is a result of divergent differentiation of malignant epithelial cells. During this process tumor cells lose their epithelial features, and acquire mesenchymal characteristics, which provides them higher APSTRAKTI 79 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. capacity for migration and metastasis.This phenotype can be encountered in all RCC subtypes, including clear cell, papillary, chromophobe RCC, and carcinomaof collecting duct. Sarcomatoid component may resemble fibrosarcoma or undifferentiated pleomorphic sarcoma. Less often heterologous differentiation can be found, with histologic patterns resembling rhabdomyosarcoma, chondrosarcoma, or osteosarcoma. Rhabdoid phenotype is an aggressive form of divergent differentiation which has been described in clear cell RCC, papillary RCC, as well as in chromophobe RCC (CRRCC). CRRCC comprise about 6% of RCC, and has better prognosis compared to other RCC subtypes. Sarcomatoid differentiation is found in 8% of these tumors, and is an indicator of poor prognosis, as it is in other RCC types. Sarcomatoid component may represent terminally dedifferentiated clone which can arise from any RCC subtype, or can develop from a special clone. Although sRCC is most frequently found in high grade tumors, the occurrence of sarcomatoid differentiation in RCC, Fuhrman 1/2, detected in 30% of the cases, denies the claim that sarcomatoid differentiation is a continual process of classic RCC dedifferentiation, but a consequence of sarcomatoid stem cell activation within the tumor. In a case of sarcomatoid differentiation in renal carcinoma it is necessary to detect focuses of any morphological type of renal cell carcinoma, and to verify the immunohistochemical positivity of sarcomatoid component to epithelial and mesenchymal markers. Their epithelial origin is confirmed by the expression of cytokeratins, and EMA. PAX8, CAIX, and CD10 can be used to confirm the renal origin, which is of particular importance in finding of sarcomatoid cells in needle biopsy, as well as in metastatic RCC. CAIX, p53, and Bcl-2 can play a major role in transformation of RCC to highly malignant neoplasm with sarcomatoid differentiation. The expression of CAIX, p53, and Bcl-2 is indicator of poor prognosis and worse survival of the patients with sRCC. Significant micromorphological parameters that may influence the clinical course of the disease comprise percentage of sarcomatoid differentiation (>50%), presence of vascular invasion, extent of necrosis, and advanced TNM stage. Type and grade of sarcomatoid component, as well as RCC subtype do not influence the clinical outcome. The prognosis of patients with sRCC is worse compared to prognosis of other histologic forms of RCC. Sarcomatoid differentiation in RCC is a significant cause of mortality, with average survival of 4-9 months after diagnosis. The majority of unclassified RCCs contains variable percent of tumor cells with sarcomatoid morphology, without recognizable epithelial component. About 3% of RCC are exclusively sarcomatoid. These tumors are larger, more often invade adrenal glands and other adjacent organs, metastasize more frequently into regional lymph nodes and bones, and have significantly shorter survival (average is 4.3 months). Differential diagnosis of sRCC should exclude primary renal sarcoma, sarcomatoid urothelial carcinoma, and angiomyolipoma. Micromorphologically sRCC may resemble classic sarcoma, however it should be taken into account that primary renal sarcomas are extremely rare in adults, and comprise less than 1% of renal malignancies. The half of primary renal sarcomas are leiomyosarcomas, consisting of smooth muscle component, which is extremely rare in sRCC. In sarcomatoid urothelial carcinoma, the location of tumor is of significance, also the presence of carcinoma in situ, recurrence of urothelial carcinoma, and immunohistochemical positivity to CKhmw and p63. In angiomyolipoma, immunoreactivity to HMB45, as well as the presence of focuses with classic morphology, excludes sarcomatoid RCC. Conclusion: Sarcomatoid differentiation in renal cell carcinoma is a result of divergent differentiation of malignant epithelial cell, and can be found in all renal cell carcinoma subtypes. During this process tumor cells lose their epithelial features, and acquire mesenchymal characteristics, which provides them higher capacity for migration and metastasis. It is very important to recognize the presence of sarcomatoid differentiation in renal cell carcinoma, since it is an indicator of poor prognosis irrespective of RCC subtype.

The design and construction of new biological systems in the way engineers design electronic or mechanical systems is the primary goal of synthetic biology. The ability to create and modify life forms and easy access to information to do so has raised a number of issues related to ethics and security. In the era of rapid development of biotechnology, and the perception of the consequent risks to the environment and health, the ethics of knowledge becomes a matter of practical significance. The concern about the misuse of knowledge from synthetic biology influences new risk reduction strategies, which can have significant effects on scientific progress. This paper will provide an overview of the main bioethical and biosafety issues of synthetic biology.

Složeni problemi politraumatizovanih pacijenata su veliki izazov za lekare. Brojne povrede kod takvih pacijenata zahtevaju brzo reagovanje po principu prioriteta kojim se greške svode na minimum. Za lečenje trauma pacijenata neophodno je znanje, iskustvo i veština lekara da bi brzo i sveobuhvatno sagledao povređenog i da bi mu ukazao pravovremenu pomoć. Lečenje se izvodi fokusirajući se na prioritetne povrede pacijenta, prateći protokol postupaka koji lekara sistematski vodi tokom zbrinjavanja od najtežih ka lakšim povredama. Ovakve pacijente zbrinjava interdisciplinarni tim zdravstvenih radnika, u kome svako mora da zna svoje mesto i obaveze. Na čelu tima je najiskusniji lekar koji definiše redosled postupaka tokom inicijalnog zbrinjavanja. Samo organizovanim pristupom pandemijskom problemu trauma pacijenata može se pozitivno uticati na smanjenje neposrednog i odloženog mortaliteta i morbiditeta povređenih. U radu je revijalno prikazan pristup politraumatizovanom pacijentu uz inicijalno zbrinjavanje, baziran na prioritetima i prateći protokol koji obezbeđuje najveću efikasnost u lečenju.

Parathyroid gland adenoma belongs to the benign tumor group and is the commonest originator of the primary hyperthyroidism which emerges owing to the both increased and uncontrolled secretion of parathyroid hormone due to the one or more parathyroid glands hyperfunction. The paper outlines the woman case, who was at the prison sentence enduring, and as a result of the supraventricular tachycardia and hemodynamic instability she was hospitalized at the Clinical centre, Kragujevac. The obduction diagnosed atherosclerosis of severe degree, left ventricle hypertrophy, nephrolithiasis, whereas the organs’ cut-outs pathohistological examination showed parathyroid gland adenoma. The cause of death of the particular patient was the myocardial infarction. Parathyroid adenoma of the patient was not detected in time because of the state of neglect and her way of life. The primary hyperthyroidism has significantly speeded up the myocardial damage and the blood vessel atherosclerotic changes.

Laryngeal lipomas are a rare form of a benign mesenchymal tumour containing fatty tissue. They can occur at any subcutaneous location part of the body, particularly in the trunk and lower and upper limbs where fat tissue is more abundant. We present the case of a 66-year-old man complaining of long lasting (3 years) discomphort in his throat, with no breathing or glutition problems. CT scans showed a 3.0-cm fat-containing mass involving the left aryepiglottic fold. The patient was taken to the operating room for excision of the mass using a laryngofissure approach. The final pathologic diagnosis was lipoma. We describe a case of large laryngeal lipoma removed through an external surgical approach in order to prevent any possible recurrence or malignant alteration.

We present the case of a 46-year-old patient diagnosed with a large solid tumor localized in the right mesentery, and due to the mesenteric position and tumor structure, diagnostic suspicion of GIST was proposal as the most frequent tumor lesion of this localization. After a few days, the patient was discharged from the hospital without postoperative complication, in further follow-up without relapse.