The role of IL-33/ST2 signaling pathway in development of breast carcinoma necrosis

Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, IL-RL1, ST2) signalni put promoviše rast tumora i razvoj metastaza inhibicijom antitumorskog imunskog odgovora. IL-33 je protein sa anti- i proinflamatornom ulogom koji funkcioniše kao transkripcioni faktor i klasičan citokin sa ulogom alarmina. Nekrotične ćelije sekretuju imunoregulatorne citokina uključujući IL-33 koji je član IL-1 familije citokina. Prethodne studije sugerišu da IL-33 promoviše ekspresiju i oslobađanje vaskularnog endotelnog faktora rasta (VEGF) u mastocitima i ukazuju na njegovu proangiogenu ulogu aktivacijom endotelnih ćelija preko IL-33R. Međutim, značaj aktivacije IL-33/IL-33R signalnog puta u angiogenezi i tumorskoj nekrozi nije u potpunosti jasna. Cilj naše studije je bio da se ispita uloga signalnog puta IL-33/IL-33R u tumorskoj nekrozi i angiogenezi karcinoma dojke. Delecija gena za IL-33R u BALB/c miševa pojačava tumorsku nekrozu u isporava rast tumora u eksperimentalnom modelu 4T1 karcinoma dojke što je povezano sa smanjenom ekspresijom vaskularnog endotelnog faktora rasta i IL-33 u ćelijama tumora dojke. Ekspresija IL-33 u ćelijama karcinoma dojke raste tokom vremena u IL-33R+/+ ali ne i u IL-33R-/-. Rezultat ukazuje na mehanizam pozitivne povratne sprege IL-33/IL-33R osovine. Analizirali smo ekspresije IL-33. IL-33R, i VEGF.a, kao i mikrovaskularnu gustinu (MVD) u tumorima 40 pacijenkinja sa karcinomom dojke sa prisutnom ili odsutnom nekrozom u tkivu tumora. Detektovali smo značajno veću ekspresiju IL-33. IL-33R i VEGF-a u tkivu karcinoma dojke bez detektabilne nekroze. Ekspresije IL-33 i IL-33R koreliraju sa ekspresijom VEGF-a u tumorskim ćelijama. Takođe, ekspresija VEGF je bila u pozitivnoj korelaciji sa MVD u perinekrotičnom rubu tumora. IL-33 poput IL-1β pokauje proangiogenu ulogu i kontroliše produkciju VEGF-a. IL-1β pojačava ekspresiju VEGF-a i njegovih receptora na endotelnim ćelijama a zajedno sa VEGF-om promoviše tumorsku angiogenezu. Kao i IL-1, IL-33 aktivira IL-1R3 (IL-1RAcP) ukazujuć da inhibicija ovog protein primenom anti-IL-1R3 antitela inhibira angiogenezu tumora i pojačava tumorsku nekrozu u tkivu carcinoma dojke usled gubitka vaskularne podpore. Na osnovu ovih rezultata smatramo da IL-33 oslobođen iz nekrotičnih ćelija facilitira ekspresiju VEGF-a u okolnim tumorskim ćelijama promovišući angiogenezu što je potvrđeno većom MVD u perinekrotičnoj zoni humanog carcinoma dojke. Naši rezultati ukazuju da IL-33/IL-33R signalni put igra važnu ulogu u rastu tumora pojačavanjem ekspresije proangiogenog VEGF-a i inhibicijom tumorske nekroze. U dodatku na ranija istraživanja, naši rezultati ukazuju na suprotnu ulogu intracelularnog i sekretovanog IL-33. Naša studija pokazuje dodatni mehanizam kojim IL-33/IL-33R osovina učestvuje u karcinogenezi i daje racionalno objašnjenje za potencijalnu blokadu IL-33 kao terapijskog modaliteta u lečenju humanog karcinoma dojke.Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, IL-RL1, ST2) signaling pathway promotes mammary cancer growth and metastasis by inhibiting anti-tumor immunity. IL-33 is dual function protein with roles as a nuclear factor and a classical cytokine and functions as a prototypic „alarmin”. Necrotic cells release immunoregulatory cytokines, including IL-33, a member of the IL-1 family of cytokines. Previous studies suggest that IL-33 directly facilitated vascular endothelial growth factor (VEGF) expression and secretion in primed mast and showed proangiogenic role of IL-33 by inducing endothelial proangiogenic activity via IL-33R expressed on endothelial cells.However, the role of IL-33/IL-33R axis in neoangiogenesis and tumor necrosis is not elucidated. Therefore, the aim of this study was to investigate the role of IL-33/IL-33R axis in mammary tumor necrosis and angiogenesis. Deletion of IL-33R gene in BALB/c mice enhanced tumor necrosis and attenuated tumor growth in 4T1 breast cancer model, which was associated with markedly decreased expression of VEGF and IL-33 in mammary tumor cells. IL-33 expression in mammary tumor cells significantly increased over time in IL-33R+ /+ mice, but not in IL-33R-/- mice the findings that reflect positive feedback mechanism in IL-33/IL-33R axis We next analyzed IL-33, IL-33R and VEGF expression and microvascular density (MVD) in breast tumors from 40 female patients with absent or present tumor necrosis. We found significantly higher expression of IL-33, IL-33R and VEGF in breast cancer tissues with absent tumor necrosis. Both, IL-33 and IL-33R expression correlated with VEGF expression in tumor cells. Further, VEGF expression positively correlated with MVD in perinecrotic zone. IL-33 is very much like IL-1 in that both IL-1β and IL-33 are proangiogenic and control the production of VEGF. IL-1β increases expression of VEGF and its receptors on endothelial cells and acts together with VEGF in promoting tumor mediated angiogenesis. Thus, the neutralization of IL-1β reduced tumor growth and the tumor-induced angiogenesis. As IL-1 and IL- 33 both use IL-1R3 (IL-1RAcP), it may be speculated that anti-IL-1R3 antibodies may reduce angiogenesis and increase tumor necrosis in breast cancer due to loss of vascular supply. On the basis of these observations we suggest that IL-33 released by necrotic cells may facilitate VEGF expression on nearby tumor cells, which could lead to enhanced angiogenesis as demonstrated by high-grade MVD in perinecrotic zone in human breast cancer tissue. Taking together, our data indicate that IL-33/IL-33R pathway is critically involved in mammary tumor growth by facilitating expression of pro-angiogenic VEGF in tumor cells and attenuating tumor necrosis. Additionally, results indicate oposite functions of intracellular and secreted IL-33. Thus, this study revealed an additional mechanism by which IL-33/IL-33R pathway may be involved in tumorigenesis and provide rationale for blocking IL-33 as a therapeutic modality in human breast carcinoma

The role of IL-33/ST2 signaling pathway in development of breast carcinoma necrosis

Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, IL-RL1, ST2) signalni put promoviše rast tumora i razvoj metastaza inhibicijom antitumorskog imunskog odgovora. IL-33 je protein sa anti- i proinflamatornom ulogom koji funkcioniše kao transkripcioni faktor i klasičan citokin sa ulogom alarmina. Nekrotične ćelije sekretuju imunoregulatorne citokina uključujući IL-33 koji je član IL-1 familije citokina. Prethodne studije sugerišu da IL-33 promoviše ekspresiju i oslobađanje vaskularnog endotelnog faktora rasta (VEGF) u mastocitima i ukazuju na njegovu proangiogenu ulogu aktivacijom endotelnih ćelija preko IL-33R. Međutim, značaj aktivacije IL-33/IL-33R signalnog puta u angiogenezi i tumorskoj nekrozi nije u potpunosti jasna. Cilj naše studije je bio da se ispita uloga signalnog puta IL-33/IL-33R u tumorskoj nekrozi i angiogenezi karcinoma dojke. Delecija gena za IL-33R u BALB/c miševa pojačava tumorsku nekrozu u isporava rast tumora u eksperimentalnom modelu 4T1 karcinoma dojke što je povezano sa smanjenom ekspresijom vaskularnog endotelnog faktora rasta i IL-33 u ćelijama tumora dojke. Ekspresija IL-33 u ćelijama karcinoma dojke raste tokom vremena u IL-33R+/+ ali ne i u IL-33R-/-. Rezultat ukazuje na mehanizam pozitivne povratne sprege IL-33/IL-33R osovine. Analizirali smo ekspresije IL-33. IL-33R, i VEGF.a, kao i mikrovaskularnu gustinu (MVD) u tumorima 40 pacijenkinja sa karcinomom dojke sa prisutnom ili odsutnom nekrozom u tkivu tumora. Detektovali smo značajno veću ekspresiju IL-33. IL-33R i VEGF-a u tkivu karcinoma dojke bez detektabilne nekroze. Ekspresije IL-33 i IL-33R koreliraju sa ekspresijom VEGF-a u tumorskim ćelijama. Takođe, ekspresija VEGF je bila u pozitivnoj korelaciji sa MVD u perinekrotičnom rubu tumora. IL-33 poput IL-1β pokauje proangiogenu ulogu i kontroliše produkciju VEGF-a. IL-1β pojačava ekspresiju VEGF-a i njegovih receptora na endotelnim ćelijama a zajedno sa VEGF-om promoviše tumorsku angiogenezu. Kao i IL-1, IL-33 aktivira IL-1R3 (IL-1RAcP) ukazujuć da inhibicija ovog protein primenom anti-IL-1R3 antitela inhibira angiogenezu tumora i pojačava tumorsku nekrozu u tkivu carcinoma dojke usled gubitka vaskularne podpore. Na osnovu ovih rezultata smatramo da IL-33 oslobođen iz nekrotičnih ćelija facilitira ekspresiju VEGF-a u okolnim tumorskim ćelijama promovišući angiogenezu što je potvrđeno većom MVD u perinekrotičnoj zoni humanog carcinoma dojke. Naši rezultati ukazuju da IL-33/IL-33R signalni put igra važnu ulogu u rastu tumora pojačavanjem ekspresije proangiogenog VEGF-a i inhibicijom tumorske nekroze. U dodatku na ranija istraživanja, naši rezultati ukazuju na suprotnu ulogu intracelularnog i sekretovanog IL-33. Naša studija pokazuje dodatni mehanizam kojim IL-33/IL-33R osovina učestvuje u karcinogenezi i daje racionalno objašnjenje za potencijalnu blokadu IL-33 kao terapijskog modaliteta u lečenju humanog karcinoma dojke.Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, IL-RL1, ST2) signaling pathway promotes mammary cancer growth and metastasis by inhibiting anti-tumor immunity. IL-33 is dual function protein with roles as a nuclear factor and a classical cytokine and functions as a prototypic „alarmin”. Necrotic cells release immunoregulatory cytokines, including IL-33, a member of the IL-1 family of cytokines. Previous studies suggest that IL-33 directly facilitated vascular endothelial growth factor (VEGF) expression and secretion in primed mast and showed proangiogenic role of IL-33 by inducing endothelial proangiogenic activity via IL-33R expressed on endothelial cells.However, the role of IL-33/IL-33R axis in neoangiogenesis and tumor necrosis is not elucidated. Therefore, the aim of this study was to investigate the role of IL-33/IL-33R axis in mammary tumor necrosis and angiogenesis. Deletion of IL-33R gene in BALB/c mice enhanced tumor necrosis and attenuated tumor growth in 4T1 breast cancer model, which was associated with markedly decreased expression of VEGF and IL-33 in mammary tumor cells. IL-33 expression in mammary tumor cells significantly increased over time in IL-33R+ /+ mice, but not in IL-33R-/- mice the findings that reflect positive feedback mechanism in IL-33/IL-33R axis We next analyzed IL-33, IL-33R and VEGF expression and microvascular density (MVD) in breast tumors from 40 female patients with absent or present tumor necrosis. We found significantly higher expression of IL-33, IL-33R and VEGF in breast cancer tissues with absent tumor necrosis. Both, IL-33 and IL-33R expression correlated with VEGF expression in tumor cells. Further, VEGF expression positively correlated with MVD in perinecrotic zone. IL-33 is very much like IL-1 in that both IL-1β and IL-33 are proangiogenic and control the production of VEGF. IL-1β increases expression of VEGF and its receptors on endothelial cells and acts together with VEGF in promoting tumor mediated angiogenesis. Thus, the neutralization of IL-1β reduced tumor growth and the tumor-induced angiogenesis. As IL-1 and IL- 33 both use IL-1R3 (IL-1RAcP), it may be speculated that anti-IL-1R3 antibodies may reduce angiogenesis and increase tumor necrosis in breast cancer due to loss of vascular supply. On the basis of these observations we suggest that IL-33 released by necrotic cells may facilitate VEGF expression on nearby tumor cells, which could lead to enhanced angiogenesis as demonstrated by high-grade MVD in perinecrotic zone in human breast cancer tissue. Taking together, our data indicate that IL-33/IL-33R pathway is critically involved in mammary tumor growth by facilitating expression of pro-angiogenic VEGF in tumor cells and attenuating tumor necrosis. Additionally, results indicate oposite functions of intracellular and secreted IL-33. Thus, this study revealed an additional mechanism by which IL-33/IL-33R pathway may be involved in tumorigenesis and provide rationale for blocking IL-33 as a therapeutic modality in human breast carcinoma

Influence of picosecond laser irradiation on nickel-based superalloy surface microstructure

The investigation presented in this paper was carried out on the nickel-based superalloy, Nimonic 263, a material widely used at elevated temperatures and pressures. The samples were exposed to a Nd3+:YAG pulsed laser, at a wavelength of 1064 nm and a pulse duration of 170 ps, and the estimated threshold damage was 2 mJ. Different pulse energies and numbers of pulses were applied in air and helium-enriched atmospheres. Spots obtained by the laser interaction with the material were observed by optical and scanning electron microscopes and analyzed by energy-dispersive spectroscopy. Vickers microhardness tests were performed. In this paper, the changes that had occurred at the sample surface microstructure as a result of laser-material interaction are discussed with the aim of contributing to the determination of optimal laser parameters in the laser surface treatment process.3rd International School and Conference on Photonics, Aug 29-Sep 02, 2011, Belgrade, Serbi

Influence of picosecond laser irradiation on nickel base superalloy surface microstructure

III International School and Conference on Photonics : PHOTONICA2011 : book of abstracts; August 29- September 2, 2011; Belgrad

Influence of Picosecond Laser Pulses on the Microstructure of Austenitic Materials

We investigate samples of austenitic materials - stainless steel and iron-based superalloy - which are widely used at high temperatures and pressures. The samples were exposed to Nd(3+):YAG laser pulses with a wavelength of 1064 nm and a pulse duration of 170 ps. We employ different pulse energies and number of pulses. The spots appearing after the laser irradiation were examined by optical and scanning electron microscopy and analyzed by energy-dispersive spectroscopy. We also perform Vickers microhardness tests. We discuss the microstructure changes caused by different energy and number of pulses in air and in a He-enriched atmosphere with the aim to determine optimum laser parameters in surface-treatment technology

Potential drug-drug interactions among patients with spontaneous intracerebral hemorrhage treated at the Neurological Intensive Care Unit: a single-center experience

Our aim was to determine the prevalence of potential drug-drug interactions (pDDIs) and to identify relevant factors associated with the occurrence of the most dangerous or contraindicated pDDIs (pCDDIs) in hospitalized patients with spontaneous intracerebral hemorrhage (sICH). A retrospective cross-sectional study was performed enrolling all consecutive patients with sICH treated at the Neurological Intensive Care Unit, Clinical Center in Kragujevac, Serbia, during the three-year period (2012-2014). The inclusion criteria encompassed patients aged 18 years and over, those diagnosed with ICH, and those prescribed at least two drugs during hospitalization, while we did not include patients whose hospitalization lasted less than 7 days, those who were diagnosed with other neurological diseases and patients with incomplete medical files. For each day of hospitalization, the online checker Micromedex® software was used to identify pDDIs and classify them according to severity. A total of 110 participants were analysed. A high prevalence of pDDIs (98.2%) was observed. The median number of pDDIs regardless of severity, was 8.00 (IQR 4.75-13.00;1-30). The pairs of drugs involving cardiovascular medicines were the most commonly identified pDDIs. Twenty percent of the total number of participants was exposed to pCDDIs. The use of multiple drugs from different pharmacological-chemical subgroups and the prescribing of anticoagulant therapy significantly increase the chance of pCDDI (aOR with 95% CI 1.19 (1.05-1.35) and 7.40 (1.13-48.96), respectively). This study indicates a high prevalence of pDDIs and pCDDIs in patients with sICH. The use of anticoagulant therapy appears to be the only modifiable clinically relevant predictor of pCDDIs

Synovial sarcoma of carotid space

Synovial sarcomas are malignant tumors of mesenchymal origin, extremely rarely located in the area of the head and neck. Histologically they can be monophasic, biphasic or poorly differentiated with numerous differential diagnostic dilemmas. A 54-year-old male with synovial sarcoma of the carotid space is presented. The patient refused suggested postoperative radiotherapy and, nine months after the primary surgery, local relapse was verified. Following surgical resection of the local relapse, postoperative radiotherapy treatment was utilized. Ten months after the second surgery, secondary deposits in the lungs were radiographically confirmed, and local recurrence was noticed again. Treatment was continued with symptomatic therapy and eleven months later patient died. Synovial sarcomas of the carotid space are extremely rare, with complex surgical approaches and pathohistological differential diagnostic dilemmas. Diagnosis requires determination of the immunophenotype of the tumor cells, whereas therapy requires an aggressive surgical approach and postoperative radiotherapy

Hypercalcemic type of small cell carcinoma of the ovary

Introduction. Extrapulmonary small cell carcinoma is a rare, prognostically bad tumor category. Primary, it can be localized in every organ, even in the ovary, where, due to its clinical specificities, it represents a challenge in diagnosis, as well as in therapy. Small cell ovarian carcinoma (SCOC) is biologically very aggressive malignant tumor of unknown histogenesis. We presented a rare case of SCOC with hypercalcemia of aggressive course and fatal outcome in a postmenopausal woman at International Federation of Gynecology and Obstetrics (FIGO) Ia stage. Case report. A 60-year-old woman, Caucasian, came to the doctor because of discomfort in the lower abdomen and pain of greater intensity in last few days. Ultrasound examination and CT scan of the abdomen confirmed the presence of large adnexal masses of cystic-solid appearance with the largest diameter of 13 cm, regular structure of the other gynecological organs, without verifying the existence of metastatic deposits. All the results of laboratory analysis gave normal values, except for calcium, which was elevated. Explorative laparotomy with complete hysterectomy, bilateral salpingo-oophorectomy, dissection of lymph nodes and omentectomy were conducted. Based on pathohistological analysis of the operative material, SCOC at FIGO Ia stage was diagnosed. No complications were observed in a postsurgery period and after 10 days the patient was discharged in a good condition and with normal calcemia. The treatment was continued with concurrent radiotherapy and chemotherapy. However, in spite of overall treatment, the disease progressed, and the patient died of disseminated metastatic disease, 26 months after the diagnosis. Conclusion. Small cell carcinoma localized in the ovary is generally a tumor category with bad prognosis depending on the stage of the disease

Translation to Serbian, cultural adaptation, reliability testing and validation of the questionnaire estimating the fear of injections

Background/Aim. The two-part questionnaire called Injection Phobia Scale (IPS)-Anxiety and IPS-Avoidance represents one of the most commonly used questionnaires for assessing the fear of injections. The aim of the present study was to translate and culturally adapt this questionnaire from English into Serbian as well as to assess reliability and validity of the translation. Methods. The translation and cultural adaptation of the IPS–Anxiety and IPS–Avoidance was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Reliability testing, factor analysis and validation of Serbian translation of IPS-Anxiety and IPS-Avoidance were carried out on a sample of 485 students of pharmacy, or medicine at the University of Kragujevac, Serbia. Results. Serbian translation of IPS-Anxiety and IPSAvoidance demonstrated high internal consistency with Cronbach’s alpha of 0.934 for IPS-Anxiety and 0.911 for IPS-Avoidance. Factor analysis of IPS-Anxiety showed that there are two domains, which we have called as Direct Experience (9 items) and Indirect Experience (9 items); factor analysis of IPS-Avoidance also pointed out on two domains referring to direct and indirect fear of injections. Female students scored higher on the scale showing more extensive injection phobia than male students. It is also interesting that students of pharmacy have higher level of injection phobia than students of medicine, and those students of the fifth year of study feel more fear of injections than students from the first four years. Conclusion. Serbian translation of IPS-Anxiety and IPS-Avoidance showed good psychometric properties on population consisted of students medicine and pharmacy. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175007