Nives Jonjić

University of Rijeka

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Ksenija Lučin

University of Rijeka

Toni Valković

University of Rijeka

SŠ

Sanja Štifter

Aarhus University Hospital

Koviljka Matušan‐Ilijaš

University of Rijeka

Ita Hadžisejdić

University of Rijeka

Elvira Mustać

University of Rijeka

Emina Babarović

University of Rijeka

Blaženka Grahovac

University of Rijeka

Irena Seili‐Bekafigo

University of Rijeka

Antica Duletić‐Načinović

University of Rijeka

Cooperative Institutions

University of Rijeka

248

University Hospital Centre Zagreb

151

Klinički Bolnički Centar Rijeka

127

University of Zagreb

Istituti di Ricovero e Cura a Carattere Scientifico

University of Milan

Sisters of Charity Hospital

University of Split

Humanitas University

Mario Negri Institute for Pharmacological Research

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Perforin expression in skin lesions of psoriatic patients

Larisa Prpić Massari Marija Kaštelan Franjo Gruber Gordana Zamolo Nives Jonjić

Psoriasis is T cell mediated autoimmune skin disease characterized by infiltration of inflammatory cells, especially T lymphocytes and production of inflammatory cytokines, mostly of Th1 type. Oscillations in phenotype of T lymphocytes are observed in peripheral blood (PB) and skin lesions, depending on stage of disease. CD4+ T cell predominance in exacerbated psoriatic plaques and CD8+ T cells in resolutive lesions are demonstrated. Cell mediated cytotoxicity reactions (CMC) are reactions mediated by secretion of cytolytic molecule perforin and granzyme or binding of FasL (CD95L) with Fas receptor (CD95) on target cell. CD8+ T lymphocytes and to a certain degree CD4+ T lymphocytes as well as NK cells mediate in CMC. Perforin (P) is cytolytic molecule expressed in the granules of cytolytic cells both CTL and NK cells, released in the contact with the target cells subsequently exerting either necrotic or apoptotic (in collaborations with serine esterases) cell death. Our former results point on participation of cytolytic mechanisms in immunopathogenesis of psoriasis. Perforin expression is upregulated in peripheral blood T lymphocytes (especially CD8 phenotype) and CD56+ NK cells in exacerbation phase of psoriasis vulgaris compared to remission. Thus, role of cytolytic pathway mediated by perforin is recognized in psoriasis in PBL and in lesions but still insufficiently defined. The aim of our new investigation was to analyze expression of perforin in the psoriatic skin lesions and highlight a role of perforin mediated cytotoxicity in pathophysiology of disease. Skin biopsies of eight psoriatic patients, four in exacerbation and four in remission phase of psoriasis vulgaris were investigated. They were obtained from inside border of stable plaque (in a case of remission) and newly exacerbating plaque (exacerbating phase) and from uninvolved skin of the same patients biopsied at least 3 cm away of affected skin. Single immunoenzyme staining was performed using biotin-streptavidin-peroxidase method. Our preliminary results showed stronger perforin expression in involved psoriatic skin in exacerbating phase compared to remission. The same tendency of increasing number of cells in exacerbation phase was noticed among CD56+ NK population. These results point on the potential role of cytolytic mechanisms mediated by perforin compared to remission of disease.

Granzyme

Granzyme A

Fas ligand

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C124 NK cell immunohistochemistry – a new prognostic marker of bladder cancer recurrence?

European Urology Supplements (2009)

Kristian Krpina Emina Sinožić Gordana Djordjević Nives Jonjić Željko Fučkar

10.1016/s1569-9056(09)75149-8

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Pretreatment Serum Levelof Osteopontin and Vascular Endothelial Growth Factor Might Have a Prognostic Value in Patients with diffuse Large B-Cell Lymphoma

Antica Duletić Načinović Tajana Juranovic Toni Valković Duška Petranović Ivan Host

Osteopontin

Value (mathematics)

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Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-κB in Renal Cell Tumors

Croatian Medical Journal (2008)

Gordana Đorđević Koviljka Matušan‐Ilijaš Emina Sinožić Giuseppe Damante Dora Fabbro

AimTo assess the relationship between protein and messenger RNA (mRNA) levels of vascular endothelial growth factor (VEGF) and subcellular localization of nuclear factor-kappa B (NF-κB), proliferation rate of tumor cells, and clinicopathological characteristics of renal cell tumors.MethodsWe analyzed 31 one renal cell tumors – 22 clear cell renal cell carcinomas (CCRCC) and 9 other histologic types (non-CCRCC). VEGF expression and subcellular localization of p65 member of NF-κB and Ki67 were immunohistochemically evaluated for the proliferation rate of tumor cells. Expression of VEGF mRNA was assessed using quantitative real-time polymerase chain reaction after total RNA extraction from snap-frozen tumor tissue samples.ResultsCytoplasmic localization of VEGF protein in renal cell tumors showed a perimembranous and diffuse pattern, the former being more evident in CCRCC (27.1 ± 18.9 vs 3.3 ± 10 % tumors, P = 0.001) and the latter in non-CCRCC type (71.7 ± 23.2 vs 31.1 ± 22.1 % tumors, P < 0.001). Heterogeneity in VEGF gene expression was more pronounced in CCRCC type than in non-CCRCC type (P = 0.004). In addition, perimembranous VEGF pattern was associated with higher VEGF mRNA levels (P = 0.006) and diffuse VEGF pattern with lower VEGF mRNA levels (P < 0.001). Nuclear and cytoplasmic staining of NF-κB/p65 was observed in the majority of tumor cells. A significant association was recorded between cytoplasmic NK-κB/65 staining and VEGF staining of diffuse pattern (P = 0.026). Association between NF-κB/65 and proliferation rate of tumor cells was significant for cytoplasmic staining (P = 0.039) but not for nuclear NFkB/p65 staining (P = 0.099).ConclusionHigher but inhomogeneous expression of VEGF in tumor cells, especially in CCRCCs, is associated with NF-κB/65 activity. This indicates that both VEGF and NF-κB/65 may be important in renal carcinogenesis, representing a possible molecular target in the treatment of renal cell carcinoma.

10.3325/cmj.2008.5.608

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Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma

Virchows Archiv (2001)

Toni Valković Frane Dobrila Mauro Melato Franco Sasso Clara Rizzardi

Tumor progression

Lymphangiogenesis

Vascular permeability

10.1007/s004280100458

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Endothelial Growth Factor in Association with Clinical Parameters in Patients with Multiple Myeloma

Toni Valković Emina Babarović Merica Aralica Sanja Štifter Antica Duletić‐Načinović

Background: the role of osteopontin (OPN), glyco-phosphoprotein produced by variety of tissues, has been widely investigated in the progression of many solid tumors, but on the other side, there are not many studies performed in multiple myeloma (MM). The role of Vascular Endothelial Growth Factor (VEGF) in tumor angiogenesis, as well as in MM, has been extensively analysed, but the significance of its serum level is still not well recognize. The aim of the present study was to determine the serum levels of both above mentioned cytokines and compare their values with clinical parameters of myeloma patients. Methods: serum level of OPN and VEGF was determinated by ELISA in 44 newly-diagnosed, reviously untreated myeloma patients (21 men, 22 women ; median age of 69, range 44 – 86) and 24 age-matched healthy persons who consisted control group. The obtained values were correlated with main clinical parameters such as anaemia (hemoglobine value 20 g/L below the lower limit of normal), renal dysfunction (serum creatinine level above the uper limit of normal) and bone disease (any of lytic lesions or severe osteopenia with compressive fractures on standard radiographs of the bones). The level of cytokines were also correlated with serum beta-2 microglobulin as a prognostic factor related to biological behaviour of MM, and Durie-Salmon Staging System as a measure of tumor mass. Results: serum value of OPN was significantly higher in myeloma patients (median 6. 5, range 0. 3 – 21. 7) in compare to control group (medain 2. 4, range 0. 2 – 8. 9) (p<0. 0001), while these difference could not be observed with VEGF (52. 5 versus 60. 5) (p=0. 6673). Serum level of beta2-microglobuline was positively associated with value of OPN (p=0. 0461) but not with VEGF (p=0. 79). Patients with lower Durie-Salmon Stage had significantly lower both- OPN and VEGF serum levels (p=0. 0456, p=0, 0371 respectively). Higher OPN serum value was found in MM patients with evident bone lesions (p=0. 0268), while this difference was not observed with VEGF (p= 0. 7962). There was no correlation between serum levels of OPN and anaemia (p=0. 2991) or increased serum creatinine (p=0. 1338). VEGF serum level, also, did not correlated with anemia (p=0. 4309) and renal dysfunction (p=0. 5119). Conclusion: our preliminary results support the serum level of OPN as a dual marker of tumor aggressiveness and bone destrucion. On the contrary, present study did not confirm similar clinical value of VEGF serum level which represent a critical angiogenic factor in tumor micro-eco system. However, in our investigation both cytokines positively correlated with tumor burden. Further analysis with more included patient sholud provide definitive information about possible role of OPN as a useful clinical biomarker for monitoring of bone disease and tumor mass, as well as prognostic factor during course of disease.

Osteopontin

Osteopenia

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Identification of prognostic factors in diffuse large B-cell lymphoma (DLBCL)

Liječnički vjesnik (2007)

Antica Duletić‐Načinović Sanja Štifter Ksenija Lučin Toni Valković Duška Petranović

There is need to identify new biological parameters which could improve our understanding of NHL biology and predict the behaviour of the disease.Aim is to highlight the clinical significance of the proliferation rate, cell death and angiogenesis in DLBCL....

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Serum IL-6, IL-8, IL-10 and beta-2-microglobulin (β 2-M) in association with interanational prognostic index (IPI)in patients with diffuse large B cell lymphoma (DLBCL)

Liječnički vjesnik (2007)

Antica Duletić‐Načinović Sanja Štifter Ksenija Lučin Željka Škunca Toni Valković

The IPI, IL-6, IL-8, IL10 and β 2-M are associated with the outcome of DLBCL patients. Aim of this study was to determine wether those parameters combined with IPI would better stratify the DLBCL patients in predicting their prognosis....

Beta-2 microglobulin

International Prognostic Index

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Osteopontin Expression Correlates with Angiogenesis and Survival in Malignant Astrocytoma

Pathology & Oncology Research (2008)

Koviljka Matušan‐Ilijaš Senija Behrem Nives Jonjić Kamelija Žarković Ksenija Lučin

Osteopontin

Anaplastic astrocytoma

Microvessel

10.1007/s12253-008-9058-4

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Rare forms of systemic mastocytosis

Gorana Aralica Čedna Tomasović‐Lončarić Nives Jonjić Višnja Hariš Toni Valković

Unutar skupine sistemskih mastocitoza, dio cine one udružene s drugim klonalnim nemastocitnim hematoloskim bolestima. U literaturi je prateca neoplazma najcesce iz skupine MDS/MPN (CMML) te iz skupine MPNa (PMF i PV). U ovom izvjestaju prikazana su dva bolesnika s dijagnozama SM- MPN.

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