Kamelija Zarkovic

Klinički Bolnički Centar Split, Spalato, Splitsko-Dalmatinska, Croatia

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Publications (79)176.84 Total impact

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    ABSTRACT: Chronic exposure to ultraviolet (UV) radiations causes oxidative stress, which is involved in photoaging and actinic elastosis. UV and reactive oxygen species generate lipid peroxidation products, including the α,β-unsaturated carbonyl compounds such as acrolein or 4-hydroxynonenal (4-HNE). These aldehydes can modify proteins of the extracellular matrix, but their role in the pathogenesis of photoaging is not clarified. The aim of this study was to investigate whether these aldehydes contribute to alter elastin metabolism and whether topical carbonyl scavengers delay UV-induced skin photoaging. Hairless mice (4-6 weeks old) daily exposed to UV-A (20 Joules/cm(2)/day, up to 600 Joules/cm(2)) exhibited the typical features of photoaging, associated with a significant increase in 4-HNE- and acrolein-adduct content and elastotic material deposition. Immunofluorescence studies showed the accumulation of 4-HNE-adducts on elastin in the dermis of UV-A-exposed mice. This was mimicked in vitro by incubating orcein-elastin with 4-HNE or acrolein, which altered its digestion by leukocyte-elastase, a feature possibly involved in the accumulation of elastotic material. A daily topical application of carnosine completely reversed the development of photoaging alterations, and 4-HNE-adduct formation on elastin. These data emphasize the role of 4-HNE and acrolein in the mechanism of photoaging, and the preventive effect of carbonyl scavengers.Journal of Investigative Dermatology accepted article preview online, 04 March 2015. doi:10.1038/jid.2015.84.
    Journal of Investigative Dermatology 03/2015; 135(7). DOI:10.1038/jid.2015.84 · 6.37 Impact Factor
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    ABSTRACT: Vascular endothelial cell (VEC) senescence is considered an early event in the development of atherosclerotic lesions. Stressful stimuli, in particular oxidative stress, have been linked to premature senescence in the vasculature. Foam cells are a major source of reactive oxygen species and may play a role in the induction of VEC senescence; hence, we investigated their involvement in the induction of VEC senescence in a co-culture transwell system. Primary bovine aortic endothelial cells, exposed to the secretome of THP-1 monocyte-derived foam cells, were analysed for the induction of senescence. Senescence associated b-galactosidase activity and the expression of p16 and p21 were increased, whereas phosphorylated retinoblastoma protein was reduced. This senescent phenotype was mediated by 4-hydroxnonenal (4-HNE), a lipid per-oxidation product secreted from foam cells; scavenging of 4-HNE in the co-culture medium blunted this effect. Furthermore, both foam cells and 4-HNE increased the expression of the pro-oxidant thioredoxin-interacting protein (TXNIP). Molecular manipulation of TXNIP expression confirmed its involvement in foam cell-induced senescence. Previous studies showed that peroxisome proliferator-activated receptor (PPAR)d was activated by 4-hydroalkenals, such as 4-HNE. Pharmacological interventions supported the involvement of the 4-HNE-PPARd axis in the induction of TXNIP and VEC senescence. The association of TXNIP with VEC senescence was further supported by immunofluorescent staining of human carotid plaques in which the expression of both TXNIP and p21 was augmented in endothelial cells. Collectively, these findings suggest that foam cell-released 4-HNE activates PPARd in VEC, leading to increased TXNIP expression and consequently to senescence. Keywords: atherosclerosis senescence foam cells VEC 4-HNE PPARd TXNIP
    Journal of Cellular and Molecular Medicine 01/2015; · 3.70 Impact Factor
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    ABSTRACT: Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by 4-HNE. These data indicate a complex role for lipid peroxidation and in particular for 4-HNE in elastin homeostasis, in the vascular wall remodeling during aging and atherosclerosis development.
    12/2014; 50. DOI:10.1016/j.redox.2014.12.008
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    ABSTRACT: In Ethiopians, like in other Africans, the incidence of otosclerosis is lower than in Western and Asian populations. Unfortunately, due to the lack of available otorhinolaryngology specialists many patients are not treated and suffer the progression of the disease and severe hearing loss. This program of the Global ENT Outreach Organization (GEO) together with the Ethiopian partners was done to help some of these patients and in parallel to evaluate the presence of the oxidative stress bioactive marker 4-hydroxynonenal (HNE), which is known as major lipid peroxidation product and the second messenger of free radicals, in the otosclerotic bone specimens. Namely, we described recently that as HNE acts as a bone growth regulator associated with pathogenesis of otosclerosis. The prospective study conducted at the ENT Department of the Migbare Senay General Hospital, Addis Ababa, Ethiopia in June 2012, under the auspices of the Global ENT Outreach Organization, USA. Altogether 36 patients (male = 12, female = 24) underwent surgery due to the previous otosclerosis diagnosis based on the clinical and audiometric findings. The bone samples were harvested from patients with intraoperatively confirmed otosclerosis diagnosis. Immunohistochemistry for HNE-modified proteins was carried out on formalin-fixed paraffin-embedded specimens. The presence of HNE was found in almost all bone samples analyzed, without particular difference in the HNE distribution pattern between the otosclerotic and respective control bone specimens. Although there was no significant association between the HNE appearance and otosclerotic bone outgrowth observed, several cases have shown tendency of higher HNE expression in patients with more severe hearing loss. The results of the present study are in contrast with our previous findings obtained on European patients most likely due to the differences between studied population groups.
    Archiv für Klinische und Experimentelle Ohren- Nasen- und Kehlkopfheilkunde 09/2014; DOI:10.1007/s00405-014-3284-z · 1.61 Impact Factor
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    ABSTRACT: Abstract The prevalence of metabolic syndrome components including obesity, dyslipidemia, insulin resistance and hepatic steatosis is rapidly increasing in wealthy societies. It is accepted that inflammation/oxidative stress are involved in the initiation/evolution of the metabolic syndrome features. The present work was designed to evaluate the effects of three major cellular ROS production systems on obesity, glucose tolerance and hepatic steatosis development and on oxidative stress onset. To do so, forty young male Sprague Dawley rats were divided into 5 groups: 1-control group, 2-high fat (HF) group (60% energy from fat), 3-HF+MitoQ (mitochondrial ROS scavenger), 4-HF+Apocynin (NADPH oxidase inhibitor), 5-HF+Allopurinol (xanthine oxidase inhibitor). After 8 weeks of these treatments, surrogate metabolic syndrome, mitochondrial function and oxidative stress markers were measured in blood and liver. As expected, rats fed the high fat diet exhibited increased body weight, glucose intolerance, overt hepatic steatosis and increased hepatic oxidative stress. The impacts of the studied ROS inhibitors on these aspects of the metabolic syndrome were markedly different. MitoQ showed the most clinically relevant effects, attenuating body weight gain and glucose intolerance provoked by the HF diet. Both Apocynin and Allopurinol showed limited effects suggesting secondary roles of xanthine oxidase or NADPH oxidase-dependent ROS production in the onset of oxidative stress-dependent obesity, glucose intolerance and hepatic steatosis process. Thus, MitoQ revealed the central role of mitochondrial oxidative stress in the development of metabolic syndrome and suggested that mitochondria-targeted antioxidants may be worth considering as potentially helpful therapies for metabolic syndrome features.
    Free Radical Research 07/2014; DOI:10.3109/10715762.2014.945079 · 2.99 Impact Factor
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    ABSTRACT: Elastin is a long-life protein and a key-component of connective tissues. The tissular elastin content decreases during chronological aging, and the mechanisms underlying its slow repair are not known. Lipid oxidation products that accumulate in aged tissues may generate protein dysfunction. We hypothesized that 4-hydroxynonenal (4-HNE), a highly reactive α,β-aldehydic product generated from polyunsaturated fatty acid peroxidation, could contribute to inhibit elastin repair by antagonizing the elastogenic signalling of Transforming Growth Factor-β1 (TGF-β1) in skin fibroblasts. We report that low 4-HNE concentration (2µmol/L), inhibits the upregulation of tropoelastin expression stimulated by TGF-β1, in human and murine fibroblasts. The study of signaling pathways potentially involved in the regulation of elastin expression, showed that 4-HNE did not block the phosphorylation of Smad3, an early step of TGF-β1 signaling, but inhibited the nuclear translocation of Smad2. Concomitantly, 4-HNE modified and stimulated the phosphorylation of the Epidermal Growth Factor receptor (EGFR) and subsequently ERK1/2 activation, leading to the phosphorylation/stabilization of the Smad transcriptional corepressor TGIF, which antagonizes TGF-β1 signaling. Inhibitors of EGFR (AG1478), Mek/ERK (PD98059), EGFR-specific siRNAs, reversed the inhibitory effect of 4-HNE on TGF-β1-induced nuclear translocation of Smad2 and tropoelastin synthesis. In vivo studies on aortas from aged C57BL/6 mice, showed that EGFR is modified by 4-HNE, in correlation with an increased 4-HNE-adduct accumulation and decreased elastin content. Altogether, these data suggest that 4-HNE inhibits the elastogenic activity of TGF-β1, by modifying and activating the EGFR/ERK/TGIF pathway, which may contribute to alter elastin repair in chronological aging and oxidative stress-associated aging processes.
    Free Radical Biology and Medicine 02/2014; 71. DOI:10.1016/j.freeradbiomed.2014.02.015 · 5.71 Impact Factor
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    Free Radical Biology and Medicine 09/2013; 65:S14-S15. DOI:10.1016/j.freeradbiomed.2013.08.139 · 5.71 Impact Factor
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    ABSTRACT: Despite huge advances in medicine, glioblastoma multiforme (GBM) remains a highly lethal, fast-growing tumour that cannot be cured by currently available therapies. However, extracranial and extraneural dissemination of GBM is extremely rare, but is being recognised in different imaging studies. To date, the cause of the GBM metastatic spread still remains under discussion. It probably develops at the time of intracranial progression following a surgical procedure. According to other hypothesis, the metastases are a consequence of spontaneous tumour transdural extension or haematogenous dissemination. We present a case of a 59-year-old woman with symptomatic leptomeningeal and intramedullary metastases of GBM who has been previously surgically treated with primary subtotal resection and underwent a repeated surgery during adjuvant radiotherapy and chemotherapy with temozolomide. Today, the main goal of surgery and chemoradiotherapy is to prevent neurologic deterioration and improve health-related quality of life. With this paper, we want to present this rare entity and emphasise the importance of a multidisciplinary approach, a key function in the management of brain tumour patients. The prognosis is still very poor although prolongation of survival can be obtained. Finally, although rare, our case strongly suggests that clinicians should be familiar with the possibility of the extracranial spread of GBM because as treatment improvements provide better control of the primary tumour and improving survival, metastatic disease will be increasingly encountered.
    World Journal of Surgical Oncology 03/2013; 11:55. DOI:10.1186/1477-7819-11-55 · 1.20 Impact Factor
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    ABSTRACT: There is growing body of evidence that oxidative stress, i.e. excess in production of reactive oxygen species, can lead to covalent modification of proteins with bioactive aldehydes that are mostly produced under lipid peroxidation of polyunsaturated fatty acids. Thus generated reactive aldehydes are considered as second messengers of free radicals because they react with major bioactive macromolecules, in particular with various humoral and cellular proteins changing their structure and functions. Therefore, the aldehydic-protein adducts, in particular those involving 4-hydroxy-2-nonenal, malondialdehyde and acrolein can be valuable biomarkers of numerous pathophysiological processes. The development of immunochemical methods is increasing the possibilities to study such non-enzymatic protein modifications, on the one hand, while on the other hand the increase of knowledge on bioactivities of the aldehydes and their protein adducts might lead to better prevention, diagnosis and treatments of pathophysiological processes associated with lipid peroxidation and oxidative stress in general. This article is part of a Special Issue entitled: Protein Modifications.
    Journal of proteomics 02/2013; DOI:10.1016/j.jprot.2013.02.004 · 3.93 Impact Factor
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    ABSTRACT: Otosclerosis is a complex disease characterized by an abnormal bone turnover of the otic capsule resulting in conductive hearing loss. Recent findings have shown that Angiotensin II (Ang II), a major effector peptide of the renin-angiotensin system, plays important role in pathophysiology of otosclerosis, most likely by its pro-inflammatory effects on the bone cells. Since reactive oxygen species play a role both in inflammation and in cellular signalling pathway of Ang II, the appearance of the "second messenger of free radicals" the aldehyde 4-hydroxynonenal (HNE) protein adducts in otosclerotic bone has been analysed. Immunohistochemical analysis of HNE-modified proteins on tissue samples of the stapedial bones performed on 15 otosclerotic patients and 6 controls, revealed regular HNE-protein adducts presence in the subperiosteal parts of control bone specimens, while irregular areas of the pronounced HNE-protein adducts presence were found within stapedial bone in case of otosclerosis. To study possible interference of HNE and Ang II in human bone cell proliferation, differentiation and induction of apoptosis we used an in vitro model of osteoblast-like cells. HNE interacted with Ang II in a dose-dependent manner, both by forming HNE-Ang II adducts, as revealed by immunoblotting, and by modification of effects on cultured cells. Namely, treatment with 0.1nM Ang II and 2.5μM HNE stimulated proliferation, while treatment with 10μM HNE or in combination with Ang II (0.1, 0.5 and 1nM) decreased cell proliferation. Moreover, 10μM HNE alone and with Ang II (except if 1nM Ang II was used) increased cellular differentiation and apoptosis. HNE 5μM did not affect differentiation or significantly changed apoptosis. On the other hand, when cells were treated with lower concentrations of HNE and Ang II we have observed decrease in cellular differentiation (combination of 1.0 or 2.5μM HNE with 0.1nM Ang II) and decrease in apoptosis (0.1 and 0.5nM Ang II). Cellular necrosis was increased with 5 and 10μM HNE if given alone or combined with Ang II, while 0.5nM Ang II and combination of 1μM HNE with Ang II (0.1 and 0.5nM) reduced necrosis. These results indicate that HNE and Ang II might act mutually dependent in regulation of the bone cell growth and in pathophysiology of otosclerosis.
    Free Radical Biology and Medicine 12/2012; 57. DOI:10.1016/j.freeradbiomed.2012.11.023 · 5.71 Impact Factor
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    ABSTRACT: The involvement of granulocytes in immune response against cancer is not well understood. Depending on the cytokine milieu in which they act and on their oxidative burst, granulocytes may play either an inhibitory or stimulatory role in tumour growth. Unsaturated fatty acids, essential components of cellular membranes and storage lipids, are susceptible to granulocyte-derived reactive oxygen species (ROS). ROS can induce lipid peroxidation (LPO) resulting in the destruction of biomembranes. Thus, murine W256 tumour progressing and tumour regressing animal models were used to study the involvement of plasma inflammatory mediators and oxidative burst of circulating granulocytes in malignant destruction and detrimental tumour growth. The involvement of LPO-derived aldehydes (i.e. acrolein, 4-hydroxy-2-nonenal and malondialdehyde) and myeloperoxidase (MPO) appearance in the granulocyte anti-cancer response were further evaluated. The results obtained revealed a significant increase in neutrophil elastase in animals with regressing tumour. Furthermore, the presence of MPO in tumour microenvironment was accompanied by the formation of acrolein only 5 h after tumour transplantation and its presence increased during tumour regression. Later, at an early stage of tumour regression, the presence of other LPO-derived aldehydes were also observed. The results obtained suggest that elevated neutrophil elastase and initiation of LPO may play an important role in the tumour development leading to tumour regression.
    Clinical & Experimental Immunology 11/2012; 170(2):178-85. DOI:10.1111/j.1365-2249.2012.04639.x · 3.28 Impact Factor
  • Clinical neurology and neurosurgery 10/2012; 115(7). DOI:10.1016/j.clineuro.2012.09.018 · 1.25 Impact Factor
  • The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 09/2012; 39(5):689-90. · 1.60 Impact Factor
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    ABSTRACT: PET/CT is starting to play an important role in evaluating fever of unknown origin (FUO), due to its ability to localize and delineate areas of high metabolic activity, such as neoplastic proliferation and inflammation, including vasculitis. We present a case of giant cell arteritis (GCA) in a 72-year-old female patient admitted to our department with a 4-month history of FUO, weight loss and fatigue, without specific symptoms or signs. Laboratory investigations suggested acute phase response, with a pronounced erythrocyte sedimentation rate, high CRP level and microcytic anemia. A thorough diagnostic evaluation was performed to exclude an unknown primary tumor, which was initially suspected due to a positive family history of cancer. Surprisingly, PET/CT revealed large vessel vasculitis affecting the ascending, descending and abdominal aorta, as well as subclavian, proximal brachial and carotid arteries bilaterally. Biopsy of the superficial temporal artery confirmed the diagnosis of GCA. Treatment with methylprednisolone and azathioprine led to resolution of clinical symptoms and normalization of laboratory parameters. In addition to the use of PET/CT in the evaluation of FUO, its value as a method complementary to temporal artery biopsy is also discussed.
    Rheumatology International 03/2012; 33(9). DOI:10.1007/s00296-012-2425-1 · 1.63 Impact Factor
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    ABSTRACT: Primary spinal melanomas are extremely rare lesions. In 1906, Hirschberg reported the first primary spinal melanoma, and since then only 40 new cases have been reported. A 47-year-old man was admitted suffering from low back pain, fatigue and loss of body weight persisting for three months. He had a 17-year-old history of an operated primary spinal melanoma from T7-T9, which had remained stable for these 17 years. Routine laboratory findings and clinical symptoms aroused suspicion of a metastatic disease. Multislice computed tomography and magnetic resonance imaging revealed stage-IV melanoma with thoracic, abdominal and skeletal metastases without the recurrence of the primary process. Transiliac crest core bone biopsy confirmed the diagnosis of metastatic melanoma. It is important to know that in all cases of back ore skeletal pain and unexplained weight loss, malignancy must always be considered in the differential diagnosis, especially in the subjects with a positive medical history. Patients who have back, skeletal, or joint pain that is unresponsive to a few weeks of conservative treatment or have known risk factors with or without serious etiology, are candidates for imaging studies. The present case demonstrates that complete surgical resection alone may result in a favourable outcome, but regular medical follow-up for an extended period, with the purpose of an early detection of a metastatic disease, is highly recommended.
    World Journal of Surgical Oncology 11/2011; 9:150. DOI:10.1186/1477-7819-9-150 · 1.20 Impact Factor
  • The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 09/2011; 38(5):774-6. · 1.60 Impact Factor
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    ABSTRACT: Trimethyltin (TMT), an organotin compound considered a useful tool to obtain an experimental model of neurodegeneration, exhibits neurotoxicant effects selectively localised in the limbic system and especially in the hippocampus, which are different in the rat and in mice. In the rat hippocampus, we investigated the expression of aldehyde 4-hydroxynonenal, a major bioactive marker of membrane lipid peroxidation, heat shock protein (HSP) 110/105 family members, markers of oxidative stress, and the neuroinflammatory marker cyclooxygenase-2 after TMT-intoxication at various time points after treatment. Our data show that TMT-induced neurodegeneration in the rat hippocampus is associated specifically with oxidative stress and lipid peroxidation, but not with HSP expression, indicating species-specific differences in the neurotoxicity of TMT between rats and mice.
    Neurochemical Research 06/2011; 36(8):1490-500. DOI:10.1007/s11064-011-0478-2 · 2.55 Impact Factor
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    ABSTRACT: Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 μg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 μg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen.
    European journal of pharmacology 05/2011; 667(1-3):322-9. DOI:10.1016/j.ejphar.2011.05.038 · 2.68 Impact Factor
  • Central European neurosurgery 05/2011; 72(2):104-6. DOI:10.1055/s-0030-1253411 · 0.87 Impact Factor
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    ABSTRACT: The increased expression of c-myc is related to neoplastic transformation and angiogenesis. Therefore, the assessment of expression of c-myc in endothelial cells and neovascularization could help to determine the biological behavior of the tumor. We analyzed neovascularization and c-myc expression in 36 medulloblastoma specimens. The results were shown by determining immunohistochemical staining index (ISI), the sum of staining intensity (SI) and the percentage of positive cells (PPC) in the blood vessels endothelium of the tumor. We also performed the microvessel count (MVC) in 10 high-power fields (400X) with the most prominent vascularization and expressed it as microvessel density per mm2 (MVD). C-myc immunostaining intensity index in blood vessel endothelium is grouped into four groups, 0--no reaction, I-weak reaction (ISI = 1 or 2), II--moderate reaction (ISI = 3 or 4), III--strong reaction (ISI = 5 or 6). Statistically significant differences (p = 0.0214) have been found between groups 0 and 1 compared to groups 2 and 3. A higher percentage of positive cells has been found in male patients than in female ones (p = 0.0483). C-myc PPC 0 or 1 has on the average smaller density of blood vessels per mm2 than c-myc PPC 2 or 3, but the difference is not statistically significant. C-myc ISI 0 or 1 has, on the average, smaller density of blood vessels per mm2 than c-myc ISI 2 or 3, but the difference is not statistically significant. We concluded that c-myc staining intensity was associated with higher microvessels density.
    Collegium antropologicum 03/2011; 35(1):39-42. · 0.61 Impact Factor

Publication Stats

1k Citations
176.84 Total Impact Points

Institutions

  • 2009–2015
    • Klinički Bolnički Centar Split
      Spalato, Splitsko-Dalmatinska, Croatia
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1995–2015
    • University of Zagreb
      • • Department of Pathology
      • • Department of Pharmacology
      Zagrabia, Grad Zagreb, Croatia
  • 2013
    • University Hospital Centre Zagreb
      • Department of Pathology and Cytology
      Zagrabia, Grad Zagreb, Croatia
  • 2011
    • Hackensack University Medical Center
      Хакенсак, New Jersey, United States
  • 2010
    • General Hospital Dubrovnik
      Ragusa, Dubrovačko-Neretvanska, Croatia
  • 2001
    • KBC Osijek
      Osik, Osječko-Baranjska, Croatia
    • Karl-Franzens-Universität Graz
      Gratz, Styria, Austria
  • 2000
    • University Clinical Hospital Center "Sestre Milosrdnice"
      Zagrabia, Grad Zagreb, Croatia