Daya simpan cumi-cumi dipengaruhi oleh aktivitas enzim katepsin yang menyebabkan kemunduran mutu cumi-cumi pada hari ke tiga setelah fase post rigor. Aktivitas inhibitor katepsin alami dari ikan ...patin berpotensi menghambat kemunduran mutu ikan jenis lain. Penelitian ini bertujuan untuk menganalisis senyawa inhibitor enzim katepsin dari kulit ikan patin terhadap kemunduran mutu cumi-cumi. Penelitian didesain dengan rancangan acak dengan pola dua faktorial. Faktor pertama adalah konsentrasi inhibitor enzim katepsin yang diekstrak dari kulit ikan patin, dengan empat variasi yaitu 1:0; 1:1; 2:3; dan 3:2. Faktor kedua adalah lama rendaman/inkubasi cumi-cumi pada fase post rigor selama 3, 7, dan 9 hari dalam ekstrak inhibitor. Setelah direndam, aktivitas enzim katepsin pada cumi-cumi diukur dengan metode spektrofotometri. Setelah didapatkan absorbansi maka aktivitas enzim dan persentase penghambatannya dihitung. Hasil uji Two Way Annova menunjukan bahwa konsentrasi berbeda nyata dengan peresentase penghambatan sedangkan lama penyimpanan tidak berbeda nyata dengan taraf kepercayaan 0,05. Konsentrasi kemudian diuji lanjut dengan Duncan dan konsentrasi yang paling efektif untuk menghambat aktivitas enzim adalah konsentrasi 3:2 dengan persentase penghambatan 57%.
Abstract
Objectives
Sulfonamide group is an important scaffold used for generating new building blocks with diverse biological activities. Considering priority of the sulfonamide structure, seven new ...sulfathiazole derivatives were synthesized and evaluated for their antiproliferative activity, in this study.
Materials and methods
Compounds
2a–g
were synthesized using a two-step synthetic procedure starting from commercially available sulfathiazole. The antiproliferative activity of the compounds was investigated against A549 and NIH/3T3 cell lines by MTT assay, matrix metalloproteinase-9 (MMP-9) and cathepsin inhibition tests.
Results
Compound
2b
bearing triazole ring exhibited highest inhibitory activity (IC
50
: 12.33 μg/mL) with selective profile which was better than cisplatin and it also inhibited MMP-9 with 53.67% percentage. Compounds
2c
and
2e
inhibited cathepsin L with percentages of 62.75 and 57.25%, whereas cathepsin D was poorly inhibited by the compounds.
Conclusions
Target compounds exhibited high to moderate antiproliferative activity and they displayed higher MMP-9 inhibition than cathepsin inhibition activity.
2b
and
2e
were identified as the most active compounds when evaluated, biologically.
Proses kemunduran mutu ikan dapat disebabkan oleh adanya aktivitas enzim terutama enzim proteolitik, salah satunya adalah katepsin yang merupakan kelompok protease sistein. Protease sistein merupakan ...kelompok enzim pendegradasi protein. Untuk mencegah terjadinya proteolisis yang destruktif yang berakibat pada besarnya losses ikan segar, inhibitor untuk katepsin sangat dibutuhkan. Tujuan penelitian ini adalah untuk mengetahui potensi kulit ikan patin Siam, Jambal, dan Pasupati sebagai sumber inhibitor katepsin, serta memekatkan dan mengkarakterisasi inhibitor katepsin yang diperoleh. Hasil penelitian menunjukkan bahwa ketiga jenis kulit ikan patin memiliki aktivitas penghambatan terhadap katepsin, tetapi yang memiliki penghambatan terbaik adalah yang berasal dari ikan patin jenis Siam dengan nilai persentase penghambatan sebesar 74,67%. Hal ini diduga karena kesesuaian substrat dengan inhibitornya Pemekatan menggunakan ammonium sulfat 70% menunjukkan adanya peningkatan aktivitas penghambatan spesifik sebesar 1,4479 U/mg dengan kelipatan pemurnian sebesar 2,77 kali. Inhibitor enzim katepsin tersebut secara optimum bekerja pada suhu 40 °C dan pH 8.
Cathepsin S (CTSS) is a cysteine protease involved in atherogenesis. We compared the plasma CTSS as well as other biomarkers of atherosclerosis in patients with abdominal aortic aneurysms (AAA) and ...aortoiliac occlusive disease (AOD), aiming to identify the underlying pathogenic mechanisms of the disease development. Also, we hypothesised that the level of plasma CTSS simultaneously increases with a decrease of plasma high-density lipoprotein cholesterol (HDL-C) values.
33 patients with AAA and 34 patients with AOD were included in this study.
There was no difference in the level of plasma CTSS between the two analysed groups (p=0.833). In the patients with AAA, the plasma CTSS was correlated with HDL-C (r = -0.377, p = 0.034) and total bilirubin (r =0.500, p = 0.003) while, unexpectedly, it was not correlated with cystatin C (Cys C) (r =0.083, p = 0.652). In the patients with AOD, the plasma CTSS correlated with triglycerides (r = 0.597, p< 0.001), only. When the patients were divided according to HDL-C (with HDL-C ≤0.90 and HDL-C >0.90 mmol/L), the plasma CTSS values differed among these groups (31.27
.25.61 μg/L, respectively, p<0.001).
These results provide the first evidence that CTSS negatively correlated with HDL-C and bilirubin in patients with AAA. It is possible that differences in the association of the CTSS and other markers of atherosclerosis can determine whether atherosclerotic aorta will develop dilatation or stenosis.
Background: High-density lipoproteins (HDL) have atheroprotective biological properties: antioxidative, anti-apoptotic, anti-inflammatory, and they have the efflux capacity of cellular cholesterol. ...Plasma mRNA analysis can be used to investigate statin pleiotropy in vivo as a new analytical tool for non-invasive assessment of gene expression in vascular beds. The aim of this study was to assess the pleiotropic effects of atorvastatin in stable angina patients with highrisk values (group A) as compared with patients who had borderline and desirable HDL-cholesterol (HDL-C) values (group B).
Methods: The atorvastatin therapy (20 mg/day) was given to forty-three patients with stable angina for 10 weeks. We investigated three statin pleiotropy-targeted genes: intercellular adhesion molecule-1, chemokine (C-C motif) ligand 2 and cathepsin S and assessed by gel electrophoresis gradient the effects of atorvastatin on HDL size and subclasses.
Results: In group A, after therapy, HDL-C concentration was significantly increased but not in group B. Atorvastatin lowered plasma chemokine (C-C motif) ligand 2 and intercellular adhesion molecule-1 mRNA levels in both groups, but did not change the plasma cathepsin S mRNA levels. In group A only, baseline total bilirubin showed negative cor relations with the genes of cathepsin S (r=-0.506; p=0.023) and significantly increased after therapy.
Conclusion: HDL-C and bilirubin can be promising therapeutic targets in the treatment of cardiovascular diseases. Analysis of cell-free mRNA in plasma might become a useful tool for estimating statin pleiotropy
Uvod: Lipoproteini velike gustine (HDL) imaju ateroprotektivne biološke osobine: antioksidativne, antiapoptotičke, antiinflamatorne kao i kapacitet da izvlače holesterol iz ćelija. Analiza plazmatske mRNA može da se koristi za ispitivanje plejotropnih efekata statina in vivo kao novo analitičko sredstvo za neinvazivnu procenu ekspresije gena u zidu krvnog suda. Cilj ove studije je bio da se procene plejotropni efekti atorvastatina kod pacijenata sa stabilnom anginom sa visokorizičnim vrednostima (grupa A) u odnosu na pacijente sa graničnim i poželjnim vrednostima HDL holesterola (HDL- C) (grupa B).
Metode: Četrdesettri pacijenta sa stabilnom anginom su primala terapiju atorvastatinom (20 mg/dan) 10 nedelja. Mi smo ispitivali tri gena značajna za plejotropno delovanje statina: intracelularni adhezioni molekul-1, hemokin (C-C motiv) ligand 2 i katepsin S i procenjivali smo efekte atorvastatina na veliCinu i raspodelu HDL subfrakcija promoću elektroforeze na poliakrilamidnom gradijent gelu.
Rezuttati: U grupi A, posle terapije, HDL-C koncentracija se značajno povećala, ali ne i u grupi B. Atoivastatin je snizio plazmatski nivo hemokin (C-C motiv) liganda 2 i intracelularnog adhezionog molekula-1 mRNA u obe grupe, ali nije promenio plazmatski nivo gena za katepsin S. Samo u grupi A, ukupni bilirubin je pokazao negativnu korelaciju sa genom za katepsin S (r=-0,506; p=0,023) pre zapotinjanja terapije i značajni porast nakon terapije atorvastatinom.
Zaključak: HDL-C i bilirubin mogu biti obećavajući terapijski ciljevi u lečenju kardiovaskularnih bolesti. Analiza slobodne mRNA (eng. cell-free mRNA) u plazmi može postati korisno sredstvo za procenu plejotropnog delovanja statina
High-density lipoproteins (HDL) have athero-protective biological properties: antioxidative, anti-apoptotic, anti-inflammatory, and they have the efflux capacity of cellular cholesterol. Plasma mRNA ...analysis can be used to investigate statin pleiotropy
as a new analytical tool for non-invasive assessment of gene expression in vascular beds. The aim of this study was to assess the pleiotropic effects of atorvastatin in stable angina patients with high-risk values (group A) as compared with patients who had borderline and desirable HDL-cholesterol (HDL-C) values (group B).
The atorvastatin therapy (20 mg/day) was given to forty-three patients with stable angina for 10 weeks. We investigated three statin pleiotropy-targeted genes: inter-cellular adhesion molecule-1, chemokine (C-C motif) ligand 2 and cathepsin S and assessed by gel electrophoresis gradient the effects of atorvastatin on HDL size and subclasses.
In group A, after therapy, HDL-C concentration was significantly increased but not in group B. Atorvastatin lowered plasma chemokine (C-C motif) ligand 2 and intercellular adhesion molecule-1 mRNA levels in both groups, but did not change the plasma cathepsin S mRNA levels. In group A only, baseline total bilirubin showed negative correlations with the genes of cathepsin S (r=-0.506; p=0.023) and significantly increased after therapy.
HDL-C and bilirubin can be promising therapeutic targets in the treatment of cardiovascular diseases. Analysis of cell-free mRNA in plasma might become a useful tool for estimating statin pleiotropy.
Provider: - Institution: - Data provided by Europeana Collections- Peri-implantitis is inflammatory process characterized by supporting bone loss of loaded oral implants. The pathognomonic ...characteristic of peri-implantitis is supporting bone loss of the loaded implant. This process is based on inflammatory osteoclastogenesis which simultaneously represent the central pathologic process of the disorder. Inflammatory osteoclastogenesis implies maturation of pre-osteoclasts and enhancement of the activity of maturated osteoclasts which are induced by achieving of the critical concentrations of proinflammatory mediators. Clinical characteristics of the peri-implantitis are still not strictly defined and they vary because in the physiological conditions the values of clinical parameters varies among individuals, for example peri-implant sulcus depth represents the individual determinant which could be from 0.5mm to 4mm as well. Simultaneously, the marginal bone loss is the physiological characteristic around implants in function, which is the most intensive in the first year of loading represented by the -0.78mm in the mesial sites and -0.85mm at the distal sites, and after that the process is constant and bone loss at the year level is approximately 0.2mm. The mentioned value is the average values that individually vary and it depends of the implant type, abutments and numerous other factors. From that reason the relative clinical attachment level (rCAL), nether radiological proof of bone loss could be accepted as the absolute indicators of the pathological bone loss. In the peri-implant diagnostics the most frequently are used the few different diagnostic procedures in the combination to give the complete diagnostic view. These diagnostic methods include: evaluation of clinical parameters, radiological analyses, microbiological analyses and quantitative and qualitative analyses of PICF. The PICF analysis is one of the most attractive methods in current implantology, where the one of the most precious values is providing of the direct information on peri-implant tissues d based on that providing information on early disease onset in the phase of reversible damage. This limitation of clinical methods results in time loss proportionally decreasing treatment success, and frequently resulting in inappropriate treatment planning. Based on that, evaluation of biomarkers in PICF sample compensates limitations of conventional diagnostic procedures without capability to provide accurate information on early disease. Numerous studies have been conducted to identify the biomolecules accurately reflecting peri-implant tissue condition, but since the pathology of local metabolism is complex, the method for evaluation is still under standardization. Objective. The objective of the study was to investigate potential of RANK, sRANKL, OPG, Cathepsin-K, Sclerostin and VEGF as biomarkers of implant supporting bone loss. Material and methods. Study included three groups of systemically healthy non smokers with osseointegrated endosseal implants loaded for at least one year (35 with peri-implantitis, 30 with peri-mucositis and 30 with healthy peri-implant tissues). Exclusion criteria were the following: antibiotics usage in the preceding three months and anti-inflammatorics in preceding two months from the moment of sampling, menstruation, pregnancy and lactation, smoking and periodontal/peri-implant treatment during last year. The following clinical measurements have been performed in 6 points (bucco-mesial, bucco -medial, bucco -distal, oro-distal, oro-medial and oro-mesial): Bleeding on Probing (BOP) measured 15 seconds after probing and recorded as presence (1) or absence (0), Visible plaque accumulation (PI) measured along the mucosal margin and recorded as presence (1) or absence (0), Probing Pocket Depths (PPD) in mm and Relative Clinical Attachment Level (rCAL) (expressed in mm) using a periodontal probe graded in mm (North Carolina–Hu-Friedy, Chicago, IL, USA). In the case of few similar pathological processes in the same patient, the site representing the greatest defect was sampled, and in the case of defects showing similar clinical characteristics, the most accessible was included. PICF samples were collected from the mesial aspects of one representative implant site in each individual participating in the study. The specimens were retrieved 24 h after the clinical examination to avoid any contamination with blood, from both peri-implant and periodontal sites, selected from those demonstrating the deepest probing depth. The samples were retrieved using the filter paper technique, and obtained volume was evaluated using calibrated Periotron 6000 (Interstate Drug Exchange, Amityville, NY, USA). Commercial enzyme linked immunosorbent kits (ELISA) were used for evaluation of biomarkers in PICF samples: Human RANK/TNFRSF11A (DuoSet, R&D Systems Inc., Minneapolis, MN, USA), ampli-sRANKL, OPG, cathepsin-K i sclerostin (Biomedica Gruppe, Vienna, Austria) i VEGF (Human VEGF ELISA Development Kit, Promokine, PromoCell GmbH, Heidelberg, Germany). Results. In all tested PICF samples were detected RANK, sRANKL, OPG, cathepsin-K and VEGF, indicating the concentrations above detection limit, but only 6% of the samples were positive on sclerostin. RANK concentration was significantly higher in peri-implantitis when compared to healthy periimplant tissues (p=0.002), and it was higher when compared to peri-mucositis as well (p=0.021). sRANKL values were significantly higher in peri-implantitis when compared to healthy peri-implant tissues (p=0.010), but not when compared to peri-mucositis, nether perimucositis an healthy peri-implant tissues. OPG concentration was significantly higher in peri implantitis when compared to healthy peri-implant tissues (p=0.031), and that was single significance obtained for this marker. sRANKL/OPG relative ration did not show significant difference in distribution between investigated groups. Cathepsin-K were in general higher in inflammed sites, but the single significance was reached among peri-mucositis and healthy peri-implant tissues (p=0.039). Sclerostin was detected in small sample size, but the differences were clearly higher in peri-implantitis group when compared to both two groups. VEGF concentration was significantly higher in peri-implantitis when compared to healthy peri-implant tissues (p=0.000) and peri-mucositis as well (p=0.014). RANK and sRANKL showed significantly positive correlation with all measured clinical parameters, and OPG showed significantly positive correlation with all measured clinical parameters as well, with exception of PI (p=0.121), and an identical case was with sclerostin. VEGF showed no significant correlations with clinical parameters. Conclusion. RANK, sRANKL, OPG, sclerostin and VEGF are biomarkers related to peri-implantitis. Cathepsin-K was the marker related to peri-mucositis. Evaluated in this study are differently distributed in different jaws regions and in PICF samples of implants with different diameter. RANK and OPG were significantly elevated in frontal maxillary region, indicating more intensive osteolytic processes in this region. RANK and cathepsin-K were significantly increased in the group o implants with highest diameter, which supports on molecular level the previous results of clinical studies that showed positive correlation between implant diameter and implant loss.- Peri-implantitis predstavlja inflamatorni proces koji se karakteriše gubitkom potporne kosti opterećenog oralnog implantata. Osnovna patološka karakteristika peri-implantitisa je gubitak potporne kosti implantata u funkciji. Ovaj proces je zasnovan na inflamatornoj osteoklastogenezi koja ujedno predstavlja centralni patološki proces peri-implantitisa. Inflamatorna osteoklastogeneza predstavlja proces sazrevanja pre-osteoklasta i pojačavanje aktivnosti zrelih osteoklasta pod uticajem kritičnih koncentracija pro-inflamatornih medijatora. Kliničke karakteristike peri-implantitisa nisu strogo definisane i variraju iz prostog razloga jer dubina peri-implantnog sulkusa značajno varira s'toga dubina džepa predstavlja individualnu determinantu. Istovremeno, proces gubitka marginalne kosti predstavlja fiziološku pojavu koja je najintezivnija u prvoj godini opterećenja, i istraživanja su pokazala da iznosi -0.78mm mezijalno i -0.85mm distalno, a zatim se kontinurano odvija i na godišnjem nivou iznosi oko 0.2mm. Pomenuta vrednost iznosi prosečnu vrednost ali ona takođe individualno varira i uslovljena je tipom implantata, dizajnom abatmenta i mnogim drugim faktorima. Iz tog razloga se relativni nivo pripojnog epitela (rCAL) kao ni radiološki evidentan gubitak kosti ne mogu usvojiti kao apsolutni indikatori patološkog gubitka kosti. U dijagnostici stanja peri-implantnih tkiva koristi se nekoliko tipova metoda i najčešće u kombinaciji radi što potpunijeg postavljanja dijagnoze. Dijagnostičke metode uključuju: određivanje kliničkih parametara, radiološke analize, mikrobiološke analize i kvalitativne i kvantitativne analize peri-implantnte krevikularne tečnosti (PICF). Analiza PICF predstavlja jednu od najatraktivnijih metoda u savremenoj implantologiji, pri čemu je njena najveća vrednost u tome što daje direktne informacije o stanju peri-implantinh tkiva i zasnovano na tome poseduje mogućnost da pokaže rane znake oboljenja peri-implantnih tkiva u fazi gde su tkivne promene reverzibilne. Ovo ograničenje kliničkih metoda rezultira u propuštanju vremena od momenta pojave bolesti koje proporcijonalno umanjuje uspeh terapije, a često i u izboru neadekvatnog terapijskog plana. Zasnovano na tome, metoda merenja specifičnih biomarkera u uzorku PICF nadomešćuje ograničenja konvencionalnih kliničkih dijagnostičkih metoda koje daju informacije u stadijumu razvijene bolesti. Brojne studije se sprovode u cilju identifikacije biomolekula koji pouzdano reflektuje stanje peri-implantnih tkiva, ali kako je patol
Ravnoteža razgradnje i stvaranja kosti važna je za normalan proces pregradnje i održavanja koštane mase. Genetski, hormonski, imunološki i drugi čimbenici utječu na pregradnju kosti tijekom cijelog ...života. Poremećaj koštane pregradnje ključni je patofiziološki mehanizam nastanka osteoporoze i predstavlja složen proces u kojem sudjeluju koštane stanice, citokini i njihovi receptori. Danas je već poznata važna uloga RANK/RANKL/OPG sustava u patofiziologiji osteoporoze, ali se i dalje istražuju važni unutarstanični signalni putovi u nastanku osteoporoze i drugih metaboličkih bolesti kosti.
Svrha ovog istraživanja bila je imunohistokemijski utvrditi izraženost proteina nm23 i katepsina D u oralnim pločastim karcinomima, usporediti ju s patohistološkim nalazima, pojavom područnih ...presadnica i procijeniti njihovu vrijednost u prognozi bolesti. Ispitivano je 107 tkivnih uzoraka bolesne i 77 zdrave ustne sluznice. Uočena je pojačana difuzna izraženost proteina nm23 i katepsina D u bolesnom tkivu. Usporedbom proteina nm23 i katepsina D u tumorskim stanicama i tumorskoj stromi, te tipa reakcije s pT, stupnjem diferencijacije, načinom invazije i izraženošću tumorske strome, nađena je znakovita povezanost izraženosti proteina nm23 u tumorskim stanicama sa stupnjem diferencijacije, proteina nm23s izraženošću tumorske strome i načinom invazije, te katepsina D sa stupnjem diferencijacije tumora. Najvažniji prognostički pokazatelj
u oralnim pločastim karcinomima su metastaze u područnim limfnim čvorovima. Rezultati istraživanja pokazuju važnost tumorske strome za metastatski potencijal ostnog ustnog pločastog karcinoma.
Provider: - Institution: - Data provided by Europeana Collections- Breast carcinoma is the most common malignancy and one of the leading causes of death from cancer among women in industrial ...countries. During the first 3 years of follow-up, early breast carcinoma is characterized by the maximum number of distant metastases, independent of applied therapy. Identification of the tumor/tumor-host characteristics that would specifically indicate patients with low/high risk for metastatic disease represents an important research goal. pS2 and cathepsin D were investigated in order to determine cut-off values for defining elevated expression and the status of biomarkers, providing the basis to identify groups of patients with low/high risk for relapse in early breast carcinoma. The relationship between classical and biochemical prognostic/predictive factors and concentrations of pS2 and cathepsin D allowed us to define the cut-off values for the expression of pS2 (15 ng/mg) and cathepsin D (39 pmol/mg) in breast carcinoma which have a biological relevance, in terms of defining the estrogen-dependent vs. estrogen-independent expression. Analysis of the first 3 years of follow-up on the basis of cathepsin D status indicated biological relevance, i.e. the role of the protein within the processes of proliferation and apoptosis, and allowed us to determine its clinical significance, i.e. to define high-risk groups (pN + pT2 CD-, pN + III CD-, I CD +) and low-risk group of patients (I CD-), regardless of applied therapy. Analysis of the first 3 years of follow-up on the basis of pS2 status indicated biological relevance, i.e. the anti- roliferative and anti-apoptotic as well as the role of this protein in dissemination of malignant cells, and allowed us to determine its clinical significance, i.e. to define high-risk (post pN + pS2-, pT2 III pS2-, pre II ER+ PR+ pS2+) and low-risk groups of patients (post II ER+ PR+ pS2+, pre II ER+ PR+ pS2-), regardless of applied therapy.- Karcinom dojke je najzastupljenije maligno oboljenje i jedan od vodećih uzroka smrtnosti od malignih oboljenja među ženama u industrijski-razvijenim zemljama. Tok bolesti ranog karcinoma dojke u prve 3 godine praćenja toka bolesti se karakteriše pojavom maksimalnog broja udaljenih metastaza koji je nezavisan od primenjene terapije. Identifikacija karakteristika tumora/domaćina tumora koje bi preciznije ukazale na pacijente sa niskim/visokim rizikom za pojavu metastatske bolesti predstavlja važan predmet istraživanja. Cilj ovog istraživanja je bio određivanja granične vrednosti za definisanje povišene ekspresije i, posledično, statusa molekulskih biomarkera, pS2 i katepsina D, kao i identifikovanje grupe pacijentkinja sa niskim/visokim rizikom za relaps, u zavisnosti od statusa biomarkera, u ranom karcinomu dojke. Analiza povezanosti klasičnih i biohemijskih faktora prognoze/predikcije toka bolesti sa koncentracijama pS2 i katepsina D je omogućila definisanje graničnih vrednosti, za ekspresiju pS2 (15 ng/mg) i za ekspresiju katepsina D (39 pmol/mg) u karcinomu dojke, koje imaju i biološki značaj, u smislu definisanja estrogen-zavisne naspram estrogen-nezavisne ekspresije. Analiza toka bolesti pacijentkinja na osnovu statusa katepsina D, u periodu od 3 godine nakon hirurške terapije, je ukazala na biološki značaj, tj. na ulogu proteina u procesima proliferacije i apoptoze, i omogućila da se odredi njegov klinički značaj, tj. da se definišu visoko-rizične grupe (pN+ pT2 CD-, pN+ III CD-, I CD+), kao i nisko-rizična grupa pacijentkinja (I CD-), bez obzira na primenjenu terapiju. Analiza toka bolesti pacijentkinja na osnovu statusa pS2, u periodu od 3 godine nakon hirurške terapije, je ukazala na biološki značaj proteina, tj. na njegovu anti-proliferativnu i anti-apoptotsku, kao i ulogu ovog proteina u rasejavanju malignih ćelija, i omogućila da se odredi njegov klinički značaj, tj. da se definišu visoko-rizične (post pN+ pS2-, pT2 III pS2-, pre II ER+ PR+ pS2+) i nisko-rizične grupe pacijentkinja (post II ER+ PR+ pS2+, pre II ER+ PR+ pS2-), bez obzira na primenjenu terapiju.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
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