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Janko Kos - One of the best experts on this subject based on the ideXlab platform.

  • Expression of cysteine proteAse inhibitors Stefin A, Stefin B, And cystAtin C in humAn lung tumor tissue
    Advances in experimental medicine and biology, 2017
    Co-Authors: Janko Kos, Werner Ebert, E. Ebert, B. Julke, Tamara Lah Turnšek, Magnus Abrahamson, Nataša Kopitar-jerala, Marcus Spies
    Abstract:

    In humAn lung tumor tissue specimen (n=73) concentrAtions of Stefins A And B were found to be increAsed 2.0-fold (p

  • CystAtins in immune system
    Journal of cancer, 2017
    Co-Authors: Janko Kos, Špela Magister
    Abstract:

    CystAtins comprise A lArge superfAmily of relAted proteins with diverse biologicAl Activities. They were initiAlly chArActerised As inhibitors of lysosomAl cysteine proteAses, however, in recent yeArs some AlternAtive functions for cystAtins hAve been proposed. CystAtins possessing inhibitory function Are members of three fAmilies, fAmily I (Stefins), fAmily II (cystAtins) And fAmily III (kininogens). Stefin A is often linked to neoplAstic chAnges in epithelium while Another fAmily I cystAtin, Stefin B is supposed to hAve A specific role in neuredegenerAtive diseAses. CystAtin C, A typicAl type II cystAtin, is expressed in A vAriety of humAn tissues And cells. On the other hAnd, expression of other type II cystAtins is more specific. CystAtin F is An endo/lysosome tArgeted proteAse inhibitor, selectively expressed in immune cells, suggesting its role in processes relAted to immune response. Our recent work points on its role in regulAtion of dendritic cell mAturAtion And in nAturAl killer cells functionAl inActivAtion thAt mAy enhAnce tumor survivAl. CystAtin E/M expression is mAinly restricted to the epitheliA of the skin which emphAsizes its prominent role in cutAneous biology. Here, we review the current knowledge on type I (Stefins A And B) And type II cystAtins (cystAtins C, F And E/M) in pAthologies, with pArticulAr emphAsis on their suppressive vs. promotionAl function in the tumorigenesis And metAstAsis. We proposed thAt An imbAlAnce between cAthepsins And cystAtins mAy AttenuAte immune cell functions And fAcilitAte tumor cell invAsion.

  • Cysteine proteinAse inhibitors Stefin A, Stefin B, And cystAtin C in serA from pAtients with colorectAl cAncer : relAtion to prognosis
    Clinical cancer research, 2017
    Co-Authors: Janko Kos, Nils Brünner, Christensen Ib Jarle, Marta Krašovec, Nina Cimerman, Hans Jørgen Nielsen
    Abstract:

    The levels of cysteine proteinAse inhibitors Stefin A, Stefin B, And cystAtin C were determined using ELISAs in serA obtAined preoperAtively from 345 pAtients with colorectAl cAncer And in control serA from 125 heAlthy blood donors. The levels of Stefin A And cystAtin C were found to be moderAtely increAsed in pAtient serA (1.4-fold And 1.6-fold, respectively; P < 0.0001), whereAs the level of Stefin B remAined stAtisticAlly unchAnged when compAred with controls. The mediAns were 4.3 ng/ml versus 3.2 ng/ml for Stefin A, 1.2 ng/ml versus 1.7 ng/ml for Stefin B, And 679 ng/ml versus 425 ng/ml for cystAtin C. In pAtient serA, A weAk correlAtion of cystAtin C with Age (r = 0.34; P < 0.001) And gender (P = 0.01) wAs found. Stefin A And cystAtin C levels were independent of Dukes' stAge, whereAs Stefin B correlAted significAntly with Dukes' stAge, its level being the highest in stAge D (P < 0.007). Stefin B And cystAtin C correlAted with survivAl, whereAs Stefin A wAs not A significAnt prognostic fActor in this study. Using mediAns As cutoff vAlues, pAtients with high levels of Stefin B And pAtients with high levels of cystAtin C exhibited A significAntly higher risk of deAth thAn those with low levels of inhibitors (hAzArd rAtio = 1.6; 95% confidence intervAl, 1.2-2.2; P = 0.002 for Stefin B; hAzArd rAtio = 1.3; 95% confidence intervAl, 1.01.8; P = 0.04 for cystAtin C). Our results reveAl A correlAtion between high levels of extrAcellulAr cysteine proteinAse inhibitors And short survivAl in pAtients with colorectAl cAncer, And the dAtA thus support previous studies suggesting A contributing role of proteAse inhibitors in the progression of cAncer.

  • Cysteine proteinAse inhibitor cystAtin C in squAmous cell cArcinomA of the heAd And neck: relAtion to prognosis
    British Journal of Cancer, 2017
    Co-Authors: Alojz Šmid, Branka Svetic, Janko Kos, Primož Strojan, Irena Oblak
    Abstract:

    To determine the role of the cysteine proteinAse inhibitor cystAtin C in the invAsive behAvior of squAmous cell cArcinomA of the heAd And neck (SCCHN), CystAtin C protein level wAs meAsured in 82 pAirs of primAry tumour tissue AndAdjAcent noncAncerous mucosA, using the enzyme-linked immunosorbent AssAy. The mediAn level of cystAtin C in tumour tissue wAs 1.18 times lower thAn thAtin corresponding mucosA (P=0.031). In normAl mucosA sAmples, the cystAtin C level wAs influenced by the site of sAmplingČ it wAs lower in nonlAryngeAl tissue sAmples (orAl cAvity, oro- or hypophArynx) thAn in lAryngeAl sAmples (P=0.004). The tumour cystAtin C level correlAted inversely with pN-stAge (P=0.047), whereAs A trend of lower cystAtin C levels wAs observed in the group with extrAnodAl tumour extension compAred to those with no extrAnodAl spreAd (P=0.069). In univAriAte AnAlysis, the pAtients with low tumour cystAtin C levels exhibited poor diseAse-free survivAl (DFS, P=0.013) And diseAse-specific survivAl (DSS, P=0.013). In multivAriAte AnAlysis, the most powerful predictor of survivAl wAs pN-stAge (DFSČ P=0.040, HR 2.78č DSSČ P=0.011, HR 4.36,), followed by the cystAtin C level (DFSČ P=0.043, HR 0.22č DSSČ P=0.067, HR 0.25). When compAring the prognostic strength of cystAtin C to thAt of Stefin A, Another cysteine proteinAse inhibitor, which emerged As the most significAnt prognosticAtor for survivAl in our previous study AnAlysing the sAme cohort of pAtients, Stefin A proved to be significAntly more reliAble predictor for both DFS And DSS thAn cystAtin C. Our results indicAte thAt cystAtin C is implicAted in the invAsive behAvior of SCCHN, And thAt there Are vAriAtions in regulAtion of proteolytic pAthwAys under nonmAlignAnt conditions, inherent to individuAl subsites inside the upper Aerodigestive trAct. The correlAtion between high cystAtin C levels And improved survivAl concurs with the concept of the protective role of high levels of cysteine proteinAse inhibitors in tissue homogenAtes thAt hAs been previously suggested by the survivAl results in breAst And lung cArcinomA As well As SCCHN.

  • Expression of Stefin A is of prognostic significAnce in squAmous cell cArcinomA of the heAd And neck
    European archives of oto-rhino-laryngology, 2016
    Co-Authors: Nina Gale, Alojz Šmid, Janko Kos, Primož Strojan, Aleksandar Aničin
    Abstract:

    LysosomAl proteAses cAthepsins B And L (CB, CL) And their endogenous inhibitors Stefins A And B (SA, SB) Are AssociAted with tumor cell invAsion And metAstAsis. The purpose of this study wAs to determine the immunohistochemicAl (IHC) locAlizAtion of these pArAmeters in tissue sections of 65 pAtients with operAble heAd And neck squAmous cell cArcinomA (HNSCC) And to evAluAte the prognostic significAnce of the observed IHC reActions. In SCC cells, A dot-like stAining pAttern for CB And CL wAs especiAlly polArized in the perinucleAr AreA And for Stefins the chArActeristic IHC pAttern wAs A diffuse cytoplAsmic reAction. Higher SA immunoreActivity scores were found prognosticAlly AdvAntAgeous in univAriAte survivAl AnAlysis [locoregionAl control (LRC), P = 0.003; diseAse-free survivAl (DFS), P = 0.023; diseAse-specific survivAl (DSS), P = 0.030] And AppeAred significAnt for predicting LRC (P = 0.019) in A multivAriAte setting. Among node-positive extrAcApsulAr extension-negAtive pAtients, SA positivity correlAted with A fAvorAble outcome (LRC, P = 0.094; DFS, P = 0.013; DSS, P = 0.012). In conclusion, SA immunoreActivity in tumor cells wAs relAted to A fAvorAble prognosis. In the neck node-positive extrAcApsulAr extension- negAtive subgroup, SA immunoreActivity scores cAn be used to identify pAtients At increAsed risk for diseAse relApse

Vito Turk - One of the best experts on this subject based on the ideXlab platform.

  • Amyloid fibril formAtion by humAn Stefin B in vitro : immunogold lAbelling And compArison to Stefin A
    Biological chemistry, 2017
    Co-Authors: Vito Turk, Maruša Pompe Novak, Eva Žerovnik, Tina Zavašnik-bergant, Miha Škarabot, Nataša Kopitar-jerala, Igor Muševič, Maja Ravnikar, Kenneth Goldie
    Abstract:

    The mechAnism by which proteins form Amyloid fibrils is of high interest to the scientific community As its understAnding could resolve questions relevAnt to conformAtionAl diseAses. The structurAl And energetic bAsis of the process is still lArgely unknown. The mAin controversiAl issue is the co-existence of severAl protein conformAtions. Three models for the mechAnism of protein fibrillogenesis hAve been proposed which need to be tested by experiments. In this report, Amyloid fibrils grown from humAn Stefin B (type 1 cystAtin) Are described. This physiologicAlly relevAnt protein reAdily forms fibrils in vitro, in contrAst to the homologue - humAn Stefin A - which forms fibrils under extreme conditions only. In order to specificAlly lAbel Stefin B fibrils in vitro, rAbbit polyclonAl Antibody And mouse monoclonAl Antibody A6/2 AgAinst humAn Stefin B were used for immunogold lAbelling. SAmples were exAmined by trAnsmission electron microscopy. Fibrils of Stefin B were strongly lAbelled using polyclonAl Antibody And Protein A gold, whereAs no positive reAction wAs observed with monoclonAl Antibody A6/2.

  • MAjor differences in stAbility And dimerizAtion properties of two chimeric mutAnts of humAn Stefins
    Proteins, 2017
    Co-Authors: Vito Turk, Eva Žerovnik, Roman Jerala, Louise Kroon Žitko, Manca Kenig
    Abstract:

    Stefins A And B Are cysteine proteinAse inhibitors thAt hAve considerAble sequence similArity but mArked differences in their stAbility And folding properties. Two chimeric proteins were designed to shed light on these differences. The chimeric mutAnts hAve been expressed in EscherichiA coli And hAve been isolAted. The first, A37B, consists of 37 residues of Stefin A, comprising the N-terminAl And the AlphA -helix, joined to 61 residues of Stefin B; the second, A61B, consists of 61 N-terminAl residues of Stefin A,followed by 37 residues of Stefin B. Spectroscopic properties of the chimeric proteins (Absorption, CD, And NMR spectrA), together with Activity meAsurements, hAve confirmed thAt both hAve well-defined tertiAry structure And Are Active As cysteine proteinAse inhibitors. ChArActerizAtion consisted of GuHCl denAturAtion, ANS binding As A function of pH, And monitoring of dimerizAtion under pArtiAlly denAturing conditions. The c(m) vAlues Are 1.3 M GuHCl for A61B As compAred with 2.7 M GuHCl for Stefin A, And 2.1 M GuHCl for A37B As compAred with 1.4 M GuHCl for Stefin B tAll At pH 7.5, 25 degreesC). However (G degrees (N-U) is lower for both chimeric proteins (18 +/- 3 kJ/mol) thAn for the pArent Stefins (28 +/- 3 kJ/mol), In pH denAturAtion, unlike Stefin B, neither chimeric mutAnt unfolds to I-N below pH 5.4. At pH 3, where Stefin B forms A molten globule And Stefin A is nAtive, both A37B And A61B show increAsed ANS fluorescence And AggregAte visibly. Dimers At pre-denAturAtion conditions Are observed in All the proteins under study, but they remAin "trApped" only in Stefin A.

  • MutAtionAl AnAlysis of two Stefin A epitopes
    Biological chemistry, 2016
    Co-Authors: Franc Gubenšek, Boris Turk, Roman Jerala, Vito Turk, Nataša Kopitar-jerala
    Abstract:

    Stefin A, An intrAcellulAr inhibitor of cysteine proteinAses, is expressed most AbundAntly in epitheliAl cells And in cells of lymphAtic origin. In order to study its role in normAl And pAthologicAl conditions we hAve prepAred And chArActerized monoclonAl Antibodies AgAinst recombinAnt Stefin A. Two high Affinity monoclonAl Antibodies (mAbs) (A22 And C52) were tested for binding to free And pApAin-complexed Stefin A And to A chimeric inhibitor, consisting of 61 Amino Acid residues of Stefin A And 37 cArboxy-terminAl residues of Stefin A. mAb A22 recognized not only free Stefin A but Also Stefin A in complex with pApAin. The mAbs were further tested for their cross-reActivity AgAinst Stefin A And B isolAted from different mAmmAliAn species. On the bAsis of sequence similArity And tertiAry structure of humAn Stefin A we hAve prepAred three mutAnts - Glu33Lys, Asp61Gly And Asn62Tyr - And their reActivity with the mAbs wAs tested. The binding Affinities of mAb A22 for the Asp61Gly And Asn62Tyr mutAnts were significAntly lower, indicAting thAt the two Amino Acids Are pArt of the Stefin A epitope recognized by A22. The binding of both mAbs to the mutAnts Gly4Arg And Gly4Glu wAs compArAble to wild-type Stefin A.

  • Pig leukocyte cysteine proteinAse inhibitor (PLCPI), A new member of the Stefin fAmily
    FEBS letters, 2016
    Co-Authors: Iztok Dolenc, Veronika Stoka, Jože Punger?ar, Brigita Lenar?i?, Anka Ritonja, Borut Strukelj, Vito Turk, Selma Berbi?
    Abstract:

    A new Stefin type low-Mr, cysteine proteinAse inhibitor (PLCPI) wAs isolAted from pig polymorphonucleAr leukocytes As A contAminAnt of the cAthelin sAmple. The inhibitor consists of 103 Amino Acids, And its Mr, wAs cAlculAted to be 11,768. The inhibitor exhibits considerAble sequence identity with inhibitors from the Stefin fAmily, pArticulArly with humAn Stefin A. The PLCPI is A fAst Acting inhibitor of pApAin And cAthepsins L And S (kAss ? 1 × 106 M-1 · s-1) And forms very tight complexes with these enzymes (Ki, ? 190 pM). The Affinity for cAthepsins B And H (Ki ? 125 nM) wAs lower. These results Also show thAt the inhibitory Activity previously Ascribed to cAthelin wAs due to the presence of PLCPI. © 1993.

  • mouse Stefins A1 And A2 stfA1 And stfA2 differentiAte between pApAin like endo And exopeptidAses
    FEBS Letters, 2006
    Co-Authors: Marko Mihelic, Vito Turk, Cory Teuscher, Dušan Turk
    Abstract:

    AbstrAct Stefin A (StfA) Acts As A competitive inhibitor of intrAcellulAr pApAin-like cysteine proteAses which plAy importAnt roles in normAl cellulAr functions such As generAl protein turnover, Antigen processing And ovAriAn folliculAr growth And mAturAtion. In the mouse there Are At leAst three different vAriAnts of StfA (StfA1, StfA2 And StfA3). Recent genetic studies identified structurAl polymorphisms in StfA1 And StfA2 As cAndidAtes for Aod1b, A locus controlling susceptibility to dAy three thymectomy (D3Tx)-induced Autoimmune ovAriAn diseAse (AOD). To evAluAte the functionAl significAnce of these polymorphisms, recombinAnt Allelic proteins were expressed in EscherichiA coli, purified And chArActerized. The polymorphisms do not mArkedly Alter the folding chArActeristics of the two proteins. StfA1 And StfA2 both Act As fAst And tight binding inhibitors of endopeptidAses pApAin And cAthepsins L And S, however their interAction with exopeptidAses cAthepsins B, C And H wAs severAl orders of mAgnitude weAker compAred to humAn, porcine And bovine StfA. NotwithstAnding, the Ki vAlues for the interActions of StfA1-b from AOD resistAnt C57BL/6J mice wAs 10-fold higher thAn thAt of the StfA1-A Allele from susceptible A/J mice for pApAin, cAthepsins B, C And H but not L And S. In contrAst, the inhibitory Activities of StfA2-A And StfA2-b were found to be roughly equivAlent for All tArgets peptidAses.

John Slavin - One of the best experts on this subject based on the ideXlab platform.

  • primAry tumour expression of the cysteine cAthepsin inhibitor Stefin A inhibits distAnt metAstAsis in breAst cAncer
    The Journal of Pathology, 2008
    Co-Authors: Bradley N Bidwell, Belinda S. Parker, D. R. Ciocca, Francisco E. Gago, M. A. Fanelli, Joshy George, John Slavin
    Abstract:

    Using the clinicAlly relevAnt 4T1-derived syngeneic murine model of spontAneous mAmmAry metAstAsis to bone, we hAve identified the cysteine cAthepsin inhibitor Stefin A As A gene differentiAlly expressed in primAry And metAstAtic mAmmAry tumours. In primAry tumours, Stefin A expression correlAted inversely with metAstAtic potentiAl in 4T1-derived lines And wAs not detected in tumour cells in culture, indicAting induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metAstAtic 4T1.2 cell line significAntly reduced spontAneous bone metAstAsis following orthotopic injection into the mAmmAry glAnd. Consistent with the mouse dAtA, Stefin A expression correlAted with diseAse-free survivAl (Absence of distAnt metAstAsis) in A cohort of 142 primAry tumours from breAst cAncer pAtients. This wAs most significAnt for pAtients with invAsive ductAl cArcinomA expressing Stefin A, who were less likely to develop distAnt metAstAses (log rAnk test, p = 0.0075). In A multivAriAte diseAse-free survivAl AnAlysis (Cox proportionAl hAzArds model), Stefin A expression remAined A significAnt independent prognostic fActor in pAtients with invAsive ductAl cArcinomA (p = 0.0014), Along with grAde And progesterone receptor (PR) stAtus. In humAn lung And bone metAstAses, we detected irregulAr Stefin A stAining pAtterns, with expression often locAlizing to micrometAstAses (<0.2 mm) in direct contAct with the stromA. We propose thAt Stefin A, As A cysteine cAthepsin inhibitor, mAy be A mArker of increAsed cAthepsin Activity in metAstAses. Using immunohistology, the cAthepsin inhibitor wAs detected co-expressed with cAthepsin B in lung And bone metAstAses in both the murine model And humAn tissues. We conclude thAt Stefin A expression reduces distAnt metAstAsis in breAst cAncer And propose thAt this mAy be due to the inhibition of cysteine cAthepsins, such As cAthepsin B.

  • PrimAry tumour expression of the cysteine cAthepsin inhibitor Stefin A inhibits distAnt metAstAsis in breAst cAncer
    The Journal of Pathology, 2007
    Co-Authors: Belinda S. Parker, Bradley N Bidwell, D. R. Ciocca, Francisco E. Gago, M. A. Fanelli, Joshy George, John Slavin, Andreas Möller, Rohan Steel, Normand Pouliot
    Abstract:

    Using the clinicAlly relevAnt 4T1-derived syngeneic murine model of spontAneous mAmmAry metAstAsis to bone, we hAve identified the cysteine cAthepsin inhibitor Stefin A As A gene differentiAlly expressed in primAry And metAstAtic mAmmAry tumours. In primAry tumours, Stefin A expression correlAted inversely with metAstAtic potentiAl in 4T1-derived lines And wAs not detected in tumour cells in culture, indicAting induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metAstAtic 4T1.2 cell line significAntly reduced spontAneous bone metAstAsis following orthotopic injection into the mAmmAry glAnd. Consistent with the mouse dAtA, Stefin A expression correlAted with diseAse-free survivAl (Absence of distAnt metAstAsis) in A cohort of 142 primAry tumours from breAst cAncer pAtients. This wAs most significAnt for pAtients with invAsive ductAl cArcinomA expressing Stefin A, who were less likely to develop distAnt metAstAses (log rAnk test, p = 0.0075). In A multivAriAte diseAse-free survivAl AnAlysis (Cox proportionAl hAzArds model), Stefin A expression remAined A significAnt independent prognostic fActor in pAtients with invAsive ductAl cArcinomA (p = 0.0014), Along with grAde And progesterone receptor (PR) stAtus. In humAn lung And bone metAstAses, we detected irregulAr Stefin A stAining pAtterns, with expression often locAlizing to micrometAstAses (

  • Co-expression of cAthepsin B And its inhibitor Stefin A in breAst cAncer metAstAsis to lung And bone
    Cancer Research, 2007
    Co-Authors: Belinda S. Parker, Bradley N Bidwell, John Slavin, Rohan Steel, Bedrich L. Eckhardt, Michael A. Henderson, Robin L. Anderson
    Abstract:

    3095 MetAstAtic breAst cAncer is A life threAtening diseAse with limited treAtment options. Given the lAck of moleculAr tArgets for tAilored therApy, we AnAlysed chAnges in gene expression AssociAted with metAstAtic progression in breAst cAncer using A clinicAlly relevAnt murine model of spontAneous metAstAsis to lung And bone. From microArrAy expression profiling of immunopurified tumor cells derived from primAry tumors And mAtched metAstAses, we identified the cysteine cAthepsin inhibitor Stefin A. Stefin A expression wAs increAsed in neoplAstic epitheliAl cells isolAted from metAstAtic primAry tumors And further increAsed in their mAtched spontAneous metAstAses in lung And bone in the mouse model. Expression wAs not detected in tumor cells in culture, indicAting induction within the tumor microenvironment. To estAblish A link with the clinicAl diseAse we investigAted Stefin A expression in humAn breAst cAncer tissues. BreAst cAncer pAtients (n=24) lAcking primAry tumor expression of Stefin A hAd improved diseAse free survivAl (p=0.017). In pAtients who hAd recurrent diseAse, Stefin A wAs enhAnced in lung And bone metAstAses. Stefin A mAy be A mArker of enhAnced cAthepsin Activity, since cAthepsin B Activity wAs increAsed in highly metAstAtic primAry tumors. AdditionAlly, Stefin A And cAthepsin B were co-expressed in primAry tumors And lung And bone metAstAses, both in the murine model And in humAn tissues. We conclude thAt Stefin A is expressed in metAstAtic breAst tumors And in distAnt metAstAses, Acting As A mArker of ActivAted cysteine cAthepsins, which Are potentiAl therApeutic tArgets for metAstAtic diseAse.

Tamara T. Lah - One of the best experts on this subject based on the ideXlab platform.

  • immunohistochemicAl stAining of cAthepsins b l And Stefin A in humAn hypophysis And pituitAry AdenomAs
    Anticancer Research, 2005
    Co-Authors: Tadej Strojnik, Tamara T. Lah, Boris Zidanik
    Abstract:

    BAckground: New biologicAl mArkers Are needed for diAgnosis of AtypicAl pituitAry AdenomA. The study Aimed to evAluAte cAthepsins B And L And inhibitor Stefin A in relAtion to their Aggressive progression. PAtients And Methods: We evAluAted 19 AdenomAs And 10 normAl hypophyses. AdenomAs were divided According to their histologicAl feAtures And According to their functionAl Activity, e.g. hormones secretion. ImmunohistochemicAl lAbelling wAs scored for cAthepsins And Stefin A. Results: High immunohistochemicAl scores for cAthepsins B And L were more frequent in AtypicAl pituitAry AdenomA. Higher cAthepsin B scores were Also observed in functionAl compAred with non-functionAl tumours, independently of their histology. Stefin A lAbelling wAs observed in 90% of normAl hypophyses, but only in 10% of AdenomAs. Conclusion: The levels of cAthepsins B And L Antigens Are significAntly higher in histologicAlly AtypicAl AdenomAs. CAthepsin B is Also A mArker of functionAl Activity of the neoplAstic glAnds. Therefore, we propose thAt this enzyme is evAluAted As A diAgnostic mArker for tumour progression in non-functionAl AdenomAs, to distinguish AtypicAl from benign tumours. PituitAry tumours (AdenomAs) constitute ApproximAtely 10% of All symptomAtic intrAcrAniAl tumours, Although Autopsy studies indicAte A higher incidence, suggesting thAt the smAll non-functionAl AdenomAs Are clinicAlly silent. It hAs been estimAted, from both clinicAl And post-mortem studies, thAt pituitAry AdenomAs occur in Around 20% of the normAl populAtion, but only A minority of these Are symptomAtic (1). AdenomAs Arise primArily from the Anterior pArt (Adenohypophysis) of the pituitAry glAnd (2). PituitAry tumours usuAlly present due to endocrinologicAl disturbAnce or to mAss effect. RAdiologicAl clAssificAtion, devised by HArdy, is bAsed upon tumour size, the presence or Absence of vArious extensions And the degree of locAl invAsion (3, 4). DecAdes of clinicAl, immunohistochemicAl And ultrAstructurAl studies resulted in the World HeAlth OrgAnizAtion (WHO) clAssificAtion of pituitAry AdenomAs (5, 6), firmly bAsed on hormone production (6, 7). HistologicAl clAssificAtion of AdenohypophysiAl tumours (WHO 2000) includes typicAl And AtypicAl AdenomA, cArcinomA, soft tissue tumours, secondAry tumours And tumour-like lesions (6).

  • CompArison of potentiAl biologicAl mArkers cAthepsin B, cAthepsin L, Stefin A And Stefin B with urokinAse And plAsminogen ActivAtor inhibitor-1 And clinicopAthologicAl dAtA of breAst cArcinomA pAtients
    Cancer Detection and Prevention, 2002
    Co-Authors: Natasa Levicar, Janko Kos, Snježana Frkovič-grazio, Andrej Blejec, Rastko Golouh, Ivan Vrhovec, Tamara T. Lah
    Abstract:

    AbstrAct Cysteine, serine And metAlloproteinAses And their respective inhibitors Are involved in tumor cell invAsion And mAy hAve prognostic vAlue for the outcome of mAlignAnt diseAse. The Aim of the study wAs to compAre the expression of new potentiAl biologicAl tumor mArkers, the lysosomAl cysteine proteinAses And their endogenous inhibitors, with thAt of the serine proteinAses And their inhibitors in breAst cAncinomA And to relAte their levels to the clinicopAthologicAl fActors of the diseAse. Enzyme-linked immunosorbent AssAys (ELISAs) were used to meAsure cysteine cAthepsin B (CAtB) And cAthepsin L (CAtL) And their inhibitors, Stefin A (StA) And Stefin B (StB), together with urokinAse (u-PA) And plAsminogen ActivAtor inhibitor-1 (PAI-1), in 150 cytosols of primAry invAsive breAst cArcinomA. A good correlAtion wAs found between the levels of the two cysteine proteinAses but only A moderAte one between those of the cysteine And serine proteinAses. u-PA And PAI-1 levels correlAted positively with histologicAl grAde And negAtively with estrogen receptor (ER) stAtus. PAI-1 correlAted with most clinicopAthologicAl fActors thAt indicAte the progression of the diseAse, while cAthepsins And Stefins were independent of these fActors. In the totAl group of pAtients, high u-PA And PAI-1 And low StB levels correlAted significAntly with shorter diseAse-free survivAl (DFS), while CAtB, CAtL And StA did not. In lymph node negAtive pAtients, high CAtB And CAtL were Also AssociAted with shorter DFS, while u-PA remAined the most significAnt of All these biologicAl mArkers. In conclusion, this retrospective study showed u-PA to be of better prognostic relevAnce thAn the cysteine proteinAses, though CAtB And CAtL were relevAnt for prognosis in lymph node negAtive breAst cAncer pAtients.

  • Expression of cysteine peptidAse cAthepsin L And its inhibitors Stefins A And B in relAtion to tumorigenicity of breAst cAncer cell lines.
    Cancer Letters, 2002
    Co-Authors: Irena Zajc, Ales Bervar, Natasa Sever, Tamara T. Lah
    Abstract:

    The in vitro invAsiveness of humAn breAst cAncer cell lines wAs compAred with their reported tumorigenicity in vivo, increAsing from MCF7, MDA-MB468, MDA-MB231 to MDA-MB435 cells. The invAsiveness roughly corresponded to the tumorigenicity of the cell lines. The levels of cAthepsin L mRNA And protein correlAted with the invAsiveness of the cells. Stefin A protein decreAsed with the invAsiveness And the reported tumorigenicity, whereAs Stefin B protein wAs significAntly lower in All MDA-MB lines compAred with the leAst invAsive And tumorigenic MCF7 line. Our results suggest thAt the imbAlAnce between cAthepsin L And the Stefins contributes to the development of A mAlignAnt cell phenotype.

  • cAthepsin b And its inhibitor Stefin A in brAin tumors
    Pflügers Archiv: European Journal of Physiology, 2000
    Co-Authors: Tadej Strojnik, Janko Kos, Rastko Golouh, Boris Zidanik, Irena Zajc, Ales Bervar, Vinko Dolenc, Tamara T. Lah
    Abstract:

    Cysteine proteAse cAthepsin B (CAtB) And its endogenous inhibitor Stefin A (StA) plAy An importAnt role in tumor progression. IncreAse of CAtB expression And lower levels of its inhibitors were AssociAted with tumor mAlignAncy in brAin tumors. In this study of 100 pAtients, CAtB wAs locAlized by immunostAining to both, tumor And endotheliAl cells of primAry brAin tissue. SignificAnt correlAtion with poor prognosis wAs found by univAriAte Cox's regression model. Intense overAll immunostAining And immunostAining in endotheliAl cells Alone were prognostic for survivAl (p=0.003 in both). When compAring CAtB expression At mRNA level, we found considerAble differences between center And periphery of A tumor As well As between different tumor sAmples. StA mRNA wAs only detected in benign, but not in mAlignAnt tissues. We suggest thAt screening of cysteine-proteAse genes expression cAn be Applied in clinicAl prognosis of brAin tumors.

  • The expression of lysosomAl proteinAses And their inhibitors in breAst cAncer: Possible relAtionship to prognosis of the diseAse
    Pathology & Oncology Research, 1997
    Co-Authors: Tamara T. Lah, Janko Kos, Andrej Blejec, Rastko Golouh, Ivan Vrhovec, Snežana FrkoviČ-georgio, Vito Turk
    Abstract:

    Proteolytic enzymes hAve been proposed As new biologicAl prognostic indicAtors to fAcilitAte decisions About treAtment of breAst cAncer pAtients following surgery. We reported eArlier thAt the Activities of cysteine proteinAses (CP), cAthepsin (CAt) B And cAthepsin (CAt) L And the expression of Stefin A might be AssociAted with breAst tumor progression And prognosis. Here, the protein concentrAtions of CAts D, B And L And Stefin A hAve been meAsured in A series of 60 mAtched pAirs of breAst tumours And control AdjAcent tissues, using ELIS As developed in our lAborAtory. MediAn tumor concentrAtions of CAt D (47 pm/mg), CAt B (222 ng/mg) And CAt L (88 ng/mg) were significAntly (p

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  • cAthepsin b inhibition limits bone metAstAsis in breAst cAncer
    Cancer Research, 2012
    Co-Authors: Nimali P Withana, Mansoureh Sameni, Arulselvi Anbalagan, Clare Y Slaney, Mary B Olive, Bradley N Bidwell, Laura E Edgington, Galia Blum, Ling Wang, Kamiar Moin
    Abstract:

    MetAstAsis to bone is A mAjor cAuse of morbidity in breAst cAncer pAtients, emphAsizing the importAnce of identifying moleculAr drivers of bone metAstAsis for new therApeutic tArgets. The endogenous cysteine cAthepsin inhibitor Stefin A is A suppressor of breAst cAncer metAstAsis to bone thAt is coexpressed with cAthepsin B in bone metAstAses. In this study, we used the immunocompetent 4T1.2 model of breAst cAncer which exhibits spontAneous bone metAstAsis to evAluAte the function And therApeutic tArgeting potentiAl of cAthepsin B in this setting of AdvAnced diseAse. CAthepsin B AbundAncy in the model mimicked humAn diseAse, both At the level of primAry tumors And mAtched spinAl metAstAses. RNA interference–mediAted knockdown of cAthepsin B in tumor cells reduced collAgen I degrAdAtion in vitro And bone metAstAsis in vivo . SimilArly, intrAperitoneAl AdministrAtion of the highly selective cAthepsin B inhibitor CA-074 reduced metAstAsis in tumor-beAring AnimAls, A reduction thAt wAs not reproduced by the broAd spectrum cysteine cAthepsin inhibitor JPM-OEt. NotAbly, metAstAsis suppression by CA-074 wAs mAintAined in A lAte treAtment setting, pointing to A role in metAstAtic outgrowth. Together, our findings estAblished A prometAstAtic role for cAthepsin B in distAnt metAstAsis And illustrAted the therApeutic benefits of its selective inhibition in vivo . CAncer Res; 72(5); 1199–209. ©2012 AACR .

  • FunctionAl expression of recombinAnt humAn Stefin A in mAmmAliAn And bActeriAl cells.
    Protein Expression and Purification, 2007
    Co-Authors: Catharine C. Calkins, Bonnie F Sloane, Julie Dosescu, Nancy A. Day, Wei Ping Ren, Rafael Fridman, Kamiar Moin
    Abstract:

    RecombinAnt humAn cysteine proteAse inhibitor, Stefin A, wAs expressed in both E. coli And BSC-1 monkey kidney cells utilizing pET And recombinAnt VAcciniA virus systems, respectively. The expressed protein wAs purified And AnAlyzed by SDS-PAGE And western blot AnAlysis utilizing A polyclonAl Antibody AgAinst rAt cystAtin α. In both cAses the purified protein AppeAred As A single bAnd corresponding to the moleculAr weight of Stefin A (~10 kDA). ViAbility of the expressed Stefin A wAs determined by the inhibition of the plAnt cysteine proteAse, pApAin. RecombinAnt humAn Stefin A expressed in both E. coli And BSC-1 cells wAs shown to Almost completely inhibit pApAin. The expression of A fully functionAl recombinAnt humAn Stefin A in the bActeriAl system provides A highly efficient tool for the production of lArge quAntities of the protein. This cAn be An importAnt tool in kinetic studies As well As in production of Antibodies for other AnAlyticAl studies (immunoblot, immunohistochemicAl studies, etc.). Expression in the mAmmAliAn cells on the other hAnd, cAn provide A significAnt reseArch tool to study the functionAl roles of Stefin A in the mAmmAliAn systems such As the regulAtion of cysteine proteAses.

  • CAthepsin B And its endogenous inhibitors: the role in tumor mAlignAncy
    Cancer and Metastasis Reviews, 1990
    Co-Authors: Bonnie F Sloane, Kamiar Moin, Evzen Krepela, Jurij Rozhin
    Abstract:

    SeverAl lysosomAl proteinAses including the cysteine proteinAse cAthepsin B hAve been implicAted in mAlignAnt progression of tumors. MAny investigAtors hAve demonstrAted correlAtions between increAsed Activity of cAthepsin B And increAsed metAstAtic cApAbility of AnimAl tumors or mAlignAncy of humAn tumors. Such increAses in cAthepsin B Activity in mAlignAnt tumors mAy reflect AlterAtions in synthesis, in ActivAtion And processing, And/or in intrAcellulAr trAfficking And delivery As well As in the endogenous inhibitors of cAthepsin B. IncreAses in mRNA trAnscripts for cAthepsin B hAve been observed in both murine And humAn tumors And multiple trAnscripts for cAthepsin B hAve been identified, but An AssociAtion of multiple trAnscripts with mAlignAncy hAs not been confirmed. CAthepsin B precursors found in humAn mAlignAnt Ascites fluid do not possess mAnnose-rich cArbohydrAtes suggesting thAt A defect in the post trAnslAtionAl processing of cArbohydrAte moieties on tumor cAthepsin B mAy be responsible for the releAse of cAthepsin B observed in mAny tumor systems. However, the intrAcellulAr trAfficking of cAthepsin B responsible for its AssociAtion with plAsmA membrAne/endosomAl systems And for its releAse willrequire further study As both lAtent, precursor forms of cAthepsin B And nAtive forms of cAthepsin B Are involved. We speculAte thAt mAlignAnt tumor cells Adherent to bAsement membrAne Are cApAble of forming A digestive microenvironment in which lysosomAl proteinAses such As cAthepsin B function optimAlly, A microenvironment similAr to thAt formed between Adherent osteoclAsts And bone. One of the endogenous cysteine proteinAse inhibitors, Stefin A, Also is Affected by mAlignAncy. Reduced expression (mRNA And protein) of Stefin A is found As well As A reduction in its inhibitory cApAcity AgAinst cysteine proteinAses. The dAtA to dAte At both the moleculAr And protein levels supporting A functionAl role(s) for cAthepsin B And its endogenous inhibitors in cAncer progression Are only correlAtive. ExperimentAl ApproAches utilizing well-defined model systems in conjunction with genetic mAnipulAtion of cAthepsin B And its endogenous inhibitors Are needed to provide convincing evidence thAt cAthepsin B hAs An importAnt role in cAncer.

  • CAthepsin B And its endogenous inhibitors: the role in tumor mAlignAncy
    Cancer and Metastasis Reviews, 1990
    Co-Authors: Bonnie F Sloane, Kamiar Moin, Evzen Krepela, Jurij Rozhin
    Abstract:

    SeverAl lysosomAl proteinAses including the cysteine proteinAse cAthepsin B hAve been implicAted in mAlignAnt progression of tumors. MAny investigAtors hAve demonstrAted correlAtions between increAsed Activity of cAthepsin B And increAsed metAstAtic cApAbility of AnimAl tumors or mAlignAncy of humAn tumors. Such increAses in cAthepsin B Activity in mAlignAnt tumors mAy reflect AlterAtions in synthesis, in ActivAtion And processing, And/or in intrAcellulAr trAfficking And delivery As well As in the endogenous inhibitors of cAthepsin B. IncreAses in mRNA trAnscripts for cAthepsin B hAve been observed in both murine And humAn tumors And multiple trAnscripts for cAthepsin B hAve been identified, but An AssociAtion of multiple trAnscripts with mAlignAncy hAs not been confirmed. CAthepsin B precursors found in humAn mAlignAnt Ascites fluid do not possess mAnnose-rich cArbohydrAtes suggesting thAt A defect in the post trAnslAtionAl processing of cArbohydrAte moieties on tumor cAthepsin B mAy be responsible for the releAse of cAthepsin B observed in mAny tumor systems. However, the intrAcellulAr trAfficking of cAthepsin B responsible for its AssociAtion with plAsmA membrAne/endosomAl systems And for its releAse willrequire further study As both lAtent, precursor forms of cAthepsin B And nAtive forms of cAthepsin B Are involved. We speculAte thAt mAlignAnt tumor cells Adherent to bAsement membrAne Are cApAble of forming A digestive microenvironment in which lysosomAl proteinAses such As cAthepsin B function optimAlly, A microenvironment similAr to thAt formed between Adherent osteoclAsts And bone. One of the endogenous cysteine proteinAse inhibitors, Stefin A, Also is Affected by mAlignAncy. Reduced expression (mRNA And protein) of Stefin A is found As well As A reduction in its inhibitory cApAcity AgAinst cysteine proteinAses. The dAtA to dAte At both the moleculAr And protein levels supporting A functionAl role(s) for cAthepsin B And its endogenous inhibitors in cAncer progression Are only correlAtive. ExperimentAl ApproAches utilizing well-defined model systems in conjunction with genetic mAnipulAtion of cAthepsin B And its endogenous inhibitors Are needed to provide convincing evidence thAt cAthepsin B hAs An importAnt role in cAncer.