<p>Difuzni krupnoćelijski B limfom je najče&scaron;ći limfom na svetu i obuhvata do 30% non Hodgkin limfoma u zapadnim zemljama i veći procenat u zemljama u razvoju i nerazvijenim zemljama. Obično nastaje de novo ali može nastati sekundarno kao rezultat progresije manje agresivnih limfoma. U većini slučajeva počinje u limfnim čvorovima. Histolo&scaron;ka slika nije uniformna kod svih podtipova DLBCL, zbog morfolo&scaron;kog diverziteta tumorskih ćelija i zbog pratećih neneoplastičnih procesa. Na&scaron;e istraživanje obuhvata 92 bolesnika koji su dijagnostikovani i lečeni na Institutu za onkologiju Vojvodine od 2003. do 2011. godine, od kojih je 66 imalo kompletna imunohistohemijska ispitivanja. Svi su lečeni standardnim protokolom koji uključuje rituksimab. Ispitivali smo morfolo&scaron;ki i imunohistohemijski podtip, ekspresiju imunohistohemijskih markera, pol, starost, stadijum, nodalno/ekstranodalno ishodi&scaron;te i preživljavanje. CD20 je bio pozitivan u svim dostupnim uzorcima. MUM1 u 62,07%, CD10 u 20,23%, BCL6 u 51,72%, CD30 u 10,81%, CD5 u 8,05%, Ki-67 u 30-92%, BCL2 u 39,33%, BAFFR u 46,15%, TACI u 43,94%, BCMA u 10,61%, VEGF u 27,7%, COX2 u 63,64%, CD43 u 18,52%, EBV LMP u 37,88%. Među obolelim ženama je statistički značajno veći procenat MUM1 pozitivnih i BAFFR pozitivnih bolesnika nego među obolelim mu&scaron;karcima. Kod starijih ispitanika je statistički signifikantno ređa ekspresija CD30, COX2, TACI i BCMA. Kod ekstranodalnih limfoma ekspresija TACI je če&scaron;ća nego kod nodalnih limfoma. Ispitanici sa pozitivnom ekspresijom COX2 i ispitanici sa pozitivnom ekspresijom TACI imaju značajno izraženiju ekspresiju Ki-67. Bolesnici sa negativnom ekspresijom BCL2 imaju statistički značajnu korelaciju sa negativnom ekspresijom CD5 i negativnom ekspresijom CD43. Bolesnici sa pozitivnom ekspresijom CD30 imaju statistički značajnu pozitivnu korelaciju sa ekspresijom BCMA. Ispitanici sa pozitivnom ekspresijom COX2 imaju statistički značajnu pozitivnu korelaciju sa ekpresijom TACI. Markeri aktivacije i diferencijacije limfocita nemaju statistički značajnu pozitivnu korelaciju sa boljom prognozom. Markeri signalnih puteva angiogeneze i inflamacije nemaju statistički značajnu pozitivnu korelaciju sa lo&scaron;ijom prognozom. Izgleda da treba biti racionalan i upotrebiti samo osnovna antitela za određivanje imunohistohemijskog podtipa i antitela potrebna za diferencijalnu dijagnozu. Čini se da je prognostički značaj imunohistohemijskih antitela (osim CD20) danas kada se u terapiji koristi Rituximab minimalan.</p> / <p>Diffuse large B-cell lymphoma is the most common lymphoma in the world and represents up to 30% of all NHL in western countries and more in developing and undeveloped countries. It is usually a primary disease but also it can develop secondary as a result of progression of low grade lymphomas. In most cases the disease begins in lymph nodes. Histological features are not uniform in all subtypes of DLBCL due to morphological diversity and following non-neoplastic processes. Our research includes 92 patients whom are diagnosed and treated at the Institute for Oncology of Vojvodina since 2003. to 2011. and 66 among them have complete immunohistochemical findings. All of them are treated with standard protocols including Rituximab. We have examined morphological and immunohistochemical subtype, expression of immunohistochemical markers, sex, age, stadium, nodal / extranodal origin and survival. CD20 was positive in all available samples. MUM1 in 62,07%, CD10 in 20,23%, BCL6 in 51,72%, CD30 in 10,81%, CD5 in 8,05%, Ki-67 in 30-92%, BCL2 in 39,33%, BAFFR in 46,15%, TACI in 43,94%, BCMA in 10,61%, VEGF in 27,7%, COX2 in 63,64%, CD43 in 18,52%, EBV LMP in 37,88%. Female patients have significantly more often MUM1 and BAFFR expression compared to male patients. Older patients have significantly less often CD30, COX2, TACI and BCMA expression. Extranodal lymphomas have more frequent TACI expression then nodal ones. Patients with COX2 expression and patients with TACI expression have significantly higher Ki-67 expression. Patients without BCL2 expression have a significant correlation with CD5 negative expression and CD43 negative expression. Patients with CD30 expression have significant correlation with BCMA expression. Patients with COX2 expression have significant correlation with TACI expression. Markers of activation and differentiation of lymphocytes do not have significant correlation with better prognosis. Markers of signaling pathways for angiogenesis and inflammation do not have a significant correlation with worst prognosis. It seems that we should be rational and use only basic antibodies for determination if immunohistochemical subtype and antibodies necessary for differential diagnosis. It seems that prognostic significance of immunohistochemical antibodies (except CD20) is minimal today in Rituximab era.</p>

<p>Akrilamid (CASR No. 79-06-1) predstavlja veoma reaktivni, hidrosolubilni&nbsp;monomer za koji se smatra da ima toksične i potencijalno kancerogene efekte po&nbsp;zdravlje ljudi. &Scaron;tetne posledice akrilamida i njegovog jo&scaron; reaktivnijeg metabolita,&nbsp;glicidamida, su dokazane kod eksperimentalnih životinja i podrazumevale su&nbsp;neurotoksičnost, genotoksičnost i kancerogenost. Epidemiolo&scaron;ke studije rađene na&nbsp;ljudima pokazale su da akrilamid izaziva neurotoksične efekte, dok se genotoksičnost i&nbsp;kancerogenost jo&scaron; smatraju potencijalnim efektima, a zasnivaju se na podacima koji su&nbsp;dobijeni u okviru istraživanja na laboratorijskim životinjama. Njegove &scaron;tetne posledice&nbsp;na jetru, posebno kod mladog organizma, jo&scaron; uvek nisu dovoljno istražene.</p><p>Akrilamid se spontano formira u hrani koja je bogata ugljenim hidratima, tokom&nbsp;termičke obrade namirnica na visokim temperaturama. Ovaj monomer se formira&nbsp;tokom tzv. neenzimatske Mallard-ove reakcije, kojom se dobijaju smeđe komponente&nbsp;u hrani. U namirnicama ovaj monomer se formira reakcijom između redukujućih&nbsp;&scaron;ećera (uglavnom glukoze ili fruktoze) i aminokiseline (dominantno asparagina).</p><p>Imajući na umu da je jetra centralni organ za metabolizam akrilamida, ovo&nbsp;istraživanje &nbsp;je imalo za cilj da ispita glavne histolo&scaron;ke i biohemijske promene na jetri&nbsp;juvenilnog organizma pacova, nakon njegove subhronične ekspozicije akrilamidu.&nbsp;Istraživanje je &nbsp;rađeno na 3 eksperimentalne grupe peripubertalnih/juvenilnih mužjaka&nbsp;Wistar pacova, od kojih su dve bile tretirane vodenim rastvorom akrilamida u dozi od&nbsp;25 ili 50 &nbsp;mg/kg telesne mase, dok je treća grupa služila kao kontrola i primala&nbsp;destilovanu vodu. Životinje su bile tretirane oralno, putem gavaže, 5 dana nedeljno,&nbsp;tokom 3 nedelje. Nakon 24 h od poslednjeg tretmana, životinje su uvedene u etarsku &nbsp;anesteziju i dekapitovane, a zatim su prikupljeni krv i uzorci tkiva jetre.</p><p>Tkivo jetre je uzeto iz srednjeg lobusa, fiksirano u 10% neutralnom puferisanom &nbsp;formalinu tokom 24 h i obrađeno prema standardnom protokolu za parafinsko kalupljenje. Ukalupljeni uzorci jetre su zatim isečeni na serijske preseke tkiva debljine&nbsp;5 &micro;m, a zatim bojeni histohemijskim i imunohistohemijskim metodama. Uzorci krvi su&nbsp;pripremljeni za serolo&scaron;ku analizu.&nbsp;</p><p>Histolo&scaron;ka analiza preseka bojenih hematoksilin-eozin (H&amp;E) metodom nije &nbsp;zabeležila prisustvo značajnih razlika u op&scaron;toj arhitekturi jetre i njenoj lobularnoj &nbsp;organizaciji među eksperimentalnim grupama. Stereolo&scaron;ka analiza je ukazala na &nbsp;<br />mikrostrukturne promene kod hepatocita i jetrinih sinusoida. Rezultati sugeri&scaron;u, na&nbsp;dozno-zavisno povećanje volumena hepatocita, njihove citoplazme i nukleusa, i doznozavsino smanjenje volumena sinusoida, u odnosu na kontrolne uzorke jetre.</p><p>Analiza glikogena je rađena na presecima jetre bojenim metodom Periodic acid&ndash;<br />Schiff-a (PAS), gde se uočilo smanjenje količine glikogena u grupi tretiranoj nižom &nbsp;dozom akrilamida, dok je u grupi tretiranoj većom dozom uočena njegova&nbsp;<br />akumulacija, u odnosu na kontrolne životinje.</p><p>Imunopozitivnost hepatocita na marker proliferacije, Ki-67, bila je smanjena u&nbsp;grupi pacova tretiranoj nižom dozom, a bila povećana u grupi tretiranoj većom dozom&nbsp;akrilamida pri komparaciji sa kontrolom. Stereolo&scaron;ki nalazi su potvrdili inicijalnu&nbsp;histolo&scaron;ku analizu.</p><p>Imunopozitivnost hepatocita na marker apoptoze, Caspase 3, je bila smanjena&nbsp;<br />kod obe grupe životinja tretiranih akrilamidom u odnosu na kontrolu. Nasuprot tome,&nbsp;<br />imunopozitivnost neparenhimskih ćelija jetre, pretežno Kupffer-ovih ćelija, je bila&nbsp;<br />uvećana u obe tretirane grupe pri komparaciji sa kontrolom.</p><p>Imunopozitivnost Kupffer-ovih ćelija na marker CD68 je bila smanjena u&nbsp;uzorcima jetre kod oba tretmana akrilamidom u odnosu na kontrolu.</p><p>Populacija mastocita, prikazana toluidine-blue (TB) metodom bojenja, bila je&nbsp;uvećana &nbsp;kod obe grupe pacova tretiranih akrilamidom u poređenju sa kontrolom.&nbsp;Povećanje brojnosti ovih ćelija je bilo posebno prominentno kod njihove degranulisane &nbsp;subpopulacije. Stereolo&scaron;ka analiza je potvrdila histolo&scaron;ke nalaze.&nbsp;</p><p>Serumska analiza je pokazala uvećanu aktivnost aspartat aminotrasferaze (AST) i&nbsp;<br />smanjenu aktivnost alanin aminotrasferaze (ALT) kod obe grupe životinja tretiranih &nbsp;<br />akrilamidom u odnosu na kontrolu. Aktivnost alkalne fosfataze (ALP) je bila uvećana&nbsp;<br />u grupi tretiranoj nižom dozom, a smanjena u grupi tretiranoj većom dozom&nbsp;<br />akrilamida, u odnosu na kontrolu. Vrednosti koncentracije ukupnih serumskih proteina&nbsp;kao i koncentracije C reaktivnog proteina (CRP) nisu pokazale značajnije promene&nbsp;među eksperimentalnim grupama.</p><p>Oba akrilamidna tretmana su izazvala gubitak telesne mase kod tretiranih&nbsp;pacova, u odnosu na kontrolne životinje.&nbsp;Postojeći podaci ukazuju prominentni hepatotoksični potencijal akrilamida koji može&nbsp;poremetiti mikrostrukturne osobine i funkcionalni status hepatocita kod jetre mladog&nbsp;organizma. Akrilamid može značajno poremetiti funkcionalnost jetre, obzirom da se&nbsp;promene na celularnom nivou mogu relativno brzo odraziti na nivo tkiva, a kasnije&nbsp;ugroziti i homeostazu celog organizma.</p> / <p>Acrylamide&nbsp; (CASR No. 79-06- 1)&nbsp; is highly reactive, water-soluble monomer which is considered as toxic and potentially cancer causing chemical to humans. Adverse health effects regarding acrylamide and its more reactive metabolite,glycidamide, were detected in experimental animals, and&nbsp; included neurotoxicity, genotoxicity, and&nbsp;&nbsp; carcinogenicity.&nbsp; Human epidemiological studies claim that acrylamide has neurotoxic effects, while&nbsp; genotoxicity and carcinogenicity are considered as&nbsp; potential human health risks only on the basis of animal studies. Its harmful effects on the liver, especially in a young organism, are still to be elucidated.</p><p>Acrylamide&nbsp; is spontaneously formed in&nbsp; carbohydrate-rich food during high-temperature&nbsp; processing. It is&nbsp; formed during heat-induced non-enzymatic reaction, also known as&nbsp; the Maillard browning reaction, between reducing sugars (glucose and fructose), and free amino acids (mainly asparagine).</p><p>Having in mind&nbsp; that&nbsp; acrylamide&nbsp; metabolism takes place in a liver,&nbsp; the study aimed to investigate the main histological and&nbsp; biochemical changes in the liver of juvenile rat following subchronic acrylamide intoxication. Study was performed on peripubertal/juvenile male Wistar rats, divided in 3 experimental groups, two of which were treated with acrylamide in doses of 25 or 50 mg/kg of body weight, while the third group served as the control and received distilled water. Animals were treated orally, via gavage, 5 days a week, during 3 weeks. Animals&nbsp; were anesthetized by&nbsp;&nbsp; ether inhalation and decapitated 24 hrs after the last treatment.</p><p>Liver tissue was sampled from the middle lobe, fixed in&nbsp; 10% neutral&nbsp; buffered formalin for 24 hrs,&nbsp; routinely processed for paraffin&nbsp; embedding&nbsp; and cut into 5-&micro;m thick serial sections for subsequent histochemical and immunohistochemical staining.Blood samples were collected for subsequent biochemical analysis .</p><p>Histological examination of haematoxylin and eosin (H&amp;E) stained sections did not point to any major alteration in main in liver lobular architecture or organization among the experimental groups. Stereological analysis revealed a microstructural changes in hepatocytes and liver sinusoids. The analysis detected a dose-dependant increase in the volume of hepatocytes, their cytoplasm and nuclei, and dose-dependant decrease in the volume of liver sinusoids compared to the control, respectively.</p><p>Glycogen analysis was performed on Periodic acid&ndash;Schiff (PAS) stained sections which showed glycogen reduction in the low-dose group, and its accumulation in the high-dose group, compared to the control, respectively.</p><p>Imunopositivity in hepatocytes for Ki-67 protein, a known marker for proliferation, showed a decrease in low-dose group, while in high- dose group was detected its increase compared to the control, respectively. Stereological analysis confirmed initial histological observation.</p><p>Caspase 3 immunopositivity, a known marker for apoptosis, proved to be decreased in hepatocytes in both acrylamide-treated groups when compared to the control. One the other hand, immunopositivity was increased in non-parenchymal&nbsp; cell, predominantly in Kupffer cells, in comparison to the control. Immunopositivity for CD68, a marker for Kupffer cells, proved to be decreased in both acrylamide-treated groups when compared to the control.</p><p>Population of the mast cells, visualized on toluidine blue (TB) stained sections, showed its increase in both acrylamide-treated groups, in comparison to the control. The increase was especially prominent regarding a degranulated subpopulation of these cells. Subsequent stereological analysis confirmed histological findings.</p><p>Serum analysis showed increased&nbsp; activity of&nbsp; aspartate aminotransferase (AST), and decreased&nbsp; activity&nbsp; of alanine aminotransferase (ALT) in&nbsp; both AA-treated groups, while the&nbsp; activity&nbsp; of alkaline phosphatase (ALP)&nbsp; was increased in low-dose, but&nbsp;&nbsp; decreased in high- dose group compared to the control, respectively.&nbsp; The concentration of total serum proteins as well as concentration of C reactive protein (CRP) did not show any major changes among the experimental groups.</p><p>Body weight measurements showed that all acrylamide-treated rats lost their body weight as opposed to the control rats whose body mass increased.</p><p>Present results suggest a prominent hepatotoxic potential of acrylamide which might alter the microstructural features and functional status in hepatocytes of&nbsp; immature liver.&nbsp; Acrylamide may cause significant perturbation in liver functionality which may be reflected from cellular to the tissue level, thereby endangering the whole body&rsquo;s homeostasis.</p>

<p>U grliću materice se histolo&scaron;ki razlikuju dva regiona: ektocerviks (vaginalna porcija) i endocervikalni deo. Osnovna histolo&scaron;ka razlika između ovih delova se ogleda u epitelu koji oblaže sluznicu. Histolo&scaron;ke osobenosti endocervikalnog dela grlića materice u dostupnoj literaturi nisu detaljno proučene i postoje mnoga neodgovorena pitanja u pogledu op&scaron;tih kvantitativnih morfolo&scaron;kih karakteristika, kao i u pogledu dobno zavisnih promena ovih parametara. Takođe, podaci u vezi odeljka i tipa ćelijske populacije odgovorne za regeneracija epitela u endocerviksu su u dostupnoj literaturi heterogeni i nisu jasno precizirani. U ovoj studiji su morfometrijskim metodama (linearnim i stereolo&scaron;kim merenjem) analizirani histolo&scaron;ki preparati grlića materice obojeni standarnim hematoksilin /eozin bojenjem i imunohistohemijskim metodama (Ki-67, p63 i CK17) s ciljem da se odrede prosečne i referentne vrednosti op&scaron;tih histolo&scaron;kih parametara i ćelijske populacije odgovorne za regeneraciju epitela endocervikalnog dela grlića materice. Analiziran je broj endocervikalnih žlezda po santimetru dužine endocerviksa, dubina endocervikalnih žlezda, visina endocervikalnog epitela, volumenske gustine strome, žlezda, lumena žlezda i epitela, kao i volumenske gustine proliferativnih ćelija (p63+/CK17+ u odnosu na p63-/CK17-) u endocervikalnom epitelu. Obrađeno je ukupno 140 isečaka grlića materice, koji su podeljeni u dve grupe: grupa bez patolo&scaron;kih promena i grupa sa odabranim benignim procesima u endocerviksu. Isečci bez patolo&scaron;kih promena su podeljeni na osnovu godina starosti pacijentkinja u 5 podgrupa kako bi se utvrdilo da li postoje dobno zavisne razlike u vrednostima navedenih parametara. Na osnovu rezultata ovog istraživanja referentna vrednost broja endocervikalnih žlezda po santimetru dužine je 13 - 29 žl/cm, dubine endocervikalnih žlezda je 1,3 - 4 mm a visine epitelnih ćelija endocerviksa je 24 - 46 &mu;m. Kod žena starosti preko 60 godina broj bazalnih ćelija endocervikalnog epitela opada u odnosu na mlađe pacijentkinje. Kod perimenopauzalnih žena, starosti od 40 do 49 godina, je nađena najveća prosečna vrednost dubine endocervikalnih žlezda, prosečne visine epitela endocerviksa, kao i najveći ukupni proliferativni indeks u endocervikalnom epitelu. U svim ispitivanim grupama, analizom volumenskih gustina regeneratornih ćelija endocervikalne sluznice (Ki-67 pozitivnih ćelija) u odnosu na druge imunohistomijske karakteristike (p63 i CK17 pozitivnost), rezultati dobijeni u ovoj disertaciji ukazuju na činjenicu da u endocervikalnom delu grlića materice postoje dva izvora regeneratornih ćelija.</p> / <p>In histologic terms, there are two different regions in the cervix: ectocervix (vaginal portion) and endocervical part. The main histologic difference between these two parts is reflected in the epithelium that coats the mucous. Histologic irregularities of the endocervical part of the cervix have not been studied in details in the available literature and there are many unanswered questions relating to general quantitative morphological features, as well as regarding age-dependent changes of such parameters. In addition, data from the available literature relating to the section and type of cell population responsible for epithelium regeneration in endocervix is heterogenous and not sufficiently precise. In this study, morphometric methods were used (by linear and stereologic measuring) to conduct histologic analysis of cervical preparations stained by standard hematoxylin/eosin stains, and immunohistochemical methods (Ki-67, p63 and CK17) with a goal to determine the average and reference values of general histologic parameters and cell populations responsible for regeneration of the epithelium of the endocervical part of cervix. The number of endocervical glands per centimetre of endocervix lenght, the depth of endocervical glands, the hight of endocervical epithelium, volumetric densities of stroma, glands, glands&#39; lumen and epithelium, as well the volumetric densities of proliferative cells (p63+/CK17+ in relation to p63-/CK17-) in endocervical epithelium were analysed. A total of 140 cervical cuttings was processed, and they were divided into two groups: a group without pathologic changes and a group with chosen benign processes in the endocervix. Cuttings with no pathologic changes were divided into 5 subgroups on the basis of patients&#39; age in order to determine if there are any age-dependent differences in the values of the mentioned parameters. On the basis of the results of this research, the reference value for the number of endocervical glands per centimetre of lenght is 13 - 29 gl/cm, for the depth of endocervical glands is 1.3 - 4 mm and for the hight of endocervical epithelium cells is 24 - 46 &mu;m. With women older than 60, the number of basal cells of endocervical epithelium drops compared to younger patients. The biggest average value of the depth of endocervical glands, average hight of endocervical epithelium, as well as the biggest total proliferative index in the endocervical epithelium were found with women in perimenopause, age between 40 and 49. In all examined groups, by analysing the volumetric densities of regenerative cells of the endocervical mucus (Ki-67 positive cells) in relation to other immunohistochemical features (p63 and CK17 positivity), the results obtained in this dissertation indicate that there are two sources of regerative cells in the endocervical part of the cervix.</p>

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5.4pt;mso-para-margin-top:0in;mso-para-margin-right:0in;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0in;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"Times New Roman";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;}</style><![endif]--></p><p class="MsoNormal" style="text-align:justify">Uvod: Aristolohična kiselina I je nefrotoksična i kancerogena supstanca koja je odgovorna za nefropatiju koja nastaje usled kori&scaron;ćenja herbalnih preparata i čajeva za mr&scaron;avljenje. S obzirom da se ova supstanca može naći u korovskim biljkama, smatra se jednim od glavnih ekotoksikolo&scaron;kih uzroka za nastanak balkanske endemske nefropatije čiji definitivan uzrok jo&scaron; uvek nije otkriven. Toksičnost ove supstance je dokazana na brojnim animalnim modelima, međutim mehanizmi koji dovode do o&scaron;tećenja bubrežnog parenhima jo&scaron; u potpunosti nisu razja&scaron;njeni.<span style="mso-spacerun:yes">&nbsp; </span>Cilj: Doktorska disertacija je koncipirana sa ciljem da se utvrdi uticaj toksičnog jedinjenja aristolohične kiseline I na histopatolo&scaron;ke i imunohistohemijske karakteristike tubulointersticijuma i glomerula bubrega kod mi&scaron;eva, kao i na biohemijske parametre krvi i urina koji ukazuju na o&scaron;tećenje bubrega. Materijal i metode: U ekperimentu je kori&scaron;ćeno 64 mi&scaron;a soja NMRI koji su podeljeni u tri grupe: eksperimentalna grupa (n=32) koja je dobijala aristolohičnu kiselinu I rastvorenu u polietilen glikolu (2,5% PEG 400) u dozi od 10 mg/kg telesne mase, negativna kontrolna grupa koja je dobijala 2,5% PEG 400 (n=16) i kontrolna grupa koja je dobijala fiziolo&scaron;ki rastovor (n=16). Sve životinje su tretirane intraperitonealno svakodnevno tokom sedam dana. Tokom eksperimenta 8., 17., 29. i 59. dana sakupljan je dvadesetčetvoročasovni urin 8 životinja iz eksperimentalne grupe, 4 životinje iz negativne kontrolne i 4 životinje iz kontrolne grupe. Životinje su žrtvovane 9., 18., 30. i 60. dana, uzeta im je krv, dok su bubrezi posebno odvojeni radi histopatolo&scaron;ke analize. Na bubrežnom tkivu sprovedene su histohemijske, imunohistohemijske i morfometrijske analize, dok su na uzorcima seruma i urina sprovedene biohemijske analize. Dobijeni rezultati su testirani adekvatnim statističkim metodama i prikazani su tabelarno i grafički. Rezultati: Nefrotoksin aristolohična kiselina I nakon 7 dana aplikacije izaziva značajno o&scaron;tećenje bubrežnog parenhima. Pri aplikaciji 2,5% PEG 400 i fiziolo&scaron;kog rastvora ne dolazi do vidljivog o&scaron;tećenja bubrežnog parenhima. Histopatolo&scaron;ku sliku u ranoj fazi eksperimenta (9. i 18. dan) karakteri&scaron;e akutna tubulska nekroza proksimalnih tubula. U kasnijoj fazi (30. i 60. dana) uočava se histopatolo&scaron;ka slika hroničnog intersticijalnog nefritisa sa obilnim mononuklearnim ćelijskim infiltratima limfocitnog porekla kao i postojanje blage intersticijalne fibroze. Kod eksperimentalnih životinja je morfometrijskim metodama utvrđen veći stepen bubrežnog o&scaron;tećenja tubulointersticijuma i smanjen broj podocita u glomerulu u odnosu na kontrolne grupe. Biohemijske analize kod većine eksperimentalnih životinja su pokazale veće koncentracije serumske uree nego kod kontrolnih grupa. Takođe je dokazana albuminurija u kasnijoj fazi eksperimenta koja je veća kod životinja izloženih aristolohičnoj kiselini I nego kod životinja iz kontrolnih grupa. Zaključak: Kori&scaron;ćenjem morfometrijskih metoda u okviru histopatolo&scaron;kih i imunohistohemijskih ispitivanja, uz adekvatne biohemijske analize, može se zaključiti da je aristolohična kiselina I izuzetno nefrotoksično jedinjenje koje izaziva izrazite<span style="mso-spacerun:yes">&nbsp; </span>promene tubulointersticijuma i glomerula. Podaci ovog istraživanja predstavljaju polaznu osnovu za dalja istraživanja dijagnostike u ranoj fazi nefropatija izazvanih aristolohičnim kiselinama.<span style="mso-spacerun:yes">&nbsp; </span></p> / <p>Introduction: Aristolochic acid I is a nephrotoxic and carcinogenic substance responsible for nephropathy caused by the use of herbal preparations and teas for slimminng regimen. Since this substance can be found in plants, it is considered one of the major ecotoxicological causes for the emergence of balkan endemic nephropathy whose definitive cause has not yet been revealed. The toxicity of this substance has been proven on numerous animal models, but pathophysiological mechanisms of kidney injury still remain unclear. Aim: The doctoral dissertation was designed to determine the influence of aristolochic acid on the histopathological and immunohistochemical characteristics of tubulointerstitium and glomerulus in mice, as well as the biochemical parameters of blood and urine that indicate kidney injury. Material and methods: For this study, 64 mouse of NMRI strain is used. They are divided into three groups: an experimental group (n=32) that received aristolochic acid I dissolved in polyethylene glycol (2.5% PEG 400) at a dose of 10 mg/kg of body weight, a negative control group that received 2.5% PEG 400 (n=16) and a control group that received only saline (n=16). All animals were treated intraperitoneally daily for seven days. During the experiment on the 8th, 17th, 29th and 59th day, twenty-four-hour urine was collected from 8 animals from the experimental group, 4 animals from the negative control and 4 animals from the control group. Animals were sacrificed on the 9th, 18th, 30th and 60th days, their blood was taken, while the kidneys were taken for histopathological analysis. Histochemical, immunohistochemical and morphometric analyzes were performed on renal tissue, while biochemical analyzes were performed on serum and urine samples. Obtained results were tested with adequate statistical methods and presented in a tables and graphs. Results: After 7 days of application nefrotoxin aristolochic acid I causes significant kidney injury. After application of 2.5% PEG 400 and saline, there was no visible damage to kidney parenchyma. Histopathological changes at the early stage of the experiment (9th and 18th day) were characterized by acute tubular necrosis of proximal tubules. At a later stage (30th and 60th day), chronic interstitial nephritis was observed in kidneys, with abundant mononuclear cell infiltrates in interstitium and presence of mild interstitial fibrosis. In experimental animals, a higher tubulointerstitial score of kidney injury and a decrease in the number of the podocytes in glomerulus were determined by morphometric methods, compared to the control groups. Biochemical analyzes in most experimental animals showed higher blood urea nitrogen concentrations than in control groups. High concentration of albumin in urine can be found in later stages of the experiment, and those concentrations were higher in animals exposed to aristolochic acid I than in animals from control groups.&nbsp; Conclusion: Using morphometric, histopathological and immunohistochemical methods, with adequate biochemical analysis, aristolochic acid I is proven to be an extremely nephrotoxic compound that causes drastic changes in tubulointerstitium and glomeruli of kidney parenhyma. Data from this study can be used for further research into early diagnosis of aristolochic acid nephropathy.</p>

<p>HER2 Gene-Protein Assay (GPA) је посебно погодан за истовремено процењивање експресије HER2 протеина и статуса амплификације HER2 гена на нивоу појединачних ћелија и њихово повезивање са ћелијском морфологијом. Циљ истраживања био је испитати да ли су постојећи критеријуми препоручени од стране ASCO/CAP довољни за дијагностиковање HER2 позитивности код пацијенткиња које показују интратуморску хетерогеност, како у примарним туморима тако и у метастазама у регионалне лимфне чворове, учесталост HER2 хетерогености у макрометастазама лоцираним у лимфним чворовима, те да ли постоји јасна корелација између хетерогености нађене у примарном тумору дојке и припадајућим метастазама у лимфним чворовима. Испитивање је обухватило 41 од планиране 51 пацијенткиње које су испуниле све критеријуме укључивања. Репрезентативни парафински блокови метастатских лимфних чворова одабрани су из архивираног материјала, обојени GPA методом и процењени у складу са критеријумима ASCO/CAP 2013. Анализирано је 120 ћелија у хистолошком резу сваког метастатског лимфног чвора. Статус HER2 се разликовао између примарног тумора и његових метастаза у 13,2% (5/38) случајева. Један случај HER2 позитивног примарног тумора имао је HER2 негативне метастазе, два додатна случаја са HER2 позитивним примарним тумором су имала метастазе са статусом граничне амплификације без прекомерне експресије HER2 протеина и два случаја са HER2 негативним примарним тумором су имала метастазе са статусом граничне амплификације без прекомерне експресије HER2 протеина. У 17.4% (4/23) случајева са HER2 не-амплификованим примарним тумором метастазе су постале граничне у статусу генске амплификације. Једна од четири метастазе HER2 негативног примарног тумора показала је мали фокус HER2 позитивних туморских ћелија (&lt;3% тумора). Микрохетерогеност је анализирана у 108 лимфних чворова код 38 пацијенткиња и уочена у 22 лимфна чвора, тј. код четири пацијенткиње у свим анализираним лимфним чворовима, док је код једне пацијенткиње од 4 анализирана лимфна чвора микрохетерогеност потврђена у једном лимфном чвору. На основу добијених резултата може се закључити да постојећи критеријуми препоручени од стране ASCO/CAP применом прихваћених метода нису довољни за дијагностиковање HER2 позитивности код пацијенткиња које показују интратуморску и интертуморску хетерогеност како у примарним туморима тако и у метастазама, те да постоји статистички високо сигнификантан број макрометастаза лоцираних у лимфним чворовима које показују HER2 хетерогеност и позитивна корелација између хетерогености нађене у примарним туморима и припадајућим метастазама у лимфним чворовима.</p> / <p>HER2 Gene-Protein Assay (GPA) je posebno pogodan za istovremeno procenjivanje ekspresije HER2 proteina i statusa amplifikacije HER2 gena na nivou pojedinačnih ćelija i njihovo povezivanje sa ćelijskom morfologijom. Cilj istraživanja bio je ispitati da li su postojeći kriterijumi preporučeni od strane ASCO/CAP dovoljni za dijagnostikovanje HER2 pozitivnosti kod pacijentkinja koje pokazuju intratumorsku heterogenost, kako u primarnim tumorima tako i u metastazama u regionalne limfne čvorove, učestalost HER2 heterogenosti u makrometastazama lociranim u limfnim čvorovima, te da li postoji jasna korelacija između heterogenosti nađene u primarnom tumoru dojke i pripadajućim metastazama u limfnim čvorovima. Ispitivanje je obuhvatilo 41 od planirane 51 pacijentkinje koje su ispunile sve kriterijume uključivanja. Reprezentativni parafinski blokovi metastatskih limfnih čvorova odabrani su iz arhiviranog materijala, obojeni GPA metodom i procenjeni u skladu sa kriterijumima ASCO/CAP 2013. Analizirano je 120 ćelija u histološkom rezu svakog metastatskog limfnog čvora. Status HER2 se razlikovao između primarnog tumora i njegovih metastaza u 13,2% (5/38) slučajeva. Jedan slučaj HER2 pozitivnog primarnog tumora imao je HER2 negativne metastaze, dva dodatna slučaja sa HER2 pozitivnim primarnim tumorom su imala metastaze sa statusom granične amplifikacije bez prekomerne ekspresije HER2 proteina i dva slučaja sa HER2 negativnim primarnim tumorom su imala metastaze sa statusom granične amplifikacije bez prekomerne ekspresije HER2 proteina. U 17.4% (4/23) slučajeva sa HER2 ne-amplifikovanim primarnim tumorom metastaze su postale granične u statusu genske amplifikacije. Jedna od četiri metastaze HER2 negativnog primarnog tumora pokazala je mali fokus HER2 pozitivnih tumorskih ćelija (&lt;3% tumora). Mikroheterogenost je analizirana u 108 limfnih čvorova kod 38 pacijentkinja i uočena u 22 limfna čvora, tj. kod četiri pacijentkinje u svim analiziranim limfnim čvorovima, dok je kod jedne pacijentkinje od 4 analizirana limfna čvora mikroheterogenost potvrđena u jednom limfnom čvoru. Na osnovu dobijenih rezultata može se zaključiti da postojeći kriterijumi preporučeni od strane ASCO/CAP primenom prihvaćenih metoda nisu dovoljni za dijagnostikovanje HER2 pozitivnosti kod pacijentkinja koje pokazuju intratumorsku i intertumorsku heterogenost kako u primarnim tumorima tako i u metastazama, te da postoji statistički visoko signifikantan broj makrometastaza lociranih u limfnim čvorovima koje pokazuju HER2 heterogenost i pozitivna korelacija između heterogenosti nađene u primarnim tumorima i pripadajućim metastazama u limfnim čvorovima.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>ilija vogel</o:Author> <o:Version>16.00</o:Version> </o:DocumentProperties> <o:OfficeDocumentSettings> <o:AllowPNG/> </o:OfficeDocumentSettings></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> 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<p>Receptor humanog epidermalnog faktora rasta 2 (HER2) pripada porodici receptora protein-tirozin kinaze čija je aktivacija povezana sa proliferacijom malignih ćelija, inhibicijom apoptoze, tumorskom angiogenezom i sposobnosti invazije i metastaziranja. Povećana proteinska ekspresija HER2 receptora može nastati kao posledica amplifikacije gena i/ili transkripcijskih promena. Ekspresija HER2 receptora u humanim tumorima povezuje se sa agresivnijim pona&scaron;anjem i lo&scaron;ijom prognozom. Učestalost povećane proteinske ekspresije HER2 receptora u nesitnoćelijskim karcinomima pluća (NSCLC) je najvi&scaron;e zastupljena u adenokarcinomu u odnosu na druge histolo&scaron;ke tipove. Identifikacija HER2 pozitivnih NSCLC omogućava određivanje grupe pacijenata koji bi bili kandidati za specifičnu terapiju. Problem predstavlja izbor metode detekcije HER2 receptora i nepostojanje utvrđenog protokola za očitavanje rezultata kao &scaron;to postoji kod karcinoma dojke i želuca. Osnovni ciljevi ove doktorske disertacije su bili: da se odredi učestalost povećane proteinske ekspresije HER2 receptora u adenokarcinomu pluća; da se uporede rezultati povećane proteinske ekspresije HER2 receptora dobijene kori&scaron;ćenjem HER2 antitela &bdquo;Hercep Test Dako&ldquo; i &bdquo;Ventana anti-HER2/neu (4B5)&ldquo; antitela; da se uporedi prisustvo amplifikacije HER2 gena pomoću in situ hibridizacije (ISH) (Dual IHC HER2 kit;Ventana Medical Systems) retestiranjem uzoraka kod kojih je povećana proteinska ekspresija HER2 receptora ocenjena sa 2+ i 3+ dobijena &bdquo;Hercep Test Dako&ldquo; sa prisustnom amplifikacijom HER2 gena na uzorcima koji su pomoću &bdquo;Ventana anti-HER2/neu (4B5)&ldquo; ocenjeni sa 2+ i 3+; da se uporedi učestalost povećane proteinske ekspresije HER2 receptora i prisustva HER2 genske amplifikacije kod različitih histolo&scaron;kih podtipova adenokarcinoma pluća; da se utvrdi da li je povećana proteinska ekspresija HER2 receptora u adenokarcinomu pluća i/ili prisustvo genske amplifikacije povezano sa demografskim (starost i pol pacijenta) parametrima, pu&scaron;ačkim statusom, pojavom metastaza u regionalnim limfnim čvorovima i udaljenim organima, infiltracijom pleure i okolnih struktura, odnosno stadijumom bolesti. Povećana proteinska ekspresija HER2 receptora u adenokarcinomu pluća iznosi 7,4% za Hercep Test Dako i 2,7% za Ventana anti-HER2/neu (4B5) antitelo. Kod pozitivne ekspresije slažu se u 2%, dok se kod negativne ekspresije slažu u 91,9% slučajeva, &scaron;to je ukupno 93,9%. Učestalost amplifikacije HER2 gena kod adenokarcinoma pluća je 17,6%, od toga je kod 2,7% slučajeva prisutna high grade amplifikacija. Postoji statistički značajna povezanost između povećane proteinske ekspresije HER2 receptora dobijene upotrebom HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela i amplifikacije HER2 gena. Amplifikacija HER2 gena prisutna je kod 90,9% pacijenata sa povećanom proteinskom ekspresijom HER2 receptora koja se dobije upotrebom HercepTest Dako i kod 75% upotrebom Ventana anti-HER2/neu (4B5) antitela. Povećana proteinska ekspresija HER2 receptora dobijena pomoću HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela je najče&scaron;ća kod solidnog predominantnog tipa adenokarcinoma u patolo&scaron;kom T2a deskriptoru i IB stadijumu i acinarnog predominantnog tipa adenokarcinoma u patolo&scaron;kom T1b deskriptoru i IA stadijumu. Amplifikacija HER2 gena je najče&scaron;ća kod solidnog a zatim kod acinarnog i papilarnog predominantnog tipa adenokarcinoma. Povećana proteinska ekspresija HER2 receptora dobijena pomoću HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela i amplifikacija HER2 gena se najče&scaron;će javljaju kod mu&scaron;karaca, pu&scaron;ača, u starosnoj dobi od 61-70 godina, tumora veličine 31-50 mm, N0 i M0 statusu bolesti, bez prisustva tumorske infiltracije pleure i okolnih struktura.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Tanja Lakic</o:Author> <o:Version>12.00</o:Version> </o:DocumentProperties></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> 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Name="Bibliography"/> <w:LsdException Locked="false" Priority="39" QFormat="true" Name="TOC Heading"/> </w:LatentStyles></xml><![endif]--><!--[if gte mso 10]><style> /* Style Definitions */ table.MsoNormalTable{mso-style-name:"Table Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--></p><p class="Default"><span style="font-size:11.5pt">Human epidermal growth factor 2 (HER2) is a member of the epidermal growth factor family having tyrosine kinase activity, which is directly linked to malignant cells proliferation, apoptosis inhibition, tumor angiogenesis and ability for invasion and metastasis. Increased protein expression of HER2 receptors can be the consequence of gene amplification and/or transcription changes. Expression of HER2 receptors in human tumors is associated with more aggressive behavior and worse prognosis. Incidence of increased protein expression of HER2 receptors in non-small-cell lung carcinoma (NSCLS) is mainly represented in adenocarcinoma, in comparison with other histological types. Identification of HER2 positive NSCLC enables determination of a group of patients who would be candidates for specific therapy. The problem occurs in choosing the method of detection of HER2 receptors and non-existence of determined protocol for reading the results, as the one ones which exist for breast and gastric carcinoma. The main objectives of this PhD dissertation were: to determine the incidence of increased protein expression of HER2 receptors in lung adenocarcinoma; to compare the results of the increased protein expression of HER2 receptors obtained by using HER2 antibodies &quot;HercepTest Dako&quot; and &quot;Ventana anti-HER2/neu (4B5)&quot; antibodies; to compare the presence of HER2 gene amplification by in situ hybridization (ISH) (Dual IHC HER2 kit: Ventana Medical Systems) by retesting the samples in which the increased protein expression of HER2 receptors was graded with 2+ and 3+, obtained by &quot;HercepTest Dako&quot; with present gene HER2 amplification on samples obtained by &quot;Ventana anti-HER2/neu (4B5) and graded with 2+ and 3+; to compare the incidence of increased protein expression of HER2 receptors and presence of HER2 gene amplification in different histological subtypes of lung adenocarcinoma; to determine if the increased protein expression of HER2 receptors in lung adenocarcinoma and/or presence of gene amplification is related to demographic (age and sex of the patient) parameters, smoking status, appearance of metastases in regional lymphatic nodes, distant organs, infiltration of pleura and surrounding structures, and stage of the disease. Increased protein expression of HER2 in lung adenocarcinoma is 7.4% for HercepTest Dako and 2.7% for Ventana anti-HER2/neu (4B5) antibody. In positive expression they are correlated in 2%, while in negative expression they are correlated in 91.9% cases, which is overall 93.9%. The incidence of HER2 gene amplification in lung adenocarcinoma is 17.6%, from that in 2.7% of the cases high grade amplification is present. There is a statistically significant correlation between increased protein expression of HER2 receptors obtained by use of HercepTest Dako and Ventana anti-HER2 /neu (4B5) antibody and amplification of HER2 genes. Amplification of HER2 genes is present in 90.9% of patients with increased protein expression of HER2 receptors, which is obtained by using HercepTest Dako and in 75% patients by using Ventana anti-HER2/neu (4B5) antibody. Increased protein expression of HER2 receptors obtained by HercepTest Dako and Ventana anti-Her2/neu (4B5) antibody is most common in solid predominant type of adenocarcinoma in pathological T2a descriptor and IB stadium and acinar predominant type of adenocarcinoma in pathological T1b descriptor and IA stadium. Amplification of HER2 genes is most common in solid, and then in acinar and papillary predominant type of adenocarcinoma. Increased protein expression of HER2 receptors obtained by HercepTest Dako and Ventana anti-HER2/neu (4B5) antibody and amplification of HER2 genes most commonly occurs in men, smokers, at the age of 61-70 years, tumor size 31-50 mm, NO and MO disease status, without presence of tumor infiltration of pleura and surrounding structures. </span></p>