Veterinary medicine - Repository of PHD, master's thesis
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Secondary malignancies after autologous stem cell transplantation
No full textAutologna transplantacija krvotvornih matičnih stanica (ATKMS) koristi se već više od 40 godina kao standardna terapija liječenja oboljelih od multiplog mijeloma (MM) i u relapsima Hodgkinova i non-Hodgkinova limfoma. Njena prednost je omogućavanje primjene visokih doza kemoterapije te za razliku od alogenične transplantacije nema rizik pojave bolesti presatka protiv primatelja jer je bolesnik i donor i primatelj. Upotreba ATKMS dokazano povećava ukupno preživljenje bolesnika sa MM, bolju kontrolu bolesti te time i pozitivno utječe na njihovu kvalitetu života. Međutim, u novije vrijeme sve se više istraživanja posvećuje negativnim dugotrajnim posljedicama takvog liječenja, posebice zbog uočene pojave sekundarnih tumora godinama nakon transplantacije koja je povećanjem preživljenja sve češća. Sekundarni tumori (ST) nastali kao posljedica terapije mogu biti hematološki, kao što su akutna mijeloična leukemija i mijelodisplastični sindrom, te solidni, od kojih su najčešći melanomi, gastrointestinalni i urogenitalni. Oko 5% transplantiranih razvije ST unutar 5 godina od ATKMS , a rizik za njihovu pojavu raste s vremenom nakon transplantacije i višestruko je veći nego rizik kod opće populacije. Među najvažnijim čimbenicima rizika ističe se izloženost citotoksičnim lijekovima kao što su alkilirajući agensi te inhibitori topoizomeraze koji se koriste u različitim kombinacijama ovisno o režimu liječenja hematoloških malignih bolesti kao i za kondicioniranje prije ATKMS. U novije vrijeme, sa pojavom ST povezuje se i upotreba lenalidomida koji se sve intenzivnije koristi u terapiji održavanja kod bolesnika s MM. Uz to, u nastanku ST utjecaj imaju i prethodno zračenje bolesnika u liječenju limfoma, ali i zračenje cijelog tijela u sklopu kondicioniranja prije ATKMS. Mehanizam nastanka ST nakon ATKMS kompleksan je i ne temelji se isključivo na utjecaju citotoksičnih lijekova i zračenja na DNK i nastanak novih mutacija već i na faktore kao što su genetska predispozicija i funkcija imunološkog sustava. Kroz različite genetske mehanizme kao što su metilacija DNK, nastanak točkastih mutacija i translokacije kromosoma koje dovode do nastanka fuzijskih onkoproteina, postiže se povoljan okoliš za nastanak tumora zbog promjene funkcije gena zaduženih za proliferaciju, supresiju tumora ili signalne puteve uključene u diferencijaciju i rast stanica. Za prevenciju, dijagnostiku i liječenje ST trenutno ne postoje smjernice, međutim postoje određene preporuke kao što je poticanje bolesnika na odaziv na redovne testove probira za opću populaciju i na kontrole te odlazak liječniku kod pojave bilo kakvih novih neuobičajenih simptoma.Autologous Hematopoietic Stem Cell Transplantation (AHSCT) has been used for over 40 years as a standard treatment for patients with multiple myeloma (MM), as well as in relapsed cases of Hodgkin and non-Hodgkin lymphoma. Its main advantage lies in enabling the administration of high-dose chemotherapy, and unlike allogeneic transplantation, it carries no risk of graft-versus-host disease, as the patient serves as both donor and recipient. AHSCT has been proven to increase overall survival in MM patients, improve disease control, and consequently enhance their quality of life. However, in recent years, increasing attention has been paid to the potential long-term adverse effects of this treatment, particularly due to the observed emergence of secondary malignancies years after transplantation which has become more frequent as patient survival improves. Secondary malignancies (SM) may be hematological, such as acute myeloid leukemia and myelodysplastic syndrome, or solid tumors, the most common being melanomas, gastrointestinal and urogenital malignancies. Approximately 5% of transplanted patients develop an SM within five years following AHSCT, and the risk continues to increase over time, being several-fold higher compared to the general population. One of the most significant risk factors is exposure to cytotoxic agents, such as alkylating agents and topoisomerase inhibitors, which are used in various combinations depending on the treatment regimen for hematological malignancies and in conditioning regimens prior to AHSCT. More recently, the use of lenalidomide, which is increasingly applied in maintenance therapy for MM patients, has also been associated with the development of SM. In addition, prior radiation therapy for lymphoma and total body irradiation as part of conditioning before AHSCT also contribute to malignancy development. The mechanism behind SM formation after AHSCT is complex and not solely based on the DNA-damaging effects of cytotoxic drugs and radiation, but also involves factors such as genetic predisposition and immune system function. Through various genetic mechanisms including DNA methylation, point mutations, and chromosomal translocations that result in fusion oncogenes, a tumor-promoting environment is created by altering the function of genes responsible for cell proliferation, tumor suppression, or signaling pathways involved in cell differentiation and growth. Currently, there are no formal guidelines for the prevention, diagnosis, or treatment of SM after AHSCT. However, certain recommendations do exist, such as encouraging patients to participate in regular screening programs recommended for the general population, attend routine follow-up appointments, and consult a physician upon noticing any new or unusual symptoms
Cardiovascular Complications of Oncological Treatment
No full textProduženo preživljenje onkoloških bolesnika posljedica je značajnog napretka u liječenju malignih bolesti, no istodobno se sve češće bilježe komplikacije povezane s terapijom. Kardiovaskularne komplikacije onkološkog liječenja predstavljaju ozbiljan klinički problem, gdje i u slučaju izlječenja od same onkološke bolesti, oštećenje srca i krvnih žila može ugroziti ishod liječenja i kvalitetu života. Kardiovaskularne komplikacije povezane s onkološkim liječenjem najčešće se javljaju u obliku srčane disfunkcije i zatajivanja srca, miokarditisa, vaskularne toksičnosti, arterijske hipertenzije te aritmija. Ove kategorije obuhvaćaju širok spektar kliničkih manifestacija koje mogu značajno utjecati na tijek liječenja i ukupnu prognozu bolesnika. U patofiziološkom smislu, oštećenja nastaju kroz različite mehanizme – izravnu citotoksičnost, oksidativni stres, imunološke reakcije i poremećaje vaskularne homeostaze. Rizični čimbenici uključuju stariju dob, prethodne kardiovaskularne bolesti, kumulativnu dozu citostatika i istovremenu primjenu više modaliteta liječenja. Rana dijagnostika temelji se na praćenju biomarkera, elektrokardiografiji i naprednim slikovnim metodama – osobito ehokardiografiji i kardijalnoj magnetskoj rezonanciji. Prevencija uključuje optimizaciju terapijskih protokola, kardiološku procjenu prije početka liječenja i kontinuirani nadzor tijekom terapije te praćenje nakon terapije. Multidisciplinarni pristup, koji uključuje suradnju onkologa, kardiologa i ostalih stručnjaka, ključan je za prepoznavanje, prevenciju i liječenje ovih komplikacija. Kardio-onkologija kao područje medicine u razvoju omogućuje bolju ravnotežu između antitumorske učinkovitosti i očuvanja kardiovaskularnog zdravlja, osobito u dugotrajnom praćenju preživjelih onkoloških bolesnika.The prolonged survival of oncology patients is a result of significant advances in the treatment of malignant diseases. However, complications associated with therapy are increasingly being observed. Cardiovascular complications of oncological treatment represent a serious clinical problem, where even in cases of cancer remission, damage to the heart and blood vessels can compromise treatment outcomes and quality of life. The most common cardiovascular complications related to oncological therapy include cardiac dysfunction and heart failure, myocarditis, vascular toxicity, arterial hypertension, and arrhythmias. These categories encompass a wide range of clinical manifestations that can significantly impact the course of treatment and the overall prognosis of the patient. From a pathophysiological perspective, the damage arises through various mechanisms – direct cytotoxicity, oxidative stress, immune reactions, and disruption of vascular homeostasis. Risk factors include advanced age, pre-existing cardiovascular disease, cumulative doses of cytotoxic drugs, and the concurrent use of multiple therapeutic modalities. Early diagnosis relies on monitoring biomarkers, electrocardiography, and advanced imaging techniques – particularly echocardiography and cardiac magnetic resonance imaging. Preventive strategies involve optimizing therapeutic protocols, conducting cardiological assessment before starting treatment, continuous monitoring during therapy, and post-treatment follow-up. A multidisciplinary approach involving collaboration among oncologists, cardiologists, and other specialists is essential for the recognition, prevention, and management of these complications. Cardio-oncology, as an emerging medical discipline, enables a better balance between antitumor efficacy and the preservation of cardiovascular health, particularly in the long-term follow-up of cancer survivors
Bullous dermatoses of childhood
No full textAutoimune bulozne dermatoze (AIBD) predstavljaju skupinu bolesti koje su karakterizirane pojavom mjehura i vezikula na koži i/ili sluznicama. Mjehuri nastaju kao rezultat patološke autoimune reakcije usmjerene protiv strukturnih komponenti dezmosoma te komponenti unutar područja bazalne membrane. Autoimune bulozne dermatoze pripadaju rijetkim bolestima stoga je važno naglasiti da su u pedijatrijskoj populaciji iznimno rijetke te njihova dijagnostika i liječenje mogu predstavljati izazov. U dječjoj dobi najčešće bolesti iz skupine AIBD su linearna IgA dermatoza i herpetiformni dermatitis. AIBD se mogu javiti u bilo kojoj životnoj dobi unutar pedijatrijske skupine, uključujući i novorođenačko razdoblje. Klinička slika u djece često je slična onoj u odraslih bolesnika, iako mogu postojati određene osobitosti, osobito u distribuciji promjena i zahvaćenosti sluznica. Zlatni dijagnostički standard u dijagnosticiranju AIBD-a u dječjoj dobi kao i u odraslih jest direktna imunofluorescencija. Međutim, za postavljanje točne dijagnoze nužno je objedinjavanje podataka dobivenih anamnezom, kliničkim pregledom, patohistološkim nalazom te serološkim testovima. Liječenje ovih bolesti u pedijatrijskoj dobi zahtijeva poseban oprez, budući da najčešće korišteni lijekovi – sistemski kortikosteroidi – mogu imati negativan učinak na rast, razvoj i pubertetski napredak djeteta. Uz kortikosteroide, sve se više koriste alternativne terapijske opcije poput dapsona, imunosupresivnih lijekova i bioloških lijekova (npr. rituksimab), koji pokazuju dobru učinkovitost i često bolji sigurnosni profil kod dugotrajne primjene u dječjoj dobi. S obzirom na potencijalne nuspojave i moguće dugoročne posljedice terapije, nameće se potreba za daljnjim istraživanjima novih lijekova koji bi bili učinkovitiji, a pritom sigurniji za bolesnike s AIBD, uključujući i djecu. Iako dijagnostika i liječenje AIBD-a u dječjoj populaciji nose brojne izazove, ohrabrujući je podatak da je prognoza u djece povoljnija u usporedbi s odraslima s blažim kliničkim tijekom i boljim terapijskim odgovorom.Autoimmune bullous dermatoses represent a group of disorders characterized by the formation of blisters and vesicles on the skin and/or mucous membranes. These blisters result from a pathological autoimmune response directed against structural components of desmosomes as well as elements within the basement membrane zone. AIBDs are classified as rare diseases, and it is important to emphasize that they are exceptionally rare in the pediatric population, making their diagnosis and treatment particularly challenging. In childhood, the most common diseases within the AIBD group are linear IgA dermatosis and dermatitis herpetiformis. AIBDs can occur at any age within the pediatric population, including the neonatal period. The clinical presentation in children often resembles that seen in adult patients, although certain specific features may be present particularly in terms of lesion distribution and mucosal involvement. The gold standard for diagnosing AIBDs in both children and adults is direct immunofluorescence. However, to establish an accurate diagnosis, it is necessary to integrate findings from medical history, clinical examination, histopathological analysis and serological tests. Treatment of these diseases in childhood requires particular caution, as the most commonly used medications-systemic corticosteroids-may negatively impact growth, development, and pubertal progression. In addition to corticosteroids, alternative therapeutic options such as dapsone, immunosuppressive agents, and biologic therapies (e.g., rituximab) are increasingly being used, showing good efficacy and often a better safety profile for long-term use in children. Given the potential side effects and possible long-term consequences of treatment, there is a need for further research into new medications that are both more effective and safer for patients with AIBD, including children. Although the diagnosis and treatment of AIBD in the pediatric population present numerous challenges, it is encouraging that the prognosis in children is generally more favorable compared to adults with a milder clinical course and better therapeutic response
Renoprotective strategies in cardiac surgery patients
No full textAkutno bubrežno oštećenje povezano s kardiokirurškim zahvatima (CSA-AKI) prepoznato je kao izrazito česta postoperativna komplikacija. Zabilježeno je u 5–43 % odraslih i 52 % djece, uz povišenu smrtnost i udvostručene troškove hospitalizacije u odnosu na bolesnike bez oštećenja. Patofiziologija bubrežne ozljede temeljena je na ne-pulsatilnom protoku, hipoperfuziji i hipoksiji medule, povišenom središnjem venskom tlaku i gubitku autoregulacije perfuzije. Aktivacija komplementa i upalni odgovor posredovan citokinima pridruženi su ovim mehanizmima, a tubularne stanice dodatno su oštećene hemolizom, oksidativnim stresom, hemodilucijom i transfuzijom. Dijagnoza se prvenstveno postavlja na temelju Kidney Disease: Improving Global Outcomes (KDIGO) kriterija. Takav pristup ima ograničenu osjetljivost, te se njime oštećenje prepoznaje tek nakon gubitka 50 % glomerularne filtracije s odmakom od 48–72 sata. Stoga je predloženo uvođenje panela s kombinacijom ranih biomarkera bubrežne ozljede, koji omogućuje otkrivanje subkliničkih oštećenja i raniju intervenciju. U svrhu sprječavanja CSA-AKI-ja preoperativno je naglašena važnost optimizacije volumnog statusa, korekcije anemije, stroge kontrole glikemije i odgode zahvata nakon kontrastnih pretraga. Intraoperativno su preporučene individualizirana perfuzija uz održavanje adekvatnog srednjeg arterijskog tlaka, restriktivni transfuzijski pristup, balansirana forsirana diureza i daljinsko ishemijsko prekondicioniranje. Ispitivani farmakološki renoprotektivni agensi, uključujući RMC-035, L-glutamat, peptid EA-230 i ANP, nisu pokazali učinkovitost za rutinsku primjenu. U ranom postoperativnom razdoblju naglasak je stavljen na KDIGO paket mjera, usmjeren na hemodinamsku stabilizaciju, praćenje diureze, prilagodbu doza bubrežno eliminiranih lijekova i izbjegavanje nefrotoksičnih agensa. Optimalni ishodi postižu se individualiziranim pristupom kojim su integrirani rano prepoznavanje rizika, multimodalna potpora i kontinuirano prilagođavanje terapijskih intervencija.Cardiac surgery-associated acute kidney injury (CSA-AKI) has been recognised as an extremely common postoperative complication. It has been documented in 5–43 % of adults and 52 % of children, with increased mortality and doubled hospital costs when compared with patients without injury. Its pathophysiology is attributed to non-pulsatile flow, medullary hypoperfusion and hypoxia, elevated central venous pressure and loss of autoregulatory perfusion. Activation of complement and a cytokine-mediated inflammatory response are added to these mechanisms, and tubular cells are further damaged by haemolysis, oxidative stress, haemodilution, and transfusion. Diagnosis is primarily established according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria; however, with this approach the injury is detected only after a loss of approximately 50 % of glomerular filtration and with a delay of 48–72 hours, thereby underscoring limited sensitivity. Therefore, the introduction of panels combining early biomarkers has been proposed, enabling detection of subclinical injury and earlier intervention. To prevent CSA-AKI, preoperative emphasis has been placed on volume optimisation, correction of anaemia, strict glycaemic control, and postponement of surgery after contrast studies. Intraoperative measures include individualised perfusion while maintaining an adequate mean arterial pressure, a restrictive transfusion strategy, balanced forced diuresis, and remote ischaemic preconditioning. Although pharmacological renoprotective agents – including RMC-035, L-glutamate, the EA-230 peptide, and ANP – have also been investigated, their effectiveness for routine use has not yet been determined. In the early postoperative period, focus has been placed on the KDIGO care bundle, directed toward haemodynamic stabilisation, urine-output monitoring, dose adjustment of renally eliminated drugs, and avoidance of nephrotoxic agents. Optimal outcomes are achieved through an individualised approach in which early recognition, multimodal support, and continuously adapted therapeutic interventions are integrated
Minimally invasive thoracic surgery
No full textMinimalno invazivna torakalna kirurgija (MITS), koja uključuje video-asistiranu torakoskopsku kirurgiju (VATS) i robotski asistiranu torakalnu kirurgiju (RATS), u posljednja je tri desetljeća doživjela značajan razvoj i sve širu primjenu. Ovaj rad prikazuje povijesni kontekst, osnovna načela, tehničke aspekte, indikacije, kontraindikacije te prednosti i nedostatke obje metode. Cilj rada bio je usporediti minimalno invazivne metode s klasičnim kirurškim pristupima, analizirati njihove ishode i prikazati trenutne izazove u njihovoj primjeni.
VATS se temelji na uporabi videooptičkih instrumenata koji se uvode kroz male incizije, pri čemu kirurg izravno upravlja instrumentima. RATS, iako tehnički složeniji i skuplji, omogućuje znatno bolju vizualizaciju operativnog polja, veću preciznost pokreta te manju traumatizaciju tkiva zahvaljujući robotskoj tehnologiji. Obje metode bilježe bolje kratkoročne ishode u usporedbi s otvorenom torakotomijom: nižu postoperativnu smrtnost, manje komplikacija, kraći boravak u bolnici i brži oporavak.
Analizom dostupne literature prikazani su i dugoročni rezultati liječenja, koji su pokazali da minimalno invazivne metode ne kompromitiraju onkološku sigurnost, budući da omogućuju jednaku stopu potpune (R0) resekcije i odgovarajuću disekciju limfnih čvorova. Osim toga, detaljno su opisani anestetički zahtjevi i izazovi, uključujući primjenu neintubiranih pristupa i protokola za upravljanje postoperativnom boli.
Važan aspekt rada obuhvaća i troškovnu analizu, pri čemu je VATS identificiran kao isplativija metoda, dok bi RATS, uz daljnji razvoj tehnologije i povećanje operativnog volumena, mogao postati široko prihvaćen u većim zdravstvenim ustanovama.
Zaključno, MITS predstavlja napredan kirurški pristup koji kombinira sigurnost, učinkovitost i pacijentovu dobrobit. Uz daljnju edukaciju kirurga i tehnički napredak, očekuje se dodatno širenje ovih metoda u svakodnevnu kliničku praksu.Video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracic surgery (RATS) have experienced significant development and increasingly wider application over the past three decades. This paper presents the historical context, basic principles, technical aspects, indications, contraindications, as well as the advantages and disadvantages of both methods. The aim of the paper was to compare minimally invasive methods with classical surgical approaches, analyze their outcomes, and present current challenges in their application.
VATS is based on the use of video-optical instruments introduced through small incisions, with the surgeon directly controlling the instruments. RATS, although technically more complex and costly, allows significantly better visualization of the operative field, greater precision of movements, and less tissue trauma thanks to robotic technology. Both methods show better short-term outcomes compared to open thoracotomy: lower postoperative mortality, fewer complications, shorter hospital stay, and faster recovery.
Analysis of the available literature also presents long-term treatment results, which have shown that minimally invasive methods do not compromise oncological safety, as they allow an equal rate of complete (R0) resection and appropriate lymph node dissection. Additionally, anesthetic requirements and challenges are described in detail, including the application of non-intubated approaches and protocols for postoperative pain management.
An important aspect of the paper includes a cost analysis, where VATS is identified as the more cost-effective method, while RATS, with further technological development and increased surgical volume, could become widely accepted in larger healthcare institutions.
In conclusion, MITS represents an advanced surgical approach that combines safety, efficiency, and patient well-being. With further surgeon education and technical advancement, further expansion of these methods is expected
Insights into biological therapy
No full textBiološka terapija predstavlja najnapredniji oblik liječenja u suvremenoj medicini. Riječ je o lijekovima koji se proizvode iz bioloških izvora, a uključuju rekombinantne peptide i proteine, monoklonska protutijela, imunološke lijekove (poput seruma, cjepiva i alergena), imunokonjugate, te lijekove za gensku i staničnu terapiju. U posljednjih desetljeća razvijeni su i biosimilari, koji su visoko slične kopije referentnih bioloških lijekova, ali zbog složenosti proizvodnog procesa nisu identični poput generičkih kemijskih lijekova. Njihova proizvodnja i odobravanje strogo su regulirani kako bi se osigurala sigurnost i učinkovitost. Biološki lijekovi imaju važnu ulogu u liječenju brojnih bolesti, uključujući tumore, upalne bolesti crijeva, reumatološke bolesti, kožne bolesti i dislipidemije. Njihova terapijska učinkovitost omogućila je ne samo ublažavanje simptoma, već i promjenu prirodnog tijeka bolesti, produljenje remisije, smanjenje komplikacija i poboljšanje kvalitete života pacijenata. Njihova primjena dovela je do znatnog napretka u ishodima liječenja, osobito kod onkoloških i autoimunih bolesti. Unatoč brojnim prednostima, biološka terapija ima i određene nedostatke. Zbog velike molekulske složenosti, ovi su lijekovi osjetljivi na vanjske uvjete i imaju veći imunogeni potencijal, što može rezultirati nuspojavama poput imunosupresije, autoimunosti, križne reaktivnosti ili prekomjerne imunološke aktivacije. Za razliku od nuspojava kemijskih lijekova, koje su često povezane s farmakološkim učinkom, nuspojave bioloških lijekova češće su posljedica njihova specifičnog biološkog djelovanja. Zbog toga je predložena nova klasifikacija nuspojava bioloških lijekova, koja ih dijeli u pet skupina označenih grčkim slovima (α, β, γ, δ i ε). Iako zahtijevaju parenteralnu primjenu i velika financijska izdavanja, sve veća prisutnost biosimilara povećava dostupnost biološke terapije, čime se dodatno naglašava njezina važnost u modernoj kliničkoj praksi.Biological therapy represents the most advanced form of treatment in modern medicine. These are drugs derived from biological sources, including recombinant peptides and proteins, monoclonal antibodies, immunological agents (such as sera, vaccines, and allergens), immunoconjugates, and gene and cell therapy products. In recent decades, biosimilars have also been developed which are highly similar copies of reference biologics. However, due to the complexity of their production, they are not identical to generic chemical drugs. Their manufacturing and approval processes are strictly regulated to ensure safety and efficacy. Biological drugs play a crucial role in the treatment of numerous diseases, including cancer, inflammatory bowel disease, rheumatologic disorders, skin diseases and dyslipidemias. Their therapeutic effectiveness has enabled not only symptom control but also modification of the natural course of disease, prolonged remission, reduction of complications, and improved patient quality of life. They have significantly improved treatment outcomes, particularly in oncology and autoimmune diseases. Despite their advantages, biological therapies also have certain drawbacks. Due to their large molecular size and structural complexity, these drugs are sensitive to external factors and carry a higher immunogenic potential, which may lead to adverse effects such as immunosuppression, autoimmunity, cross-reactivity, or excessive immune activation. Unlike adverse effects of chemical drugs, which are usually related to pharmacological actions, adverse reactions to biologics are often linked to their specific biological targets and mechanisms. For this reason, a new classification of biologic-related adverse drug reactions has been proposed, dividing them into five types, labeled with Greek letters (α, β, γ, δ, and ε). Although biologicals require parenteral administration and come at a high cost, the growing availability of biosimilars is improving accessibility, further reinforcing their importance in contemporary clinical practice
Effect of IL-6 cytokine signaling modulation on the maturation of osteoblast lineage cells cultured from mouse bone marrow
No full textInterleukin 6 (IL-6) pleiotropni je citokin koji vezanjem na membranske podjedinice receptora, IL-6R i signalni glikoprotein gp130, ostvaruje klasičnu signalizaciju. Trans-signalizaciju aktivira kompleks citokina i solubilnog receptora (sIL-6R) vezanjem na membranski gp130. Cilj ovoga rada je istražiti učinak modulatora signaliziranja citokinom IL-6 na diferencijaciju mišjih osteoblasta in vitro.
U radu su optimizirani uvjeti osteoblastogene kulture mišje koštane srži i fenotipizirane nezrele stanice osteoblastogene loze protočnom citometrijom. Analiziran je izražaj osteoblastnih diferencijacijskih gena i podjedinica receptora za IL-6 tijekom sazrijevanja osteoblasta in vitro postupkom qPCR. Ispitan je o dozi ovisan učinak agonista klasične signalizacije (citokin IL-6), agonista trans-signalizacije (fuzijski protein IL-6/sIL-6R), antagonista trans-signalizacije (sgp130:Fc) i antagonista obje vrste signalizacije (protutijelo anti-IL-6) na sazrijevanje osteoblasta in vitro.
Utvrdili smo da stanice mišje koštane srži sedmi dan kulture izražavaju mezenhimske biljege osteoblastnih prethodnika. Izražaj podjedinica receptora za IL-6 usporedno s izražajem diferencijacijskih gena čini kultivirane osteoblaste podložnima učinku modulatora signalizacije. Aktivacija klasične signalizacije i inhibicija trans-signalizacije potiču sazrijevanje osteoblasta, dok aktivacija trans-signalizacije inhibira sazrijevanje osteoblasta in vitro. Istovremena inhibicija klasične i trans-signalizacije nema značajne učinke.
Zaključili smo da klasična signalizacija citokinom IL-6 potiče, dok trans-signalizacija koči diferencijaciju osteoblasta in vitro što može uputiti na terapijsku primjenu njezine inhibicije u koštanim bolestima.Interleukin 6 (IL-6) is a pleiotropic cytokine that activates classical signaling by binding membrane receptor subunits, IL-6R, and signaling glycoprotein gp130. Trans-signaling is activated by the soluble receptor(sIL-6R)/IL-6 complex, which binds membrane gp130. Our study aimed to investigate the effects of IL-6 signaling modulators on the differentiation of mouse osteoblasts in vitro.
We optimized the conditions of osteoblastogenic mouse bone marrow culture and phenotyped immature osteoblastogenic lineage cells by flow cytometry. The expression of osteoblast differentiation genes and IL-6R subunits during osteoblast maturation in vitro was analyzed using quantitative PCR (qPCR). The dose-dependent effect of classical signaling agonist (IL-6), trans-signaling agonist (IL-6/sIL-6R fusion protein), trans-signaling antagonist (sgp130:Fc), and antagonist of both signaling types (anti-IL-6 antibody) was tested.
We found that mouse bone marrow cells express mesenchymal markers of osteoblast progenitors on the seventh day of culture. The simultaneous expression of IL-6 receptor subunits and differentiation genes renders cultured osteoblasts susceptible to signaling modulators. Activation of classical and inhibition of trans-signaling promote, while activation of trans-signaling inhibits osteoblast maturation in vitro. Simultaneous inhibition of classical and trans-signaling has no significant effects.
We concluded that IL-6 classical signaling promotes, while trans-signaling inhibits osteoblast differentiation in vitro, indicating the possible therapeutic application of its inhibition in bone diseases
Signs of arterial and respiratory function impairment in children with inflammatory bowel disease
No full textUvod: Cilj ovog istraživanja je ispitati promjene na arterijama i dišnom sustavu djece s upalnom bolečću crijeva (IBD), njihovu međusobnu povezanost te povezanost s upalnim parametrima, trajanjem i aktivnošću bolesti.
Ispitanici i metode: Radi se o presječnom istraživanju parova, a uključeno je 55-tero bolesnika s novootkrivenom bolešću, 53-je u remisiji te 53-je zdravih ispitanika. Debljina intime-medije karotidnih arterija mjerena je ultrazvučno, a ostali arterijski parametri oscilometrijski. Plućna funkcija procijenjena je spirometrijom, a frakcija izdahnutog dušičnog oksida (FeNO) kemiluminiscentnim analizatorom.
Rezultati: Nismo uočili statistički značajnu razliku među skupinama u brzini pulsnog vala kroz aortu (PWVao)(P=0.515), markeru krutosti arterija. Bolesnici s IBD-om imaju značajno niži augmentacijski indeks (Aix)( P<0.001) te višu srčanu frekvenciju (HR)(P=0.001), što korelira s trajanjem bolesti (ρ(159)=0.22, P=0.006). Nismo uočili značajnu razliku u parametrima spirometrije, dok je FeNO parametar viši kod aktivne bolesti (P=0.025).
Zaključak: Kod djece s IBD-om još nema strukturnih promjena na arterijama, no izmijenjeni oblik pulsnog vala te povišen HR parametar, koji korelira s trajanjem bolesti, reflektiraju rane funkcionalne promjene. Kod aktivne bolesti upalom je zahvaćen i dišni sustav, premda je respiratorna funkcija, mjerena spirometrijom, još uvijek normalna.Introduction: The aim was to examine the arterial and respiratory changes in children with inflammatory bowel disease (IBD), their interrelationship and the relationship with inflammatory parameters, disease duration and activity.
Subjects and methods: This cross-sectional case-control study included 55 patients with the newly diagnosed disease, 53 in remission and 53 healthy subjects. The carotid intima-media thickness was measured by ultrasound, and the other arterial parameters were measured by oscillometry. Lung function was assessed by spirometry, and fraction of exhaled nitric oxide (FeNO) by chemiluminescence analyser.
Results: There is no statistically significant difference in the pulse wave velocity (PWVao)(P=0.515), an arterial stiffness marker. IBD patients have a lower augmentation index (Aix)(P<0.001). The heart rate correlates with the disease duration (ρ(159)=0.22, P=0.006). Spirometry is normal, while FeNO is higher in active disease (P=0.025).
Conclusion: In children with IBD, the arteries have no structural changes. However, the altered pulse wave and the heart rate that increases with the disease duration, reflect early functional changes. In active disease, inflammation also affects the respiratory system, although respiratory function measured by spirometry is still normal
Autophagy and the role of osteogenic macrophages in chronic Philadelphia-negative myeloproliferative neoplasm
No full textUvod: Cilj našeg rada je bio ispitati autofagiju i osteogene makrofage u koštanoj srži oboljelih od mijelofibroze.
Ispitanici i metode: Metodom RT-PCR smo analizirali ekspresiju biljega autofagije (Beclin-1 i LC3B-II), Onkostatina M i SPARC u stanicama koštane srži oboljelih od mijelofibroze (74 ispitanika) u odnosu na kontrolnu skupinu (11 ispitanika). Na uzorcima bioptata kosti od 81 ispitanika oboljelog od mijelofibroze smo imunohistokemijski istražili izražaj Beclin-1, LC3B-II, Onkostatina M i SPARC te udio osteogenih makrofaga fenotipa CD169, F4/80.
Rezultati: Na temelju rezultata RT-PCR-a nije bilo statistički značajne razlike u ekspresiji Beclin-1, LC3B-II, Onkostatina M i SPARC između oboljelih od mijelofibroze i kontrolnih ispitanika. Nakon stratifikacije ekspresije LC3B-II kod oboljelih od primarne mijelofibroze, viša ekspresija je bila statistički značajno povezana s nižim DIPSS-om. Viša ekspresija Beclin-1 bila je statistički značajno povezana s boljim preživljenjem bolesnika. Imunohistokemijskom analizom su biljezi autofagije bili dominantno izraženi u megakariocitima i granulocitima. Najveći dio oboljelih od mijelofibroze nije imunohistokemijski imao pozitivnu reakciju na biljeg osteogenih makrofaga CD169.
Zaključak: Rezultati našeg istraživanja govore u prilog da autofagija možda ima povoljan učinak na prognozu i preživljenje oboljenih od mijelofibroze.Introduction: The aim of our research was to investigate autophagy and osteogenic macrophages in the bone marrow of patients with myelofibrosis.
Subjects and methods: Using the RT-PCR method, we analyzed the expression of autophagy markers (Beclin-1 and LC3B-II), Oncostatin M and SPARC in bone marrow of patients with myelofibrosis (74 participants) compared to the control group (11 participants). We immunohistochemically investigated the expression of Beclin-1, LC3B-II, Oncostatin M, SPARC and the proportion of CD169, F4/80 phenotype osteogenic macrophages on bone biopsy samples from 81 patients suffering from myelofibrosis.
Results: Based on the results of RT-PCR, there was no statistically significant difference in the expression of Beclin-1, LC3B-II, Oncostatin M and SPARC between patients with myelofibrosis and control subjects. After stratification of LC3B-II expression in patients with primary myelofibrosis, higher expression was statistically significantly associated with lower DIPSS. Higher Beclin-1 expression was statistically significantly associated with better patient survival. By immunohistochemical analysis, autophagy markers were dominantly expressed in megakaryocytes and granulocytes. The majority of patients with myelofibrosis didn't have a positive reaction to marker CD169 of osteogenic macrophages.
Conclusion: The results of our research suggest that autophagy may have a beneficial effect on the prognosis and survival of patients with myelofibrosis
Laryngeal Carcinoma Characteristics Associated with Positive Margins and Endoscopic Understaging
No full textBackground/Objectives: The study aims to analyse the factors associated with positive margins and endoscopic understaging in laryngeal carcinoma. It also aims to assess the diagnostic accuracy of Narrow Band Imaging (NBI) in comparison to White Light Endoscopy (WLE) and other diagnostic methods.
Methods: In this retrospective comparative cohort analysis, 206 patients who underwent endoscopic laser surgery for T1 and T2a glottic squamous cell carcinoma between 1 January 2016 and 30 April 2023 were included. The data were collected from endoscopy, CT, histopathology, and NBI images. Statistical analysis was performed and associations between variables were analysed using binary logistic regression and receiver operating characteristic analysis.
Results: The types of cordectomy performed included type III (51 patients), type IV (40 patients), and type VI (23 patients). Positive margins were found in 14.01% of patients, with significant correlations observed between positive margins and bilateral laryngeal carcinoma, right-sided laryngeal carcinoma, higher clinical and histopathologic T categories, and higher NBI grade. Endoscopic understaging versus histopathologic T category correlated with various factors, including cordectomy type, tumour size, and clinical T category. The NBI findings correlated with positive margins but did not correlate with endoscopic understaging.
Conclusions: The study highlights several clinical and pathological factors associated with positive margins and endoscopic understaging in laryngeal carcinoma. NBI demonstrated high diagnostic accuracy, correlating with histopathological results and serving as an independent predictive factor for positive margins. Recognizing these factors is crucial for improving preoperative assessments, refining treatment strategies, and enhancing patient care