Checkpoint inhibitors in therapy of malignant diseases

Broj osoba oboljelih od malignih bolesti u stalnom je porastu, a maligne su bolesti drugi najčešći uzrok smrti u Republici Hrvatskoj. Imunoterapija je jedna od metoda liječenja raka, a za razliku od ostalih terapijskih koncepata, prvenstveno ima za cilj spriječiti metastatsko širenje bolesti i poboljšati kvalitetu života oboljelih. Pristupi koji se primjenjuju u imunoterapiji temelje se na nadopunjavanju ili stimulaciji imunosnog sustava preko mnoštva spojeva među kojima su i antitijela protiv kontrolnih točaka T-limfocita. Te autoregulacijske molekule služe održavanju imunosne ravnoteže, odnosno sprječavaju pretjerani imunosni odgovor i autoimune reakcije, no sprječavaju potpuni potencijal T-limfocita u borbi protiv tumora te su stoga postale zanimljiva terapijska meta. U proteklom desetljeću odobreno je nekoliko antitijela koje ciljaju kontrolne točke na T-limfocitima, ali i onih koji ciljaju neke druge molekule kao što su ligandi prisutni na različitim tumorima. U nekim indikacijama, ovakva se terapija može koristiti kao monoterapija, međutim većina indikacija uključuje kombiniranu terapiju dvaju protutijela ili kombinacije s drugim vrstama terapije kao što su radioterapija, kemoterapija bazirana na platini ili s inhibitorima tirozin kinaze. Međutim, zbog samog mehanizma djelovanja antitijela, često se javljaju imunosno posredovane nuspojave. Također, iniciranje terapije inhibitorima kontrolnih točaka općenito je otežano niskom stopom odgovora kod nekih pacijenata. Zbog toga je potrebno imati prediktivne biomarkere kojima bi se uspješnije mogle odrediti skupine pacijenata koji bi odgovorili na takvu terapiju, ali i odrediti toksičnost u pojedinih pacijenata te poboljšao ishod terapije. Nakon inicijalnih odobrenja, daljnja su istraživanja i odobrenja išla u smjeru proširivanja indikacija, kao i istraživanja novih molekula signalnog puta na koje se može djelovati, a koje uključuju i druge stanice osim T-limfocita, kao što su NK stanice, dendritičke stanice i makrofage. Osim na razvoj molekula s inhibitornim djelovanjem, sve je više istraživanja fokusirano na razvoj agonista kostimulacije T-limfocita poput onih koji ciljaju OX40, CD137 i GITR. Upravo se te nove molekule smatraju potencijalnim novim oružjem protiv raka. Daljnja istraživanja razvit će kombinacijske skupove biomarkera za predviđanje ishoda terapije i izbjegavanje imunosno posredovanih nuspojava. Također, potrebno je razviti integriraniji pristup kako bi se identificirale podskupine pacijenata pogodne za pojedini tip imunosne terapije.The number of patients suffering from malignant diseases is constantly increasing; malignant diseases are the second most common cause of death in the Republic of Croatia. Immunotherapy is a type of cancer treatment, and unlike the other therapeutic concepts, it primarily aims to prevent a metastatic spread of the disease and improve the quality of life. The approaches used in immunotherapy are based on stimulating the immune system with the variety of compounds, including antibodies against T-cell checkpoints. These molecules are maintaining the immune balance i.e., they prevent an excessive immune response and autoimmune reactions, but they also prevent the full T-cell potential in fighting tumors and have, therefore, become an interesting therapeutic target. In the past decade, several antibodies have been approved that target T-cell checkpoints and other molecules, such as ligands present in various tumors. For some indications, checkpoint inhibitors may be used as a monotherapy; however, most indications involve a combination therapy consisting of two antibodies or combinations with radiotherapy, platinum-based chemotherapy or with tyrosine kinase inhibitors. However, immune-mediated adverse reactions often occur due to the mechanism of action of such therapy. Also, initiating therapy with checkpoint inhibitors is generally hampered by the low response rate in some patients. Therefore, it is necessary to have predictive biomarkers that could more successfully determine the groups of patients who would respond to such therapy, but also to determine toxicity in individual patients and improve the therapy outcome. Following initial approvals, further research and approvals go in the direction of expanding indications as well as studying new molecules that could be targeted beyond T-cells. These molecules include NK cells, dendritic cells, macrophages, and more. In addition, besides on molecules with inhibitory activity, recent research has focused on T-cell costimulation agonists such as those targeting OX40, CD137, and GITR. These new molecules are considered a potential new weapon against cancer. Further research will develop combination sets of biomarkers to predict therapy outcomes and avoid immune-mediated adverse reactions. Also, more integrated approaches should be developed to identify subgroups of patients suitable for each type of the aforementioned immune therapy

Checkpoint inhibitors in therapy of malignant diseases

Broj osoba oboljelih od malignih bolesti u stalnom je porastu, a maligne su bolesti drugi najčešći uzrok smrti u Republici Hrvatskoj. Imunoterapija je jedna od metoda liječenja raka, a za razliku od ostalih terapijskih koncepata, prvenstveno ima za cilj spriječiti metastatsko širenje bolesti i poboljšati kvalitetu života oboljelih. Pristupi koji se primjenjuju u imunoterapiji temelje se na nadopunjavanju ili stimulaciji imunosnog sustava preko mnoštva spojeva među kojima su i antitijela protiv kontrolnih točaka T-limfocita. Te autoregulacijske molekule služe održavanju imunosne ravnoteže, odnosno sprječavaju pretjerani imunosni odgovor i autoimune reakcije, no sprječavaju potpuni potencijal T-limfocita u borbi protiv tumora te su stoga postale zanimljiva terapijska meta. U proteklom desetljeću odobreno je nekoliko antitijela koje ciljaju kontrolne točke na T-limfocitima, ali i onih koji ciljaju neke druge molekule kao što su ligandi prisutni na različitim tumorima. U nekim indikacijama, ovakva se terapija može koristiti kao monoterapija, međutim većina indikacija uključuje kombiniranu terapiju dvaju protutijela ili kombinacije s drugim vrstama terapije kao što su radioterapija, kemoterapija bazirana na platini ili s inhibitorima tirozin kinaze. Međutim, zbog samog mehanizma djelovanja antitijela, često se javljaju imunosno posredovane nuspojave. Također, iniciranje terapije inhibitorima kontrolnih točaka općenito je otežano niskom stopom odgovora kod nekih pacijenata. Zbog toga je potrebno imati prediktivne biomarkere kojima bi se uspješnije mogle odrediti skupine pacijenata koji bi odgovorili na takvu terapiju, ali i odrediti toksičnost u pojedinih pacijenata te poboljšao ishod terapije. Nakon inicijalnih odobrenja, daljnja su istraživanja i odobrenja išla u smjeru proširivanja indikacija, kao i istraživanja novih molekula signalnog puta na koje se može djelovati, a koje uključuju i druge stanice osim T-limfocita, kao što su NK stanice, dendritičke stanice i makrofage. Osim na razvoj molekula s inhibitornim djelovanjem, sve je više istraživanja fokusirano na razvoj agonista kostimulacije T-limfocita poput onih koji ciljaju OX40, CD137 i GITR. Upravo se te nove molekule smatraju potencijalnim novim oružjem protiv raka. Daljnja istraživanja razvit će kombinacijske skupove biomarkera za predviđanje ishoda terapije i izbjegavanje imunosno posredovanih nuspojava. Također, potrebno je razviti integriraniji pristup kako bi se identificirale podskupine pacijenata pogodne za pojedini tip imunosne terapije.The number of patients suffering from malignant diseases is constantly increasing; malignant diseases are the second most common cause of death in the Republic of Croatia. Immunotherapy is a type of cancer treatment, and unlike the other therapeutic concepts, it primarily aims to prevent a metastatic spread of the disease and improve the quality of life. The approaches used in immunotherapy are based on stimulating the immune system with the variety of compounds, including antibodies against T-cell checkpoints. These molecules are maintaining the immune balance i.e., they prevent an excessive immune response and autoimmune reactions, but they also prevent the full T-cell potential in fighting tumors and have, therefore, become an interesting therapeutic target. In the past decade, several antibodies have been approved that target T-cell checkpoints and other molecules, such as ligands present in various tumors. For some indications, checkpoint inhibitors may be used as a monotherapy; however, most indications involve a combination therapy consisting of two antibodies or combinations with radiotherapy, platinum-based chemotherapy or with tyrosine kinase inhibitors. However, immune-mediated adverse reactions often occur due to the mechanism of action of such therapy. Also, initiating therapy with checkpoint inhibitors is generally hampered by the low response rate in some patients. Therefore, it is necessary to have predictive biomarkers that could more successfully determine the groups of patients who would respond to such therapy, but also to determine toxicity in individual patients and improve the therapy outcome. Following initial approvals, further research and approvals go in the direction of expanding indications as well as studying new molecules that could be targeted beyond T-cells. These molecules include NK cells, dendritic cells, macrophages, and more. In addition, besides on molecules with inhibitory activity, recent research has focused on T-cell costimulation agonists such as those targeting OX40, CD137, and GITR. These new molecules are considered a potential new weapon against cancer. Further research will develop combination sets of biomarkers to predict therapy outcomes and avoid immune-mediated adverse reactions. Also, more integrated approaches should be developed to identify subgroups of patients suitable for each type of the aforementioned immune therapy

Checkpoint inhibitors in therapy of malignant diseases

Broj osoba oboljelih od malignih bolesti u stalnom je porastu, a maligne su bolesti drugi najčešći uzrok smrti u Republici Hrvatskoj. Imunoterapija je jedna od metoda liječenja raka, a za razliku od ostalih terapijskih koncepata, prvenstveno ima za cilj spriječiti metastatsko širenje bolesti i poboljšati kvalitetu života oboljelih. Pristupi koji se primjenjuju u imunoterapiji temelje se na nadopunjavanju ili stimulaciji imunosnog sustava preko mnoštva spojeva među kojima su i antitijela protiv kontrolnih točaka T-limfocita. Te autoregulacijske molekule služe održavanju imunosne ravnoteže, odnosno sprječavaju pretjerani imunosni odgovor i autoimune reakcije, no sprječavaju potpuni potencijal T-limfocita u borbi protiv tumora te su stoga postale zanimljiva terapijska meta. U proteklom desetljeću odobreno je nekoliko antitijela koje ciljaju kontrolne točke na T-limfocitima, ali i onih koji ciljaju neke druge molekule kao što su ligandi prisutni na različitim tumorima. U nekim indikacijama, ovakva se terapija može koristiti kao monoterapija, međutim većina indikacija uključuje kombiniranu terapiju dvaju protutijela ili kombinacije s drugim vrstama terapije kao što su radioterapija, kemoterapija bazirana na platini ili s inhibitorima tirozin kinaze. Međutim, zbog samog mehanizma djelovanja antitijela, često se javljaju imunosno posredovane nuspojave. Također, iniciranje terapije inhibitorima kontrolnih točaka općenito je otežano niskom stopom odgovora kod nekih pacijenata. Zbog toga je potrebno imati prediktivne biomarkere kojima bi se uspješnije mogle odrediti skupine pacijenata koji bi odgovorili na takvu terapiju, ali i odrediti toksičnost u pojedinih pacijenata te poboljšao ishod terapije. Nakon inicijalnih odobrenja, daljnja su istraživanja i odobrenja išla u smjeru proširivanja indikacija, kao i istraživanja novih molekula signalnog puta na koje se može djelovati, a koje uključuju i druge stanice osim T-limfocita, kao što su NK stanice, dendritičke stanice i makrofage. Osim na razvoj molekula s inhibitornim djelovanjem, sve je više istraživanja fokusirano na razvoj agonista kostimulacije T-limfocita poput onih koji ciljaju OX40, CD137 i GITR. Upravo se te nove molekule smatraju potencijalnim novim oružjem protiv raka. Daljnja istraživanja razvit će kombinacijske skupove biomarkera za predviđanje ishoda terapije i izbjegavanje imunosno posredovanih nuspojava. Također, potrebno je razviti integriraniji pristup kako bi se identificirale podskupine pacijenata pogodne za pojedini tip imunosne terapije.The number of patients suffering from malignant diseases is constantly increasing; malignant diseases are the second most common cause of death in the Republic of Croatia. Immunotherapy is a type of cancer treatment, and unlike the other therapeutic concepts, it primarily aims to prevent a metastatic spread of the disease and improve the quality of life. The approaches used in immunotherapy are based on stimulating the immune system with the variety of compounds, including antibodies against T-cell checkpoints. These molecules are maintaining the immune balance i.e., they prevent an excessive immune response and autoimmune reactions, but they also prevent the full T-cell potential in fighting tumors and have, therefore, become an interesting therapeutic target. In the past decade, several antibodies have been approved that target T-cell checkpoints and other molecules, such as ligands present in various tumors. For some indications, checkpoint inhibitors may be used as a monotherapy; however, most indications involve a combination therapy consisting of two antibodies or combinations with radiotherapy, platinum-based chemotherapy or with tyrosine kinase inhibitors. However, immune-mediated adverse reactions often occur due to the mechanism of action of such therapy. Also, initiating therapy with checkpoint inhibitors is generally hampered by the low response rate in some patients. Therefore, it is necessary to have predictive biomarkers that could more successfully determine the groups of patients who would respond to such therapy, but also to determine toxicity in individual patients and improve the therapy outcome. Following initial approvals, further research and approvals go in the direction of expanding indications as well as studying new molecules that could be targeted beyond T-cells. These molecules include NK cells, dendritic cells, macrophages, and more. In addition, besides on molecules with inhibitory activity, recent research has focused on T-cell costimulation agonists such as those targeting OX40, CD137, and GITR. These new molecules are considered a potential new weapon against cancer. Further research will develop combination sets of biomarkers to predict therapy outcomes and avoid immune-mediated adverse reactions. Also, more integrated approaches should be developed to identify subgroups of patients suitable for each type of the aforementioned immune therapy

Utjecaj odabranih ksenobiotika na boju urina

Use of any xenobiotic can result in adverse effects which are often results of the effects of xenobiotic itself, its metabolites and complexes with endobiotics. Adverse effects can sometimes be serious, even life-threatening, and sometimes completely harmless. One type of adverse effects is change of urine colour after application of some xenobiotics. Urine colour change due to the xenobiotics application can be result of the colour of xenobiotic itself or the colour of its metabolites. Possible metabolic reactions that can result in urine discoloration include different oxidoreductions, mostly catalysed by cytochrome 450 enzymes, different conjugations, bacterial reactions, photolysis, complexation of metal cations and even chemical reaction with urinary catheter. Even though these adverse effects are mostly harmless, patients often develop fear and discomfort which can lead to reduced adherence in case of some drugs. Therefore, education of patients as well as health professionals about possible urine colour change after application of some xenobiotics is of importance. In this paper, effects of selected xenobiotics on the urine colour and their biochemical basis are given