Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development

IMMUNOTHERAPEUTIC APPROACHES FOR ALZHEIMERS DISEASE

Alzheimerova bolest (AB) je progresivna neurodegenerativna bolest koja kulminira teškom demencijom. Pod pojmom demencija se smatra gubitak kognitivnih sposobnosti koji je kroničan i ireverzibilan. Može se javiti u bilo kojoj dobi, ali uglavnom zahvaća starije. AB zahvaća oko 4% bolesnika u dobi od 65 do 74 godina te 30% onih iznad 85 godina. Pacijenti inicijalno imaju probleme s gubitkom kratkotrajne memorije, a zatim slijedi zbunjenost, agitacija, poremećaji u ponašanju te potpuni gubitak kognitivnih sposobnosti. AB je multifaktorijalna bolest, što znači da ima genetsku i okolišnu pozadinu. Bolest se javlja u dva oblika, nasljednom i sporadičnom, a sporadični oblik može također imati genetsku podlogu u svom razvoju. Mutacije u tri različita gena povezane su s obiteljskom poviješću bolesti: u genu koji kodira za amiloid-β prekursorski protein (APP), zatim u genu za PSEN1 (Presenilin 1) i genu za PSEN2 (Presenilin 2). Sporadični oblik, koji se još naziva i kasni oblik bolesti se javlja nakon 65. godine života te je najčešći oblik Alzheimerove bolesti. Polimorfizam gena za apolipoprotein E, potvrđen je kao rizični čimbenik. Patohistološko obilježje AB su pojava plakova amiloida-β (Aβ) i neurofibrilarnih čvorova u kojima se nakuplja fibrilarni protein Tau. Postoji nekoliko hipoteza o patologiji Alzheimerove bolesti. Sve više prihvaćen model za razvoj novih terapija je amiloidna hipoteza koja kaže da je odlaganje Aβ glavni uzrok Alzheimerove bolesti, nakon čega slijedi nakupljanje Tau kao izravna posljedica ove akumulacije. Ova hipoteza sugerira da terapije otklanjanja Aβ mogu biti korisne u liječenju Alzheimerove bolesti. Ovdje ću opisati četiri različita antitijela koja se ispituju i koja ciljaju Aβ. Također, ovaj rad opisuje protutijela koja ciljaju Tau, kao jedan od glavnih ciljeva terapije Alzheimerove bolesti. Nakon desetljeća istraživanja ove bolesti, lijek koji bi je izliječio i dalje ne postoji. Korištenje imunoterapije u Alzheimerovoj bolesti je izazvalo veliko zanimanje. Iako dosadašnji pokušaji još nisu bili toliko uspješni u Comment [JB1]: Zar se ne podrazumijeva da nasljedni oblik bolesti ima genetsku podlogu? Možda bi logičnije bilo da se to kaže samo za sporadični oblik. usporavanju napredovanja bolesti, uspjeli su značajno smanjiti nakupljanje Aβ. Sve u svemu čini se da je imunoterapija jedno od najvećih dostignuća u borbi protiv ove teške bolesti i niz pokušaja poboljšanja te terapije su u tijeku.Alzheimer's disease (AD) is a progressive neurodegenerative disease that culminates with severe dementia. Dementia is a loss of cognition and it is chronic and irreversible. It can occur at any age, but mostly affects the elderly. It affects approximately 4% of patients aged 65 to 74 and 30% of those older than 85 years. Patients initially have problems with the loss of short-term memory, followed by confusion, agitation, behavioral disorders, and severe loss of cognitive abilities. AD is a multifactorial disease, meaning that it has a genetic and environmental background. The disease occurs in two forms; familiar and sporadic, and sporadic form can also have a genetic basis in development. Mutations in three different genes are linked to the family history of the disease; mutations in the gene encoding the amyloid-β APP protein precursor, then mutations in PSEN1 gene (Presenilin 1) and gene for PSEN2 (Presenilin 2). The sporadic form, also known as the late form of the disease, occurs after age of 65 and is the most common form of Alzheimer's disease. Polymorphism of the Apolipoprotein E gene, was confirmed as a risk factor. Characteristic features of AD are the appearance of amyloid-β (Aβ) plaques and neurofibrillary tangles, made of fibrillar protein Tau. There are several hypotheses about the pathology of AD. More accepted model for development new therapies is the amyloid hypothesis that says that deposition of amyloid β protein (Aβ) is the main cause of Comment [JB2]: Ako je niz pokušaja, onda je jednina. Comment [JB3]: Ja bi sve stavila malim slovom Alzheimer disease which is followed by the accrual of tangles as the direct consequence of this accumulation. This hypothesis strongly suggests that targeting Aβ could be beneficial for treatment of AD. Here I report four different antibodies that are being tested and which target Aβ. Also, this thesis describes antibodies that target Tau, as one of the main goals in immunotherapy of AD. After decades of investigating AD, no cure is currently available for this disease. The use of immunotherapy in AD has caught some serious attention. Although attempts that have been made so far have not yet been successful in changing the disease course, they were able to substantially diminish Aβ load. Overall, it seems that immunotherapy is one of the most promising achievements in the fight against this devastating disease and efforts to improve it are undergoing

IMMUNOTHERAPEUTIC APPROACHES FOR ALZHEIMERS DISEASE

Alzheimerova bolest (AB) je progresivna neurodegenerativna bolest koja kulminira teškom demencijom. Pod pojmom demencija se smatra gubitak kognitivnih sposobnosti koji je kroničan i ireverzibilan. Može se javiti u bilo kojoj dobi, ali uglavnom zahvaća starije. AB zahvaća oko 4% bolesnika u dobi od 65 do 74 godina te 30% onih iznad 85 godina. Pacijenti inicijalno imaju probleme s gubitkom kratkotrajne memorije, a zatim slijedi zbunjenost, agitacija, poremećaji u ponašanju te potpuni gubitak kognitivnih sposobnosti. AB je multifaktorijalna bolest, što znači da ima genetsku i okolišnu pozadinu. Bolest se javlja u dva oblika, nasljednom i sporadičnom, a sporadični oblik može također imati genetsku podlogu u svom razvoju. Mutacije u tri različita gena povezane su s obiteljskom poviješću bolesti: u genu koji kodira za amiloid-β prekursorski protein (APP), zatim u genu za PSEN1 (Presenilin 1) i genu za PSEN2 (Presenilin 2). Sporadični oblik, koji se još naziva i kasni oblik bolesti se javlja nakon 65. godine života te je najčešći oblik Alzheimerove bolesti. Polimorfizam gena za apolipoprotein E, potvrđen je kao rizični čimbenik. Patohistološko obilježje AB su pojava plakova amiloida-β (Aβ) i neurofibrilarnih čvorova u kojima se nakuplja fibrilarni protein Tau. Postoji nekoliko hipoteza o patologiji Alzheimerove bolesti. Sve više prihvaćen model za razvoj novih terapija je amiloidna hipoteza koja kaže da je odlaganje Aβ glavni uzrok Alzheimerove bolesti, nakon čega slijedi nakupljanje Tau kao izravna posljedica ove akumulacije. Ova hipoteza sugerira da terapije otklanjanja Aβ mogu biti korisne u liječenju Alzheimerove bolesti. Ovdje ću opisati četiri različita antitijela koja se ispituju i koja ciljaju Aβ. Također, ovaj rad opisuje protutijela koja ciljaju Tau, kao jedan od glavnih ciljeva terapije Alzheimerove bolesti. Nakon desetljeća istraživanja ove bolesti, lijek koji bi je izliječio i dalje ne postoji. Korištenje imunoterapije u Alzheimerovoj bolesti je izazvalo veliko zanimanje. Iako dosadašnji pokušaji još nisu bili toliko uspješni u Comment [JB1]: Zar se ne podrazumijeva da nasljedni oblik bolesti ima genetsku podlogu? Možda bi logičnije bilo da se to kaže samo za sporadični oblik. usporavanju napredovanja bolesti, uspjeli su značajno smanjiti nakupljanje Aβ. Sve u svemu čini se da je imunoterapija jedno od najvećih dostignuća u borbi protiv ove teške bolesti i niz pokušaja poboljšanja te terapije su u tijeku.Alzheimer's disease (AD) is a progressive neurodegenerative disease that culminates with severe dementia. Dementia is a loss of cognition and it is chronic and irreversible. It can occur at any age, but mostly affects the elderly. It affects approximately 4% of patients aged 65 to 74 and 30% of those older than 85 years. Patients initially have problems with the loss of short-term memory, followed by confusion, agitation, behavioral disorders, and severe loss of cognitive abilities. AD is a multifactorial disease, meaning that it has a genetic and environmental background. The disease occurs in two forms; familiar and sporadic, and sporadic form can also have a genetic basis in development. Mutations in three different genes are linked to the family history of the disease; mutations in the gene encoding the amyloid-β APP protein precursor, then mutations in PSEN1 gene (Presenilin 1) and gene for PSEN2 (Presenilin 2). The sporadic form, also known as the late form of the disease, occurs after age of 65 and is the most common form of Alzheimer's disease. Polymorphism of the Apolipoprotein E gene, was confirmed as a risk factor. Characteristic features of AD are the appearance of amyloid-β (Aβ) plaques and neurofibrillary tangles, made of fibrillar protein Tau. There are several hypotheses about the pathology of AD. More accepted model for development new therapies is the amyloid hypothesis that says that deposition of amyloid β protein (Aβ) is the main cause of Comment [JB2]: Ako je niz pokušaja, onda je jednina. Comment [JB3]: Ja bi sve stavila malim slovom Alzheimer disease which is followed by the accrual of tangles as the direct consequence of this accumulation. This hypothesis strongly suggests that targeting Aβ could be beneficial for treatment of AD. Here I report four different antibodies that are being tested and which target Aβ. Also, this thesis describes antibodies that target Tau, as one of the main goals in immunotherapy of AD. After decades of investigating AD, no cure is currently available for this disease. The use of immunotherapy in AD has caught some serious attention. Although attempts that have been made so far have not yet been successful in changing the disease course, they were able to substantially diminish Aβ load. Overall, it seems that immunotherapy is one of the most promising achievements in the fight against this devastating disease and efforts to improve it are undergoing

IMMUNOTHERAPEUTIC APPROACHES FOR ALZHEIMERS DISEASE

Alzheimerova bolest (AB) je progresivna neurodegenerativna bolest koja kulminira teškom demencijom. Pod pojmom demencija se smatra gubitak kognitivnih sposobnosti koji je kroničan i ireverzibilan. Može se javiti u bilo kojoj dobi, ali uglavnom zahvaća starije. AB zahvaća oko 4% bolesnika u dobi od 65 do 74 godina te 30% onih iznad 85 godina. Pacijenti inicijalno imaju probleme s gubitkom kratkotrajne memorije, a zatim slijedi zbunjenost, agitacija, poremećaji u ponašanju te potpuni gubitak kognitivnih sposobnosti. AB je multifaktorijalna bolest, što znači da ima genetsku i okolišnu pozadinu. Bolest se javlja u dva oblika, nasljednom i sporadičnom, a sporadični oblik može također imati genetsku podlogu u svom razvoju. Mutacije u tri različita gena povezane su s obiteljskom poviješću bolesti: u genu koji kodira za amiloid-β prekursorski protein (APP), zatim u genu za PSEN1 (Presenilin 1) i genu za PSEN2 (Presenilin 2). Sporadični oblik, koji se još naziva i kasni oblik bolesti se javlja nakon 65. godine života te je najčešći oblik Alzheimerove bolesti. Polimorfizam gena za apolipoprotein E, potvrđen je kao rizični čimbenik. Patohistološko obilježje AB su pojava plakova amiloida-β (Aβ) i neurofibrilarnih čvorova u kojima se nakuplja fibrilarni protein Tau. Postoji nekoliko hipoteza o patologiji Alzheimerove bolesti. Sve više prihvaćen model za razvoj novih terapija je amiloidna hipoteza koja kaže da je odlaganje Aβ glavni uzrok Alzheimerove bolesti, nakon čega slijedi nakupljanje Tau kao izravna posljedica ove akumulacije. Ova hipoteza sugerira da terapije otklanjanja Aβ mogu biti korisne u liječenju Alzheimerove bolesti. Ovdje ću opisati četiri različita antitijela koja se ispituju i koja ciljaju Aβ. Također, ovaj rad opisuje protutijela koja ciljaju Tau, kao jedan od glavnih ciljeva terapije Alzheimerove bolesti. Nakon desetljeća istraživanja ove bolesti, lijek koji bi je izliječio i dalje ne postoji. Korištenje imunoterapije u Alzheimerovoj bolesti je izazvalo veliko zanimanje. Iako dosadašnji pokušaji još nisu bili toliko uspješni u Comment [JB1]: Zar se ne podrazumijeva da nasljedni oblik bolesti ima genetsku podlogu? Možda bi logičnije bilo da se to kaže samo za sporadični oblik. usporavanju napredovanja bolesti, uspjeli su značajno smanjiti nakupljanje Aβ. Sve u svemu čini se da je imunoterapija jedno od najvećih dostignuća u borbi protiv ove teške bolesti i niz pokušaja poboljšanja te terapije su u tijeku.Alzheimer's disease (AD) is a progressive neurodegenerative disease that culminates with severe dementia. Dementia is a loss of cognition and it is chronic and irreversible. It can occur at any age, but mostly affects the elderly. It affects approximately 4% of patients aged 65 to 74 and 30% of those older than 85 years. Patients initially have problems with the loss of short-term memory, followed by confusion, agitation, behavioral disorders, and severe loss of cognitive abilities. AD is a multifactorial disease, meaning that it has a genetic and environmental background. The disease occurs in two forms; familiar and sporadic, and sporadic form can also have a genetic basis in development. Mutations in three different genes are linked to the family history of the disease; mutations in the gene encoding the amyloid-β APP protein precursor, then mutations in PSEN1 gene (Presenilin 1) and gene for PSEN2 (Presenilin 2). The sporadic form, also known as the late form of the disease, occurs after age of 65 and is the most common form of Alzheimer's disease. Polymorphism of the Apolipoprotein E gene, was confirmed as a risk factor. Characteristic features of AD are the appearance of amyloid-β (Aβ) plaques and neurofibrillary tangles, made of fibrillar protein Tau. There are several hypotheses about the pathology of AD. More accepted model for development new therapies is the amyloid hypothesis that says that deposition of amyloid β protein (Aβ) is the main cause of Comment [JB2]: Ako je niz pokušaja, onda je jednina. Comment [JB3]: Ja bi sve stavila malim slovom Alzheimer disease which is followed by the accrual of tangles as the direct consequence of this accumulation. This hypothesis strongly suggests that targeting Aβ could be beneficial for treatment of AD. Here I report four different antibodies that are being tested and which target Aβ. Also, this thesis describes antibodies that target Tau, as one of the main goals in immunotherapy of AD. After decades of investigating AD, no cure is currently available for this disease. The use of immunotherapy in AD has caught some serious attention. Although attempts that have been made so far have not yet been successful in changing the disease course, they were able to substantially diminish Aβ load. Overall, it seems that immunotherapy is one of the most promising achievements in the fight against this devastating disease and efforts to improve it are undergoing

Urological complications after kidney transplantation – experience from Referral Center in Croatia

Cilj: Prikazati učestalost uroloških komplikacija nakon transplantacije bubrega u našem transplantacijskom centru. Ispitanici i metode: Retrospektivnim istraživanjem bili su obuhvaćeni svi pacijenti u Kliničkom bolničkom centru Rijeka u kojih je između 30. siječnja 1971. godine i 31. prosinca 2018. godine učinjena transplantacija bubrega. Rezultati: U promatranom razdoblju u našem transplantacijskom centru učinjeno je 1160 transplantacija bubrega. Urološke komplikacije imala su ukupno 154 pacijenta (13,3 %). Najčešće komplikacije su bile stenoza uretera u 52 pacijenta (4,5 %), urinarna fistula u 50 pacijenata (4,3 %), retencija urina u 23 pacijenta (1,9 %) te urolitijaza u 8 pacijenata (0,7 %). U većine pacijenata je provedeno kirurško liječenje. U posljednje vrijeme značajno se povećalo rješavanje uroloških komplikacija korištenjem minimalno-invazivnih metoda. U dvoje pacijenata (0,17 %) je zbog uroloških komplikacija došlo do gubitka grafta, a u troje pacijenata (0,25 %) su one dovele do smrtnog ishoda. Zaključak: Urološke komplikacije u našoj transplantacijskoj populaciji nisu česte. U pacijenata u kojih je potrebno kirurško liječenje endourološke metode predstavljaju danas inicijalnu metodu liječenja.Aim: To evaluate the incidence of urological complications after kidney transplantation in our transplant center. Patients and Methods: We retrospectively analyzed all patients with kidney transplantation operated in University Hospital Rijeka from January 30st 1971 to December 31st 2018. Results: In the observed period 1160 kidney transplantations were performed in our transplant center. Urological complications were noticed in the 154 patients (13.3%). The most frequent complications were ureteral stenosis in 52 patients (4.5%), urinary fistula in 50 patients (4.3%), urinary retention in 23 patients (1.9%) and urolithiasis in the 8 patients (0.7%). The majority of the patients underwent surgical treatment. Recently, minimally invasive surgery was the method of choice for treatment of urological complications. In two patients (0,17%) urological complications caused graft loss and in the three patients (0,25%) this complications lead to death. Conclusion: Urological complications are not frequent in our transplant population. In the group of patients that required surgical treatment endourology methods are currently the initial treatment modality

Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Repurposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FLUAV), niclosamide against HSV-2, brequinar against human immunodeficiency virus 1 (HIV-1), and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vitro and in vivo tests

Chemical, Physical and Biological Triggers of Evolutionary Sonserved Bcl-xL-Mediated Apoptosis

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development

Chemical, Physical and Biological Triggers of Evolutionary Sonserved Bcl-xL-Mediated Apoptosis

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development