HUNTINGTONOVA BOLEST Pogledić, Ivana; Relja, Maja
Liječnički vjesnik,
12/2012, Letnik:
134, Številka:
11-12
Journal Article
Recenzirano
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Huntingtonova bolest i/ili koreja (HD) autosomno je dominantna neurodegenerativna bolest koja nikada ne preskače generacije. Prvi ju je opisao George Huntington 1872. godine. Prevalencija u svijetu ...je 8–10 na 100 000 stanovnika, dok je u nas objavljeno 4,46 na 100 000 stanovnika. Započinje uglavnom između 30. i 50. godine života i završava smrtno za 15–20 godina. Bolest je to ponavljanja tripleta CAG, a karakterizira ju ekspanzija poliglutaminskog slijeda. Broj trinukleotidnih CAG-ponavljanja negativno korelira s dobi javljanja prvih simptoma, kao i s težinom kliničke slike. Za sada ne postoji selektivna terapija Huntingtonove koreje, a kao simptomatsko liječenje najdjelotvorniji su blokatori dopamina.
Presence of Ecotoxicologically Relevant Pgp and MRP Transcripts and Proteins in Cyprinid Fish Klobu _ar, Roberta (Division for Marine and Environmental Research, Ruđer Bošković Institute, Zagreb, Croatia); Žaja, Roko (Division for Marine and Environmental Research, Ruđer Bošković Institute, Zagreb, Croatia); Franjević, Damjan (Division of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia) ...
Arhiv za higijenu rada i toksikologiju,
06/2010, Letnik:
61, Številka:
2
Journal Article
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One of the most intriguing defence strategies which aquatic organisms developed through evolution is multixenobiotic resistance (MXR). The key mediators of MXR activity are ATP-binding cassette (ABC) ...transport proteins. They provide resistance of aquatic organisms by binding xenobiotics and extruding them from cells in an energy-dependent manner. Since Cyprinid fish species are common target in freshwater biomonitoring programs, we have studied the presence of two main MDR/MXR efflux transporters P-glycoprotein (Pgp, Abcb1) and MRP-like protein(s) (Abcc) in the liver of five Cyprinid species: common carp, European chub, sneep, barbel, and silver prussian carp. Their presence was evaluated on the mRNA and protein level. Various pairs of primers were designed to clone homologous fragments of MXR-related genes. At the protein level, we used Western blotting with specific monoclonal antibodies against human Pgp (Abcb1, Ab C219), MRP1 (Abcc1; Ab MRPm6) or MRP2 (Abcc2; Ab M2I-4). Transcripts of both key types of MXR transporters were identified in all species examined and here we provide the phylogenetic analysis of new partial sequences. Immunochemical determinations with mammalian antibodies failed to identify the presence of MRP(s), but Pgp expression was found in all five Cyprinid species. These results support that MXR is a defence system mediated by both Pgp and MRP types of ABC transport proteins.
Mehanizam multiksenobioti _ke otpornosti (MXR) stani _ni je obrambeni sustav odgovoran za svojstvo istovremene otpornosti na razli _ite ksenobiotike, koje se o _ituje smanjenjem akumulacije, odnosno povećanjem izbacivanja potencijalno toksi _nih tvari iz stanica vodenih organizama. MXR-mehanizam pokazuje odlike analogne fenomenu istovremene otpornosti na razli _ite lijekove (engl. multidrug resistance, MDR) prvi put dokazanom u tumorskim stanicama. Posredovan je istim ABC transportnim proteinima kao i MDR. Istraživanja vezana uz MXR vodenih životinja uglavnom su imala težište na određivanju prisutnosti i funkcije P-glikoproteina (Pgp). Budući da se ribe iz reda šaranki _esto rabe u biomonitoringu slatkovodnih voda, cilj ovog istraživanja bilo je određivanje prisutnosti dvaju glavnih MDR/MXR-tipova proteina - Pgp i MRP-tip proteina - u jetri iz pet vrsta šaranki; šarana (Cyprinus carpio), klena (Sqalius cephalus), mrene (Barbus barbus), babuške (Carassius auratus gibelio) i podusta (Chondrostoma nasus). Njihova prisutnost utvrđena je na razini mRNA te na proteinskoj razini. Razli _iti parovi po _etnica dizajnirani su kako bi se identificirali homologni fragmenti gena sli _nih MXR-u. Detekcija na razini proteina napravljena je putem Western blot analize s pomoću specifi _nih monoklonskih protutijela proizvedenih da prepoznaju konzervirane epitope; Pgp (C219), MRP1 (MRPm6) ili MRP2 (M2I-4) u sisavaca. Transkripti obaju klju _nih MXR-transportera identificirani su u svim jedinkama, a napravljena je i filogenetska analiza dobivenih sekvenci. Imunokemijskom detekcijom s protutijelima sisavaca nismo uspjeli detektirati prisutnost MRP-proteina, dok je Pgp-ekspresija potvrđena u svih pet vrsta šaranki. Nove spoznaje da je za MXR-mehanizam zaslužno više transportnih proteina zasigurno će pridonijeti potpunijoj karakterizaciji MXR-a kao integralnog dijela detoksikacijskog, odnosno temeljnog obrambenog sustava vodenih organizama te njegovoj znanstvenoj afirmaciji kao vjerodostojnog pokazatelja kvalitete okoliša.
In this study, we aimed to investigate the prognostic value of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and programmed cell death ligand 2 (PD-L2) expressions ...on immune and cancer cells in terms of survival in patients with lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.
Between January 2000 and December 2012, a total of 191 patients (172 males, 19 females; mean age: 60.3±8.4 years; range, 38 to 78 years) who were diagnosed with non-small cell lung cancer and underwent anatomic resection and mediastinal lymph node dissection were retrospectively analyzed. The patients were evaluated in three groups including lung squamous cell carcinoma (n=61), adenocarcinoma (n=66), and large-cell carcinoma (n=64). The survival rates of all three groups were compared in terms of immunohistochemical expression levels of PD-1, PD-L1, and PD-L2.
The mean follow-up was 71.8±47.9 months. In all histological subtypes, PD-1 expressions on tumor and immune cells were observed in 33% (61/191) and in 53.1% (102/191) of the patients, respectively. Higher expression levels of PD-L1 and PD-L2 at any intensity on tumor and immune cells were defined only in lung adenocarcinomas, and PD-L1 and PD-L2 values were detected in 36.4% (22/64) of these patients. The PD-L1 expressions on tumor and immune cells were observed in 41.7% (10/24) and 25% (6/24) of the patients, respectively. The PD-L2 expressions on tumor and immune cells were detected in 16.7% (4/24) and 8.4% (2/24) of the patients, respectively. Univariate and multivariate analyses revealed that PD-1 expression in tumor cells was an independent prognostic factor in all histological subtypes.
Our study results suggest that PD-1 expression is a poor prognostic factor for overall survival in patients with completely resected adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.
The high levels of variation in surface epitopes can be considered as an evolutionary hallmark of immune selection. New computational tools enable analysis of this variation by identifying codons ...that exhibit high rates of amino acid changes relative to the synonymous substitution rate. In the outer membrane protein P1 of Haemophilus influenzae, a vaccine candidate for nontypeable strains, we identified four codons with this attribute in domains that did not correspond to known or assumed B- and T-cell epitopes of OMP-P1. These codons flank hypervariable domains and do not appear to be false positives as judged from parsimony and maximum likelihood analyses. Some closely spaced positively selected codons have been previously considered part of a transmembrane domain, which would render this region unsuited for inclusion in a vaccine. Secondary structure analysis, three-dimensional structural database searches, and homology modeling using FadL of E. coli as a structural homologue, however, revealed that all positively selected codons are located in or near extracellular looping domains. The spacing and level of diversity of these positively selected and exposed codons in OMP-P1 suggest that vaccine targets based on these and conserved flanking residues may provide broad coverage in H. influenzae.
Tijekom posljednjih petnaestak godina za istraživanje uloge različiti h proteina i mehanizama
nastanka bolesti primjenjuju se sistemski pristupi i analize kojima se istovremeno
prate globalne ...promjene razine ekspresije velikog broja gena i/ili proteina. Imajući na umu
složene interakcije na razini stanica i činjenicu kako je većina bolesti multi faktorijalnog podrijetla,
takav sistemski pristup najbolji je način stjecanja uvida u funkciju nekog proteina i/ili
mehanizme nastanka bolesti . Proteini “Trefoil Factor Family” ili proteini TFF (TFF1,TFF2, TFF3)
otkriveni su prije više od 25 godina, te je ubrzo postalo jasno kako je njihova uloga u organizmu
iznimno kompleksna. Tek je sistemski pristup istraživanju analize uloge proteina TFF2
razjasnio njegovu ulogu u organizmu pokazujući vezu s imunološkim sustavom.
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