BACKGROUND: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. METHODS: In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. FINDINGS: Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7-15.0]) than in the chemotherapy alone group (median 9.6 months [95% CI 9.1-9.7) (HR 0.51 [95% CI 0.34-0.77]; p=0.0012), especially in patients with BRCA mutations (HR 0.21 [0.08-0.55]; p=0.0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. INTERPRETATION: Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. FUNDING: AstraZeneca.

• MeSH
• aplikace orální MeSH
• časové faktory MeSH
• cílená molekulární terapie MeSH
• dospělí MeSH
• ftalaziny aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory enzymů aplikace a dávkování   škodlivé účinky   MeSH
• intravenózní podání MeSH
• karboplatina aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * MeSH
• mladý dospělý MeSH
• mutace MeSH
• nádory cystické, mucinózní a serózní farmakoterapie   enzymologie   mortalita   patologie   MeSH
• nádory vaječníků farmakoterapie   enzymologie   genetika   mortalita   patologie   MeSH
• paclitaxel aplikace a dávkování   MeSH
• PARP inhibitory * MeSH
• piperaziny aplikace a dávkování   škodlivé účinky   MeSH
• poly(ADP-ribosa)polymerasy metabolismus   MeSH
• přežití bez známek nemoci MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• ftalaziny MeSH
• inhibitory enzymů MeSH
• karboplatina MeSH
• olaparib MeSH Prohlížeč
• paclitaxel MeSH
• PARP inhibitory * MeSH
• piperaziny MeSH
• poly(ADP-ribosa)polymerasy MeSH
• protein BRCA1 MeSH
• protein BRCA2 MeSH
• protinádorové látky MeSH

Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with a tremendous increase in morbidity as well as treatment costs. The ultimate goal of inhibitor control is antibody elimination. Immune tolerance induction (ITI) is the only clinically established approach for developing antigen-specific tolerance to FVIII. This work aims to establish a novel cost-effective strategy to produce FVIII molecules in fusion with cholera toxin B (CTB) subunit at the N terminus using the Bacillus subtilis expression system for oral tolerance, as the current clinical immune tolerance protocols are expensive. Regions of B-Domain Deleted (BDD)-FVIII that have potential epitopes were identified by employing Bepipred linear epitope prediction; 2 or more epitopes in each domain were combined and cDNA encoding these regions were fused with CTB and cloned in the Bacillus subtilis expression vector pHT43 and expression analysis was carried out. The expressed CTB-fused FVIII epitope domains showed strong binding affinity towards the CTB-receptor GM1 ganglioside. To conclude, Bacillus subtilis expressing FVIII molecules might be a promising candidate for exploring for the induction of oral immune tolerance.

• Klíčová slova
• Bacillus subtilis, Cholera toxin B, Epitopes, Factor VIII, Ganglioside receptor(GM1), Haemophilia A, Oral tolerance,
• MeSH
• aplikace orální MeSH
• Bacillus subtilis * genetika   imunologie   metabolismus   MeSH
• cholerový toxin * genetika   imunologie   MeSH
• epitopy * imunologie   genetika   MeSH
• exprese genu MeSH
• faktor VIII * imunologie   genetika   MeSH
• imunologická tolerance * MeSH
• lidé MeSH
• rekombinantní fúzní proteiny * imunologie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholerový toxin * MeSH
• epitopy * MeSH
• faktor VIII * MeSH
• rekombinantní fúzní proteiny * MeSH

Changes in ADA and PNP activities in the spleens and thymuses of mice were studied after a single administration of cyclophosphamide (CY, 200 mg/kg) and after whole-body gamma irradiation (5.5 Gy), applied alone or three days after CY application. In the first days after the treatment the enzyme activities were significantly depressed (p less than 0.01) with the exception of ADA in the spleen, where a high elevation (220-380%) in relation to controls was observed. During the regeneration period a pronounced rise of PNP activity in the spleen occurred mainly after a combined application of CY and irradiation (270%). In the thymus the regeneration was manifested by a mild increase of both ADA and PNP activities towards control values. The findings suggest that the expressive changes of ADA and PNP activities, participating in the purine salvage pathway, may, after a cytotoxic treatment, influence the nucleotide pool and DNA synthesis in lymphoid organs.

• MeSH
• adenosindeaminasa metabolismus   účinky záření   MeSH
• celotělové ozáření MeSH
• cyklofosfamid farmakologie   MeSH
• injekce intraperitoneální MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• purinnukleosidfosforylasa metabolismus   účinky záření   MeSH
• slezina účinky léků   enzymologie   účinky záření   MeSH
• thymus účinky léků   enzymologie   účinky záření   MeSH
• velikost orgánu MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• záření gama MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosindeaminasa MeSH
• cyklofosfamid MeSH
• purinnukleosidfosforylasa MeSH