Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in ovo with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci: HRAS, EGFR, MET, and RON Insertionally mutated genes correlated with tumor type: HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs, and EGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of EGFR and RON, also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated EGFR and RON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII and sfRON).IMPORTANCE These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.

• Klíčová slova
• avian retroviruses, insertional mutagenesis, retroviral oncogenesis,
• MeSH
• cholangiokarcinom genetika   virologie   MeSH
• geny erbB-1 * MeSH
• hemangiosarkom genetika   virologie   MeSH
• hepatocelulární karcinom genetika   virologie   MeSH
• integrace viru MeSH
• inzerční mutageneze * MeSH
• karcinogeneze * MeSH
• kur domácí genetika   MeSH
• lidé MeSH
• nádory jater genetika   virologie   MeSH
• onkogeny MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• proviry genetika   fyziologie   MeSH
• ptačí proteiny genetika   MeSH
• tyrosinkinasové receptory genetika   MeSH
• virus ptačí myeloblastózy genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protoonkogenní proteiny c-met MeSH
• ptačí proteiny MeSH
• RON protein MeSH Prohlížeč
• tyrosinkinasové receptory MeSH

Valvular heart disease leads to ventricular pressure and/or volume overload. Pressure overload leads to fibrosis, which might regress with its resolution, but the limits and details of this reverse remodeling are not known. To gain more insight into the extent and nature of cardiac fibrosis in valve disease, we analyzed needle biopsies taken from the interventricular septum of patients undergoing surgery for valve replacement focusing on the expression and distribution of major extracellular matrix protein involved in this process. Proteomic analysis performed using mass spectrometry revealed an excellent correlation between the expression of collagen type I and III, but there was little correlation with the immunohistochemical staining performed on sister sections, which included antibodies against collagen I, III, fibronectin, sarcomeric actin, and histochemistry for wheat germ agglutinin. Surprisingly, the immunofluorescence intensity did not correlate significantly with the gold standard for fibrosis quantification, which was performed using Picrosirius Red (PSR) staining, unless multiplexed on the same tissue section. There was also little correlation between the immunohistochemical markers and pressure gradient severity. It appears that at least in humans, the immunohistochemical pattern of fibrosis is not clearly correlated with standard Picrosirius Red staining on sister sections or quantitative proteomic data, possibly due to tissue heterogeneity at microscale, comorbidities, or other patient-specific factors. For precise correlation of different types of staining, multiplexing on the same section is the best approach.

• Klíčová slova
• Collagen, Fibronectin, Fibrosis, Pressure overload, Valvular heart disease,
• MeSH
• aortální insuficience metabolismus   patologie   chirurgie   MeSH
• aortální stenóza * metabolismus   patologie   chirurgie   MeSH
• extracelulární matrix - proteiny * metabolismus   analýza   MeSH
• fibróza * metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezikomorová přepážka patologie   metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• extracelulární matrix - proteiny * MeSH

BACKGROUND: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). METHODS: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. FINDINGS: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P < .001) and in patients with non-GHD short stature. INTERPRETATION: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. FUND: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.

• Klíčová slova
• Genetics, Growth hormone deficiency, Hypopituitarism, Pituitary, Short stature,
• MeSH
• dítě MeSH
• fenotyp MeSH
• homeodoménové proteiny genetika   MeSH
• hypofýza růst a vývoj   metabolismus   MeSH
• hypofyzární nanismus genetika   metabolismus   patofyziologie   MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• lidský růstový hormon genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• protein Gli2 s motivem zinkových prstů genetika   MeSH
• proteiny s homeodoménou LIM genetika   MeSH
• receptory hormonů regulujících hypofyzární hormony MeSH
• receptory neuropeptidů MeSH
• transkripční faktor Pit-1 genetika   MeSH
• transkripční faktory SOXB1 genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• GHRHR protein, human MeSH Prohlížeč
• GLI2 protein, human MeSH Prohlížeč
• HESX1 protein, human MeSH Prohlížeč
• homeodoménové proteiny MeSH
• jaderné proteiny MeSH
• Lhx3 protein MeSH Prohlížeč
• LHX4 protein, human MeSH Prohlížeč
• lidský růstový hormon MeSH
• POU1F1 protein, human MeSH Prohlížeč
• Prophet of Pit-1 protein MeSH Prohlížeč
• protein Gli2 s motivem zinkových prstů MeSH
• proteiny s homeodoménou LIM MeSH
• receptory hormonů regulujících hypofyzární hormony MeSH
• receptory neuropeptidů MeSH
• SOX3 protein, human MeSH Prohlížeč
• transkripční faktor Pit-1 MeSH
• transkripční faktory SOXB1 MeSH
• transkripční faktory MeSH

OBJECTIVE: Obesity is linked with a state of increased oxidative stress, which plays an important role in the etiology of atherosclerosis and type 2 diabetes mellitus. The aim of our study was to evaluate the effect of rapid weight loss on oxidative stress markers in obese individuals with metabolic syndrome (MetS). DESIGN AND METHODS: We measured oxidative stress markers in 40 obese subjects with metabolic syndrome (MetS+), 40 obese subjects without metabolic syndrome (MetS-), and 20 lean controls (LC) at baseline and after three months of very low caloric diet. RESULTS: Oxidized low density lipoprotein (ox-LDL) levels decreased by 12% in MetS+ subjects, associated with a reduction in total cholesterol (TC), even after adjustment for age and sex. Lipoprotein associated phospholipase A₂ (Lp-PLA₂) activity decreased by 4.7% in MetS+ subjects, associated with a drop in LDL-cholesterol (LDL-C), TC, and insulin levels. Multivariate logistic regression analysis showed that a model including ox-LDL, LpPLA₂ activity, and myeloperoxidase (MPO) improved prediction of MetS status among obese individuals compared to each oxidative stress marker alone. CONCLUSIONS: Oxidative stress markers were predictive of MetS in obese subjects, suggesting a higher oxidative stress. Rapid weight loss resulted in a decline in oxidative stress markers, especially in MetS+ patients.

• MeSH
• biologické markery krev   MeSH
• C-reaktivní protein metabolismus   MeSH
• hmotnostní úbytek * MeSH
• inzulin krev   MeSH
• kalorická restrikce MeSH
• LDL-cholesterol krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipoproteiny LDL krev   MeSH
• metabolický syndrom krev   etiologie   patofyziologie   prevence a kontrola   MeSH
• obezita krev   komplikace   patofyziologie   MeSH
• oxidační stres MeSH
• triglyceridy krev   MeSH
• zánět krev   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• srovnávací studie MeSH
• Názvy látek
• biologické markery MeSH
• C-reaktivní protein MeSH
• inzulin MeSH
• LDL-cholesterol MeSH
• lipoproteiny LDL MeSH
• oxidized low density lipoprotein MeSH Prohlížeč
• triglyceridy MeSH

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
• antitumorózní látky aplikace a dávkování   škodlivé účinky   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 po terapii bez příznaků nemoci MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• protokoly antitumorózní 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
• antitumorózní látky MeSH
• 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

Lopinavir (LPV) is a second-generation HIV protease inhibitor (PI) designed to overcome resistance development in patients undergoing long-term antiviral therapy. The mutation of isoleucine at position 47 of the HIV protease (PR) to alanine is associated with a high level of resistance to LPV. In this study, we show that recombinant PR containing a single I47A substitution has the inhibition constant (K(i) ) value for lopinavir by two orders of magnitude higher than for the wild-type PR. The addition of the I47A substitution to the background of a multiply mutated PR species from an AIDS patient showed a three-order-of-magnitude increase in K(i) in vitro relative to the patient PR without the I47A mutation. The crystal structure of I47A PR in complex with LPV showed the loss of van der Waals interactions in the S2/S2' subsites. This is caused by the loss of three side-chain methyl groups due to the I47A substitution and by structural changes in the A47 main chain that lead to structural changes in the flap antiparallel beta-strand. Furthermore, we analyzed possible interaction of the I47A mutation with secondary mutations V32I and I54V. We show that both mutations in combination with I47A synergistically increase the relative resistance to LPV in vitro. The crystal structure of the I47A/I54V PR double mutant in complex with LPV shows that the I54V mutation leads to a compaction of the flap, and molecular modeling suggests that the introduction of the I54V mutation indirectly affects the strain of the bound inhibitor in the PR binding cleft.

• MeSH
• alanin metabolismus   MeSH
• Escherichia coli genetika   MeSH
• HIV-proteasa chemie   genetika   izolace a purifikace   metabolismus   MeSH
• inhibitory HIV-proteasy chemie   metabolismus   farmakologie   MeSH
• katalýza MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• Lopinavir MeSH
• molekulární modely MeSH
• náchylnost k nemoci * MeSH
• pyrimidinony chemie   metabolismus   farmakologie   MeSH
• rekombinantní proteiny antagonisté a inhibitory   chemie   izolace a purifikace   MeSH
• sekundární struktura proteinů MeSH
• substituce aminokyselin * MeSH
• virová léková rezistence genetika   MeSH
• vodíková vazba MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alanin MeSH
• HIV-proteasa MeSH
• inhibitory HIV-proteasy MeSH
• Lopinavir MeSH
• pyrimidinony MeSH
• rekombinantní proteiny MeSH

S28463 (S28), a ligand for Toll-like receptor 7/8, has been shown to have antiinflammatory properties in rodent models of allergic asthma. The principle goal of this study was to assess whether these antiinflammatory effects can also be observed in a nonhuman primate (NHP) model of allergic asthma. NHPs were sensitized then challenged with natural allergen, Ascaris suum extract. The animals were treated with S28 orally before each allergen challenge. The protective effect of S28 in NHPs was assessed by measuring various asthma-related phenotypes. We also characterized the metabolomic and proteomic signatures of the lung environment and plasma to identify markers associated with the disease and treatment. Our data demonstrate that clinically relevant parameters, such as wheal and flare response, blood IgE levels, recruitment of white blood cells to the bronchoalveolar space, and lung responsiveness, are decreased in the S28-treated allergic NHPs compared with nontreated allergic NHPs. Furthermore, we also identified markers that can distinguish allergic from nonallergic or allergic and drug-treated NHPs, such as metabolites, phosphocreatine and glutathione, in the plasma and BAL fluid, respectively; and inflammatory cytokines, IL-5 and IL-13, in the bronchoalveolar lavage fluid. Our preclinical study demonstrates that S28 has potential as a treatment for allergic asthma in primate species closely related to humans. Combined with our previous findings, we demonstrate that S28 is effective in different models of asthma and in different species, and has the antiinflammatory properties clinically relevant for the treatment of allergic asthma.

• Klíčová slova
• experimental model, inflammation, metabolomics, proteomics, treatment,
• MeSH
• alergeny toxicita   MeSH
• Ascaris suum chemie   imunologie   MeSH
• bronchiální astma * chemicky indukované   imunologie   patologie   MeSH
• interleukin-13 imunologie   MeSH
• interleukin-5 imunologie   MeSH
• Macaca fascicularis MeSH
• proteiny červů toxicita   MeSH
• toll-like receptor 7 * agonisté   imunologie   MeSH
• toll-like receptor 8 * agonisté   imunologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alergeny MeSH
• interleukin-13 MeSH
• interleukin-5 MeSH
• proteiny červů MeSH
• toll-like receptor 7 * MeSH
• toll-like receptor 8 * MeSH

OBJECTIVE: To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. METHODS: This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. RESULTS: Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. CONCLUSION: ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. TRIAL REGISTRATION: This study was registered on www.ClinicalTrials.gov (NCT01981473).

• MeSH
• adalimumab škodlivé účinky   imunologie   farmakologie   terapeutické užití   MeSH
• antirevmatika imunologie   farmakologie   terapeutické užití   MeSH
• bezpečnost MeSH
• etanercept škodlivé účinky   imunologie   farmakologie   terapeutické užití   MeSH
• infliximab škodlivé účinky   imunologie   farmakologie   terapeutické užití   MeSH
• internacionalita MeSH
• lidé středního věku MeSH
• lidé MeSH
• protilátky imunologie   MeSH
• revmatoidní artritida farmakoterapie   imunologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adalimumab MeSH
• antirevmatika MeSH
• etanercept MeSH
• infliximab MeSH
• protilátky MeSH

Across much of central Europe, the Linearbandkeramik (LBK) represents the first Neolithic communities. Arising in Transdanubia around 5500 cal. BC the LBK spread west to the Rhine within two to three hundred years, carrying elements of a mixed agricultural economy and a relatively homogeneous material culture. Colonisation of new regions during this progress would have required economic adaptations to varied ecological conditions within the landscape. This paper investigates whether such adaptation at a local scale affected health patterns and altered the dietary habits of populations that otherwise shared a common cultural and biological origin. Analysis of non-specific stress (linear enamel hypoplasia, porotic hyperostosis, cribra orbitalia) within five LBK populations from across central Europe in conjunction with published carbon and nitrogen stable isotope data from each site revealed a high prevalence of porotic hyperostosis and cribra orbitalia in western populations that was associated with a lower animal protein intake. Hypoplastic enamel was more frequently observed in eastern populations however, and may reflect geographic differences in childhood morbidity and mortality as a result of variation in social practices relating to weaning. Local socio-economic adaptations within the LBK were therefore an important factor in the exposure of populations to non-specific stress.

• MeSH
• antropologie fyzická MeSH
• archeologie MeSH
• biologická adaptace MeSH
• hyperostóza epidemiologie   MeSH
• hypoplazie zubní skloviny epidemiologie   MeSH
• mitochondriální DNA genetika   MeSH
• odstavení MeSH
• sociální přizpůsobení MeSH
• stravovací zvyklosti MeSH
• tělesné pozůstatky anatomie a histologie   MeSH
• zdravotnické přehledy MeSH
• zemědělci MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• mitochondriální DNA MeSH

INTRODUCTION: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged ≤40 years. METHODS AND ANALYSIS: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle. ETHICS AND DISSEMINATION: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.

• Klíčová slova
• breast tumours, epidemiology, histopathology,
• MeSH
• časové faktory MeSH
• dospělí MeSH
• exprese genu MeSH
• kohortové studie MeSH
• lidé MeSH
• nádory prsu genetika   metabolismus   patologie   chirurgie   MeSH
• prognóza MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• registrace MeSH
• výzkumný projekt * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ERBB2 protein, human MeSH Prohlížeč
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH
• receptory progesteronu MeSH