BACKGROUND: The CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of CTLA4 with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases. METHODS: Six polymorphisms within the CTLA4 region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the CTLA4 variants and other genetic factors known to confer the disease susceptibility. RESULTS: No crude associations with Crohn's disease were found for the tested CTLA4 variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the NOD2 (the p.Leu1007fsX1008, rs5743293) or the IL23R (p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of CTLA4 CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with CTLA4 was apparent only in the strata defined by presence minor alleles at the NOD2 rs5743293 (here the CTLA4 CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or IL23R rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked CTLA4 markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014). CONCLUSIONS: A protective effect of a CTLA4 haplotype was unmasked after stratification for the risk variants in the NOD2 and IL23R genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.

• MeSH
• alely MeSH
• antigen CTLA-4 MeSH
• běloši genetika   MeSH
• CD antigeny MeSH
• Crohnova nemoc epidemiologie   genetika   MeSH
• cytotoxické T-lymfocyty MeSH
• genotyp MeSH
• haplotypy MeSH
• idiopatické střevní záněty genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• polymorfismus genetický MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Within fossil- and solid-fuel dependent geographic locations, mechanisms of air pollution-induced asthma remains unknown. In particular, sources of greater genetic susceptibility to airborne carcinogen, namely, benzo[a]pyrene (B[a]P) has never been investigated beyond that of a few well known genes. OBJECTIVES: To deepen our understanding on how the genotypic variations within the candidate genes contribute to the variability in the children's susceptibility to ambient B[a]P on doctor-diagnosed asthma. METHODS: Clinically confirmed asthmatic versus healthy control children (aged, 7-15) were enrolled from historically polluted and rural background regions in Czech Republic. Contemporaneous ambient B[a]P concentration was obtained from the routine monitoring network. The sputum DNA was genotyped for 95 genes. B[a]P interaction with SNPs was studied by two-stage, semi-agnostic screening of 621 SNPs. RESULTS: The median B[a]P within the highly polluted urban center was 8-times higher than that in the background region (7.8 vs. 1.1 ng/m3) during the period of investigation. Within the baseline model, which considered B[a]P exposure-only, the second tertile range was associated with a significantly reduced odds (aOR = 0.28) of asthma (95% CI, 0.16 to 0.50) compared to those at the lowest range. However, the highest range of B[a]P was associated with 3.18-times greater odds of the outcome (95% CI, 1.77 to 5.71). Within the gene-environment interaction models, joint occurrence of a high B[a]P exposure range and having a high-risk genotype at CTLA4 gene (rs11571316) was associated with 9-times greater odds (95% CI, 4.56-18.36) of the asthma diagnosis. Similarly, rs11571319 at CTLA4 and a high B[a]P exposure range was associated with a 8-times greater odds (95% CI, 3.95-14.27) of asthma diagnosis. Furthermore, having TG + GG genotypes on rs1031509 near STAT4 was associated with 5-times (95% CI, 3.03-8.55) greater odds of asthma diagnosis at the highest B[a]P range, compared to the odds at the reference range. Also CYP2E1 AT + TT genotypes (rs2070673) was associated with 5-times (95% CI, 3.1-8.8) greater odds of asthma diagnosis at the highest B[a]P exposure. CONCLUSIONS: The children, who jointly experience a high B[a]P exposure (6.3-8.5 ng/m3) as well as susceptible genotypes in CTLA4 (rs11571316 and rs11571319), STAT4 (rs1031509), and CYP2E1 (rs2070673), respectively, are associated with a significantly greater odds of having doctor-diagnosed asthma, compared to those with neither risk factors.

• MeSH
• antigen CTLA-4 genetika   MeSH
• benzopyren analýza   MeSH
• bronchiální astma chemicky indukované   genetika   MeSH
• cytochrom P-450 CYP2E1 genetika   MeSH
• dítě MeSH
• genetická predispozice k nemoci * MeSH
• genotyp MeSH
• interakce genů a prostředí MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• městské obyvatelstvo MeSH
• studie případů a kontrol MeSH
• transkripční faktor STAT4 genetika   MeSH
• venkovské obyvatelstvo MeSH
• vystavení vlivu životního prostředí analýza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• znečištění ovzduší analýza   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Little is known on the genetic susceptibility to type 1 diabetes mellitus (T1DM) in the nations of the former Soviet part of south-west Asia. OBJECTIVE: The aim of the study was to characterize the genetic association of T1DM in the Azeri, the majority population of Azerbaijan. SUBJECTS AND METHODS: One hundred and sixty patients with childhood-onset T1DM, and 271 healthy unrelated controls were compared in a case-control study. All declared themselves as Azeri. The human leukocyte antigen (HLA)-DQB1, -DQA1 alelles, of DRB1*04 subtypes, and of insulin gene and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) single nucleotide polymorphisms were determined using polymerase chain reaction (PCR) techniques, the association was tested from cross-tabulations, and quantified using odds ratios (OR). In the non-HLA factors, analyses were also stratified according to the HLA-conferred risk. RESULTS: Risk for T1DM was associated with presence of the HLA-DQB1*02-DQA1*05, OR = 6.6 [95% confidence interval (CI) 4.3-10], the HLA-DQB1*0302-DQA1*03, OR = 3.9 (95% CI 2.6-6.0), and an unexpectedly high risk was observed for DQB1*0304, OR = 10.9, but the very wide CI (CI 95% 2.4-49) prompts careful interpretation. A negative association with diabetes was observed for the DQB1*0602, 0503, 0301, and 0601 alleles, as well as the DRB1*0403 subtype. A strong protection was also associated with the less frequent variant of the insulin gene (OR of the phenotypic positivity was 0.28, CI 95% 0.17-0.46), while the CTLA4 +49 A/G transition was not associated with T1DM. CONCLUSIONS: We bring the first report on both HLA, and non-HLA association of T1DM from the majority Azeri population of Azerbaijan.

• MeSH
• antigen CTLA-4 MeSH
• CD antigeny MeSH
• diabetes mellitus 1. typu genetika   MeSH
• diferenciační antigeny genetika   MeSH
• dítě MeSH
• HLA-DQ antigeny genetika   MeSH
• HLA-DR antigeny genetika   MeSH
• HLA-DRB1 řetězec MeSH
• inzulin genetika   MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

• MeSH
• antigeny CD274 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• antigeny CD279 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• inhibitory kontrolních bodů chemie   farmakologie   MeSH
• knihovny malých molekul farmakologie   chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu * MeSH
• terfenylové sloučeniny * chemie   farmakologie   MeSH
• vazba proteinů * MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Immune checkpoint blockade (ICB) using monoclonal antibodies against programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) is the treatment of choice for cancer immunotherapy. However, low tissue permeability, immunogenicity, immune-related adverse effects, and high cost could be possibly improved using alternative approaches. On the other hand, synthetic low-molecular-weight (LMW) PD-1/PD-L1 blockers have failed to progress beyond in vitro studies, mostly due to low binding affinity or poor pharmacological characteristics resulting from their limited solubility and/or stability. Here, we report the development of polymer-based anti-human PD-L1 antibody mimetics (α-hPD-L1 iBodies) by attaching the macrocyclic peptide WL12 to a N-(2-hydroxypropyl)methacrylamide copolymer. We characterized the binding properties of iBodies using surface plasmon resonance, enzyme-linked immunosorbent assay, flow cytometry, confocal microscopy, and a cellular ICB model. We found that the α-hPD-L1 iBodies specifically target human PD-L1 (hPD-L1) and block the PD-1/PD-L1 interaction in vitro, comparable to the atezolizumab, durvalumab, and avelumab licensed monoclonal antibodies targeting PD-L1. Our findings suggest that iBodies can be used as experimental tools to target hPD-L1 and could serve as a platform to potentiate the therapeutic effect of hPD-L1-targeting small molecules by improving their affinity and pharmacokinetic properties.

• MeSH
• antigeny CD274 * antagonisté a inhibitory   imunologie   metabolismus   MeSH
• inhibitory kontrolních bodů * farmakologie   chemie   MeSH
• lidé MeSH
• monoklonální protilátky chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• polymery chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Abatacept je biologický chorobu modifikující lék (biological disease-modifying anti-rheumatic drugs, bDMARD) účinný u pacientů s revmatoidní artritidou. Abatacept má dobrou klinickou účinnost u pacientů s nedostatečným účinkem syntetických chorobu modifikujících léků a inhibitorů tumor nekrotizujícího faktoru alfa a má setrvalý klinický účinek srovnatelný s ostatními bDMARD. Abatacept má dobrý bezpečnostní profil včetně rizika závažných infekcí u pacientů s nedostatečným účinkem předchozí léčby a je vhodnou volbou u pacientů po opakovaných závažných infekčních komplikacích.

Abatacept is a biologic disease modifying antirheumatic drug (bDMARD) effective in treatment of rheumatoid arthritis. Abatacept is of significant clinical and functional benefit in patients who had an inadequate response to previous synthetic disease modifying antirheumatic drugs or tumor necrosis factor a inhibitors with sustained clinical efficacy comparable with other bDMARDs. It has a good safety profile including risks of serious infections in patients with previous treatment failure and appears a suitable treatment option in patients with previous infectious complications.

• Klíčová slova
• Orencia,
• MeSH
• abatacept * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• antirevmatika MeSH
• biologická terapie škodlivé účinky   MeSH
• C-reaktivní protein MeSH
• infekce farmakoterapie   mikrobiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada léků MeSH
• revmatoidní artritida * farmakoterapie   komplikace   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• kazuistiky MeSH

OBJECTIVE: To investigate the role of rheumatoid factor (RF) status and anti-citrullinated peptide antibody (ACPA) status as predictors of abatacept (ABA) effectiveness in patients with rheumatoid arthritis (RA). METHODS: We conducted a pooled analysis of data from 9 observational RA registries in Europe (ARTIS [Sweden], ATTRA [Czech Republic], BIOBADASER [Spain], DANBIO [Denmark], GISEA [Italy], NOR-DMARD [Norway], ORA [France], Reuma.pt [Portugal], and SCQM-RA [Switzerland]). Inclusion criteria were a diagnosis of RA, initiation of ABA treatment, and available information on RF and/or ACPA status. The primary end point was continuation of ABA treatment. Secondary end points were ABA discontinuation for ineffectiveness or adverse events and response rates at 1 year (good or moderate response according to the European League Against Rheumatism criteria with LUNDEX adjustment for treatment continuation). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the study end points in relation to RF and ACPA status were calculated. RESULTS: We identified 2,942 patients with available data on RA-associated autoantibodies; data on RF status were available for 2,787 patients (77.0% of whom were RF positive), and data on ACPA status were available for 1,903 patients (71.3% of whom were ACPA positive). Even after adjustment for sociodemographic and disease- and treatment-related confounders, RF and ACPA positivity were each associated with a lower risk of ABA discontinuation for any reason (HR 0.79 [95% CI 0.69-0.90], P < 0.001 and HR 0.78 [95% CI 0.68-0.90], P < 0.001, respectively), compared to RF-negative and ACPA-negative patients. Similar associations with RF and ACPA were observed for discontinuation of ABA treatment due to ineffectiveness, with HRs of 0.72 (95% CI 0.61-0.84) and 0.74 (95% CI 0.62-0.88), respectively (both P < 0.001). CONCLUSION: Our results strongly suggest that positivity for RF or ACPA is associated with better effectiveness of ABA therapy.

• MeSH
• abatacept terapeutické užití   MeSH
• antirevmatika terapeutické užití   MeSH
• autoprotilátky krev   MeSH
• cyklické peptidy imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prediktivní hodnota testů MeSH
• registrace MeSH
• revmatoidní artritida krev   farmakoterapie   MeSH
• revmatoidní faktor krev   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

Neúčinnost „chorobu modifikujících“ farmak u části pacientů se zánětlivými artropatiemi a nepřesvědčivé výsledky studií sledujících radiologickou progresi urychlily snahu o vývoj nových, účinnějších farmak s cílem ovlivnit nejen klinickou aktivitu, ale i radiologickou progresi. Vývoj těchto nových farmak vychází ze znalostí klíčové role T- a B-lymfocytů a cytokinů produkovaných aktivovanými imunokompetentními buňkami v patogenezi zánětlivých artropatií. Mezi nejvýznamnější cytokiny patří faktor nekrotizující tumory (TNF?- „tumor necrosis factor ?“), interleukin-1 (IL-1) a interleukin-6 (IL-6). Tyto poznatky vedly k vývoji látek, specificky zaměřených na inhibici těchto buněk resp. jejich cytokinů, v prvé řadě TNF?. Léčba těmito farmaky se ukázala být vysoce účinnou u revmatoidní artritidy rezistentní na léčbu standardními „chorobu modifikujícími farmaky“ a to při sledování prakticky všech dostupných parametrů. Následovaly podobně dobré zkušenosti jsou i s léčbou spondylartritid, zejména psoriatické artritidy a ankylozující spondylitidy. V současné době jsou k dispozici 3 látky inhibující TNF?: infliximab (REMICADE), etanercept (ENBREL) a adalimumab (HUMIRA). Další výzkum na tomto poli vedl k vývoji farmak ovlivňujících aktivaci T-buněk na úrovni tzv. kostimulačních molekul (tzv. imunomodulátory, např. abatacept). Jiný přístup k „biologické léčbě“ představuje snaha ovlivnit aktivaci B-buněk, které rovněž hrají roli v genezi revmatoidní artritidy (rituximab).

The ineffectiveness of „disease-modifying“ drugs in a proportion of patients with inflammatory arthropathies and inconclusive results of studies investigating radiological progression have accelerated the efforts to develop new, more effective pharmaceuticals with an aim to affect not only clinical activity but also radiological progression. The development of these new pharmaceuticals is based on the knowledge of the key roles of T and B lymphocytes and cytokines produced by activated immunocompetent cells in the pathogenesis of inflammatory arthropathies. The most significant cytokines include tumor necrosis factor alpha (TNF?), interleukin-1 (IL-1), and interleukin-6 (IL-6). This knowledge has led to the development of substances specifically designed to inhibit these cells and/or their cytokines, primarily TNF?. Treatment with these pharmaceuticals has proved highly effective in rheumatoid arthritis resistant to treatment with standard „disease-modifying“ drugs in virtually all available parameters followed. Similarly positive experience has been gained with the treatment of spondylarthritides, particularly psoriatic arthritis and ankylosing spondylitis. Currently, three substances inhibiting TNF? are available: infliximab (REMICADE), etanercept (ENBREL), and adalimumab (HUMIRA). Further research in this field has led to the development of pharmaceuticals affecting T cell activation at the level of so-called costimulatory molecules (so-called immunomodulators such as abatacept). Another approach to „biological therapy“ is represented by an effort to affect activation of B cells that also play a role in the genesis of rheumatoid arthritis (rituximab).

• Klíčová slova
• Fc-fusion protein, Remicade, Enbrel, Humira, Orencia,
• MeSH
• abatacept MeSH
• adalimumab MeSH
• antirevmatika farmakologie   MeSH
• biologická terapie metody   trendy   MeSH
• denosumab MeSH
• etanercept MeSH
• imunoglobulin G MeSH
• imunokonjugáty MeSH
• infliximab MeSH
• lidé MeSH
• ligand RANK MeSH
• mediátory zánětu MeSH
• monoklonální protilátky MeSH
• receptory TNF MeSH
• rekombinantní fúzní proteiny MeSH
• revmatické nemoci farmakoterapie   MeSH
• TNF-alfa účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Od uvedení anti-CTLA4 protilátky ipilimumab v roce 2011 v paliativní léčbě maligního melanomu, s do té doby nevídanými výsledky, se imunoterapie pevně etablovala v léčbě řady zhoubných nádorů. Od srovnávání účinnosti imunoterapie se standardem léčby ve druhé a první linii paliativní léčby se vzhledem k povzbudivým výsledkům začíná imunoterapie inhibitory kontrolních bodů (anti-CTLA-4, anti-PD1, anti-PD-L1) prosazovat v adjuvantní indikaci či v rámci tumor-agnostického přístupu, nádory horního gastrointestinálního traktu (GIT) nevyjímaje. Přehledový článek nabízí shrnutí proběhlých klinických studií s použitím imunoterapie checkpoint inhibitory v léčbě nádorů horního GIT.

Since the introduction of the anti-CTLA4 antibody ipilimumab in 2011 in the palliative treatment of malignant melanoma with previously unprecedented results, immunotherapy has become firmly established in the treatment of a number of cancers. Given the encouraging results of immunotherapy in the first-line and the second-line setting compared to standard of care, checkpoint inhibitors (anti-CTLA-4, anti-PD1, anti-PD-L1) begin to permeate into the adjuvant setting or within the tumor-agnostic approach, including upper gastrointestinal (GI) tumors. This review offers a summary of clinical trials investigating immunotherapy with checkpoint inhibitors in the treatment of upper GI tumors.

• MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory jícnu * farmakoterapie   imunologie   MeSH
• nádory žaludku * farmakoterapie   imunologie   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients. METHODS: We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients' outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing. RESULTS: A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A*01 and or A*02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A*01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1. CONCLUSIONS: This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.

• MeSH
• alely MeSH
• analýza přežití MeSH
• HLA antigeny metabolismus   MeSH
• inhibitory kontrolních bodů farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory plic genetika   mortalita   MeSH
• nemalobuněčný karcinom plic genetika   mortalita   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH