One of the most common mechanisms of immune evasion in MSI colorectal cancers (CRCs) is loss of HLA class I expression due to mutations in B2M gene which can become a negative predictor for checkpoint blockade therapy. The aim of this study was the determination of prevalence of B2M somatic mutations in MSI CRC patients and relationship between B2M mutations and lymphocytes infiltration and other clinicopathological features as well as detection of methylation changes in B2M promoter region which can be another mechanism of immune escape. In our study, 37 MSI-H and 5 MSI-L patients were selected for screening of B2M mutational and methylation status. The characterization of patients was based on standard histopathological diagnosis and TNM classification; BRAF, KRAS mutations, tumor-infiltrating lymphocytes and peritumoral lymphoid reaction were also determined. MSI analysis was performed using fragment analysis. B2M mutations were identified by Sanger sequencing, and methylation of CpG islands in promoter region was detected by methylation-specific PCR. Heterozygous mutations in the B2M gene were detected in five MSI-H patients (13.5%), while the mutation c.45_48delTTCT was determined in four patients and mutation c.276delC was found in two patients. One of these five patients was compound heterozygote harboring both mutations. Methylation of the promoter region of the B2M gene was observed in one patient with MSI-H colorectal cancer. Detection of genetic and epigenetic changes in B2M gene could be important in personalized therapy for CRC patients as these changes may be one of the mechanisms of secondary resistance of MSI positive tumors to immunotherapy.

• MeSH
• beta-2-mikroglobulin genetika   MeSH
• CpG ostrůvky MeSH
• dospělí MeSH
• down regulace MeSH
• epigeneze genetická MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA * MeSH
• mikrosatelitní nestabilita * MeSH
• mutace MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

In the majority of human tumors, downregulation of major histocompatibility complex class I (MHC‑I) expression contributes to the escape from the host immune system and resistance to immunotherapy. Relevant animal models are therefore needed to enhance the efficacy of cancer immunotherapy. As loss of β‑2 microglobulin expression results in irreversible downregulation of surface MHC‑I molecules in various human tumors, the β‑2 microglobulin gene (B2m) was deactivated in a mouse oncogenic TC‑1 cell line and a TC‑1/dB2m cell line that was negative for surface MHC‑I expression was derived. Following stimulation with interferon γ, MHC‑I heavy chains, particularly the H‑2Db molecules, were found to be expressed at low levels on the cell surface, but without β‑2 microglobulin. B2m deactivation in TC‑1/dB2m cells led to reduced proliferation and tumor growth. These cells were insensitive to DNA vaccination and only weakly responsive to combined immunotherapy with a DNA vaccine and the ODN1826 adjuvant. In vivo depletion demonstrated that NK1.1+ cells were involved in both reduced tumor growth and an antitumor effect of immunotherapy. The number of immune cells infiltrating TC‑1/dB2m‑induced tumors was comparable with that in tumors developing from TC‑1/A9 cells characterized by reversible MHC‑I downregulation. However, the composition of the cell infiltrate was different and, most importantly, infiltration with immune cells was not increased in TC‑1/dB2m tumors after immunotherapy. Therefore, the TC‑1/dB2m cell line represents a clinically relevant tumor model that may be used for enhancement of cancer immunotherapy.

• MeSH
• beta-2-mikroglobulin genetika   imunologie   MeSH
• cytotoxické T-lymfocyty imunologie   patologie   MeSH
• histokompatibilita - antigeny třídy I genetika   imunologie   MeSH
• imunoterapie MeSH
• interferon gama imunologie   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie metabolismus   MeSH
• nádory genetika   imunologie   patologie   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The selection of a suitable combination of reference genes (RGs) for data normalization is a crucial step for obtaining reliable and reproducible results from transcriptional response analysis using a reverse transcription-quantitative polymerase chain reaction. This is especially so if a three-dimensional multicellular model prepared from liver tissues originating from biologically diverse human individuals is used. The mRNA and miRNA RGs stability were studied in thirty-five human liver tissue samples and twelve precision-cut human liver slices (PCLS) treated for 24 h with dimethyl sulfoxide (controls) and PCLS treated with β-naphthoflavone (10 μM) or rifampicin (10 μM) as cytochrome P450 (CYP) inducers. Validation of RGs was performed by an expression analysis of CYP3A4 and CYP1A2 on rifampicin and β-naphthoflavone induction, respectively. Regarding mRNA, the best combination of RGs for the controls was YWHAZ and B2M, while YWHAZ and ACTB were selected for the liver samples and treated PCLS. Stability of all candidate miRNA RGs was comparable or better than that of generally used short non-coding RNA U6. The best combination for the control PCLS was miR-16-5p and miR-152-3p, in contrast to the miR-16-5b and miR-23b-3p selected for the treated PCLS. Our results showed that the candidate RGs were rather stable, especially for miRNA in human PCLS.

• MeSH
• beta-2-mikroglobulin genetika   metabolismus   MeSH
• beta-naftoflavon farmakologie   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• dimethylsulfoxid farmakologie   MeSH
• dospělí MeSH
• játra účinky léků   metabolismus   MeSH
• kvantitativní polymerázová řetězová reakce normy   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mikro RNA genetika   metabolismus   MeSH
• proteiny 14-3-3 genetika   metabolismus   MeSH
• referenční standardy MeSH
• rifampin farmakologie   MeSH
• senioři MeSH
• stanovení celkové genové exprese normy   MeSH
• systém (enzymů) cytochromů P-450 farmakologie   MeSH
• transkriptom MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce. METHODS: The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score. RESULTS: We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher β2-microglobulin. The HDF cohort had lower β2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time. CONCLUSIONS: HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.

• MeSH
• beta-2-mikroglobulin krev   MeSH
• bolesti hlavy etiologie   MeSH
• C-reaktivní protein MeSH
• chronické selhání ledvin krev   komplikace   terapie   MeSH
• dialýza ledvin škodlivé účinky   MeSH
• dítě MeSH
• fosfáty krev   MeSH
• hemodiafiltrace * škodlivé účinky   metody   MeSH
• hemoglobiny metabolismus   MeSH
• hodnocení výsledků péče pacientem MeSH
• hospitalizace MeSH
• hypertenze etiologie   MeSH
• intimomediální šíře tepenné stěny * MeSH
• krevní tlak MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• parathormon krev   MeSH
• předškolní dítě MeSH
• svalové křeče etiologie   MeSH
• tělesná výška * MeSH
• závrať etiologie   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
• srovnávací studie MeSH

In follicular lymphoma (FL), no prognostic index has been built based solely on a cohort of patients treated with initial immunochemotherapy. There is currently a need to define parsimonious clinical models for trial stratification and to add on biomolecular factors. Here, we confirmed the validity of both the follicular lymphoma international prognostic index (FLIPI) and the FLIPI2 in the large prospective PRIMA trial cohort of 1135 patients treated with initial R-chemotherapy ± R maintenance. Furthermore, we developed a new prognostic tool comprising only 2 simple parameters (bone marrow involvement and β2-microglobulin [β2m]) to predict progression-free survival (PFS). The final simplified score, called the PRIMA-PI (PRIMA-prognostic index), comprised 3 risk categories: high (β2m > 3 mg/L), low (β2m ≤ 3 mg/L without bone marrow involvement), and intermediate (β2m ≤ 3 mg/L with bone marrow involvement). Five-year PFS rates were 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively (P < .0001). In addition, achieving event-free survival (EFS) or not at 24 months (EFS24) was a strong posttreatment prognostic parameter for subsequent overall survival, and the PRIMA-PI was correlated with EFS24. The results were confirmed in a pooled external validation cohort of 479 patients from the FL2000 LYSA trial and the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. Five-year EFS in the validation cohort was 77%, 57%, and 44% in the PRIMA-PI low-, intermediate-, and high-risk groups, respectively (P < .0001). The PRIMA-PI is a novel and easy-to-compute prognostic index for patients initially treated with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores.

• MeSH
• beta-2-mikroglobulin metabolismus   MeSH
• folikulární lymfom * metabolismus   mortalita   patologie   terapie   MeSH
• imunoterapie * MeSH
• kostní dřeň metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádorové proteiny metabolismus   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH

Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.

• MeSH
• antigeny CD274 antagonisté a inhibitory   biosyntéza   genetika   imunologie   MeSH
• antigeny CD279 antagonisté a inhibitory   biosyntéza   genetika   imunologie   MeSH
• beta-2-mikroglobulin biosyntéza   genetika   imunologie   MeSH
• buňky Reedové-Sternberga účinky léků   imunologie   patologie   MeSH
• doba přežití bez progrese choroby MeSH
• histokompatibilita - antigeny třídy II biosyntéza   genetika   imunologie   MeSH
• Hodgkinova nemoc farmakoterapie   genetika   imunologie   patologie   MeSH
• kohortové studie MeSH
• lidé MeSH
• lidské chromozomy, pár 9 MeSH
• nivolumab terapeutické užití   MeSH
• prediktivní hodnota testů MeSH
• prezentace antigenu MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• beta-2-mikroglobulin MeSH
• biologické markery MeSH
• interleukin-10 MeSH
• interleukin-6 MeSH
• interleukin-8 MeSH
• lidé MeSH
• mozkomíšní mok imunologie   MeSH
• orosomukoid MeSH
• roztroušená skleróza * MeSH
• zánět MeSH
• Check Tag
• lidé MeSH

Několik publikací z nedávné doby poukazuje na nově objevené mechanismy primární a sekundární rezistence na léčbu monoklonálními protilátkami proti PD-1/PD-L1 (programmed cell death 1, membránový protein programované buněčné smrti 1/programmed cell death ligand 1, ligand membránového proteinu programované buněčné smrti 1). Z patofyziologického hlediska ji lze rozdělit na rezistenci způsobenou změněnou antigenní výbavou nádorových buněk a rezistenci podmíněnou změnami v signálních drahách. Některé z těchto mechanismů rezistence jsou ovlivnitelné cílenými léky.

Several recent studies have identified novel mechanisms of primary and secondary resistance to treatment with anti-PD-1/PD-L1 (programmed cell death 1/programmed cell death ligand 1) antibodies. They can be broadly divided into resistance due to altered antigenic load of tumor cells and mutation-related changes in signaling pathways. Some of these mechanisms of resistance can be influenced by targeted drugs.

• MeSH
• antigeny CD274 imunologie   MeSH
• antigeny CD279 imunologie   MeSH
• antigeny nádorové genetika   imunologie   MeSH
• beta-2-mikroglobulin genetika   MeSH
• chemorezistence * genetika   imunologie   MeSH
• cytokiny imunologie   MeSH
• geny MHC třídy I MeSH
• imunoterapie * MeSH
• karcinogeneze MeSH
• kontrolní body buněčného cyklu imunologie   MeSH
• lidé MeSH
• monoklonální protilátky * farmakologie   MeSH
• mutace MeSH
• nádory farmakoterapie   genetika   imunologie   MeSH
• regulace genové exprese MeSH
• Check Tag
• lidé MeSH

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Autoimmune inflammation is common in the early stages of MS. This stage is followed by the neurodegenerative process. The result of these changes is axon and myelin breakdown. Although MS is according to McDonald's revised diagnostic criteria primarily a clinical diagnosis, paraclinical investigation methods are an important part in the diagnosis of MS. In common practice, magnetic resonance imaging of the brain and spinal cord, examination of cerebrospinal fluid (CSF) and examination of visual evoked potentials are used. There are an increasing number of studies dealing with biomarkers in CSF and their role in the diagnosis and treatment of MS. We hypothesized that the levels of some markers could be changed in MS in comparison with controls. We studied five inflammatory markers [interleukin-6 (IL-6), interleukin-8, interleukin-10 (IL-10), beta-2-microglobulin, orosomucoid]. CSF and serum levels of inflammatory markers were assessed in 38 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria and in 28 subjects as a control group (CG). Levels of beta-2-microglobulin and interleukin-8 in CSF were found to be significantly higher in MS patients in comparison to CG (p < 0.001 resp. p = 0.007). No differences in other CSF markers (IL-6, IL-10 and orosomucoid) and serum levels of all markers between both groups were found. The levels of two studied inflammatory markers were found to be increased at the time of first clinical symptoms of MS. Research on the role of inflammatory and neurodegenerative markers in MS should continue.

• MeSH
• beta-2-mikroglobulin krev   MeSH
• cytokiny MeSH
• dospělí MeSH
• imunoanalýza MeSH
• lidé středního věku MeSH
• lidé MeSH
• neparametrická statistika MeSH
• orosomukoid metabolismus   MeSH
• pilotní projekty MeSH
• roztroušená skleróza krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Dialyzační amyloidóza je závažná komplikace u pacientů podstupujících dlouhodobou hemodialyzační léčbu. Způsobuje ji depozice β2-mikroglobulinu ve tkáních ve formě amyloidových fibril. Vzhledem k jeho vysoké afinitě k osteoartikulární tkáni klinické projevy zahrnují syndrom karpálního tunelu, artropatii velkých kloubů, kostní cysty, destruktivní spondylartropatii a ve vzácných případech také systémové poruchy. Mezi rizikové faktory patří dlouhodobá hemodialyzační léčba, zahájení této léčby v mladém věku, léčba konvenčním hemodialyzačním roztokem a absence použití high–flux dialyzačních membrán. Definitivní diagnóza je možná histologicky, průkazem materiálu barvením konžskou červení a nepřímou imunohistochemií značenými protilátkami proti β2-mikroglobulinu.

Dialysis-related amyloidosis is a serious complication in patients receiving long-term dialysis. It is caused by formation of β2-mikroglobulin in amyloid deposits. Because of its affinity to osteoarticular tissue clinical manifestation includes carpal tunnel syndrome, joint arthropathy, bone cysts, destructive spondylarthropathy, and, in rare cases, also systemic disorders. Risk factors are long term hemodialysis, early onset of hemodialysis, treatment with low purity dialysate and absence of using high-flux membranes. Definitive diagnosis is made by histologic examination material by congo red staining and immunostaining of amyloid deposits with labeled anti-h2-m antibody. Clinical therapeutic strategies for dialysis related amyloidosis include dialysis, medical or surgical therapy, and renal transplantation.

• Klíčová slova
• high-flux dialyzační membrána,
• MeSH
• amyloidóza * diagnóza   patofyziologie   terapie   MeSH
• beta-2-mikroglobulin krev   MeSH
• dialýza ledvin * přístrojové vybavení   škodlivé účinky   MeSH
• lidé MeSH
• membrány umělé MeSH
• nemoci kloubů etiologie   MeSH
• nemoci kostí etiologie   MeSH
• syndrom karpálního tunelu etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH