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Therapeutic options for metastatic pheochromocytoma/paraganglioma (PHEO/PGL) are limited. Here, we tested an immunotherapeutic approach based on intratumoral injections of mannan-BAM with toll-like receptor ligands into subcutaneous PHEO in a mouse model. This therapy elicited a strong innate immunity-mediated antitumor response and resulted in a significantly lower PHEO volume compared to the phosphate buffered saline (PBS)-treated group and in a significant improvement in mice survival. The cytotoxic effect of neutrophils, as innate immune cells predominantly infiltrating treated tumors, was verified in vitro. Moreover, the combination of mannan-BAM and toll-like receptor ligands with agonistic anti-CD40 was associated with increased mice survival. Subsequent tumor re-challenge also supported adaptive immunity activation, reflected primarily by long-term tumor-specific memory. These results were further verified in metastatic PHEO, where the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 into subcutaneous tumors resulted in significantly less intense bioluminescence signals of liver metastatic lesions induced by tail vein injection compared to the PBS-treated group. Subsequent experiments focusing on the depletion of T cell subpopulations confirmed the crucial role of CD8+ T cells in inhibition of bioluminescence signal intensity of liver metastatic lesions. These data call for a new therapeutic approach in patients with metastatic PHEO/PGL using immunotherapy that initially activates innate immunity followed by an adaptive immune response.
- Publikační typ
- časopisecké články MeSH
Imunitní trombocytopenie je získané, imunitně podmíněné onemocnění charakterizované izolovaným poklesem počtu krevních destiček. Hlavním klinickým projevem bývají krvácivé projevy kožně-slizničního typu, jejichž výskyt s hloubkou trombocytopenie narůstá. Často ale onemocnění probíhá zcela asymptomaticky. V poslední době došlo u tohoto onemocnění k významnému pokroku v objasnění etiopatogenetických mechanismů, které přispěly ke zlepšení léčebných možností a vedly ke změnám a zpřesnění v terminologii a klasifikaci onemocnění.
Immune thrombocytopenia is an acquired, immunologically determined disease characterized by an isolated drop in platelet count. The main clinical manifestations are hemorrhagic manifestations of cutaneous mucosal type, their occurrence increases with the depth of thrombocytopenia. On the other side the disease is often completely asymptomatic. Recently significant progress in clarifying the etiopathogenetic mechanisms, which contributed to improvement of therapeutic options and led to changes and clarification in the terminology and classification of this disease, has been achieved.
- Klíčová slova
- imunitní trombocytopenie, ITP, trombopoetin, agonisté TPO receptoru,
- MeSH
- anamnéza MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- hormony kůry nadledvin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- imunosupresiva aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- intravenózní imunoglobuliny aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- klinický obraz nemoci MeSH
- krevní obraz MeSH
- krvácení diagnóza komplikace terapie MeSH
- lidé MeSH
- monoklonální protilátky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- nemoci imunitního systému diagnóza terapie MeSH
- splenektomie metody škodlivé účinky využití MeSH
- thrombopoetin terapeutické užití MeSH
- transportní proteiny terapeutické užití MeSH
- trombocytopatie diagnóza etiologie terapie MeSH
- trombocytopenická purpura diagnóza etiologie terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
- MeSH
- antiflogistika terapeutické užití MeSH
- cytokiny krev genetika MeSH
- dítě MeSH
- dospělí MeSH
- fenotyp MeSH
- genetické nemoci vázané na chromozom X krev genetika MeSH
- imunofenotypizace MeSH
- lidé MeSH
- mutace * MeSH
- nukleotidyltransferasy genetika MeSH
- předškolní dítě MeSH
- RNA transferová genetika MeSH
- rodokmen MeSH
- sekvenování exomu MeSH
- sideroblastická anemie krev genetika MeSH
- syndromy imunologické nedostatečnosti genetika MeSH
- TNF-alfa analýza antagonisté a inhibitory MeSH
- vývojové poruchy u dětí genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Intramural MeSH
PURPOSE: To evaluate the prognostic effect of neoadjuvant chemoradiotherapy on the change of programmed death ligand 1 (PD-L1) expression in patients with locally advanced rectal adenocarcinoma, by comparing PD-L1 expression in pretreatment biopsies and PD-L1 expression in pathological specimens after neoadjuvant chemoradiotherapy. METHODS: A total of 25 patients with rectal adenocarcinoma were evaluated. Patients were treated by neoadjuvant chemoradiotherapy (radiotherapy:44Gy normofraxionation; chemotherapy: capecitabine 825 mg/m2 in two daily doses). Surgery was performed 6-8 weeks after the chemoradiotherapy completion. PD-L1 expression was determined in endoscopic biopsies and in resected specimens with immunohistochemistry. RESULTS: All 25 patients received radiotherapy without interruption, while concomitant chemotherapy was discontinued prematurely in one patient because of hematological toxicity. In 13 patients sphincter-saving surgery were performed, and 12 patients underwent rectum resection. Downstaging was noticed in 17 patients. Stable disease was found in 5 patients, and progression in 3. The median disease free survival (DFS) was not reached. Three-year DFS was 54.3% (95% CI 34.3-74.2). The median overall survival (OS) was 60 months (95% CI 48-60). Three-year OS was 75 % (95% CI 57.7-92.3). No PD-L1 expression was noticed in pretreatment biopsy and in resected tissue after chemoradiotherapy. CONCLUSION: No prognostic effect of neoadjuvant chemoradiotherapy on the change of PD-L1 expression was demonstrated in patients with locally advanced rectal adenocarcinoma.
- MeSH
- adenokarcinom farmakoterapie patologie radioterapie MeSH
- antigeny CD274 metabolismus MeSH
- chemoradioterapie metody MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory rekta farmakoterapie patologie radioterapie MeSH
- neoadjuvantní terapie metody MeSH
- prognóza MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The treatment and prognosis of metastatic melanoma have changed during the last decade to include immunotherapy or targeted therapy as standard therapeutic options for BRAF-mutated melanoma. However, predictive and/or prognostic markers are lacking, especially in clinical situations where several options are available. The aim of this study was to determine the association of pre-therapeutic blood cell count-derived ratios (BCDR) with survival in patients with BRAF-mutated metastatic melanoma. METHODS: We evaluated the prognostic role of BCDR in therapy-naïve patients with BRAF-mutated metastatic melanoma treated with immune checkpoint inhibitors or targeted therapy. The impact of BCDR on survival was analysed using univariate and multivariate Cox proportional hazard models. RESULTS: We enrolled 46 patients treated with BRAF inhibitors and 20 patients who received anti-PD-1 checkpoint inhibitors. The median progression-free survival (PFS) and overall survival (OS) were 8.3 and 18.2 months, respectively, with no statistical difference between groups. The objective response rate was 39% (30% in the anti-PD-1 and 44% in the targeted therapy groups). Baseline BCDR values were associated with improved PFS and OS in the immunotherapy group. Only the platelet-to-lymphocyte ratio (PLR) was associated with OS and PFS in the targeted therapy group. Independent prognostic indicators for PFS were lactate dehydrogenase, PLR and the lymphocyte-to-monocyte ratio (LMR) and those for OS were LMR, toxicity and the number of initial metastases. CONCLUSION: BCDR had a substantial prognostic value in patients with BRAF-mutated metastatic melanoma treated with immune checkpoint inhibitors. However, a prognostic role for BCDR seemed less apparent in patients treated with targeted therapies.
STUDY QUESTION: What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? SUMMARY ANSWER: No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). WHAT IS KNOWN ALREADY: Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. STUDY DESIGN, SIZE, DURATION: This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. MAIN RESULTS AND ROLE OF CHANCE: The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A limited number of cases were included. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.
- MeSH
- alely MeSH
- celogenomová asociační studie MeSH
- dospělí MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- germinální a embryonální nádory komplikace diagnóza epidemiologie genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- pohlavní dospělost MeSH
- prevalence MeSH
- růstový faktor kmenových buněk genetika MeSH
- syndrom rezistence na androgeny komplikace diagnóza epidemiologie genetika MeSH
- testikulární nádory komplikace diagnóza epidemiologie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
... Interactions • Receptor-Ligand Binding Occurs via Multiple Noncovalent Bonds • How Do We Describe ... ... the Strength of Receptor-Ligand Interactions? ... ... • Interactions between Receptors and Ligands Can Be Multivalent -- 33 -- 35 -- 38 -- 43 -- 47 -- 47 ... ... Immune Receptor Genes Undergo Rearrangement in Individual Lymphocytes • Levels of Receptor and Ligand ... ... Binding Can Induce Dimerization or Multimerization of Receptors -- 100 -- 100 -- Ligand Binding Can ...
Eight edition různé stránkování : barevné ilustrace ; 28 cm
- MeSH
- charakteristiky rodiny MeSH
- genetické testování MeSH
- hyperlipoproteinemie typ II epidemiologie genetika MeSH
- lidé MeSH
- průzkumy a dotazníky MeSH
- psychologie MeSH
- sociální podmínky MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Nizozemsko MeSH
BACKGROUND: The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses. METHODS: C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis. RESULTS: Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed. CONCLUSIONS: The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.
- MeSH
- biologické markery krev mozkomíšní mok MeSH
- chemokin CCL2 krev mozkomíšní mok MeSH
- chemokin CXCL10 krev mozkomíšní mok MeSH
- chemokin CXCL13 krev mozkomíšní mok MeSH
- chemokiny krev mozkomíšní mok MeSH
- dítě MeSH
- interleukin-6 krev mozkomíšní mok MeSH
- interleukin-8 krev mozkomíšní mok MeSH
- krevní obraz MeSH
- lidé MeSH
- mladiství MeSH
- nemoci centrálního nervového systému mozkomíšní mok diagnóza imunologie MeSH
- předškolní dítě MeSH
- ROC křivka MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Following the discovery of serious errors in the structure of biomacromolecules, structure validation has become a key topic of research, especially for ligands and non-standard residues. ValidatorDB (freely available at http://ncbr.muni.cz/ValidatorDB) offers a new step in this direction, in the form of a database of validation results for all ligands and non-standard residues from the Protein Data Bank (all molecules with seven or more heavy atoms). Model molecules from the wwPDB Chemical Component Dictionary are used as reference during validation. ValidatorDB covers the main aspects of validation of annotation, and additionally introduces several useful validation analyses. The most significant is the classification of chirality errors, allowing the user to distinguish between serious issues and minor inconsistencies. Other such analyses are able to report, for example, completely erroneous ligands, alternate conformations or complete identity with the model molecules. All results are systematically classified into categories, and statistical evaluations are performed. In addition to detailed validation reports for each molecule, ValidatorDB provides summaries of the validation results for the entire PDB, for sets of molecules sharing the same annotation (three-letter code) or the same PDB entry, and for user-defined selections of annotations or PDB entries.
