Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.
- MeSH
- CD8-pozitivní T-lymfocyty MeSH
- ektopické lymfoidní struktury * MeSH
- fenotyp MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory plic * MeSH
- nádory vaječníků * patologie MeSH
- nemalobuněčný karcinom plic * MeSH
- tumor infiltrující lymfocyty MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Pathogenic variants in the highly conserved OVOL2 promoter region cause posterior polymorphous corneal dystrophy (PPCD) 1 by inducing an ectopic expression of the endothelial OVOL2 mRNA. Here we produced an allelic series of Ovol2 promoter mutations in the mouse model including the heterozygous c.-307T>C variant (RefSeq NM_021220.4) causing PPCD1 in humans. Despite the high evolutionary conservation of the Ovol2 promoter, only some alterations of its sequence had phenotypic consequences in mice. Four independent sequence variants in the distal part of the Ovol2 promoter had no significant effect on endothelial Ovol2 mRNA level or caused any ocular phenotype. In contrast, the mutation c.-307T>C resulted in increased Ovol2 expression in the corneal endothelium. However, only a small fraction of adult mice c.-307T>C heterozygotes developed ocular phenotypes such as irido-corneal adhesions, and corneal opacity. Interestingly, phenotypic penetrance was increased at embryonic stages. Notably, c.-307T>C mutation is located next to the Ovol1/Ovol2 transcription factor binding site. Mice carrying an allele with a deletion encompassing the Ovol2 binding site c.-307_-320del showed significant Ovol2 gene upregulation in the cornea endothelium and exhibited phenotypes similar to the c.-307T>C mutation. In conclusion, although the mutations c.-307T>C and -307_-320del lead to a comparably strong increase in endothelial Ovol2 expression as seen in PPCD1 patients, endothelial dystrophy was not observed in the mouse model, implicating species-specific differences in endothelial cell biology. Nonetheless, the emergence of dominant ocular phenotypes associated with Ovol2 promoter variants in mice implies a potential role of this gene in eye development and disease.
- MeSH
- dědičné dystrofie rohovky * genetika MeSH
- dospělí MeSH
- fenotyp MeSH
- lidé MeSH
- messenger RNA MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- rohovkový endotel MeSH
- transkripční faktory genetika MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.
- MeSH
- ameloblasty metabolismus MeSH
- amelogenesis imperfecta * komplikace imunologie MeSH
- antigeny imunologie metabolismus MeSH
- autoimunitní polyglandulární syndromy * komplikace imunologie MeSH
- autoprotilátky * imunologie MeSH
- celiakie * komplikace imunologie MeSH
- imunoglobulin A imunologie MeSH
- lidé MeSH
- protein AIRE nedostatek MeSH
- proteiny imunologie metabolismus MeSH
- střeva imunologie metabolismus MeSH
- zubní sklovina imunologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Serotoninový syndrom je potenciálně život ohrožující toxidrom spojený se zvýšenou serotoninergní aktivitou v periferním i v centrálním nervovém systému. Je charakterizován celým spektrem klinických projevů, zahrnujícím změny mentálního stavu, vegetativní nestability a známky hyperexcitability CNS se svalovými projevy. Může vzniknout obvykle při současném podávání dvou nebo více serotoninergních látek, přičemž zvlášť nebezpečné jsou kombinace zahrnující inhibitory monoaminooxidázy (IMAO), ale vznik při monoterapii je též možný. Tento přehled popisuje patofyziologii vzniku a klinické projevy tohoto syndromu a rizikové skupiny léků se zvláštním zaměřením na léky používané při léčbě chronické bolesti.
Serotonin syndrome is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral and central nervous systems. It is characterized by a broad spectrum of clinical findings, which include mental state changes, autonomic instability, and hyperexcitability of CNS with neuromuscular abnormalities. Serotonin syndrome can arise usually by simultaneous administrations of 2 or more serotoninergic drugs, the combination including monoamine oxidase inhibitors is especially dangerous, but occurrence in monotherapy is also possible. This review describes pathophysiology and clinical manifestation of this syndrome and the drugs at risk, with a particular focus on drugs used in the treatment of chronic pain.
Obesity adversely affects bone and fat metabolism in mice and humans. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been shown to improve glucose metabolism and bone homeostasis in obesity. However, the impact of omega-3 PUFAs on bone marrow adipose tissue (BMAT) and bone marrow stromal cell (BMSC) metabolism has not been intensively studied yet. In the present study we demonstrated that omega-3 PUFA supplementation in high fat diet (HFD + F) improved bone parameters, mechanical properties along with decreased BMAT in obese mice when compared to the HFD group. Primary BMSCs isolated from HFD + F mice showed decreased adipocyte and higher osteoblast differentiation with lower senescent phenotype along with decreased osteoclast formation suggesting improved bone marrow microenvironment promoting bone formation in mice. Thus, our study highlights the beneficial effects of omega-3 PUFA-enriched diet on bone and cellular metabolism and its potential use in the treatment of metabolic bone diseases.
- MeSH
- adipozita MeSH
- kosti a kostní tkáň metabolismus MeSH
- kostní dřeň * metabolismus MeSH
- kyseliny mastné omega-3 * farmakologie metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- obezita komplikace prevence a kontrola metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- analgetika aplikace a dávkování farmakologie terapeutické užití MeSH
- bolest klasifikace MeSH
- bolesti hlavy MeSH
- bolesti zad MeSH
- lidé MeSH
- management bolesti * metody MeSH
- primární zdravotní péče MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Sacroiliac joint (SIJ) dysfunction is a chronic painful condition responsible for up to 30% of back pain. Treatment modalities include physiotherapy, intraarticular analgesic injections, ablation techniques or SIJ fusion. The severity of SIJ dysfunction is commonly assessed via subjective pain or disability scales. Quantitative gait analysis offers an objective means of evaluating patients with SIJ dysfunction prior to its surgical treatment. METHODS: Ten patients diagnosed with severe SIJ dysfunction were matched with 10 healthy controls. All individuals underwent quantitative 3D gait analysis using the Qualisys program and statistical analysis was performed to identify significant differences in gait parameters between the two groups. RESULTS: Two groups of data were obtained; angular parameters described by the Gait Profile Score (GPS) and spatiotemporal parameters described in standard SI units. Statistically significant differences were found between the patient and control group for parameters: overall GPS (P=0.049), hip abduction/adduction (P=0.017) and ankle plantar/dorsal flexion (P=0.003), stride length (P=0.002), step length (P=0.001), swing time (P=0.03) and initial double limb support (P=0.02). CONCLUSIONS: This paper is the first to perform complex quantitative gait analysis of patients with SIJ dysfunction and to compare it with healthy individuals. These results can provide clinicians with baseline gait values for these patients to objectively quantify the extent of their disease.
- MeSH
- analýza chůze MeSH
- bolest MeSH
- lidé MeSH
- nemoci páteře * chirurgie MeSH
- prospektivní studie MeSH
- sakroiliakální kloub * chirurgie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.
- MeSH
- adenosintrifosfát MeSH
- Barthův syndrom * metabolismus patologie MeSH
- glykolýza MeSH
- kardiolipiny metabolismus MeSH
- mastné kyseliny metabolismus MeSH
- myši MeSH
- proteinkinasy aktivované AMP metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
