"CZ.10 .03.01/00/22_003/0000003"
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Minimal residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM) and a valid surrogate for progression-free survival (PFS) and overall survival (OS). Recently, MRD negativity was approved as an early clinical endpoint for accelerated drug approval in MM. Nevertheless, there is limited evidence of MRD utility in real-world setting. In this retrospective multicenter study, we report outcomes of 331 newly diagnosed MM patients with MRD evaluation at Day+100 after autologous stem cell transplantation using flow cytometry with a median limit of detection of 0.001%. MRD negativity was reached in 47% of patients and was associated with significantly prolonged median PFS (49.2 months vs. 18.4 months; hazard ratios (HR) = 0.37; p < 0.001) and OS (not reached vs. 74.9 months; HR = 0.50; p = 0.007). Achieving MRD negativity was associated with PFS improvements regardless of age, International Staging System (ISS) stage, lactate dedydrogenase (LDH) level, or cytogenetic risk. Importantly, MRD positive patients benefited from lenalidomide maintenance versus no maintenance (18-months PFS: 81% vs. 46%; HR = 0.24; p = 0.002) while in MRD negative patients such benefit was not observed (p = 0.747). The outcomes of our real-world study recapitulate results from clinical trials including meta-analyses and support the idea that MRD positive patients profit more from lenalidomide maintenance than MRD negative ones.
- MeSH
- autologní transplantace MeSH
- dospělí MeSH
- lenalidomid aplikace a dávkování terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom * diagnóza mortalita terapie patologie MeSH
- prognóza MeSH
- průtoková cytometrie * metody MeSH
- retrospektivní studie MeSH
- reziduální nádor * diagnóza MeSH
- senioři MeSH
- staging nádorů MeSH
- transplantace hematopoetických kmenových buněk metody MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
The aim of this study was to test the hypothesis that individuals with an increase in HbA1c (i.e. above the regular but below the diabetic threshold) exhibit an impairment in the Achilles tendon structure and walking capacity, due to the adverse effect of the advanced glycation end-product. One hundred fifty-eight participants matched for gender, age, physical activity and BMI, were divided in two cohorts based on the HbA1c level: normal HbA1c (NGH; <39 mmol/molHb; n = 79) and altered HbA1c (AGH; >=39 mmol/molHb; n = 79). Each participant performed several walking trials to evaluate the kinematic parameters during walling at the self-selected speed and a quantitative MRI scan of the Achilles tendon (AT) to obtain its intrinsic characteristics (i.e. T2* relaxation time short and long component). The AT T2* relaxation time short component (a parameter related to the tendon collagen quality) was reduced in AGH compared to NGH. Furthermore, AGH exhibited a slower self-selected walking speed (NGH: 1.59 ± 0.18 m/s; AGH:1.54 ± 0.16 m/s) and a shorter stride length (NGH: 1.59 ± 0.13 m; AGH:1.55 ± 0.11 m). Our data suggest that a non-pathological increase in HbA1c is able to negatively affect AT collagen quality and walking capacity in healthy people. These results highlight the importance of glycemic control, even below the pathological threshold. Since diabetes could alter several biological pathways, further studies are necessary to determine which mechanisms and their timing, regarding the HbA1c rise, affect tendon composition and, consequently, walking capacity.
- MeSH
- Achillova šlacha * diagnostické zobrazování fyziologie metabolismus MeSH
- biomechanika MeSH
- chůze * fyziologie MeSH
- diabetes mellitus diagnóza MeSH
- dospělí MeSH
- glykovaný hemoglobin * metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- produkty pokročilé glykace metabolismus MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Proteomics is nowadays increasingly becoming part of the routine clinical practice of diagnostic laboratories, especially due to the advent of advanced mass spectrometry techniques. This review focuses on the application of proteomic analysis in the identification of pathological conditions in a hospital setting, with a particular focus on the analysis of protein biomarkers. In particular, the main purpose of the review is to highlight the challenges associated with the identification of specific disease-causing proteins, given their complex nature and the variety of posttranslational modifications (PTMs) they can undergo. PTMs, such as phosphorylation and glycosylation, play critical roles in protein function but can also lead to diseases if dysregulated. Proteomics plays an important role especially in various medical fields ranging from cardiology, internal medicine to hemato-oncology emphasizing the interdisciplinary nature of this field. Traditional methods such as electrophoretic or immunochemical methods have been mainstay in protein detection; however, these techniques are limited in terms of specificity and sensitivity. Examples include the diagnosis of multiple myeloma and the detection of its specific protein or amyloidosis, which relies heavily on these conventional methods, which sometimes lead to false positives or inadequate disease monitoring. Mass spectrometry in this respect emerges as a superior alternative, providing high sensitivity and specificity in the detection and quantification of specific protein sequences. This technique is particularly beneficial for monitoring minimal residual disease (MRD) in the diagnosis of multiple myeloma where traditional methods fall short. Furthermore mass spectrometry can provide precise typing of amyloid proteins, which is crucial for the appropriate treatment of amyloidosis. This review summarizes the opportunities for proteomic determination using mass spectrometry between 2012 and 2024, highlighting the transformative potential of mass spectrometry in clinical proteomics and encouraging its wider use in diagnostic laboratories.
The adaptive immune response critically hinges on the functionality of T cell receptors, governed by complex molecular mechanisms, including ubiquitination. In this study, we delved into the role of in T cell immunity, focusing on T cell-B cell conjugate formation and T cell activation. Using a CRISPR-Cas9 screening approach targeting deubiquitinases genes in Jurkat T cells, we identified BAP1 as a key positive regulator of T cell-B cell conjugate formation. Subsequent investigations into BAP1 knockout cells revealed impaired T cell activation, evidenced by decreased MAPK and NF-kB signaling pathways and reduced CD69 expression upon T cell receptor stimulation. Flow cytometry and qPCR analyses demonstrated that BAP1 deficiency leads to decreased surface expression of T cell receptor complex components and reduced mRNA levels of the co-stimulatory molecule CD28. Notably, the observed phenotypes associated with BAP1 knockout are specific to T cells and fully dependent on BAP1 catalytic activity. In-depth RNA-seq and mass spectrometry analyses further revealed that BAP1 deficiency induces broad mRNA and protein expression changes. Overall, our findings elucidate the vital role of BAP1 in T cell biology, especially in T cell-B cell conjugate formation and T cell activation, offering new insights and directions for future research in immune regulation.
- MeSH
- aktivace lymfocytů * imunologie MeSH
- B-lymfocyty * imunologie metabolismus MeSH
- Jurkat buňky MeSH
- lidé MeSH
- nádorové supresorové proteiny * metabolismus genetika MeSH
- receptory antigenů T-buněk * metabolismus MeSH
- signální transdukce MeSH
- T-lymfocyty * imunologie metabolismus MeSH
- thiolesterasa ubikvitinu * genetika metabolismus nedostatek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The canonical stop codons of the nuclear genome of the trypanosomatid Blastocrithidia nonstop are recoded. Here, we investigated the effect of this recoding on the mitochondrial genome and gene expression. Trypanosomatids possess a single mitochondrion and protein-coding transcripts of this genome require RNA editing in order to generate open reading frames of many transcripts encoded as 'cryptogenes'. Small RNAs that can number in the hundreds direct editing and produce a mitochondrial transcriptome of unusual complexity. We find B. nonstop to have a typical trypanosomatid mitochondrial genetic code, which presumably requires the mitochondrion to disable utilization of the two nucleus-encoded suppressor tRNAs, which appear to be imported into the organelle. Alterations of the protein factors responsible for mRNA editing were also documented, but they have likely originated from sources other than B. nonstop nuclear genome recoding. The population of guide RNAs directing editing is minimal, yet virtually all genes for the plethora of known editing factors are still present. Most intriguingly, despite lacking complex I cryptogene guide RNAs, these cryptogene transcripts are stochastically edited to high levels.
- MeSH
- buněčné jádro * genetika metabolismus MeSH
- editace RNA * MeSH
- genetický kód MeSH
- genom mitochondriální * MeSH
- guide RNA, Kinetoplastida genetika metabolismus MeSH
- kodon genetika MeSH
- messenger RNA genetika metabolismus MeSH
- mitochondrie genetika metabolismus MeSH
- otevřené čtecí rámce genetika MeSH
- protozoální proteiny genetika metabolismus MeSH
- RNA transferová * genetika metabolismus MeSH
- terminační kodon genetika MeSH
- Trypanosomatina genetika metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Almost all extant organisms use the same, so-called canonical, genetic code with departures from it being very rare. Even more exceptional are the instances when a eukaryote with non-canonical code can be easily cultivated and has its whole genome and transcriptome sequenced. This is the case of Blastocrithidia nonstop, a trypanosomatid flagellate that reassigned all three stop codons to encode amino acids. RESULTS: We in silico predicted the metabolism of B. nonstop and compared it with that of the well-studied human parasites Trypanosoma brucei and Leishmania major. The mapped mitochondrial, glycosomal and cytosolic metabolism contains all typical features of these diverse and important parasites. We also provided experimental validation for some of the predicted observations, concerning, specifically presence of glycosomes, cellular respiration, and assembly of the respiratory complexes. CONCLUSIONS: In an unusual comparison of metabolism between a parasitic protist with a massively altered genetic code and its close relatives that rely on a canonical code we showed that the dramatic differences on the level of nucleic acids do not seem to be reflected in the metabolisms. Moreover, although the genome of B. nonstop is extremely AT-rich, we could not find any alterations of its pyrimidine synthesis pathway when compared to other trypanosomatids. Hence, we conclude that the dramatic alteration of the genetic code of B. nonstop has no significant repercussions on the metabolism of this flagellate.
- MeSH
- Eukaryota genetika MeSH
- genetický kód MeSH
- paraziti * genetika MeSH
- terminační kodon MeSH
- Trypanosoma brucei brucei * genetika MeSH
- Trypanosomatina * genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
