INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• cílená molekulární terapie * MeSH
• imunokonjugáty farmakologie   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory * imunologie   farmakoterapie   MeSH
• patenty jako téma * MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-cbl * imunologie   antagonisté a inhibitory   MeSH
• signální transdukce účinky léků   MeSH
• T-lymfocyty imunologie   účinky léků   MeSH
• vyvíjení léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS: We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS: The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS: We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.

• MeSH
• chronická lymfatická leukemie * genetika   patologie   MeSH
• cyklin D1 genetika   metabolismus   MeSH
• inhibitor p21 cyklin-dependentní kinasy * genetika   metabolismus   MeSH
• kontrolní body buněčného cyklu * genetika   MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk genetika   MeSH
• proteiny teplotního šoku MeSH
• regulace genové exprese u leukemie MeSH
• transportní proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: This study aims to identify factors possibly contributing to complications in children with acute leukaemia. Despite diverse etiological causes, similar processes trigger the process of cell malignancy. Genomic instability has received considerable attention in this context. METHOD: We conducted chromosomal analysis of bone marrow cells and measured the micronuclei (Mn) level in buccal cells over time. Statistical reliability assessment was performed using Analysis of variance (ANOVA), and the data were analyzed and visualized using the SPSS 12 statistical analysis software package. RESULTS: On the 15th day of treatment, our findings confirmed a statistically significant correlation (χ2=3.88, P=0.04) between the number of blasts in the bone marrow and unfavourable outcome in patients with a near-tetraploid chromosome clone. Additionally, on the 33rd day of treatment, we observed a correlation between an elevated number of Mn and relapses. DISCUSSION: While it is commonly believed that a hyperdiploid clone with >50 chromosomes in childhood acute lymphoblastic leukaemia confers favorable outcome, our study revealed partially heterogeneous results and poor prognosis in patients with a near-tetraploid clone. We have also identified a correlation between the Mn level on the 33rd day of treatment and the development of complications. It is possible that the increased Mn values and the occurrence of relapses were influenced by the individual patient's sensitivity to the genotoxic effect of the medication.

• MeSH
• akutní lymfatická leukemie * genetika   MeSH
• buňky kostní dřeně patologie   MeSH
• dítě MeSH
• lidé MeSH
• mikrojaderné testy MeSH
• mikrojádra chromozomálně defektní * MeSH
• mladiství MeSH
• předškolní dítě MeSH
• prognóza MeSH
• tetraploidie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: The development of External Quality Assessment Schemes (EQAS) for clinical flow cytometry (FCM) is challenging in the context of rare (immunological) diseases. Here, we introduce a novel EQAS monitoring the primary immunodeficiency Orientation Tube (PIDOT), developed by EuroFlow, in both a 'wet' and 'dry' format. This EQAS provides feedback on the quality of individual laboratories (i.e., accuracy, reproducibility and result interpretation), while eliminating the need for sample distribution. METHODS: In the wet format, marker staining intensities (MedFIs) within landmark cell populations in PIDOT analysis performed on locally collected healthy control (HC) samples, were compared to EQAS targets. In the dry format, participants analyzed centrally distributed PIDOT flow cytometry data (n=10). RESULTS: We report the results of six EQAS rounds across 20 laboratories in 11 countries. The wet format (212 HC samples) demonstrated consistent technical performance among laboratories (median %rCV on MedFIs=34.5 %; average failure rate 17.3 %) and showed improvement upon repeated participation. The dry format demonstrated effective proficiency of participants in cell count enumeration (range %rCVs 3.1-7.1 % for the major lymphoid subsets), and in identifying lymphoid abnormalities (79.3 % alignment with reference). CONCLUSIONS: The PIDOT-EQAS allows laboratories, adhering to the standardized EuroFlow approach, to monitor interlaboratory variations without the need for sample distribution, and provides them educational support to recognize rare clinically relevant immunophenotypic patterns of primary immunodeficiencies (PID). This EQAS contributes to quality improvement of PID diagnostics and can serve as an example for future flow cytometry EQAS in the context of rare diseases.

• MeSH
• imunofenotypizace * normy   metody   MeSH
• lidé MeSH
• průtoková cytometrie * normy   metody   MeSH
• řízení kvality MeSH
• syndromy imunologické nedostatečnosti diagnóza   imunologie   MeSH
• zajištění kvality zdravotní péče MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

• MeSH
• B-lymfocyty * imunologie   MeSH
• feochromocytom * imunologie   terapie   MeSH
• imunoterapie * metody   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory nadledvin * imunologie   terapie   MeSH
• TNF-alfa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH

Primární hypofyzitida je vzácné zánětlivé onemocnění podvěsku mozkového. Klinické projevy jsou variabilní a různě závažné. Nejčastěji se vyskytují bolesti hlavy, příznaky z deficitu hormonů předního laloku hypofýzy a příznaky nedostatku vazopresinu (polyurie a polydipsie). Na magnetické rezonanci má lymfocytární hypofyzitida typický obraz symetrického zvětšení hypofýzy s normálním signálem nativně; významným znakem může být ztluštění infundibula bez deviace. Diagnóza se opírá o klinické příznaky, laboratorní vyšetření a magnetickou rezonanci. Prezentujeme případ 41leté ženy s bolestmi hlavy, přechodnou polyurií s polydipsií a hyperprolaktinemií. Koncentrační test jednoznačně nepotvrdil diagnózu diabetu insipidu, zcela však nevyloučil možnost parciálního deficitu vazopresinu. Laboratorní vyšetření prokázalo opakovaně mírnou hyperprolaktinemii (maximální hodnota 2016 mIU/l), klinicky se projevila přechodnou galaktoreou a amenoreou trvající čtyři měsíce. Na magnetické rezonanci byl zjištěn nález svědčící pro lymfocytární hypofyzitidu, který v průběhu sledování spontánně regredoval. Na primární hypofyzitidu je potřeba pomýšlet v diferenciální diagnostice. Z důvodu rizika relabujícího průběhu a rizika rozvoje hypopituitarismu je doporučeno dlouhodobé sledování.

Primary hypophysitis is a rare inflammatory disease of the pituitary gland. Clinical symptoms are variable and of varying severity. Headache, symptoms of anterior pituitary deficiency and symptoms of vasopressin deficiency (polyuria with polydipsia) are the most common. On magnetic resonance imaging, lymphocytic hypophysitis typically shows a symmetrical pituitary enlargement with a normal native signal; the presence of thickening of the infundibulum without deviation may be an important feature. Diagnosis is based on clinical symptoms, laboratory examination and magnetic resonance imaging. We present the case of a 41-year-old woman with headache, transient polyuria with polydipsia and hyperprolactinemia. The water deprivation test did not confirm the diagnosis of diabetes insipidus, but did not completely exclude the partial vasopressin deficiency. Laboratory tests showed recurrent mild hyperprolactinemia (maximum 2016 mIU/l), clinically manifested by transient galactorrhoea and amenorrhoea lasting four months. Magnetic resonance imaging revealed findings consistent with lymphocytic hypophysitis, which resolved spontaneously during follow-up. Primary hypophysitis is a very rare disease and should be considered in the differential diagnosis. Long-term follow-up is recommended because of the risk of relapse and the risk of developing hypopituitarism.

BACKGROUND: Severe combined immunodeficiency (SCID) is a fatal but treatable inborn error of immunity (IEI). Newborn screening (NBS) using T-cell receptor excision circles (TREC) has been adopted globally, with very few countries incorporating kappa recombination excision circles (KREC) to also detect early B-cell development disorders, such as X-linked agammaglobulinemia (XLA). OBJECTIVE: To evaluate the effectiveness of a 2-year pilot SCID NBS program in the Czech Republic, emphasising the utility of combined TREC/KREC screening. METHODS: Between January 2022 and December 2023, a dual TREC/KREC NBS pilot was conducted across the Czech Republic, alongside spinal muscular atrophy (SMA) screening. Approximately 200,000 newborns were screened using quantitative real-time PCR on dried blood spots collected 48-72 h after birth. RESULTS: The pilot referred 58 newborns, identifying 21 cases of IEI, including two SCID cases, with an overall incidence of TREC/KREC screenable IEI of 10.5/100,000 newborns. SCID incidence was 1/100,000. KREC screening proved invaluable, detecting 10 cases of congenital agammaglobulinemia including novel non-XLA forms, which increased the estimated incidence of agammaglobulinemia in the Czech Republic sixfold. Over one-third of low KREC results were linked to maternal immunosuppression. CONCLUSION: The Czech pilot demonstrated the effectiveness of integrated TREC/KREC NBS in detecting both T- and B-cell immunodeficiencies. As of 2024, SCID and SMA screening are included in the nationwide NBS, with KREC screening significantly improving early detection of B-cell disorders.

• MeSH
• agamaglobulinemie diagnóza   MeSH
• B-lymfocyty imunologie   MeSH
• genetické nemoci vázané na chromozom X MeSH
• lidé MeSH
• novorozenec MeSH
• novorozenecký screening * metody   MeSH
• pilotní projekty MeSH
• receptory antigenů T-buněk * genetika   MeSH
• těžká kombinovaná imunodeficience * diagnóza   genetika   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Nonobese diabetic (NOD) mice are a widely used animal model to study mechanisms leading to autoimmune diabetes. A gluten-free diet reduces and delays the incidence of diabetes in NOD mice, but the underlying mechanisms remain largely unknown. In this study, we performed single-cell transcriptomic and flow cytometry analysis of T cells and innate lymphocytes in the spleen and pancreatic lymph nodes of NOD mice fed a gluten-free or standard diet. We observed that the gluten-free diet did not induce a substantial alteration in the abundance or phenotype of any lymphocyte subset that would directly explain its protective effect against diabetes. However, the gluten-free diet induced subtle changes in the differentiation of subsets with previously proposed protective roles in diabetes development, such as Tregs, activated γδT cells, and NKT cells. Globally, the gluten-free diet paradoxically promoted activation and effector differentiation across multiple subpopulations and induced genes regulated by IL-2, IL-7, and IL-15. In contrast, the standard diet induced type I interferon-responsive genes. Overall, the gluten-free diet might prevent diabetes in NOD mice by inducing small-scale changes in multiple cell types rather than acting on a specific lymphocyte subset.

• MeSH
• aktivace lymfocytů imunologie   MeSH
• bezlepková dieta * MeSH
• buněčná diferenciace MeSH
• diabetes mellitus 1. typu * imunologie   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• T-lymfocyty - podskupiny * imunologie   MeSH
• transkriptom MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Pathogenesis of large B-cell lymphomas (LBCL) and follicular lymphomas (FL) is a multistep process associated with the development of diverse DNA alterations and consequent deregulation of critical cellular processes. Detection of tumor-associated mutations within non-tumor compartments (mainly plasma) is the basis of the 'liquid biopsy' concept. Apart from tumor mutational profiling, quantitative analysis of circulating tumor DNA (ctDNA) allows longitudinal assessment of tumor burden. ctDNA-based technologies provide a new tool for tumor diagnostics and treatment personalization. AREAS COVERED: Our review provides a comprehensive overview and summary of available ctDNA studies in LBCL and FL. The accuracy of ctDNA-based detection of lymphoma-associated DNA alterations is correlated to known LBCL and FL molecular landscape. Additionally, we summarized available evidence that supports and justifies the clinical use of ctDNA for lymphoma risk stratification, treatment response evaluation, and treatment response-adapted therapy. Lastly, we discuss other clinically important ctDNA applications: monitoring of lymphoma clonal evolution within resistance and/or relapse development and utilization of ctDNA for diagnostics in non-blood fluids and compartments (e.g. cerebrospinal fluid in primary CNS lymphomas). EXPERT OPINION: Despite certain challenges, including methodological standardization, ctDNA holds promise to soon become an integral part of lymphoma diagnostics and treatment management.

• MeSH
• cirkulující nádorová DNA * krev   genetika   MeSH
• difúzní velkobuněčný B-lymfom * diagnóza   genetika   terapie   krev   MeSH
• folikulární lymfom * diagnóza   genetika   terapie   krev   MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery * krev   genetika   MeSH
• prognóza MeSH
• tekutá biopsie metody   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Východiská: Schnitzlerovej syndróm je získané autoinflamačné ochorenie so základom v poruche prirodzenej imunity. Podozrivým je proteín MyD88 – toll-like receptor zapojený do zápalovej kaskády vyúsťujúcej aj do zvýšenej sekrécie interleukínu-1 (IL-1), kľúčového cytokínu v patogenéze a klinickej manifestácii viacerých autoinflamačných stavov. Syndróm je pomenovaný po francúzskej kožnej lekárke Liliane Schnitzler, ktorá v roku 1972 opísala kazuistickú sériu pacientov s prejavmi urtikárie v spojení s monoklonálnou gamapatiou. V klinickom obraze dominujú prejavy chronickej urtikárie, pričom histologicky ide najčastejšie o neutrofilovú dermatózu. Nevyhnutným kritériom na zadefinovanie Schnitzlerovej syndrómu je monoklonálna gamapatia, pričom až v 90 % prípadov ide o monoklonálnu IgM gamapatiu. Zvyšná skupina pacientov má prítomnú gamapatiu v triede IgG. Z vedľajších kritérií potrebných na potvrdenie syndrómu podľa Strassburgskej klasifikácie je to zvýšená nešpecifická zápalová aktivita (elevácia sérového CRP, leukocytóza), morfologické zmeny na kostiach (verifikované hyperostotické či osteosklerotické zmeny skeletu na CT, scintigraficky, alebo PET/CT s použitím rádioaktívneho natrium fluoridu NaF18), bolesti kostí či artralgia. Pacienti sú vo zvýšenom riziku rozvoja lymfoproliferačného ochorenia ako Waldenströmovej makroglobulinémie alebo low-grade lymfómu (15–20 %). Rizikom je tiež rozvoj AA amyloidózy pri dlhodobej nekontrolovanej hyperinflamácii. Akútnou, život ohrozujúcou komplikáciou môže byť syndróm aktivovaných makrofágov. Vzhľadom na imunologickú podstatu ochorenia a eleváciu zápalových cytokínov je základom anticytokínová liečba. Najlepšie výsledky sú pozorované pri anakinre (antagonista receptora pre IL-1), inou možnosťou je eventuálne kanakinumab (monoklonálna protilátka proti IL-1b). Pozitívny efekt bol opisovaný aj pri inhibítoroch Brutonovej tyrozínkinázy. Kortikoidy a konvenčné imunosupresíva nie sú dostatočne efektívne. Prípad: V predkladanom texte prezentujeme formou kazuistickej série dve pacientky so Schnitzlerovej syndrómom s raritnejšími klinickými príznakmi a s diferencovanou odpoveďou na anticytokínovú liečbu. Cieľom autorov bolo informovať a zlepšiť povedomie o tomto vzácnom ochorení a jeho možnostiach liečby. Záver: Ochorenie je chronické, liečba je len symptomatická, ale vedie k ústupu klinických príznakov a dosiahnutiu kontroly nad zápalom. Riziko vzniku hematologickej malignity anticytokínová liečba pravdepodobne neovplyvňuje.

Background: Schnitzler‘s syndrome is an acquired autoinflammatory disease with a disorder in innate immune response. The suspect is the protein MyD88 – a toll-like receptor involved in the inflammatory cascade resulting in increased secretion of interleukin-1 (IL-1), a key cytokine in the pathogenesis and clinical manifestation of several autoinflammations. The syndrome is named after the French dermatologist Liliane Schnitzler, who described a case series of patients with manifestations of urticaria and monoclonal gammapathy in 1972. The clinical picture is characterized by chronic urticaria, histologically it is most often neutrophilic dermatosis. A necessary criterion for defining Schnitzler‘s syndrome is monoclonal gammapathy. In up to 90% of cases, it is monoclonal IgM gammapathy, the remaining group of patients has IgG gammapathy. Among the secondary criteria necessary to define the syndrome according to the Strasbourg classification, non-specific inflammatory activity is present in patients (elevation of CRP, leukocytosis), morphological changes on the bones (hyperostotic or osteosclerotic changes of the skeleton verified by CT, scintigraphy or PET/CT using radioactive sodium fluoride NaF18), bone pain or arthralgia. Patients are at an increased risk of developing a lymphoproliferative disease, especially Waldenström‘s macroglobulinemia or low grade lymphoma (15–20%). There is also a risk of the development of AA amyloidosis due to long-term uncontrolled hyperinflammation. Macrophage activating syndrome can be an acute life-threatening complication, as we describe in our patient. Considering the immunological nature of the disease and the elevation of inflammatory cytokines, the basis of treatment is anticytokine therapy. The best results are seen with anakinra (IL-1 receptor antagonist), possibly canakinumab (a monoclonal antibody against IL-1b). A positive effect was also described with Bruton‘s tyrosine kinase inhibitors. Corticoids and conventional immunosuppressants are not effective enough. Case: In this text, we present a case series of two patients with Schnitzler‘s syndrome with rare clinical symptoms. The authors‘ goal was to improve awareness of this rare hematoinflammatory disease and its treatment options. Conclusion: The disease is chronic, the treatment is only symptomatic, but can lead to the reduction of clinical symptoms. Anticytokine treatment probably does not affect the risk of hematological malignancy.

• MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• imunoglobulin G imunologie   MeSH
• interleukin-1 imunologie   MeSH
• lidé MeSH
• paraproteinemie genetika   imunologie   MeSH
• senioři MeSH
• syndrom aktivovaných makrofágů diagnóza   etiologie   MeSH
• syndrom Schnitzlerové * diagnóza   farmakoterapie   genetika   imunologie   MeSH
• urtikarie diagnóza   etiologie   imunologie   MeSH
• zánět diagnóza   etiologie   imunologie   klasifikace   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH