Initiation of newborn screening (NBS) programs in Europe dates back to the 1960s. One of the most recent expansions of NBS programs was the addition of severe combined immunodeficiency (SCID) based on detection of T-cell receptor excision circles (TRECs). In this review, we present an overview of the current situation in Europe. To avoid a biased overview based on only published results, a 37-item survey on TREC-based NBS was sent to representatives of 46 European countries. With a response rate of 83%, we collected data of 38 countries. Seventeen of the 38 European countries that have completed the survey have nationally or regionally implemented TREC-based NBS. The survey results emphasize similarities and differences as well as common practices and challenges in TREC-based NBS. Because TRECs are a general surrogate marker for severe T lymphocytopenia, conditions other than SCID are also identified. Therefore, the initial definition of the target disease as "SCID" might need to be reconsidered and extended to "SCID and severe T lymphocytopenia." Even though complete harmonization of TREC-based NBS programs across Europe will remain challenging, collaboration and close partnerships will help in the move toward universal TREC-based screening for all newborns, resulting in more infants with SCID and severe T lymphocytopenia being detected each year.

• MeSH
• lidé MeSH
• lymfopenie * imunologie   diagnóza   MeSH
• novorozenec MeSH
• novorozenecký screening * MeSH
• receptory antigenů T-buněk * genetika   imunologie   MeSH
• těžká kombinovaná imunodeficience * diagnóza   epidemiologie   imunologie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH

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

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in ex vivo T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.

• MeSH
• buněčná diferenciace MeSH
• dítě MeSH
• imunofenotypizace MeSH
• kojenec MeSH
• lidé MeSH
• lymfopenie * imunologie   MeSH
• lymfopoéza * genetika   MeSH
• mladiství MeSH
• předškolní dítě MeSH
• primární imunodeficience terapie   genetika   imunologie   MeSH
• T-lymfocyty * imunologie   MeSH
• thymus imunologie   MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Patient-derived xenografts (PDXs) can be improved by implantation of a humanized niche. Nevertheless, the overall complexity of the current protocols, as well as the use of specific biomaterials and procedures, limits the wider adoption of this approach. Here, we identify the essential minimum steps required to create the humanized scaffolds and achieve successful acute myeloid leukemia (AML) engraftment. We compared seven biomaterials, which included both published and custom-designed materials. The highest level of bone marrow niche was achieved with extracellular matrix gels and custom collagen fiber, both of which allowed for a simple non-surgical implantation. The biomaterial selection did not influence the following AML infiltration. Regarding xenotransplantation, standard intravenous administration produced the most robust engraftment, even for two out of four otherwise non-engrafting AML samples. In contrast, direct intra-scaffold xenotransplantation did not offer any advantage. In summary, we demonstrate that the combination of an injectable biomaterial for scaffold creation plus an intravenous route for AML xenotransplantation provide the most convenient and robust approach to produce AML PDX using a humanized niche.

• MeSH
• akutní myeloidní leukemie * patologie   MeSH
• biokompatibilní materiály * farmakologie   aplikace a dávkování   MeSH
• heterografty MeSH
• lidé MeSH
• myši SCID MeSH
• myši MeSH
• tkáňové podpůrné struktury * chemie   MeSH
• transplantace heterologní * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Vrozené poruchy imunitního systému (PID/IEIs) představují dynamicky se rozvíjející skupinu onemocnění, která je kromě zvýšené náchylnosti k infekcím charakterizována také výskytem autoimunitních, autoinflamatorních, alergických a maligních komplikací. V dnešní době bylo popsáno kolem 500 těchto onemocnění a jejich počet se neustále zvyšuje. Výsledkem dynamickému pokroku v diagnostice a terapii těchto onemocnění je rozvoj genetické diagnostiky, zavedení screeningového vyšetření PID/IEIs u novorozenců, stejně tak jako používání nových terapeutických přístupů včetně genové terapie. V České republice bylo na počátku roku 2024 zavedeno plošné screeningové vyšetření těžké kombinované imunodeficience (SCID). Rozvoj nových technologií umožňuje zlepšení genetické diagnostiky a získávání nových poznatků týkajících se patogeneze PID/IEIs, které lze využít k vývoji cílené terapie. Symptomatická léčba pacientů s PID/IEIs je kromě antimikrobiální profylaxe a imunoglobulinové substituční léčby obohacena o terapii tzv. malými molekulami a biologickou léčbou monoklonálními protilátkami namířenými proti buňkám nebo jejich produktům. V kauzální léčbě pacientů s PID/IEIs dochází ke zlepšení postupů v provádění transplantace hematopoetických krevních buněk (HSCT) a pokrokům na poli genové terapie. Budoucí vývoj v oblasti PID/IEIs bude směřovat k dalšímu zpřesnění jejich diagnostiky a rozvoji cílené terapie včetně personalizovaného přístupu k léčbě.

Congenital disorders of the immune system PIDs/IEIs) represent a dynamically developing group of diseases characterized not only by an increased susceptibility to infections but also by the occurrence of autoimmune, autoinflammatory, allergic, and malignant complications. Around 500 of these diseases have been described to date, and their number continues to grow. The result of dynamic progress in the diagnosis and therapy of these diseases is the progress of genetic diagnostics, the introduction of screening for PID/IEIs in newborns, as well as the use of new therapeutic approaches including gene therapy. Since the beginning of 2024, nationwide screening for severe combined immunodeficiency (SCID) has been introduced in the Czech Republic. Advances in genetic diagnostic technologies have allowed for more precise diagnostics and the acquisition of new data regarding the pathogenesis of PIDs/IEIs, which can be used to develop targeted therapies. Symptomatic treatment for patients with PIDs/IEIs, in addition to antimicrobial prophylaxis and immunoglobulin replacement therapy, has been enhanced with small molecules and biological therapy using monoclonal antibodies targeted against cytokines, cells, or their products. In the causal treatment of patients with PIDs/IEIs, there have been improvements in the procedures for hematopoietic stem cell transplantation (HSCT) and advances in the field of gene therapies. Future developments in the field of PID/IEIs will focus on more precise diagnostics, targeted therapies, and a personalized approach to treatment.

• MeSH
• genetická terapie MeSH
• lidé MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• novorozenec MeSH
• plošný screening MeSH
• primární imunodeficience * diagnóza   terapie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

V České republice proběhl v letech 2022-2023 pilotní projekt novorozeneckého screeningu závažných vrozených poruch imunity, souhrnně SCID screening. Pilotní data demonstrovala vysokou efektivitu celého metodického a klinického aparátu.

In the Czech Republic, a pilot programme for newborn screening of severe iborn errors of immunity, collectively known as SCID screening, took place in 2022-2023. The pilot data demonstrated a high efficiency of the entire methodological and clinical apparatus.

• Klíčová slova
• vrozené poruchy imunity,
• MeSH
• agamaglobulinemie diagnóza   MeSH
• lidé MeSH
• nemoci imunitního systému diagnóza   MeSH
• novorozenec MeSH
• novorozenecký screening * MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Geografické názvy
• Česká republika MeSH

• MeSH
• granulom etiologie   diagnóza   MeSH
• lidé MeSH
• syndrom Nijmegen breakage * genetika   MeSH
• těžká kombinovaná imunodeficience * terapie   komplikace   diagnóza   MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• dopisy MeSH
• kazuistiky MeSH

The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.

• MeSH
• apoptóza účinky léků   MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   patologie   MeSH
• fosfohydroláza PTEN metabolismus   MeSH
• lidé MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protokoly protinádorové kombinované chemoterapie * farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 * antagonisté a inhibitory   metabolismus   MeSH
• pyrimidiny * farmakologie   terapeutické užití   MeSH
• pyrroly farmakologie   terapeutické užití   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• sulfonamidy * farmakologie   terapeutické užití   MeSH
• xenogenní modely - testy protinádorové aktivity * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

• MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• novorozenecký screening MeSH
• syndromy imunologické nedostatečnosti * MeSH
• těžká kombinovaná imunodeficience * diagnóza   terapie   MeSH
• thymus MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Radiolabelled puromycin analogues will allow the quantification of protein synthesis through nuclear medicine-based imaging. A particularly useful application could be the non-invasive longitudinal visualisation of mycobacterial activity through direct quantification of puromycin binding. This study assesses the value of [68Ga]Ga-DOTA-puromycin in the visualisation of mycobacteria through positron emission tomography combined with magnetic resonance imaging (μPET/MRI). The radiopharmaceutical was produced by previously published and validated methods. [68Ga]Ga-DOTA-Puromycin imaging was performed on severe immunodeficient mice infected with Bacille Calmette-Guérin-derived M. Bovis (BCG). Acute and chronic infection stages were examined by μPET/MRI. A follow-up group of animals acted as controls (animals bearing S. aureus-derived infection and sterile inflammation) to assess tracer selectivity. [68Ga]Ga-DOTA-puromycin-μPET/MRI images revealed the acute, widespread infection within the right upper shoulder and armpit. Also, [68Ga]Ga-DOTA-puromycin signal sensitivity measured after a 12-week period was lower than that of [18F]FDG-PET in the same animals. A suitable correlation between normalised uptake values (NUV) and gold standard histopathological analysis confirms accurate tracer accumulation in viable bacteria. The radiopharmaceutical showed infection selectivity over inflammation but accumulated in both M. Bovis and S. Aureus, lacking pathogen specificity. Overall, [68Ga]Ga-DOTA-puromycin exhibits potential as a tool for non-invasive protein synthesis visualization, albeit without pathogen selectivity.

• MeSH
• heterocyklické sloučeniny monocyklické chemie   MeSH
• magnetická rezonanční tomografie * metody   MeSH
• Mycobacterium bovis * MeSH
• mykobakteriózy diagnostické zobrazování   mikrobiologie   MeSH
• myši SCID MeSH
• myši MeSH
• organokovové sloučeniny MeSH
• pozitronová emisní tomografie * metody   MeSH
• radiofarmaka * chemie   MeSH
• radioizotopy galia * MeSH
• tuberkulóza diagnostické zobrazování   mikrobiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH