The German Center for Child and Adolescent Health - A new structure for translational research in pediatrics shaping the health of children today and future generations.

The new German Center for Child and Adolescent Health (DZKJ) founded as part of the German Centers for Health Research provides an unprecedented and unique opportunity for internationally outstanding research that contributes to the health and well-being of children and adolescents by creating a sustainable, multidisciplinary translational research center with a wide spectrum of clinical and scientific disciplines. The DZKJ attracts and motivates some of the best basic and clinical scientists in Germany inside and outside the field of pediatrics to jointly dedicate their research and creativity to unravelling the causes of both common and rare diseases and to developing innovative therapies and prevention strategies. All DZKJ partner sites will join forces for a pivotal, networked lighthouse for clinical and translational science in pediatrics in Germany and beyond.

RAG recombinase expression discriminates the development of natural killer cells.

Introduction: V(D)J recombination, initiated by recombination-activating gene (RAG) endonucleases, is a crucial process for the generation of diversified antigen receptors of T and B lymphocytes but regarded dispensable for innate natural killer (NK) lymphocytes lacking clonotypic receptors.

Methods: To explore the impact of potential rearrangements on NK cell maturation, RAG-fate mapping reporter human induced pluripotent stem cell (iPSC) lines were generated by introduction of RSS-invEGFP constructs into the AAVS1 locus using CRISPR/Cas9 and differentiated into NK cells .

Results: GFP expression was observed in up to 14% of mature NK cells characterized by a CD45 CD56CD57NKG2CKIR phenotype and unproductive genetic rearrangements in the locus.

Bridging the marrow: a co-culture-platform of leukemia cells and MS5-derived stromal cells or adipocytes.

In the context of acute lymphoblastic leukemia (ALL), the bone marrow microenvironment (BMM) plays a crucial role in providing pro-survival signals, as evident from the rapid spontaneous cell death observed in ex-vivo cultures of primary ALL cells. Among the diverse cell types within the BMM, bone marrow adipocytes (BMAd) exhibit significant plasticity and can constitute a substantial part of the BMM, especially during ALL therapy. However, conflicting data on the interaction between ALL cells and adipocytes have been reported, potentially arising from variations in culture systems and conditions.

Longitudinal analysis of humoral and cellular immunity in SARS-CoV-2 exposed families.

Identification of previous SARS-CoV-2 infection typically relies on serology, yet T-cells play a key role in the adaptive immune response against SARS-CoV-2. Here, we investigated in parallel the SARS-CoV-2-specific as well as endemic human coronavirus-specific humoral and cross-reactive cellular responses in children and adults. We analyzed clinical data and blood samples from a family cohort of 96 children and 144 adults at 3-4 and 11-12 months after their first contact with SARS-CoV-2.

Aging modulates the immunosuppressive, polarizing and metabolic functions of blood-derived myeloid-derived suppressor cells (MDSCs).

Background: Immunosenescence describes the gradual remodeling of immune responses, leading to disturbed immune homeostasis and increased susceptibility of older adults for infections, neoplasia and autoimmunity. Decline in cellular immunity is associated with intrinsic changes in the T cell compartment, but can be further pushed by age-related changes in cells regulating T cell immunity. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of T cell activation and function, whose induction requires chronic inflammation.

Benchmarking miRNA reference genes in B-cell precursor acute lymphoblastic leukemia.

MicroRNAs (miRNAs) play dual roles in acute lymphoblastic leukemia (ALL) as both tumor suppressors and oncogenes, and miRNA expression profiles can be used for patient risk stratification. Precise assessment of miRNA levels is crucial for understanding their role and function in gene regulation. Quantitative real-time polymerase chain reaction (qPCR) is a reliable, rapid, and cost-effective method for analyzing miRNA expression, assuming that appropriate normalization to stable references is performed to ensure valid data.

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.

Background: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma.

Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes.

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied.

The Alcatraz-Strategy: a roadmap to break the connectivity barrier in malignant brain tumours.

In recent years, the discovery of functional and communicative cellular tumour networks has led to a new understanding of malignant primary brain tumours. In this review, the authors shed light on the diverse nature of cell-to-cell connections in brain tumours and propose an innovative treatment approach to address the detrimental connectivity of these networks. The proposed therapeutic outlook revolves around three main strategies: (a) supramarginal resection removing a substantial portion of the communicating tumour cell front far beyond the gadolinium-enhancing tumour mass, (b) morphological isolation at the single cell level disrupting structural cell-to-cell contacts facilitated by elongated cellular membrane protrusions known as tumour microtubes (TMs), and (c) functional isolation at the single cell level blocking TM-mediated intercellular cytosolic exchange and inhibiting neuronal excitatory input into the malignant network.

The Potential Role of the Extracellular Matrix Glycoprotein Reelin in Glioblastoma Biology.

Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a successful containment strategy can be found. Reelin, an extracellular matrix glycoprotein, plays an important role in neuronal migration and serves here as a natural stop signal.

Chemotherapy for a secondary malignancy nearly restores complete chimerism in an SCID-patient after HSCT.

For patients with inborn errors of immunity (IEI) and other inborn diseases, mixed donor chimerism is a well-accepted outcome of hematopoietic stem cell transplantation (HSCT). Cytoreductive chemotherapy for a secondary malignancy is a potential challenge for the stability of the graft function after HSCT. We report on a boy with X-SCID who developed Ewing sarcoma ten years after HSCT which was successfully treated with cytoreductive chemotherapy, surgery and local radiation.

Inhibition of Survivin Homodimerization Decreases Neuroblastoma Cell Growth.

Increased expression of BIRC5/survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB), the most common extracranial tumor of childhood. Transcriptional inhibitors of survivin have been tested in adult cancers and inhibitors of survivin homodimerization are emerging. We compared genetic inhibition of survivin transcription with the inhibition of survivin homodimerization by S12 and LQZ-7I, chosen from a larger panel of survivin dimerization inhibitors with activity against NB cells.

The survivin-ran inhibitor LLP-3 decreases oxidative phosphorylation, glycolysis and growth of neuroblastoma cells.

Background: Neuroblastoma (NB), the most common extracranial solid malignancy in children, carries a poor prognosis in high-risk disease, thus requiring novel therapeutic approaches. Survivin is overexpressed in NB, has pro-mitotic and anti-apoptotic functions, and impacts on oxidative phosphorylation (OXPHOS) and aerobic glycolysis. The subcellular localization and hence function of survivin is directed by the GTPase Ran.

A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.

Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea.

Immune-epithelial cell cross-talk enhances antiviral responsiveness to SARS-CoV-2 in children.

The risk of developing severe COVID-19 rises dramatically with age. Schoolchildren are significantly less likely than older people to die from SARS-CoV-2 infection, but the molecular mechanisms underlying this age-dependence are unknown. In primary infections, innate immunity is critical due to the lack of immune memory.

Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity.

Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling.

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions.

Serum neutralizing capacity and T-cell response against the omicron BA.1 variant in seropositive children and their parents one year after SARS-CoV-2 infection.

Introduction: Durability of immune protection against reinfection with SARS-CoV-2 remains enigmatic, especially in the pediatric population and in the context of immune-evading variants of concern. Obviously, this knowledge is required for measures to contain the spread of infection and in selecting rational preventive measures.

Methods: Here, we investigated the serum neutralization capacity of 36 seropositive adults and 34 children approximately one year after infection with the ancestral Wuhan strain of SARS-CoV-2 by using a pseudovirus neutralization assay.

How to Respond to Misinformation From the Anti-Vaccine Movement.

Vaccines are doubtlessly one of the most crucial life-saving medical interventions to date. However, perplexingly, they court more public controversy than their objectively excellent safety profile warrants. While doubts about the safety of vaccines, as well as opposition to vaccine policies, can be traced back at least to the mid-19th century, the modern anti-vaccine movement has come in 3 distinct waves, or generations, each precipitating around distinct key events.