Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms.

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms.

Oncolytic influenza virus infection restores immunocompetence of lung tumor-associated alveolar macrophages.

Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells.

Evaluation of Children with SMA Type 1 Under Treatment with Nusinersen within the Expanded Access Program in Germany.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness and muscle atrophy. Nusinersen acts as a splicing modifier and has recently been approved for intrathecal treatment of SMA.

Objective: Prior to approval, nusinersen was provided to patients with SMA type 1 in Germany within an Expanded Access Program (EAP).

QIL1-dependent assembly of MICOS complex-lethal mutation in C19ORF70 resulting in liver disease and severe neurological retardation.

Seven subunits of the mitochondrial contact site and cristae junction (CJ) organizing system (MICOS) in humans have been recently described in function and structure. QIL1 (also named MIC13) is a small complex that is crucial for the maintenance and assembling of MICOS. A novel mutation of an essential splice site in the C19orf70 gene encoding QIL1 induces severe mitochondrial encephalopathy, hepatopathy and lactate acidosis consistent with psychomotor retardation.

First description of a local skin and soft tissue infection.

is an environmental fungus which can cause disseminated infections in immunocompromised patients, often leading to death. Here we report the case of a paediatric patient with an invasive wound infection due to which was successfully treated with surgical debridement and oral posaconazole.

T cell infiltration into Ewing sarcomas is associated with local expression of immune-inhibitory HLA-G.

Ewing sarcoma (EwS) is an aggressive mesenchymal cancer of bones or soft tissues. The mechanisms by which this cancer interacts with the host immune system to induce tolerance are not well understood. We hypothesized that the non-classical, immune-inhibitory HLA-molecule HLA-G contributes to immune escape of EwS.

The extraordinary challenge of treating patients with congenital rhabdoid tumors-a collaborative European effort.

Background: Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach.

Methods: A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU-RHAB), France and Moscow (2006-2016) diagnosed within the first 28 days of life was evaluated.

Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear.

Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways.

Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and G-protein-coupled receptor pathways were linked to cilia before the origin of bilateria and transient receptor potential (TRP) channels before the origin of animals.

Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors.

Rhabdoid tumors are caused by the deletion of , whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds.

Temporary Tracheal Stenting After Pulmonary Artery Sling Repair in a Newborn.

Pulmonary artery sling (PAS) is a rare disease frequently associated with severe malacia and stenosis of the trachea. We present a two-day-old newborn that underwent urgent surgery for PAS and needed prolonged respiratory support afterward. Temporary airway stenting above the level of the tracheal bifurcation was performed five days after surgery to overcome severe airway obstruction caused by tracheomalacia and laceration of the tracheal mucosa after diagnostic bronchoscopy.

Should transmission electron microscopy and ultrastructural cilia evaluation remain part of the diagnostic work-up for primary ciliary dyskinesia?

The diagnostic work-up for primary ciliary dyskinesia (PCD) traditionally includes ciliary ultrastructural assessment using transmission electron microscopy (TEM). However, the identification of genetic variants of PCD that are missed by TEM, along with the development of novel diagnostic modalities for PCD that allow structural evaluation of cilia, such as immunofluorescence analysis and the increased availability of genetic testing, calls into questioning the contemporary role of TEM in the diagnostic work-up for PCD. In this manuscript, we describe the evidence for and against the use of TEM in PCD diagnosis, in light of recent developments of PCD.

CAR T cell immunotherapy in hematology and beyond.

Chimeric T cell receptors (CARs) combine extracellular antigen recognition domains and T cell activation components in single molecules. CAR gene transfer thereby allows to generate T cells with engineered specificities. The translational development of CAR-based T cell therapies is most advanced in B cell cancers where CAR-engineered T cells against the B lineage antigen CD19 have generated impressive results in early clinical trials.

Validation of the screening tool ApneaLink in comparison to polysomnography for the diagnosis of sleep-disordered breathing in children and adolescents.

Objective: While out-of-center testing was introduced as an alternative for the diagnosis of obstructive sleep apnea in adults, polysomnography (PSG) is still considered mandatory in the diagnosis of sleep-disordered breathing (SDB) in children. The purpose of this study was to validate the outpatient screening device ApneaLink in comparison to PSG in children and adolescents for the diagnosis of SDB.

Methods: Sixty consecutive children and adolescents (10.

Programmed cell death ligand 1 (PD-L1) expression is not a predominant feature in Ewing sarcomas.

Background: Programmed cell death 1 (PD-1) receptor engagement on T cells by its ligand programmed cell death ligand 1 (PD-L1) is a key mechanism of immune escape, and antibody blockade of the interaction has emerged as an effective immunotherapeutic strategy in some cancers. The role and relevance of the PD-1 checkpoint in Ewing sarcoma (EwS) is not yet understood.

Procedure: Here, we investigated expression of PD-L1 and PD-1 in EwS by immunohistochemistry analysis of pretherapeutic tumor biopsies and in tumor xenografts following treatment with human T cells engineered to express a chimeric antigen receptor (CAR) against the tumor-associated antigen G .

Limitations of galactose therapy in phosphoglucomutase 1 deficiency.

Introduction: Phosphoglucomutase 1 deficiency (PGM1 deficiency) has been identified as both, glycogenosis and congenital disorder of glycosylation (CDG). The phenotype includes hepatopathy, myopathy, oropharyngeal malformations, heart disease and growth retardation. Oral galactose supplementation at a dosage of 1 g per kg body weight per day is regarded as the therapy of choice.

Neurotoxic side effects in children with refractory or relapsed T-cell malignancies treated with nelarabine based therapy.

The prognosis in children with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) is poor. Nelarabine (Ara-G) has successfully been used as salvage therapy in these children, but has been associated with significant, even fatal, neurotoxicities. We retrospectively analysed 52 patients with r/r T-ALL/T-LBL aged ≤19 years who were treated with Ara-G alone (n = 25) or in combination with cyclophosphamide and etoposide (n = 27).

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors.

Rhabdoid tumors (RT) are malignant neoplasms of early childhood. Despite intensive therapy, survival is poor and new treatment approaches are required. The only recurrent mutations in these tumors affect and less commonly , both subunits of the chromatin remodeling complex SWItch/Sucrose Non-Fermentable (SWI/SNF).

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies.

Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities.

Mutation of serine/threonine protein kinase 36 (STK36) causes primary ciliary dyskinesia with a central pair defect.

Primary ciliary dyskinesia (PCD) is a genetic condition of impaired ciliary beating, characterized by chronic infections of the upper and lower airways and progressive lung failure. Defects of the outer dynein arms are the most common cause of PCD. In about half of the affected individuals, PCD occurs with situs inversus (Kartagener syndrome).

Control of Multidrug-Resistant Pseudomonas aeruginosa in Allogeneic Hematopoietic Stem Cell Transplant Recipients by a Novel Bundle Including Remodeling of Sanitary and Water Supply Systems.

Background: Infections by multidrug-resistant Pseudomonas aeruginosa (MDRPa) are an important cause of morbidity and mortality in patients after allogeneic hematopoietic stem cell transplantation (HSCT). Humid environments can serve as a reservoir and source of infection by this pathogen. To minimize the risk of infection from these reservoirs, we performed extensive remodeling of sanitation and water installations as the focus of our hygiene bundle.

Munchausen by proxy syndrome mimicking systemic autoinflammatory disease: case report and review of the literature.

Background: Systemic autoinflammatory diseases (SAIDs) represent a growing number of monogenic, polygenic or multifactorial disorders that are often difficult to diagnose.

Case Presentation: Here we report a patient who was initially erroneously diagnosed and treated for SAID. Symptoms consisted of recurrent fever, erythematous and/or blistering skin lesions, angioedema, susceptibility to bleeding, external ear infections and reversible anisocoria in the absence of laboratory evidence of systemic inflammation.

Dyslipidemia after pediatric renal transplantation-The impact of immunosuppressive regimens.

Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry.