[Recommendations for the healthcare of patients with FOP].

Background: Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups.

Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP).

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease.

Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the gene was identified as the causative mutation of FOP in 2006.

Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management.

Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e.

Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in .

We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family.

Novel Treatments for Rare Cancers: The U.S. Orphan Drug Act Is Delivering-A Cross-Sectional Analysis.

Background: Rare cancers are a heterogeneous group of conditions with highly unmet medical needs. Although infrequent in individuals, rare cancers affect millions of people who deserve effective treatments. Therefore, we systematically analyzed the impact of the U.

DNA methylation in PRDM8 is indicative for dyskeratosis congenita.

Dyskeratosis congenita (DKC) is associated with impaired telomere maintenance and with clinical features of premature aging. In this study, we analysed global DNA methylation (DNAm) profiles of DKC patients. Age-associated DNAm changes were not generally accelerated in DKC, but there were significant differences to DNAm patterns of healthy controls, particularly in CpG sites related to an internal promoter region of PR domain containing 8 (PRDM8).

A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition.

The TERT gene encodes for the reverse transcriptase activity of the telomerase complex and mutations in TERT can lead to dysfunctional telomerase activity resulting in diseases such as dyskeratosis congenita (DKC). Here, we describe a novel TERT mutation at position T1129P leading to DKC with progressive bone marrow (BM) failure in homozygous members of a consanguineous family. BM hematopoietic stem cells (HSCs) of an affected family member were 300-fold reduced associated with a significantly impaired colony forming capacity in vitro and impaired repopulation activity in mouse xenografts.

The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis.

The interaction between thrombopoietin (THPO) and its receptor c-Mpl regulates downstream cytokine signaling and platelet homeostasis. Hereditary mutations of c-Mpl can either result in loss-of-function and thrombocytopenia or in gain-of-function and thrombocythemia (HT), and are important models to analyze the mechanism of c-Mpl activity. We have analyzed the effect of the c-Mpl P106L gain-of-function and the nearby loss-of-function R102P and F104S mutations, which cause HT or thrombocytopenia, respectively, on posttranslational processing, intracellular trafficking, cell surface expression, and cell proliferation.

First case of disseminated cryptococcosis in a Gorilla gorilla.

In humans, Cryptococcus mainly infects individuals with HIV infection or other types of immunosuppression. Here, we report the first case of disseminated cryptococcosis in a simian immunodeficiency virus-negative 27-year-old female Gorilla gorilla presenting with lethargy, progressive weight loss and productive cough. The diagnosis was confirmed by positive lung biopsy culture, serum cryptococcal antigen, and cerebral histopathology demonstrating encapsulated yeasts.

Pediatric case report on magnetic resonance imaging/transrectal ultrasound-fusion biopsy of rhabdomyosarcoma of the bladder/prostate: a new tool to reduce therapy-associated morbidity?

Rhabdomyosarcomas are the most common soft tissue sarcomas in children. Here we present management of an 18-month-old boy with metastatic rhabdomyosarcoma of the bladder/prostate. After radiochemotherapy, high-spatial-resolution 3-Tesla multiparametric magnetic resonance imaging (MRI) showed regressive systemic disease but a residual mass at the right seminal vesicle.

Hereditary thrombocythemia caused by a thrombopoietin (THPO) gain-of-function mutation associated with multiple myeloma and congenital limb defects.

Hereditary thrombocythemia (HT) has been described as a rare benign disorder caused by mutations in the thrombopoietin (THPO) or the c-Mpl receptor genes. Here we report two families with HT resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3.

Significance of image-defined risk factors for surgical complications in patients with abdominal neuroblastoma.

Introduction: Neuroblastoma (NB) is one of the most common malignant tumors in infancy. The commonly used International Neuroblastoma Staging System is not suitable for determining the surgical risks. To address this, we aimed to evaluate the correlation between so-called image-defined risk factors (IDRFs) and the surgical risks in abdominal neuroblastoma.

13-cis retinoic acid treatment of a patient with chemotherapy refractory nephroblastomatosis.

A 9-month-old girl presented with massive bilateral diffuse nephroblastomatosis. After response to actinomycin D and vincristine over a period of 1 year, the nephroblastomatosis continuously progressed under this treatment. As retinoic acid signaling is critical for normal renal development and nephroblastomatosis seems histologically as undifferentiated embryonal tissue, we added 13-cis retinoic acid to the chemotherapy regimen.

The uORF-containing thrombopoietin mRNA escapes nonsense-mediated decay (NMD).

Platelet production is induced by the cytokine thrombopoietin (TPO). It is physiologically critical that TPO expression is tightly regulated, because lack of TPO causes life-threatening thrombocytopenia while an excess of TPO results in thrombocytosis. The plasma concentration of TPO is controlled by a negative feedback loop involving receptor-mediated uptake of TPO by platelets.

Long-term remission of children with relapsed and secondary anaplastic large cell non-Hodgkin lymphoma (ALCL) following treatment with pulsed dexamethasone and low dose etoposide.

Anaplastic large cell lymphoma (ALCL) accounts for approximately 15% of childhood NHL. Relapsed ALCL represents a formidable challenge because outcome is poor despite the use of high-dose chemotherapy regimens. We report two patients with relapsed T-type and 0-type ALCL who achieved long-term 3rd and 4th remissions with 4-weekly oral dexamethasone (DEX) and etoposide pulses for 2 years.

Interaction of PSD-95 with potassium channels visualized by fluorescence lifetime-based resonance energy transfer imaging.

Resonance energy transfer (RET) has been extensively used to estimate the distance between two different fluorophores. This study demonstrates how protein-protein interactions can be visualized and quantified in living cells by time-correlated single-photon counting (TCSPC) imaging techniques that exploit the RET between appropriate fluorescent labels. We used this method to investigate the association of the potassium inward rectifier channel Kir2.

Surface expression of inward rectifier potassium channels is controlled by selective Golgi export.

Traffic of integral membrane proteins along the secretory pathway is not simply a default process but can be selective. Such selectivity is achieved by sequence information within the cargo protein that recruits coat protein complexes to drive the formation of transport vesicles. A number of sequence motifs have been identified in the cytoplasmic domains of ion channels that regulate early trafficking events between the endoplasmic reticulum and the Golgi complex.

A sequence motif responsible for ER export and surface expression of Kir2.0 inward rectifier K(+) channels.

Integral membrane proteins are sorted via the secretory pathway. It was proposed that this pathway is non-selective provided that the cargo protein is properly assembled and lacks an endoplasmic reticulum (ER) retention signal. However, recent experimental evidence suggests that efficient export of proteins from the ER to the Golgi complex is not simply a default pathway.