A Cystic Renal Mass in the Setting of a Pneumothorax: More Than Meets the Eye?

DICER1 syndrome is a rare hereditary cancer predisposition syndrome that has relevance to pediatric urology providers due to its association with many various pediatric genitourinary malignancies. We describe the case of a pediatric patient who was eventually diagnosed with a pathogenic DICER1 germline variant after undergoing resection of a cystic nephroma and pleuropulmonary blastoma

MEK Kinase 2 and the Adaptor Protein Lad Regulate Extracellular Signal-Regulated Kinase 5 Activation by Epidermal Growth Factor via Src

Lad is an SH2 domain-containing adaptor protein that binds MEK kinase 2 (MEKK2), a mitogen-activated protein kinase (MAPK) kinase kinase for the extracellular signal-regulated kinase 5 (ERK5) and JNK pathways. Lad and MEKK2 are in a complex in resting cells. Antisense knockdown of Lad expression and targeted gene disruption of MEKK2 expression results in loss of epidermal growth factor (EGF) and stress stimuli-induced activation of ERK5. Activation of MEKK2 and the ERK5 pathway by EGF and stress stimuli is dependent on Src kinase activity. The Lad-binding motif is encoded within amino acids 228 to 282 in the N terminus of MEKK2, and expression of this motif blocks Lad-MEKK2 interaction, resulting in inhibition of Src-dependent activation of MEKK2 and ERK5. JNK activation by EGF is similarly inhibited by loss of Lad or MEKK2 expression and by blocking the interaction of MEKK2 and Lad. Our studies demonstrate that Src kinase activity is required for ERK5 activation in response to EGF, MEKK2 expression is required for ERK5 activation by Src, Lad and MEKK2 association is required for Src activation of ERK5, and EGF and Src stimulation of ERK5-regulated MEF2-dependent promoter activity requires a functional Lad-MEKK2 signaling complex

Is polycystic kidney disease associated with malignancy in children?

BackgroundPolycystic kidney disease (PKD) is an inherited condition characterized by progressive development of end-stage renal disease, hypertension, hepatic fibrosis, and cysts in the kidney, liver, pancreas, spleen, thyroid, and epididymis. While malignancies have been reported in association with PKD in adults, the incidence of malignancies in children with PKD is not currently known.MethodsWe report on five patients with a known history of PKD who developed a malignancy as children at the University of California, Los Angeles and the University of Colorado Anschutz Medical Campus. Patients were included from 2012 to 2017.ResultsWe present five patients with a history of PKD diagnosed with a malignancy during childhood without any additional known mutations to suggest a genetic predisposition to develop cancer. This includes the first reported case of hepatocellular carcinoma in a patient with autosomal recessive polycystic kidney disease.ConclusionOur report illustrates the potential that PKD may be associated with an increased risk for developing cancer, even in children. Further research is necessary to better understand this relationship

MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells

Ligation of the high-affinity IgE receptor (FcεRI) or of c-Kit stimulates cytokine production in mast cells. We show that MEK kinase 2 (MEKK2), a MAPK kinase kinase (MAP3K) that regulates the JNK and ERK5 pathways, is required for cytokine production in embryonic stem (ES) cell-derived mast cells (ESMC). Targeted disruption of the MEKK2 or MEKK1 gene was used to abolish expression of the respective kinases in ESMC. Transcription of specific cytokines in response to IgE or c-Kit ligand was markedly reduced in MEKK2(–/–) ESMC relative to wild-type ESMC. Cytokine production in MEKK1(–/–) ESMC was similar to that of wild-type ESMC, demonstrating the specificity of MEKK2 in signaling cytokine gene regulation. MEKK2(–/–) ESMC also lost receptor-mediated stimulation of JNK. In contrast, JNK activation in response to UV irradiation was normal, showing that MEKK2 is required for receptor signaling but not for cellular stress responses. MEKK2 is the first MAP3K shown to be required for mast cell tyrosine kinase receptor signaling controlling cytokine gene expression

Safety of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis: findings from the primary analysis of the pivotal phase 2/3 study.

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune regulatory disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, the cytokine Interferon gamma (IFNy) is often markedly elevated and is considered a key contributor to the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to transplantation, the only curative therapy. Current conventional therapy for HLH comprises immunochemotherapies, which are associated with opportunistic infections, toxicity, and high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease, or intolerance with conventional HLH therapy. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study and investigate the relationship of adverse events (AE) to dose and duration of treatment

Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Phase II study on the use of emapalumab for therapy of HL