Bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in a mouse model of iron deficiency anemia.

Iron deficiency is a potent stimulator of fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism, that is classically thought to be produced by bone-embedded osteocytes. Here, we show that iron-deficient transmembrane serine protease 6 knockout (Tmprss6-/-) mice exhibit elevated circulating FGF23 and Fgf23 messenger RNA (mRNA) upregulation in the bone marrow (BM) but not the cortical bone. To clarify sites of Fgf23 promoter activity in Tmprss6-/- mice, we introduced a heterozygous enhanced green fluorescent protein (eGFP) reporter allele at the endogenous Fgf23 locus.

Hepatocellular Adenoma: Report of 2 Cases That Highlight the Relevance of Phenotype-Genotype Correlation in the Pediatric Population.

Background: Hepatocellular adenoma (HCA) in the pediatric population is very rare and there are only limited studies, especially with molecular characterization of the tumors. Main HCA subtypes recognized in the current WHO classification include -inactivated HCA (H-HCA), inflammatory HCA (IHCA), β-catenin-activated HCA (b-HCA), and β-catenin-activated IHCA (b-IHCA) and sonic hedgehog HCA (shHCA) is reported as an emerging subtype.

Methods: Clinical history, pathological information, and molecular studies for a series of 2 cases of pediatric HCA were reviewed.

Endometrial Carcinoma as the Presenting Malignancy in a Teenager With a Pathogenic TP53 Germline Mutation: A Case Report and Literature Review.

Patients with germline TP53 mutations are characterized by the occurrence of multiple early-onset malignancies. The characteristic syndrome is Li-Fraumeni syndrome (OMIM # 151623), an autosomal dominant disorder typified by premenopausal breast carcinoma, adrenal cortical tumors, bone and soft tissue sarcomas, leukemias, and tumors of the brain and spinal cord. Gynecologic malignancies are uncommonly reported in families harboring TP53 mutations, and the predominant tumor type reported is ovarian.

NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss.

The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation.

IL-1β Drives Production of FGF-23 at the Onset of Chronic Kidney Disease in Mice.

FGF-23 has arisen as an early biomarker of renal dysfunction, but at the onset of chronic kidney disease (CKD), data suggest that FGF-23 may be produced independently of the parathyroid hormone (PTH), 1,25(OH) -vitamin D signaling axis. Iron status is inversely correlated to the level of circulating FGF-23, and improvement in iron bioavailability within patients correlates with a decrease in FGF-23. Alternately, recent evidence also supports a regulatory role of inflammatory cytokines in the modulation of FGF-23 expression.

EBV-Positive Primary Large B-Cell Lymphoma: The Role of Immunohistochemistry and XPO1 in the Diagnosis of Mediastinal Lymphomas.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is described as almost always negative for Epstein-Barr virus (EBV). In the context of a mediastinal lymphoma, the distinction between PMBL, classical Hodgkin lymphoma, diffuse large B-cell lymphoma, and mediastinal gray-zone lymphoma can be very difficult; hence, EBV positivity often argues against PMBL. We present a 19-year-old man with mediastinal mass morphologically consistent with PMBL.

Analytical Validation of the Next-Generation Sequencing Assay for a Nationwide Signal-Finding Clinical Trial: Molecular Analysis for Therapy Choice Clinical Trial.

The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial is a national signal-finding precision medicine study that relies on genomic assays to screen and enroll patients with relapsed or refractory cancer after standard treatments. We report the analytical validation processes for the next-generation sequencing (NGS) assay that was tailored for regulatory compliant use in the trial. The Oncomine Cancer Panel assay and the Personal Genome Machine were used in four networked laboratories accredited for the Clinical Laboratory Improvement Amendments.

Iron-refractory iron deficiency anemia (IRIDA).

Iron deficiency anemia is a common global problem whose etiology is typically attributed to acquired inadequate dietary intake and/or chronic blood loss. However, in several kindreds multiple family members are affected with iron deficiency anemia that is unresponsive to oral iron supplementation and only partially responsive to parenteral iron therapy. The discovery that many of these cases harbor mutations in the TMPRSS6 gene led to the recognition that they represent a single clinical entity: iron-refractory iron deficiency anemia (IRIDA).

Striking the target in iron overload disorders.

The liver, a major site of body iron stores, mediates key responses that preserve systemic iron homeostasis. In this issue of the JCI, Guo et al. demonstrate that administration of antisense oligonucleotides that reduce expression of Tmprss6, a hepatic protein that plays an essential role in maintaining iron balance, can attenuate disease severity in mouse models of human iron overload disorders.

Regulation of systemic iron homeostasis.

Purpose Of Review: The circulating peptide hepcidin modulates systemic iron balance by limiting the absorption of dietary iron and the release of iron from macrophage stores. Recent studies conducted in humans, animal models, and tissue culture systems have enhanced our understanding of the molecular mechanisms by which hepcidin levels are altered in response to iron stores, inflammation, and erythropoietic activity.

Recent Findings: The bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 play key, nonredundant roles in mediating hepcidin synthesis through the BMP signaling pathway.

Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy.

Iron-refractory iron-deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in TMPRSS6. Patients have hypochromic microcytic anemia refractory to oral iron and are only partially responsive to parenteral iron administration. We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia.

Altered V-ATPase expression in renal intercalated cells isolated from B1 subunit-deficient mice by fluorescence-activated cell sorting.

Unlike human patients with mutations in the 56-kDa B1 subunit isoform of the vacuolar proton-pumping ATPase (V-ATPase), B1-deficient mice (Atp6v1b1(-/-)) do not develop metabolic acidosis under baseline conditions. This is due to the insertion of V-ATPases containing the alternative B2 subunit isoform into the apical membrane of renal medullary collecting duct intercalated cells (ICs). We previously reported that quantitative Western blots (WBs) from whole kidneys showed similar B2 protein levels in Atp6v1b1(-/-) and wild-type mice (Păunescu TG, Russo LM, Da Silva N, Kovacikova J, Mohebbi N, Van Hoek AN, McKee M, Wagner CA, Breton S, Brown D.