SRY+ Derivative X Chromosome in a Female With Apparently Typical Sexual Development.

Background: When the SRY gene is present in a 46,XX fetus, some degree of testicular development is expected. Our laboratory performed prenatal genetic testing for a fetus that had screened positive for Y chromosome material by noninvasive prenatal screening (NIPS) but that had apparently typical female development by ultrasound imaging. The aim of this study was to determine the clinical relevance of the NIPS results.

Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death.

Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance.

Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML.

The Value of Parental Testing by Next-Generation Sequencing Includes the Detection of Germline Mosaicism.

When a potential disease-causing variant is detected in a proband, parental testing is used to determine the mode of inheritance. This study demonstrates that next-generation sequencing (NGS) is uniquely well suited for parental testing, in particular because of its ability to detect clinically relevant germline mosaicism. Parental variant testing by NGS was performed in a clinical laboratory for 1 year.

Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia.

Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals.

Transplantation Dose Alters the Differentiation Program of Hematopoietic Stem Cells.

Hematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here, we find that, in the long term following transplantation, 70%-80% of donor-HSC-derived clones do not produce all measured blood cell types.

mRNA regulation of cardiac iron transporters and ferritin subunits in a mouse model of iron overload.

Iron cardiomyopathy is the leading cause of death in iron overload. Men have twice the mortality rate of women, though the cause is unknown. In hemojuvelin-knockout mice, a model of the disease, males load more cardiac iron than females.

Dose titration of deferasirox iron chelation therapy by magnetic resonance imaging for chronic iron storage disease in three adult red bald-headed uakari (Cacajao calvus rubicundus).

Iron overload is common in lemurs and some New World nonhuman primates raised in captivity, but there is no such documentation in the red bald-headed uakari (Cacajao calvus rubicundus). This study describes postmortem documentation of severe iron storage disease in one red bald-headed uakari and the use of iron chelation with oral deferasirox in the three surviving members of the colony. Magnetic resonance imaging was used to quantify pretreatment iron burden and to follow the response to therapy in two females, 22 and 28 yr of age, and one male 33 yr of age.

Sex differences and steroid modulation of cardiac iron in a mouse model of iron overload.

Iron cardiomyopathy is the leading cause of death in transfusional iron overload, and men have twice the mortality of women. Because the prevalence of cardiac iron overload increases rapidly during the second decade of life, we postulated that there are steroid-dependent sex differences in cardiac iron uptake. To test this hypothesis, we manipulated sex steroids in mice with constitutive iron absorption (homozygous hemojuvelin knockout); this model mimics the myocyte iron deposition observed in humans.

Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats.

Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells.

Interdependence of cardiac iron and calcium in a murine model of iron overload.

Iron cardiomyopathy in ß-thalassemia major patients is associated with a vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, whereas the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25-OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone [PTH]) is the strongest predictor of cardiac iron.

Spleen R2 and R2* in iron-overloaded patients with sickle cell disease and thalassemia major.

Purpose: To evaluate the magnetic properties of the spleen in chronically transfused, iron-overloaded patients with sickle cell disease (SCD) and thalassemia major (TM) and to compare splenic iron burdens to those in the liver, heart, pancreas, and kidneys.

Materials And Methods: A retrospective analysis of 63 TM and 46 SCD patients was performed. Spleen R2 and R2* values were calculated from spin-echo and gradient-echo images collected between April 2004 and September 2007.

Safety and efficacy of combined chelation therapy with deferasirox and deferoxamine in a gerbil model of iron overload.

Introduction: Combined therapy with deferoxamine (DFO) and deferasirox (DFX) may be performed empirically when DFX monotherapy fails. Given the lack of published data on this therapy, the study goal was to assess the safety and efficacy of combined DFO/DFX therapy in a gerbil model.

Methods: Thirty-two female Mongolian gerbils 8-10 weeks old were divided into 4 groups (sham chelated, DFO, DFX, DFO/DFX).