A pedigree with autosomal dominant thrombocytopenia, red cell macrocytosis, and an occurrence of t(12:21) positive pre-B acute lymphoblastic leukemia

Sampling and analyzing new families with inherited blood disorders are major steps contributing to the identification of gene(s) responsible for normal and pathologic hematopoiesis. Familial occurrences of hematological disorders alone, or as part of a syndromic disease, have been reported, and for some the underlying genetic mutation has been identified. Here we describe a new autosomal dominant inherited phenotype of thrombocytopenia and red cell macrocytosis in a four-generation pedigree. Interestingly, in the youngest generation, a 2-year-old boy presenting with these familial features has developed acute lymphoblastic leukemia characterized by a t(12;21) translocation. Tri-lineage involvement of platelets, red cells and white cells may suggest a genetic defect in an early multiliear progenitor or a stem cell. Functional assays in EBV-transformed cell lines revealed a defect in cell proliferation and tubulin dynamics. Two candidate genes, RUNX1 and FOG1, were sequenced but no pathogenic mutation was found. Identification of the underlying genetic defect(s) in this family may help in understanding the complex process of hematopoiesis.

Integration of room temperature single electron transistor with CMOS subsystem

The single electron transistor (SET) is a charge-based device that may complement the dominant metal-oxide-semiconductor field effect transistor (MOSFET) technology. As the cost of scaling MOSFET to smaller dimensions are rising and the the basic functionality of MOSFET is encountering numerous challenges at dimensions smaller than 10nm, the SET has shown the potential to become the next generation device which operates based on the tunneling of electrons. Since the electron transfer mechanism of a SET device is based on the non-dissipative electron tunneling effect, the power consumption of a SET device is extremely low, estimated to be on the order of 10^-18J. The objectives of this research are to demonstrate technologies that would enable the mass produce of SET devices that are operational at room temperature and to integrate these devices on top of an active complementary-MOSFET (CMOS) substrate. To achieve these goals, two fabrication techniques are considered in this work. The Focus Ion Beam (FIB) technique is used to fabricate the islands and the tunnel junctions of the SET device. A Ultra-Violet (UV) light based Nano-Imprint Lithography (NIL) call Step-and-Flash- Imprint Lithography (SFIL) is used to fabricate the interconnections of the SET devices. Combining these two techniques, a full array of SET devices are fabricated on a planar substrate. Test and characterization of the SET devices has shown consistent Coulomb blockade effect, an important single electron characteristic. To realize a room temperature operational SET device that function as a logic device to work along CMOS, it is important to know the device behavior at different temperatures. Based on the theory developed for a single island SET device, a thermal analysis is carried out on the multi-island SET device and the observation of changes in Coulomb blockade effect is presented. The results show that the multi-island SET device operation highly depends on temperature. The important parameters that determine the SET operation is the effective capacitance Ceff and tunneling resistance Rt . These two parameters lead to the tunneling rate of an electron in the SET device, Γ. To obtain an accurate model for SET operation, the effects of the deviation in dimensions, the trap states in the insulation, and the background charge effect have to be taken into consideration. The theoretical and experimental evidence for these non-ideal effects are presented in this work.

Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease

BACKGROUND: Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kidney disease. We hypothesized that matrix and TBM degradation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal dominant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment on MMPs. METHODS: 5-week-old male heterozygous (Cy/+) and wild-type normal (+/+) rats were treated with sirolimus (2 mg/kg/day) through drinking water for 3 months. RESULTS: The mRNA and protein levels of MMP-2 and MMP-14 were markedly increased in the kidneys of heterozygous Cy/+ animals compared to wild-type +/+ as shown by RT-PCR and Western blot analyses for MMP-2 and MMP-14, and by zymography for MMP-2. Strong MMP-2 expression was detected by immunoperoxidase staining in cystic epithelial cells that also displayed an altered, thickened TBM. Tissue inhibitor of metalloproteinases-2 (TIMP-2) expression was not changed in Cy/+ kidneys. Sirolimus treatment leads to decreased protein expression of MMP-2 and MMP-14 in Cy/+, whereas MMP-2 and MMP-14 mRNA levels and TIMP-2 protein levels were not affected by sirolimus. CONCLUSION: In summary, in kidneys of the Han:SPRD rat model of ADPKD, there is a marked upregulation of MMP-2 and MMP-14. Sirolimus treatment was associated with a marked improvement of MMP-2 and MMP-14 overexpression, and this correlated also with less matrix and TBM alterations and milder cystic disease.