Cats and Dogs, Hair and A Hero: A Quintet of New Milky Way Companions

We present five new satellites of the Milky Way discovered in Sloan Digital Sky Survey (SDSS) imaging data, four of which were followed-up with either the Subaru or the Isaac Newton Telescopes. They include four probable new dwarf galaxies -- one each in the constellations of Coma Berenices, Canes Venatici, Leo and Hercules -- together with one unusually extended globular cluster, Segue 1. We provide distances, absolute magnitudes, half-light radii and color-magnitude diagrams for all five satellites. The morphological features of the color-magnitude diagrams are generally well described by the ridge line of the old, metal-poor globular cluster M92. In the last two years, a total of ten new Milky Way satellites with effective surface brightness mu_v >~ 28 mag/sq. arcsec have been discovered in SDSS data. They are less luminous, more irregular and appear to be more metal-poor than the previously-known nine Milky Way dwarf spheroidals. The relationship between these objects and other populations is discussed. We note that there is a paucity of objects with half-light radii between ~40 pc and ~ 100 pc. We conjecture that this may represent the division between star clusters and dwarf galaxies.Comment: 10 pages, 8 figures, submitted to the Astrophysical Journa

Inhibition of Bone Morphogenetic Protein Signal Transduction Prevents the Medial Vascular Calcification Associated with Matrix Gla Protein Deficiency

Objective: Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice. Approach and Results MGP-deficient mice (MGP-/-) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP-/- mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP-/- mice survived longer than vehicle-treated MGP-/- mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP-/- and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP-/- aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189. Conclusions: Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP-/- mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice

The Neurotrophic Receptor Ntrk2 Directs Lymphoid Tissue Neovascularization during Leishmania donovani Infection

The neurotrophic tyrosine kinase receptor type 2 (Ntrk2, also known as TrkB) and its ligands brain derived neurotrophic factor (Bdnf), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) are known primarily for their multiple effects on neuronal differentiation and survival. Here, we provide evidence that Ntrk2 plays a role in the pathologic remodeling of the spleen that accompanies chronic infection. We show that in Leishmania donovani-infected mice, Ntrk2 is aberrantly expressed on splenic endothelial cells and that new maturing blood vessels within the white pulp are intimately associated with F4/80hiCD11bloCD11c+ macrophages that express Bdnf and NT-4/5 and have pro-angiogenic potential in vitro. Furthermore, administration of the small molecule Ntrk2 antagonist ANA-12 to infected mice significantly inhibited white pulp neovascularization but had no effect on red pulp vascular remodeling. We believe this to be the first evidence of the Ntrk2/neurotrophin pathway driving pathogen-induced vascular remodeling in lymphoid tissue. These studies highlight the therapeutic potential of modulating this pathway to inhibit pathological angiogenesis

WTC2005-63536 EFFECT OF CRYSTALLOGRAPHIC TEXTURE ON DEFORMATION FIELDS IN FRETTING CONTACTS

ABSTRACT Fretting contacts in the partial slip regime are simulated by a finite element model of a rigid cylinder on an elastic-crystal viscoplastic half-space. The half-space is modeled as duplex Ti-6Al-4V, a polycrystalline metal alloy consisting of equiaxed primary alpha grains and secondary lamellar alpha+beta grains. Various realistic 3-D crystallographic textures are considered. The deformation fields generated by fretting are quantified in terms of cumulative effective plastic strain distributions and plastic strain maps. The results clearly demonstrate the importance of the various sources of microstructural heterogeneity in the surface layers. The main sources of microstructural heterogeneity include the distribution of phases, slip system strength anisotropy, and crystallographic texture. In basal textured materials with fretting on the edge, the plastic strain is more evenly distributed in the subsurface regions than in other textured cases. This is explained by the greater number of grains able to deform by soft slip modes and the symmetry of this type of texture relative to the fretting orientation. Transverse and basal/transverse textures result in more heterogeneously-distributed plastic strain with strain often concentrated in narrow vein-like structures with maximum accumulation near alpha/alpha+beta grain boundaries. Elastic shakedown is more difficult to achieve in the later case. Ratcheting is the primary mechanism for cyclic plastic strain accumulation

WTC2005-63536 EFFECT OF CRYSTALLOGRAPHIC TEXTURE ON DEFORMATION FIELDS IN FRETTING CONTACTS

ABSTRACT Fretting contacts in the partial slip regime are simulated by a finite element model of a rigid cylinder on an elastic-crystal viscoplastic half-space. The half-space is modeled as duplex Ti-6Al-4V, a polycrystalline metal alloy consisting of equiaxed primary alpha grains and secondary lamellar alpha+beta grains. Various realistic 3-D crystallographic textures are considered. The deformation fields generated by fretting are quantified in terms of cumulative effective plastic strain distributions and plastic strain maps. The results clearly demonstrate the importance of the various sources of microstructural heterogeneity in the surface layers. The main sources of microstructural heterogeneity include the distribution of phases, slip system strength anisotropy, and crystallographic texture. In basal textured materials with fretting on the edge, the plastic strain is more evenly distributed in the subsurface regions than in other textured cases. This is explained by the greater number of grains able to deform by soft slip modes and the symmetry of this type of texture relative to the fretting orientation. Transverse and basal/transverse textures result in more heterogeneously-distributed plastic strain with strain often concentrated in narrow vein-like structures with maximum accumulation near alpha/alpha+beta grain boundaries. Elastic shakedown is more difficult to achieve in the later case. Ratcheting is the primary mechanism for cyclic plastic strain accumulation

High-dose sequential epirubicin and cyclophosphamide with peripheral blood stem cell support for advanced breast cancer: results of a phase II study

The aim of this study was to evaluate the feasibility of a high-dose intensity and high-dose density multicycle epirubicin and cyclophosphamide regimen with peripheral blood stem cells (PBSC) and haematopoietic growth factor (G-CSF) support in advanced breast cancer patients. From August 1994 to September 1999, 56 breast cancer patients (8 stage IIIB and 48 stage IV) received 205 courses of cyclophosphamide 3 g m−2and epirubicin 100 mg m−2every 14 days. G-CSF 5 μg kg−1day−1was administered from day 3 to neutrophil recovery. 4 courses were planned. PBSC were collected after course 1, and reinfused after courses 3 and 4, with ≥ 2 × 106CD34+ PBSC kg−1required for each reinfusion. 48 patients (86%) received all 4 planned courses. Early withdrawal was consecutive to infectious complications (n= 4), severe asthenia (n= 3), haemorrhagic cystitis (n= 1). A median number of 10.8 × 106CD34+ PBSC kg−1(range, 3–80) was harvested with 1 or 2 apheresis in 48 patients (94%). Median relative dose intensity was 91.3% (range, 72–102%). Grade 4 neutrophil toxicity was observed in 100% of patients. Febrile neutropenia was observed in 40% of courses (median duration 2 days). Red blood cells and platelets had to be transfused in 54% and 27% of courses, respectively. There were no toxic deaths. Objective response rate was 69% in stage IV patients (31/45 evaluable pts), with a 16% complete response rate. Their median progression-free and overall survivals were 22.5 and 37 months, respectively. This epirubicine-containing high-dose regimen appeared feasible, albeit with high toxicity. Time-related progression parameters exceed commonly reported ones. Controlled studies of upfront sequential high-dose chemotherapy are still needed to evaluate its real benefit. © 2001 Cancer Research Campaig

Financial toxicity and socioeconomic impact of cancer in Europe

Background: Even with universal health care, patients living with cancer often face substantial treatment-related costs and income loss in Europe. Insights into the socioeconomic impact of cancer within and across countries are needed to create awareness, inform policy, and develop targeted measurement instruments. The SEC study aims to explore the socioeconomic impact and financial toxicity of cancer and identify vulnerable patient groups across Europe. Patients and methods: To investigate experiences of a large number of patients, data were collected in a collaborative effort of hospitals and patient organizations across Europe through convenience sampling. Patients undergoing treatment currently or treated within the past 2 years could participate. A 44-item survey was developed to measure the socioeconomic impact following a cancer diagnosis. The primary outcome was the level of financial toxicity, measured by the Financial Index of Toxicity (FIT) score. To identify vulnerable groups, multiple regression analyses were used to investigate the association between the FIT score, clinical characteristics, and socioeconomic demographics, including cancer type, employment status, and country of residence. Results: A total of 2507 patients across Europe met the inclusion criteria. Fifty-six percent of the patients reported income loss and 86% additional treatment-related expenses. Sixteen percent of patients delayed or avoided medical visits, buying medication, surgery, or other health services. Next to a significant association of the country of residence, our regression models demonstrated that divorced, self-employed patients who were younger (−0.02; P = 0.000) and lower educated (0.75; P = 0.000) with a lower household income (1.21; P = 0.000) and children (0.21; P = 0.000) at the time of diagnosis reported significantly higher FIT scores compared with older patients who were married (−0.56; P = 0.000), retired (−1.55; P = 0.000), or employed (−0.56; P = 0.000). Conclusions: In every European Union country, a substantial number of patients with cancer report serious financial consequences and stress. Further research is critical to inform well-tailored policies and interventions to limit the socioeconomic impact on patients with cancer.</p