Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML

UK National Audit of Early Syphilis Management. Case notes audit: diagnosis and treatment

A national audit of 781 early syphilis cases presenting during 2002–03 in UK genitourinary medicine clinics was conducted in late 2004, organized through the Regional Audit Groups. Data were aggregated by region and National Health Service trust, allowing practice to be compared between regions, between trusts within regions, as well as to national averages and the UK National Guidelines. An enzyme immunoassay was used to diagnose 695 (89%) cases (regional range 18–100%). Use of a non-treponemal test was not recorded for 44 (6%) cases. Dark ground microscopy was used in the diagnosis of only 80 (29%) primary cases. Uptake of HIV testing was 77% (range 69–94%). Nationally, 527 (67%) treatments were parenteral, with almost equal use of benzathine penicillin G for 262 (50%, range 0–97%) cases and procaine penicillin G (PPG) for 260 cases (49%, range 3–100%). There were 14 (5%) treatments with less than the recommended 750 mg dose of PPG. One hundred and five (40%) PPG treatments were with greater than 750 mg and/or for longer than 10 days of which 76 (72%) were for early latent syphilis and/or cases with HIV infection. One hundred and ninety two (86%, range 0–100%) of all oral treatments were with doxycycline. The recommended regimen of 100 mg doxycycline twice daily for 14 days was used for 104 (53%) cases; the other 91 (47%) treatments were with a variety of regimens, mainly treatments with larger doses and/or longer treatment intervals and some combination treatments. Fourteen (2%) cases were not treated; treatment was not reported for seven (0.9%) and not known for 10 (1.3%) cases, who were treated at other centres

UK National Audit of Early Syphilis Management. Clinics audit: screening for and management of early syphilis

Data were provided by 131 clinics, and 56% of cases were managed in clinics in the London regions in 2003. Three clinics (2%) do not routinely screen new patients for syphilis, and 28 clinics (21%) do not routinely screen ‘rebook’ patients who have had a new partner. More than 80% of clinics routinely conduct cardiovascular and neurological examinations, although chest radiography is only performed by 50% of clinics and lumbar puncture by 13%. Only 19 (14%) clinics indicated not routinely using the recommended procaine penicillin G (PPG) regimen or one- or two-dose benzathine penicillin G (BPG) regimens for early syphilis, with 57% providing two doses of BPG 2.4 g, 40% providing PPG 750 mg for 10 days, and 15% providing one dose of BPG 2.4 g. Only seven clinics (5%) indicated that they provided treatment for early syphilis with PPG that is inferior to that recommended in the national guidelines. Only 18 clinics specified using the recommended dose and duration (or in excess of this) of PPG for neurosyphilis for cases with HIV infection. Provision for management of severe penicillin reaction is good, although few patients are desensitized. All clinics report that contact tracing for early syphilis is provided, and is mainly the responsibility of health advisers. Compared with auditing outcomes, audit of management policies overestimated performance in contact tracing and provision of dark ground microscopy

Uniqueness properties of the Kerr metric

We obtain a geometrical condition on vacuum, stationary, asymptotically flat spacetimes which is necessary and sufficient for the spacetime to be locally isometric to Kerr. Namely, we prove a theorem stating that an asymptotically flat, stationary, vacuum spacetime such that the so-called Killing form is an eigenvector of the self-dual Weyl tensor must be locally isometric to Kerr. Asymptotic flatness is a fundamental hypothesis of the theorem, as we demonstrate by writing down the family of metrics obtained when this requirement is dropped. This result indicates why the Kerr metric plays such an important role in general relativity. It may also be of interest in order to extend the uniqueness theorems of black holes to the non-connected and to the non-analytic case.Comment: 30 pages, LaTeX, submitted to Classical and Quantum Gravit

Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations

Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35% of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11E76K/+ mutation was markedly attenuated in Ptpn11E76K/+/Gab2-/- double mutant mice-overproduction of myeloid cells was alleviated, splenomegaly was diminished and myeloid cell infiltration in nonhematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice and, as such, their survival was much prolonged. Furthermore, treatment of Ptpn11E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML

Structure of an archaeal PCNA1-PCNA2-FEN1 complex: elucidating PCNA subunit and client enzyme specificity.

The archaeal/eukaryotic proliferating cell nuclear antigen (PCNA) toroidal clamp interacts with a host of DNA modifying enzymes, providing a stable anchorage and enhancing their respective processivities. Given the broad range of enzymes with which PCNA has been shown to interact, relatively little is known about the mode of assembly of functionally meaningful combinations of enzymes on the PCNA clamp. We have determined the X-ray crystal structure of the Sulfolobus solfataricus PCNA1-PCNA2 heterodimer, bound to a single copy of the flap endonuclease FEN1 at 2.9 A resolution. We demonstrate the specificity of interaction of the PCNA subunits to form the PCNA1-PCNA2-PCNA3 heterotrimer, as well as providing a rationale for the specific interaction of the C-terminal PIP-box motif of FEN1 for the PCNA1 subunit. The structure explains the specificity of the individual archaeal PCNA subunits for selected repair enzyme 'clients', and provides insights into the co-ordinated assembly of sequential enzymatic steps in PCNA-scaffolded DNA repair cascades

Extrema of Mass, First Law of Black Hole Mechanics and Staticity Theorem in Einstein-Maxwell-axion-dilaton Gravity

Using the ADM formulation of the Einstein-Maxwell axion-dilaton gravity we derived the formulas for the variation of mass and other asymptotic conserved quantities in the theory under consideration. Generalizing this kind of reasoning to the initial dota for the manifold with an interior boundary we got the generalized first law of black hole mechanics. We consider an asymptotically flat solution to the Einstein-Maxwell axion-dilaton gravity describing a black hole with a Killing vector field timelike at infinity, the horizon of which comprises a bifurcate Killing horizon with a bifurcate surface. Supposing that the Killing vector field is asymptotically orthogonal to the static hypersurface with boundary S and compact interior, we find that the solution is static in the exterior world, when the timelike vector field is normal to the horizon and has vanishing electric and axion- electric fields on static slices.Comment: 17 pages, Revtex, a few comments (introduction) and references adde

Uniqueness Theorem of Static Degenerate and Non-degenerate Charged Black Holes in Higher Dimensions

We prove the uniqueness theorem for static higher dimensional charged black holes spacetime containing an asymptotically flat spacelike hypersurface with compact interior and with both degenerate and non-degenerate components of the event horizon.Comment: 9 pages, RevTex, to be published in Phys.Rev.D1