Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients.

BackgroundKetoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had PSA response rate (>50% decline) of 21-62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.MethodsMen with CRPC and performance status 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of <5%); 25 patients were required. Secondary endpoints included PSA response >30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs).ResultsThirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng ml(-1) (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment.ConclusionsIn docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy

Flow micro-calorimetry and diffuse reflectance Fourier transform infrared spectroscopy studies in filled polyurethane adhesives by using dimethyl adipate as a model compound

Interactions between nano-scale filler particles (precipitated calcium carbonate, carbon black and fumed silica) and model compounds (dimethyl adipate and butan-2-one) are quantified using flow micro-calorimetry (FMC) and diffuse reflectance Fourier transform infrared spectroscopy (DRFTIRS). Carbonyl groups of dimethyl adipate interact strongly with silanol groups on the fumed silica surface but weakly with the uncoated precipitated calcium carbonate. In general, higher surface area loading imparts high level of adsorption because of the nanofiller has more adsorption sites. Carbon black is an exception likely due to the less accessible surface groups and the presence of relatively important amount of micropores. © 2013 Elsevier Ltd

The Class of All Natural Implicative Expansions of Kleene’s Strong Logic Functionally Equivalent to Łukasiewicz’s 3-Valued Logic Ł3

25 p.We consider the logics determined by the set of all natural implicative expansions of Kleene’s strong 3-valued matrix (with both only one and two designated values) and select the class of all logics functionally equivalent to Łukasiewicz’s 3-valued logic Ł3. The concept of a “natural implicative matrix” is based upon the notion of a “natural conditional” defined in Tomova (Rep Math Log 47:173–182, 2012).S

S-duality in Twistor Space

In type IIB string compactifications on a Calabi-Yau threefold, the hypermultiplet moduli space $M_H$ must carry an isometric action of the modular group SL(2,Z), inherited from the S-duality symmetry of type IIB string theory in ten dimensions. We investigate how this modular symmetry is realized at the level of the twistor space of $M_H$, and construct a general class of SL(2,Z)-invariant quaternion-Kahler metrics with two commuting isometries, parametrized by a suitably covariant family of holomorphic transition functions. This family should include $M_H$ corrected by D3-D1-D(-1)-instantons (with fivebrane corrections ignored) and, after taking a suitable rigid limit, the Coulomb branch of five-dimensional N=2 gauge theories compactified on a torus, including monopole string instantons. These results allow us to considerably simplify the derivation of the mirror map between type IIA and IIB fields in the sector where only D1-D(-1)-instantons are retained.Comment: 29 pages, 1 figur

D3-instantons, Mock Theta Series and Twistors

The D-instanton corrected hypermultiplet moduli space of type II string theory compactified on a Calabi-Yau threefold is known in the type IIA picture to be determined in terms of the generalized Donaldson-Thomas invariants, through a twistorial construction. At the same time, in the mirror type IIB picture, and in the limit where only D3-D1-D(-1)-instanton corrections are retained, it should carry an isometric action of the S-duality group SL(2,Z). We prove that this is the case in the one-instanton approximation, by constructing a holomorphic action of SL(2,Z) on the linearized twistor space. Using the modular invariance of the D4-D2-D0 black hole partition function, we show that the standard Darboux coordinates in twistor space have modular anomalies controlled by period integrals of a Siegel-Narain theta series, which can be canceled by a contact transformation generated by a holomorphic mock theta series.Comment: 42 pages; discussion of isometries is amended; misprints correcte

Nonperturbative studies of supersymmetric matrix quantum mechanics with 4 and 8 supercharges at finite temperature

We investigate thermodynamic properties of one-dimensional U(N) supersymmetric gauge theories with 4 and 8 supercharges in the planar large-N limit by Monte Carlo calculations. Unlike the 16 supercharge case, the threshold bound state with zero energy is widely believed not to exist in these models. This led A.V. Smilga to conjecture that the internal energy decreases exponentially at low temperature instead of decreasing with a power law. In the 16 supercharge case, the latter behavior was predicted from the dual black 0-brane geometry and confirmed recently by Monte Carlo calculations. Our results for the models with 4 and 8 supercharges indeed support the exponential behavior, revealing a qualitative difference from the 16 supercharge case.Comment: 16 pages, 7 figures, LaTeX2e, minor corrections in section 3, final version accepted in JHE

Dislocation Driven Chromium Precipitation in Fe-9Cr Binary Alloy: A Positron Lifetime Study

The influence of initial heat treatment on anomalous Cr precipitation within high temperature solubility region in Fe-9Cr alloy has been investigated using positron lifetime studies. Air-quenched samples with pre-existing dislocations exhibited a distinct annealing stage in positron lifetime between 800 and 1100 K corresponding to Cr-precipitation. During this stage, Transmission Electron Microscopy showed fine precipitates of average size 4 nm, dispersed throughout the sample and from EDS analysis they are found to be Cr-enriched. The existence of dislocations is found to be responsible for Cr precipitation.Comment: Revised version Submitted to Phys. Rev.

Fast, Multiphase Volume Adaptation to Hyperosmotic Shock by Escherichia coli

All living cells employ an array of different mechanisms to help them survive changes in extra cellular osmotic pressure. The difference in the concentration of chemicals in a bacterium's cytoplasm and the external environment generates an osmotic pressure that inflates the cell. It is thought that the bacterium Escherichia coli use a number of interconnected systems to adapt to changes in external pressure, allowing them to maintain turgor and live in surroundings that range more than two-hundred-fold in external osmolality. Here, we use fluorescence imaging to make the first measurements of cell volume changes over time during hyperosmotic shock and subsequent adaptation on a single cell level in vivo with a time resolution on the order of seconds. We directly observe two previously unseen phases of the cytoplasmic water efflux upon hyperosmotic shock. Furthermore, we monitor cell volume changes during the post-shock recovery and observe a two-phase response that depends on the shock magnitude. The initial phase of recovery is fast, on the order of 15–20 min and shows little cell-to-cell variation. For large sucrose shocks, a secondary phase that lasts several hours adds to the recovery. We find that cells are able to recover fully from shocks as high as 1 Osmol/kg using existing systems, but that for larger shocks, protein synthesis is required for full recovery