Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer patients: a phase II study

: Docetaxel has proven effective in advanced breast cancer. Myelosuppression and cumulative fluid retention syndrome are troublesome, potentially avoidable toxicities. In this consecutive cohort study, docetaxel (100 mg/m2 by 1 hour i.v. infusion, q3 weeks) activity and toxicity was explored in 56 anthracycline-pretreated patients (eligible: 55: median age: 51 years [range: 28-68 years]; median performance status: 0 [range: 0-3]) with metastatic breast cancer, using two different granulocyte colony-stimulating factor and steroid pre- and postmedication schedules. Twenty-nine patients (group A) received a 5-day oral prednisone premedication, and 26 (group B) received 4-day low-dose i.m. dexamethasone; group B patients also received prophylactic granulocyte colony-stimulating factor. All patients were evaluable for toxicity and 53 for response. Prophylactic granulocyte colony-stimulating factor significantly lowered the incidence of grade III-IV neutropenia and neutropenic fever (p = 0.0001 and 0.01, respectively). The incidence of moderate-severe fluid retention syndrome was lower in patients receiving i.m. dexamethasone (p = 0.08). Overall response rate was 53% (4 complete responses/24 partial responses, 95% confidence interval 39.4-66.2%); 32% have stable disease and 15% progressive disease. In 21 anthracycline-refractory/resistant patients, as well as in 10 paclitaxel-pretreated patients, the overall response rate was 50%. Docetaxel is highly active in anthracycline- and paclitaxel-pretreated metastatic breast cancer, with manageable toxicity. Optimal use of both granulocyte colony-stimulating factor support and steroid premedication deserves further investigation

A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis

Physical modelling of piles under lateral loading in unsaturated soils

In this paper, selected aspects of an experimental study conducted in a geotechnical centrifuge are discussed. The tests aimed to explore the effects of partial saturation of soil on the response of a single pile subjected to a combination of lateral force and bending moment under drained conditions. The soil used in the experiments is a low plasticity silty soil, named B-grade kaolin, characterized by a relatively high permeability compared to the typical values for clayey soils. Two different elevations of the water table and its effects on the pile response under loading are studied. The data show a marked influence of soil partial saturation on the pile response, both under working loads and ultimate loads. In particular, under working loads, the displacement of the head of the pile is appreciably lower than that measured under saturated conditions

Temperature dependence and mechanisms for vortex pinning by periodic arrays of Ni dots in Nb films

Pinning interactions between superconducting vortices in Nb and magnetic Ni dots were studied as a function of current and temperature to clarify the nature of pinning mechanisms. A strong current dependence is found for a square array of dots, with a temperature dependent optimum current for the observation of periodic pinning, that decreases with temperature as (1-T/Tc)3/2. This same temperature dependence is found for the critical current at the first matching field with a rectangular array of dots. The analysis of these results allows to narrow the possible pinning mechanisms to a combination of two: the interaction between the vortex and the magnetic moment of the dot and the proximity effect. Moreover, for the rectangular dot array, the temperature dependence of the crossover between the low field regime with a rectangular vortex lattice to the high field regime with a square configuration has been studied. It is found that the crossover field increases with decreasing temperature. This dependence indicates a change in the balance between elastic and pinning energies, associated with dynamical effects of the vortex lattice in the high field range.Comment: 12 text pages (revtex), 6 figures (1st jpeg, 2nd-6th postscript) accepted in Physical Review

Equilibration and Dynamic Phase Transitions of a Driven Vortex Lattice

We report on the observation of two types of current driven transitions in metastable vortex lattices. The metastable states, which are missed in usual slow transport measurements, are detected with a fast transport technique in the vortex lattice of undoped 2H-NbSe$_2$. The transitions are seen by following the evolution of these states when driven by a current. At low currents we observe an equilibration transition from a metastable to a stable state, followed by a dynamic crystallization transition at high currents.Comment: 5 pages, 4 figure

Elastic-to-plastic crossover below the peak effect in the vortex solid of YBa2Cu3O7 single crystals

We report on transport and ac susceptibility studies below the peak effect in twinned YBa2Cu3O7 single crystals. We find that disorder generated at the peak effect can be partially inhibited by forcing vortices to move with an ac driving current. The vortex system can be additionally ordered below a well-defined temperature where elastic interactions between vortices overcome pinning-generated stress and a plastic to elastic crossover seems to occur. The combined effect of these two processes results in vortex structures with different mobilities that give place to history effects.Comment: 4 pages, 4 figures. Published in PRB Rapid Comm., February 1, 200

Driven vortices in 3D layered superconductors: Dynamical ordering along the c-axis

We study a 3D model of driven vortices in weakly coupled layered superconductors with strong pinning. Above the critical force $F_c$, we find a plastic flow regime in which pancakes in different layers are uncoupled, corresponding to a pancake gas. At a higher $F$, there is an ``smectic flow'' regime with short-range interlayer order, corresponding to an entangled line liquid. Later, the transverse displacements freeze and vortices become correlated along the c-axis, resulting in a transverse solid. Finally, at a force $F_s$ the longitudinal displacements freeze and we find a coherent solid of rigid lines.Comment: 4 pages, 3 postscript figure

Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity

All pancreatic endocrine cell types arise from a common endocrine precursor cell population, yet the molecular mechanisms that establish and maintain the unique gene expression programs of each endocrine cell lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells to adopt specific endocrine fates. Here, we show that the transcription factor Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells. Heritable expression of Nkx6.1 in endocrine precursors of mice is sufficient to respecify non-beta endocrine precursors towards the beta cell lineage, while endocrine precursor- or beta cell-specific inactivation of Nkx6.1 converts beta cells to alternative endocrine lineages. Remaining insulin(+) cells in conditional Nkx6.1 mutants fail to express the beta cell transcription factors Pdx1 and MafA and ectopically express genes found in non-beta endocrine cells. By showing that Nkx6.1 binds to and represses the alpha cell determinant Arx, we identify Arx as a direct target of Nkx6.1. Moreover, we demonstrate that Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, thus establishing competition between Isl1 and Nkx6.1 as a critical mechanism for determining alpha versus beta cell identity. Our findings establish Nkx6.1 as a beta cell programming factor and demonstrate that repression of alternative lineage programs is a fundamental principle by which beta cells are specified and maintained. Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)-derived insulin(+) cells, our study has significant implications for developing cell replacement therapies

Moving glass theory of driven lattices with disorder

We study periodic structures, such as vortex lattices, moving in a random potential. As predicted in [T. Giamarchi, P. Le Doussal Phys. Rev. Lett. 76 3408 (1996)] the periodicity in the direction transverse to motion leads to a new class of driven systems: the Moving Glasses. We analyse using several RG techniques the properties at T=0 and $T>0$: (i) decay of translational long range order (ii) particles flow along static channels (iii) the channel pattern is highly correlated (iv) barriers to transverse motion. We demonstrate the existence of the ``transverse critical force'' at T=0. A ``static random force'' is shown to be generated by motion. Displacements grow logarithmically in $d=3$ and algebraically in $d=2$. The persistence of quasi long range translational order in $d=3$ at weak disorder, or large velocity leads to predict a topologically ordered ``Moving Bragg Glass''. This state continues the static Bragg glass and is stable at $T>0$, with non linear transverse response and linear asymptotic behavior. In $d=2$, or in $d=3$ at intermediate disorder, another moving glass exist (the Moving Transverse Glass) with smectic quasi order in the transverse direction. A phase diagram in $T$ force and disorder for static and moving structures is proposed. For correlated disorder we predict a ``moving Bose glass'' state with anisotropic transverse Meissner effect and transverse pinning. We discuss experimental consequences such as anomalous Hall effect in Wigner crystal and transverse critical current in vortex lattice.Comment: 74 pages, 27 figures, RevTe