A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.

Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8

Influence of flow confinement on the drag force on a static cylinder

The influence of confinement on the drag force $F$ on a static cylinder in a viscous flow inside a rectangular slit of aperture $h_0$ has been investigated from experimental measurements and numerical simulations. At low enough Reynolds numbers, $F$ varies linearly with the mean velocity and the viscosity, allowing for the precise determination of drag coefficients $\lambda_{||}$ and $\lambda_{\bot}$ corresponding respectively to a mean flow parallel and perpendicular to the cylinder length $L$. In the parallel configuration, the variation of $\lambda_{||}$ with the normalized diameter $\beta = d/h_0$ of the cylinder is close to that for a 2D flow invariant in the direction of the cylinder axis and does not diverge when $\beta = 1$. The variation of $\lambda_{||}$ with the distance from the midplane of the model reflects the parabolic Poiseuille profile between the plates for $\beta \ll 1$ while it remains almost constant for $\beta \sim 1$. In the perpendicular configuration, the value of $\lambda_{\bot}$ is close to that corresponding to a 2D system only if $\beta \ll 1$ and/or if the clearance between the ends of the cylinder and the side walls is very small: in that latter case, $\lambda_{\bot}$ diverges as $\beta \to 1$ due to the blockage of the flow. In other cases, the side flow between the ends of the cylinder and the side walls plays an important part to reduce $\lambda_{\bot}$: a full 3D description of the flow is needed to account for these effects

Modeling Wnt/β-catenin target gene expression in APC and Wnt gradients under wild type and mutant conditions

The Wnt/β-catenin pathway is involved in the regulation of a multitude of physiological processes by controlling the differential expression of target genes. In certain tissues such as the adult liver, the Wnt/β-catenin pathway can attain different levels of activity due to gradients of Wnt ligands and/or intracellular pathway components like APC. How graded pathway activity is converted into regionally distinct patterns of Wnt/β-catenin target gene expression is largely unknown. Here, we apply a mathematical modeling approach to investigate the impact of different regulatory mechanisms on target gene expression within Wnt or APC concentration gradients. We develop a minimal model of Wnt/beta-catenin signal transduction and combine it with various mechanisms of target gene regulation. In particular, the effects of activation, inhibition, and an incoherent feedforward loop (iFFL) are compared. To specify activation kinetics, we analyze experimental data that quantify the response of β-catenin/TCF reporter constructs to different Wnt concentrations, and demonstrate that the induction of these constructs occurs in a cooperative manner with Hill coefficients between 2 and 5. In summary, our study shows that the combination of specific gene regulatory mechanisms with a time-independent gradient of Wnt or APC is sufficient to generate distinct target gene expression patterns as have been experimentally observed in liver. We find that cooperative gene activation in combination with a TCF feedback can establish sharp borders of target gene expression in Wnt or APC gradients. In contrast, the iFFL renders gene expression independent of gradients of the upstream signaling components. Our subsequent analysis of carcinogenic pathway mutations reveals that their impact on gene expression is determined by the gene regulatory mechanism and the APC concentration of the cell in which the mutation occurs

Weak Value in Wave Function of Detector

A simple formula to read out the weak value from the wave function of the measuring device after the postselection with the initial Gaussian profile is proposed. We apply this formula for the weak value to the classical experiment of the realization of the weak measurement by the optical polarization and obtain the weak value for any pre- and post-selections. This formula automatically includes the interference effect which is necessary to yields the weak value as an outcome of the weak measurement.Comment: 3 pages, no figures, Published in Journal of the Physical Society of Japa

Boson mappings and four-particle correlations in algebraic neutron-proton pairing models

Neutron-proton pairing correlations are studied within the context of two solvable models, one based on the algebra SO(5) and the other on the algebra SO(8). Boson-mapping techniques are applied to these models and shown to provide a convenient methodological tool both for solving such problems and for gaining useful insight into general features of pairing. We first focus on the SO(5) model, which involves generalized T=1 pairing. Neither boson mean-field methods nor fermion-pair approximations are able to describe in detail neutron-proton pairing in this model. The analysis suggests, however, that the boson Hamiltonian obtained from a mapping of the fermion Hamiltonian contains a pairing force between bosons, pointing to the importance of boson-boson (or equivalently four-fermion) correlations with isospin T=0 and spin S=0. These correlations are investigated by carrying out a second boson mapping. Closed forms for the fermion wave functions are given in terms of the fermion-pair operators. Similar techniques are applied -- albeit in less detail -- to the SO(8) model, involving a competition between T=1 and T=0 pairing. Conclusions similar to those of the SO(5) analysis are reached regarding the importance of four-particle correlations in systems involving neutron-proton pairing.Comment: 31 pages, Latex, 3 Postscript figures, uses epsf.sty, submitted to Physical Review