Metformin: a modulator of bevacizumab activity in cancer? A case report.

Recurrent type I endometrial cancer ((EC)) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced (EC) treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed (EC) G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong F-18-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findingsalbeit limited to a single casesuggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation

Silicone rubber selection for passive sampling of pesticides in water.

The authors thank G. Raffin and M. Hangouet (ISA, UMR 5280) for TGA analysis and interpretation, and C. Guillemain (Irstea) for analytical support.International audienceSilicone rubber can extract organic compounds with a broad range of polarities (logKow>2-3) from aqueous samples. Such compounds include substances of major concern in the protection of aquatic ecosystems and human health, e.g. pesticides. Silicone rubbers (SRs) with various characteristics have been successfully used in sorptive methods for water sample extraction in the laboratory (SPME, SBSE), and for passive sampling in aquatic environments. However, only few studies have evaluated variability in organic compound sorption due to the origin of SRs, particularly for pesticides. The aim of this study was to select an SR for the extraction of pesticides from water samples by passive sampling. To this end we measured the impact of seven SR formulations on sorption capacity, defined by the partition coefficient (Ksw). Kinetic experiments and sorption isotherms were performed to determine extraction recovery as a selection criterion for SRs, and pesticide partition coefficients. Very large differences in affinity for pesticides were found between two kinds of SRs: "Polymerized SR kits" and "Manufactured SRs". One SR was chosen among the "Manufactured SRs", and the Ksw values of 21 pesticides were determined, filling a gap in the literature (1.50<logKow<5.51). In light of sorption properties, literature data and additional economic and technical factors, we suggest using SR from Goodfellow in future work to reduce the variability of Ksw literature values

SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc−/− MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc−/− MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc−/− than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc−/− MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc−/− MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway

Distribution of the time at which the deviation of a Brownian motion is maximum before its first-passage time

We calculate analytically the probability density $P(t_m)$ of the time $t_m$ at which a continuous-time Brownian motion (with and without drift) attains its maximum before passing through the origin for the first time. We also compute the joint probability density $P(M,t_m)$ of the maximum $M$ and $t_m$. In the driftless case, we find that $P(t_m)$ has power-law tails: $P(t_m)\sim t_m^{-3/2}$ for large $t_m$ and $P(t_m)\sim t_m^{-1/2}$ for small $t_m$. In presence of a drift towards the origin, $P(t_m)$ decays exponentially for large $t_m$. The results from numerical simulations are in excellent agreement with our analytical predictions.Comment: 13 pages, 5 figures. Published in Journal of Statistical Mechanics: Theory and Experiment (J. Stat. Mech. (2007) P10008, doi:10.1088/1742-5468/2007/10/P10008

Dynamics at barriers in bidirectional two-lane exclusion processes

A two-lane exclusion process is studied where particles move in the two lanes in opposite directions and are able to change lanes. The focus is on the steady state behavior in situations where a positive current is constrained to an extended subsystem (either by appropriate boundary conditions or by the embedding environment) where, in the absence of the constraint, the current would be negative. We have found two qualitatively different types of steady states and formulated the conditions of them in terms of the transition rates. In the first type of steady state, a localized cluster of particles forms with an anti-shock located in the subsystem and the current vanishes exponentially with the extension of the subsystem. This behavior is analogous to that of the one-lane partially asymmetric simple exclusion process, and can be realized e.g. when the local drive is induced by making the jump rates in two lanes unequal. In the second type of steady state, which is realized e.g. if the local drive is induced purely by the bias in the lane change rates, and which has thus no counterpart in the one-lane model, a delocalized cluster of particles forms which performs a diffusive motion as a whole and, as a consequence, the current vanishes inversely proportionally to the extension of the subsystem. The model is also studied in the presence of quenched disordered, where, in case of delocalization, phenomenological considerations predict anomalously slow, logarithmic decay of the current with the system size in contrast with the usual power-law.Comment: 24 pages, 13 figure

Exact distribution of the maximal height of p vicious walkers

Using path integral techniques, we compute exactly the distribution of the maximal height H_p of p nonintersecting Brownian walkers over a unit time interval in one dimension, both for excursions (p-watermelons with a wall) and bridges (p-watermelons without a wall), for all integer p\ge 1. For large p, we show that \sim \sqrt{2p} (excursions) whereas \sim \sqrt{p} (bridges). Our exact results prove that previous numerical experiments only measured the pre-asymptotic behaviors and not the correct asymptotic ones. In addition, our method establishes a physical connection between vicious walkers and random matrix theory.Comment: 4 pages, 2 figures; minor modifications, added references; published versio

Sieving and clogging in PEG-PEGDA hydrogel membranes

Hydrogels are promising systems for separation applications due to their structural characteristics (i.e. hydrophilicity and porosity). In our study, we investigate the permeation of suspensions of rigid latex particles of different sizes through free-standing hydrogel membranes prepared by photopolymerization of a mixture of poly (ethylene glycol) diacrylate (PEGDA) and large poly (ethylene glycol) (PEG) chains of 300 000 g.mol-1 in the presence of a photoinitiator. Atomic force microscopy (AFM) and cryoscanning electron microscopy (cryoSEM) were employed to characterize the structure of the hydrogel membranes. We find that the 20 nm particle permeation depends on both the PEGDA/PEG composition and the pressure applied during filtration. In contrast, we do not measure a significant permeation of the 100 nm and 1 $\mu$m particles, despite the presence of large cavities of 1 $\mu$m evidenced by cryoSEM images. We suggest that the PEG chains induce local nanoscale defects in the cross-linking of PEGDA-rich walls separating the micron size cavities, that control the permeation of particles and water. Moreover, we discuss the decline of the permeation flux observed in the presence of latex particles, compared to that of pure water. We suggest that a thin layer of particles forms on the surface of the hydrogels

SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc-/- MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc-/- MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc-/- than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc-/- MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc-/- MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway