Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells:Role of autophagy and JNK activation

Cancer cell resistance against chemotherapy is still a heavy burden to improve anticancer treatments. Autophagy activation and the development of hypoxic regions within the tumors are known to promote cancer cell resistance. Therefore, we sought to evaluate the role of autophagy and hypoxia on the taxol-induced apoptosis in MDA-MB-231 breast cancer cells. The results showed that taxol induced apoptosis after 16 h of incubation, and that hypoxia protected MDA-MB-231 cells from taxol-induced apoptosis. In parallel, taxol induced autophagy activation already after 2 h of incubation both under normoxia and hypoxia. Autophagy activation after taxol exposure was shown to be a protective mechanism against taxol-induced cell death both under normoxia and hypoxia. However, at longer incubation time, the autophagic process reached a saturation point under normoxia leading to cell death, whereas under hypoxia, autophagy flow still correctly took place allowing the cells to survive. Autophagy induction is induced after taxol exposure via mechanistic target of rapamycin (mTOR) inhibition, which is more important in cells exposed to hypoxia. Taxol also induced c-Jun N-terminal kinase (JNK) activation and phosphorylation of its substrates B-cell CLL/lymphoma 2 (Bcl(2)) and BCL2-like 1 (Bcl(XL)) under normoxia and hypoxia very early after taxol exposure. Bcl(2) and Bcl(XL) phosphorylation was decreased more importantly under hypoxia after long incubation time. The role of JNK in autophagy and apoptosis induction was studied using siRNAs. The results showed that JNK activation promotes resistance against taxol-induced apoptosis under normoxia and hypoxia without being involved in induction of autophagy. In conclusion, the resistance against taxol-induced cell death observed under hypoxia can be explained by a more effective autophagic flow activated via the classical mTOR pathway and by a mechanism involving JNK, which could be dependent on Bcl(2) and Bcl(XL) phosphorylation but independent of JNK-induced autophagy activation

Real-time dynamics of the formation of hydrated electrons upon irradiation of water clusters with extreme ultraviolet light

Free electrons in a polar liquid can form a bound state via interaction with the molecular environment. This so-called hydrated electron state in water is of fundamental importance e.g.~in cellular biology or radiation chemistry. Hydrated electrons are highly reactive radicals that can either directly interact with DNA or enzymes, or form highly excited hydrogen (H∗) after being captured by protons. Here, we investigate the formation of the hydrated electron in real-time employing XUV femtosecond pulses from a free electron laser, in this way observing the initial steps of the hydration process. Using time-resolved photoelectron spectroscopy we find formation timescales in the low picosecond range and resolve the prominent dynamics of forming excited hydrogen states

Impact of a Community Pharmacist-Delivered Information Program on the Follow-up of Type-2 Diabetic Patients: A Cluster Randomized Controlled Study.

Low-quality communication between patients and care providers and limited patient knowledge of the disease and the therapy are important factors associated with poor glycemic control in patients with type 2 diabetes. We conducted a multicenter study to determine whether structured and tailored information delivered by pharmacists to type 2 diabetic patients could improve patient treatment adherence, hemoglobin A1c (HbA1c) levels and knowledge about diabetes. One hundred seventy-four pharmacies were randomized to deliver an educational program on diet, drug treatment, disease and complications during three 30-min interviews over a 6-month period, or to provide no intervention, to type 2 diabetic patients treated with oral antidiabetic agents. Medication adherence was assessed by measuring the medication possession ratio and diabetes control by collecting HbA1c values. Levels of patient treatment self-management and disease knowledge were assessed using self-questionnaires. Three hundred seventy-seven patients were analyzed. The medication possession ratio, already very high at baseline in the intervention (94.8%) and control (92.3%) groups, did not vary significantly after 6 months with no difference between the two groups. Significant decreases in HbA1c were observed in both groups at 6 months (p < 0.001) and 12 months (p < 0.01), with significantly greater changes from baseline in the intervention group than in the control group at 6 months (- 0.5% vs. - 0.2%, p = 0.0047) and 12 months (- 0.6% vs. - 0.2%, p = 0.0057). Patients in the intervention group showed greater improvement in their ability to self-manage treatment (+ 4.86 vs. + 1.58, p = 0.0014) and in the extent of their knowledge about diabetes (+ 0.6 vs. + 0.2, p < 0.01) at 6 months versus baseline compared with the control group. Tailored information provided by the pharmacist to patients with type 2 diabetes did not significantly improve the already high adherence rates, but was associated with a significant decrease in HbA1c and an improvement of patient knowledge about diabetes. ISRCTN33776525. MSD France

Stability of quantized time-delay nonlinear systems: A Lyapunov-Krasowskii-functional approach

Lyapunov-Krasowskii functionals are used to design quantized control laws for nonlinear continuous-time systems in the presence of constant delays in the input. The quantized control law is implemented via hysteresis to prevent chattering. Under appropriate conditions, our analysis applies to stabilizable nonlinear systems for any value of the quantization density. The resulting quantized feedback is parametrized with respect to the quantization density. Moreover, the maximal allowable delay tolerated by the system is characterized as a function of the quantization density.Comment: 31 pages, 3 figures, to appear in Mathematics of Control, Signals, and System

The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures

Motivation: Biomarker discovery from high-dimensional data is a crucial problem with enormous applications in biology and medicine. It is also extremely challenging from a statistical viewpoint, but surprisingly few studies have investigated the relative strengths and weaknesses of the plethora of existing feature selection methods. Methods: We compare 32 feature selection methods on 4 public gene expression datasets for breast cancer prognosis, in terms of predictive performance, stability and functional interpretability of the signatures they produce. Results: We observe that the feature selection method has a significant influence on the accuracy, stability and interpretability of signatures. Simple filter methods generally outperform more complex embedded or wrapper methods, and ensemble feature selection has generally no positive effect. Overall a simple Student's t-test seems to provide the best results. Availability: Code and data are publicly available at http://cbio.ensmp.fr/~ahaury/

Controlled iris radiance in a diurnal fish looking at prey

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