A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value

Acute respiratory insufficiency from psittacosis

Contains fulltext : 4439.pdf (publisher's version ) (Open Access

Lesson of the Month : Acute respiratory insufficiency from psittacosis

Item does not contain fulltex

Clinical impact of abciximab on long-term outcome after complex coronary angioplasty

Glycoprotein IIb/IIIa receptor antagonists, such as abciximab, are used to reduce major adverse cardiac events (MACES) in patients undergoing percutaneous transluminal coronary angioplasty. The goal of this study was to evaluate the administration of abciximab in relation to lesion complexity and periprocedural complications. A total of 357 patients with 435 de novo lesions were included in this study. Lesions were divided into simple (type A and type B1) and complex (type B2 and type C) lesions according to the American College of Cardiology/American Heart Association Task Force lesion complexity system. Abciximab was given to unstable complex lesions and simple lesions with a periprocedural unstable complicated course. The overall incidence of MACE during the 9-month follow-up period was 17.0%. Patients treated with abciximab had a higher lesion complexity (P <0.001), dissections (P = 0.014), stents (P <0.001), and vessels involved (P <0.001). in addition, the abciximab group was characterized by a higher angina NYHA class (P = 0.005), lower TIMI flow prior to stenting (P = 0.01), and a longer total inflation time (P = 0.006). Despite these clinical differences, the occurrence of MACE within the abciximab group was slightly less than in the group without abciximab (16.2% and 17.3%, respectively). Lesion complexity was directly related to MACE in the group that did not receive abciximab (simple and stable complex lesions; P = 0.04). On the other hand, in subjects treated with abciximab, lesion complexity was not related to a higher incidence of MACE (P = 0.76). The use of abciximab equalizes the difference in outcome between simple and complex lesions. Therefore, abciximab should be advocated especially in unstable and complex percutaneous coronary interventions

La condición de la mujer en el intelectualismo liberal del siglo XIX: la mujer escrita en las novelas de Don Juan Valera

Tesis Univ. Granada. Departamento de Literatura Española. Leída el 30 de mayo de 200

The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins

The protein products of the recombination activating genes (RAG1 and RAG2) initiate the formation of immunoglobulin (Ig) and T-cell receptors, which are essential for B- and T-cell development, respectively. Mutations in the RAG genes result in severe combined immunodeficiency disease (SCID), generally characterized by the absence of mature B and T lymphocytes, but presence of natural killer (NK) cells. Biochemically, mutations in the RAG genes result either in nonfunctional proteins or in protein

Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response.

Item does not contain fulltextTLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46+/-0.21 compared with 2.17+/-0.16 arbitrary units, P=0.001) and CD11b expression (83.2+/-1.73 compared with 76.0+/-1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.1 juni 201