Identifying Drug Effects via Pathway Alterations using an Integer Linear Programming Optimization Formulation on Phosphoproteomic Data

Understanding the mechanisms of cell function and drug action is a major endeavor in the pharmaceutical industry. Drug effects are governed by the intrinsic properties of the drug (i.e., selectivity and potency) and the specific signaling transduction network of the host (i.e., normal vs. diseased cells). Here, we describe an unbiased, phosphoproteomicbased approach to identify drug effects by monitoring drug-induced topology alterations. With the proposed method, drug effects are investigated under several conditions on a cell-type specific signaling network. First, starting with a generic pathway made of logical gates, we build a cell-type specific map by constraining it to fit 13 key phopshoprotein signals under 55 experimental cases. Fitting is performed via a formulation as an Integer Linear Program (ILP) and solution by standard ILP solvers; a procedure that drastically outperforms previous fitting schemes. Then, knowing the cell topology, we monitor the same key phopshoprotein signals under the presence of drug and cytokines and we re-optimize the specific map to reveal the drug-induced topology alterations. To prove our case, we make a pathway map for the hepatocytic cell line HepG2 and we evaluate the effects of 4 drugs: 3 selective inhibitors for the Epidermal Growth Factor Receptor (EGFR) and a non selective drug. We confirm effects easily predictable from the drugs’ main target (i.e. EGFR inhibitors blocks the EGFR pathway) but we also uncover unanticipated effects due to either drug promiscuity or the cell’s specific topology. An interesting finding is that the selective EGFR inhibitor Gefitinib is able to inhibit signaling downstream the Interleukin-1alpha (IL-1α) pathway; an effect that cannot be extracted from binding affinity based approaches. Our method represents an unbiased approach to identify drug effects on a small to medium size pathways and is scalable to larger topologies with any type of signaling perturbations (small molecules, 3 RNAi etc). The method is a step towards a better picture of drug effects in pathways, the cornerstone in identifying the mechanisms of drug efficacy and toxicity

Specificity And Sensitivity for Malaria Detection by Rapid (Parahit) Detection Test and Microscopic Method

Malaria continues to be a major killer of mankind, especially in developing countries.1 It is a disease of antiquity, has proved to be a formidable deterrent to the cultural and socio-economic progress of man in tropical, subtropical and monsoon prone zones of world.2 One of the most pronounced problems in controlling the morbidity and mortality caused by malaria is limited access to effective diagnosis and treatment in areas where malaria is endemic.3 100 cases were analyzed in respect of clinical presentation by routine microscopic methods and the immune assay techniques namely pLDH antigen detection for rapid P. falciparum and P. vivax detection. More than two third (67%) positivity rate for P. falciparum blood smear. The pLDH antigen detection was positive in 58% of P. falciparum cases while 22% of P. vivax cases. Also, pLDH antigen detection immunoassay gives 100% specificity and 85.42% sensitivity

Transesophageal echocardiography for diagnosis of inadvertant closure of Inferior Vena Cava opening during minimally invasive atrial septal defect closure

Transesophageal echocardiography (TEE) is widely used in cardiac surgery. TEE provides important diagnostic and functional information before and after cardiopulmonary bypass thereby having a very important impact on perioperative clinical outcomes. We describe a case in which intraoperative TEE was instrumental in the timely diagnosis of inadvertant closure of the inferior vena cava (IVC) opening during minimally invasive surgical closure of atrial septal defect

Socio Demographic and Clinical Features of The Malaria Cases

Objective: To study the sociodemographic profile of malaria cases admitted on the basis of clinical features. Methods: With purposive sampling 100 cases were taken in these studies who were admitted with clinical findings of fever at Sayajirav Gyakwad Hospital, Vadodara. The indoor patients from April 2006 to October 2006 were retrieved using a prepared case sheet performa on the basis of patient’s demographic profile and clinical findings. Results: Out of 100 cases 66 patients were male and 44 female. Highest age group among male (46.96) as well as female (47.05) patients were more than 30 year age. The infection rate was higher among the younger age group. Hepatomegaly (46%), spleenomegaly (56%) and jaundice (49%) were associated with malaria. Interpretation and Conclusion: Malaria is responsible for major health concern in this region, particularly in rainy season and is found to affect comparatively the younger adult population