Targeting the Redox Landscape in Cancer Therapy

Reactive oxygen species (ROS) are produced predominantly by the mitochondrial electron transport chain and by NADPH oxidases in peroxisomes and in the endoplasmic reticulum. The antioxidative defense counters overproduction of ROS with detoxifying enzymes and molecular scavengers, for instance, superoxide dismutase and glutathione, in order to restore redox homeostasis. Mutations in the redox landscape can induce carcinogenesis, whereas increased ROS production can perpetuate cancer development. Moreover, cancer cells can increase production of antioxidants, leading to resistance against chemo- or radiotherapy. Research has been developing pharmaceuticals to target the redox landscape in cancer. For instance, inhibition of key players in the redox landscape aims to modulate ROS production in order to prevent tumor development or to sensitize cancer cells in radiotherapy. Besides the redox landscape of a single cell, alternative strategies take aim at the multi-cellular level. Extracellular vesicles, such as exosomes, are crucial for the development of the hypoxic tumor microenvironment, and hence are explored as target and as drug delivery systems in cancer therapy. This review summarizes the current pharmaceutical and experimental interventions of the cancer redox landscape

Evaluating the Predictivity of Virtual Screening for Abl Kinase Inhibitors to Hinder Drug Resistance

Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. ‘Dual active’ inhibitors against both targets were grouped together with inactive ligands chosen from different decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus inactive ligands, even without assuming knowledge of the binding mode. We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies

Deep Venous Thrombosis and Pulmonary Thromboembolism in a Physically Nonprepared Trekker in the Himalayas: An Autopsy Report

Deep Venous Thrombosis (DVT) and Subsequent Pulmonary Thromboembolism (PTE) in high altitude climbers is a well-known concept. The acclimatization process at high altitude is itself a thrombogenic event. Accordingly, when a physically nonprepared individual with preexisting thrombogenic risk factors attempts trekking at high altitude, they may end up with fatal thromboembolic events. Here, we report a case of a low-lander with multiple thrombogenic risk factors who developed DVT and PTE when he went for a trekking trip in the Himalayas. The risk factors, autopsy findings, and possible mechanism of developing fatal pulmonary embolism, in this case, are discussed here

Structural determinants of ligand binding to ATP dependent enzymes: Studies of Protein Kinase and Heat Shock Protein 70.

Enzymes are protein molecules that accelerate, or “catalyze”, specific chemical reactions. The reacting molecules, or substrates, bind to the enzyme which then enables their effective conversion into different product molecules. Virtually all metabolic processes in the cell need enzymes to occur at speeds fast enough to maintain life. The kinases are a large group of phosphotransferases, i.e. enzymes which catalyze the transfer of the gamma-phosphate group from an adenosine-5-triphosphate (ATP, as phosphate donor) to a hydroxyl group (acceptor) of specific substrates. Protein kinases transfer the phosphate groups to other proteins as substrates. These processes enable the cell to transfer signals between different components of the cell that control essential processes. Tyrosine protein kinases transfer them to the phenolic hydroxyl group of amino acid residues in proteins called tyrosine, while serine/threonine protein kinases transfer the phosphate groups to the alcohol group of the serine or threonine amino acid residues. Protein kinases also represent a key interest in the pharmaceutical industry, because they are considered therapeutic targets for diseases, including e.g. diabetes, neurodegenerative diseases, Alzheimer's disease, herpes simplex virus infection, malaria, but especially for cancer. Since the year 2001, some 30 cancer drugs that block the activity of cancer causing protein kinases have been approved. This project describes basic chemical research of protein-ligand interactions, using key cancer drug targets as model enzymes. The research is designed to advance basic knowledge of the chemical recognition mechanisms of enzymes, and enable the design of new and improved therapeutic inhibitors. The first part of this work, represented by two published papers and a submitted manuscript, analyzes inhibitor interactions in key tyrosine protein kinases involved in cancers, including Abl (a leukemia target) and EGFR (a lung cancer target). These analyses optimize approaches to identify new inhibitors with potentially improved protein kinase inhibition profiles to forestall the development of drug resistance. The second part analyses the ATP and potential inhibitor binding site of a different class of enzyme involved in cancer, a “heat shock protein”. Finally, a draft manuscript analyses the geometric variability of a key amino acid residue of protein kinases that is often involved in drug resistance generation. The key technologies used in this project are chemical synthesis; enzyme purification, crystallography, SPR spectroscopy, and molecular modeling

Twists and Oliver Twists in mental rotation: complementary actions as orphan processes

A growing body of work shows that compatible actions executed in parallel with cognitive tasks contribute beneficially to cognition, compared to incompatible actions. We investigate how such complementary actions are generated. Two models from imitation research, Associated Sequence Learning (ASL) and Active Intermodal Matching (AIM), were extended to develop models of complementary action generation. ASL postulates a general generation process based on learning, whereas AIM postulates a specialist process. Using a mental rotation task where participants tended to spontaneously generate parallel actions, we conducted two experiments to test the predictions of the extended models. Surprisingly, the results show that when compared to no-actions, complementary actions do not improve accuracy. The two experiments do not provide clear validation for either model of generation, but there is more support for the generalist model than the specialist one. We propose a revision to the generalist model based on this trend

Distance between Extremum Graphs

Scientific phenomena are often studied through collections of related scalar fields generated from different observations of the same phenomenon. Exploration of such data requires a robust distance measure to compare scalar fields for tasks such as identifying key events and establishing correspondence between features in the data. Towards this goal, we propose a topological data structure called the complete extremum graph and define a distance measure on it for comparing scalar fields in a feature-aware manner. We design an algorithm for computing the distance and show its applications in analysing time varying data

A rare case report of Solid Pseudopapillary Tumor of the pancreas with portal hypertension

Introduction: Solid Pseudopapillary Tumor of the pancreas (SPT) is a rare pancreatic tumor and represents 1–3% of all pancreatic tumors. It usually presents in young females with abdominal pain, nausea, vomiting and abdominal fullness. The first case report was documented in 1959 and since then multiple case reports have been documented on the various surgical approaches for SPT. However, there are not many reported cases where surgery has been performed on SPT with portal hypertension. Presentation of case: In our case report, a 19 year old girl presented with a mass in the left side of the abdomen with associated dragging pain. Ultrasound Abdomen and CT (computed tomography) confirmed an SPT with portal hypertension, with the lesion involving the body and tail of pancreas. Discussion: Although few reports are available on SPT with portal hypertension, ours is the first report on a benign SPT with sinistral portal hypertension treated with a distal pancreatectomy. The presence of portal hypertension made the excision of the tumor and delineation of the vessels very difficult. However, when great care is taken while handling the dilated vessels, dissection can be completed with minimal blood loss. Conclusion: Meticulous surgical technique along with accurate identification of vasculature will aid in the resection. Although some SPTs behave aggressively, most of them are benign and patients with SPT have an excellent prognosis

Evaluating the Predictivity of Virtual Screening for A

Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. ‘Dual active’ inhibitors against both targets were grouped together with inactive ligands chosen from different decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus inactive ligands, even without assuming knowledge of the binding mode. We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies