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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.

Background: Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro., Methods: The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot., Results: A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM)., Conclusions: The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.

We report a case of an adult patient using chronic low-dose verapamil who developed severe verapamil intoxication. A 57-year-old male patient was presented at the emergency room after a collapse of unknown etiology. The airway was compromised, and thus, an endotracheal tube was inserted. The patient deteriorated hemodynamically. Because of verapamil use and bradycardia, verapamil intoxication was suspected. The treatment was supported with intravenous fluids, calcium, inotropes, and a transvenous pacemaker. The patient progressively developed circulatory shock. Verapamil intoxication was confirmed, and therapy was adjusted accordingly. Insulin and calcium infusion were intensified, and glucagon and Intralipid® infusion were initiated. With this therapy, the patient's condition improved rapidly. We found different factors in this patient that could have precipitated this event such as diminished metabolism by cytochrome P450 iso-enzymes, a slightly diminished renal function with hypoalbuminemia, and interaction with other protein-binding drugs.

The goals of environmental legislation and associated regulations are to protect public health, natural resources, and ecosystems. In this context, monitoring programs should provide timely and relevant information so that the regulatory community can implement legislation in a cost-effective and efficient manner. The Safe Drinking Water Act (SDWA) of 1974 attempts to ensure that public water systems (PWSs) supply safe water to its consumers. As is the case with many other federal environmental statutes, SDWA monitoring has been implemented in relatively uniform fashion across the USA. In this three part series, we present over 30 years of evidence to demonstrate unique patterns in water quality contaminants over space and time, develop alternative place-based monitoring approaches that exploit such patterns, and evaluate the economic performance of such approaches to current monitoring practice. Part III: Place-based (PBA) and current SDWA monitoring approaches were implemented on test datasets (1995-2001) from 19 water systems and evaluated based on the following criteria: percent of total detections, percent detections above threshold values (e.g. 20, 50, 90% of MCL), and cost. The PBA outperformed the current SDWA monitoring requirements in terms of total detections, missed only a small proportion of detections below the MCL, and captured all detections above 50% of the MCL. Essentially the same information obtained from current compliance monitoring requirements can be gained at approximately one-eighth the cost by implementing the PBA. Temporal sampling strategies were implemented on test datasets (1995-2001) from four water systems and evaluated by the following criteria: parameter estimation, percent deviation from "true" 90th, 95th, and 99th percentiles, and number of samples versus accuracy of the estimate. Non event-based (NEB) strategies were superior in estimating percentiles 1-50, but underestimated the higher percentiles. Event-based strategies were superior in estimating 95th and 99th percentiles, and required significantly fewer samples (than NEB strategies) to estimate the "true" 95th and 99th percentiles. Incorporation of place-based information significantly improves the performance of monitoring and temporal sampling strategies in the context of surface-influenced water systems in the state of Iowa. Application of similar methods to other areas and types of water systems would likely produce similar results. Compared to current SDWA monitoring, the place based approach allows for cost-effective, enhanced characterization of local contaminants of concern.

The goals of environmental legislation and associated regulations are to protect public health, natural resources, and ecosystems. In this context, monitoring programs should provide timely and relevant information so that the regulatory community can implement legislation in a cost-effective and efficient manner. The Safe Drinking Water Act (SDWA) of 1974 attempts to ensure that public water systems (PWSs) supply safe water to its consumers. As is the case with many other federal environmental statutes, SDWA monitoring has been implemented in relatively uniform fashion across the USA. In this three part series, spatial and temporal patterns in water quality data are utilized to develop, compare, and evaluate the economic performance of alternative place-based monitoring approaches to current monitoring practice. Under the Safe Drinking Water Act (SDWA), a common list of over 90 contaminants is analyzed nationwide using EPA-authorized laboratory procedures. National and state-level summaries of SDWA data have shown that not all contaminants occur in all places at all times. This hypothesis is confirmed and extended by showing that only a few (less than seven) contaminants are of concern in any one of 19 Iowa surface water systems studied. These systems collectively serve about 350,000 people and their sizes vary between 1,200 and 120,000. The distributions of contaminants found in these systems are positively skewed, with many non-detect measurements. A screening strategy to identify such contaminants in individual systems is presented. These findings have significant implications not only for the design of alternative monitoring programs, but also in multi-billion-dollar decisions that influence the course of future drinking water infrastructure, repair, and maintenance investments.

The goals of environmental legislation and associated regulations are to protect public health, natural resources, and ecosystems. In this context, monitoring programs should provide timely and relevant information so that the regulatory community can implement legislation in a cost-effective and efficient manner. The Safe Drinking Water Act (SDWA) of 1974 attempts to ensure that public water systems (PWSs) supply safe water to its consumers. As is the case with many other federal environmental statutes, SDWA monitoring has been implemented in relatively uniform fashion across the United States. In this three part series, spatial and temporal patterns in water quality data are utilized to develop, compare, and evaluate the economic performance of alternative place-based monitoring approaches to current monitoring practice. Part II: Several factors affect the performance of monitoring strategies, including: measurable objectives, required precision in estimates, acceptable confidence levels of such estimates, available budget for sampling. In this paper, we develop place-based monitoring strategies based on extensive analysis of available historical water quality data (1960-1994) of 19 Iowa community water systems. These systems supply potable water to over 350,000 people. In the context of drinking water, the objective is to protect public health by utilizing monitoring resources to characterize contaminants that are detectable, and are close to exceeding health standards. A place-based monitoring strategy was developed in which contaminants were selected based on their historical occurrence, rather than their appearance on the SDWA contaminant list. In a subset of the water systems, the temporal frequency of monitoring for one ubiquitous contaminant, nitrate, was tailored to patterns in its historical occurrence and concentration. Three sampling allocation models (linear, quadratic, and cubic) based on historic patterns in peak occurrence were developed and evaluated. Random and fixed-interval sampling strategies within the context of such models were also developed and evaluated. Strategies were configured to incorporate a variety of options for frequency and number of samples (depending on budget and the desired precision in estimate of peak concentrations).

We report a rare case of an inguinal herniation of a large bladder diverticulum due to obstructive uropathy. Diagnostic means, therapeutic strategies and complications are discussed.

In a series of 21 patients with fractures of the neck of the femur, continuous lumbar plexus block provided effective pain relief in 17 cases. The technique for continuous lumbar plexus block is described. The technique has advantages over conventional methods of analgesia.