Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma.

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

A compact resonace-based wireless energy transfer system for implanted electronic devices

10.1109/ICEAS.2011.6147134Proceedings - 2011 International Conference on Energy, Automation and Signal, ICEAS - 2011376-37

A prototype sensor system for the early detection of microbially linked spoilage in stored wheat grain

Sensors based on composites of metal oxides were fabricated and tested extensively under high-humidity and high-flow conditions with exposure to vapours reported to increase in the headspace of wheat grain (Triticum aestivum cv Hereward) colonized by fungi. The sensors that exhibited high sensitivity to target vapours combined with high stability were selected for inclusion into a four-sensor array prototype system. A sampling protocol aligned to parallel GC-MS (gas chromatography-mass spectrometry) and human olfactory assessment studies was established for use with the sensor system. The sensor system was utilized to assess irradiated wheat samples that had been conditioned to 25% moisture content and inoculated with pathogens known to cause spoilage of grain in storage. These included the fungi Penicillium aurantiogriseum, Penicillium vulpinum, Penicillium verrucosum, Fusarium culmorum, Aspergillus niger, and Aspergillus flavus and the actinomycete, Streptomyces griseus. The sensor system successfully tracked the progress of the infections from a very early stage and the results were compared with human olfactory assessment panels run concurrently. A series of dilution studies were undertaken using previously infected grain mixed with sound grain, to improve the sensitivity and maximize the differentiation of the sensor system. An optimum set of conditions including incubation temperature, incubation time, sampling time, and flow rate were ascertained utilizing this method. The sensor system differentiated samples of sound grain from samples of sound grain with 1% (w/w) fungus infected grain added. Following laboratory trials, the prototype sensor system was evaluated in a commercial wheat grain intake facility. Thresholds calculated from laboratory tests were used to differentiate between sound and infected samples (classified by intake laboratory technicians) collected routinely from trucks delivering grain for use in food manufacture. All samples identified as having an odour-related problem by the intake laboratory gave a total system output above the set threshold and were therefore rejected by the prototype system. A number of samples passed by the intake laboratory were rejected by the prototype system, resulting in what appeared to be false positive results. However, the thresholds were selected on the basis of a limited number of samples and may need to be adjusted to minimize false positives. The output from the sensor system was also compared with moisture content values for the wheat (where available) to demonstrate that the system was not simply measuring differences in moisture. A separate study (carried out at the intake facility) assessed 37 newly harvested wheat samples of different varieties and from different geographic locations within the UK. These samples were analysed by the sensor system, using the same thresholds as before. Six samples rejected by the system were then assessed by the wheat intake laboratory, where only one sample was rejected. This rejected sample had given the highest output when exposed to the sensor system. The commercial trial highlighted the promise of this prototype for the detection of spoilage in wheat grain and a larger trial should ascertain the reliability and long-term stability of the device and therefore confirm its usefulness to the industry

Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

Funder: Jane Coffin Childs Memorial Fund for Medical Research; FundRef: http://dx.doi.org/10.13039/100001033Funder: Swedish Foundation for Strategic Research; FundRef: http://dx.doi.org/10.13039/501100001729Funder: Knut and Alice Wallenberg Foundation; FundRef: http://dx.doi.org/10.13039/501100004063Funder: Barbro Osher Pro Suecia Foundation; FundRef: http://dx.doi.org/10.13039/100008483Funder: Howard Hughes Medical Institute; FundRef: http://dx.doi.org/10.13039/100000011Funder: NIHR Cambridge BRCFunder: Lustgarten Foundation; FundRef: http://dx.doi.org/10.13039/100005979Funder: Stand Up To Cancer; FundRef: http://dx.doi.org/10.13039/100009730Funder: MIT Center for Precision Cancer MedicineFunder: Ludwig Center at MITFunder: Emerald FoundationTumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue