Biomimetic tissue-engineered systems for advancing cancer research: NCI Strategic Workshop report.

Advanced technologies and biomaterials developed for tissue engineering and regenerative medicine present tractable biomimetic systems with potential applications for cancer research. Recently, the National Cancer Institute convened a Strategic Workshop to explore the use of tissue biomanufacturing for development of dynamic, physiologically relevant in vitro and ex vivo biomimetic systems to study cancer biology and drug efficacy. The workshop provided a forum to identify current progress, research gaps, and necessary steps to advance the field. Opportunities discussed included development of tumor biomimetic systems with an emphasis on reproducibility and validation of new biomimetic tumor models, as described in this report.

Physical biology in cancer. 1. Cellular physics of cancer metastasis.

One of the major challenges in cancer research today is developing new therapeutic strategies to control metastatic disease, the spread of cancer cells from a primary tumor to seed in a distant site. Advances in diagnosis and treatment options have increased the survival rate for most patients with local tumors; however, less progress has been made in treatment of disseminated disease. According to the SEER Cancer Statistics Review, 1975-2010, in the case of breast and prostate cancers, only one in four patients diagnosed with distant metastatic disease will survive more than five years. Current research efforts largely focus on identifying biological targets, such as specific genes and signaling pathways that drive two key steps of metastasis, invasion from the primary tumor and growth in the secondary site. On the other hand, there are phenotypic traits and dynamics in the metastatic process that are not encoded by single genes or signaling pathways but, rather, a larger system of events and biophysical characteristics. Connecting genomic and pathway investigations with quantitative physical phenotypic characteristics of cells, the physical microenvironment, and the physical spatiotemporal interactions of the metastatic process provides a stronger complementary understanding of the disease.

Integrating physical sciences perspectives in cancer research.

Cancer research integrated a physical sciences perspective through team science, which fostered communication, trust, joint publication, and open access to data.

Measuring the evolution and output of cross-disciplinary collaborations within the NCI Physical Sciences-Oncology Centers Network.

Development of effective quantitative indicators and methodologies to assess the outcomes of cross-disciplinary collaborative initiatives has the potential to improve scientific program management and scientific output. This article highlights an example of a prospective evaluation that has been developed to monitor and improve progress of the National Cancer Institute Physical Sciences-Oncology Centers (PS-OC) program. Study data, including collaboration information, was captured through progress reports and compiled using the web-based analytic database: Interdisciplinary Team Reporting, Analysis, and Query Resource. Analysis of collaborations was further supported by data from the Thomson Reuters Web of Science database, MEDLINE database, and a web-based survey. Integration of novel and standard data sources was augmented by the development of automated methods to mine investigator pre-award publications, assign investigator disciplines, and distinguish cross-disciplinary publication content. The results highlight increases in cross-disciplinary authorship collaborations from pre- to post-award years among the primary investigators and confirm that a majority of cross-disciplinary collaborations have resulted in publications with cross-disciplinary content that rank in the top third of their field. With these evaluation data, PS-OC Program officials have provided ongoing feedback to participating investigators to improve center productivity and thereby facilitate a more successful initiative. Future analysis will continue to expand these methods and metrics to adapt to new advances in research evaluation and changes in the program.

Strategic workshops on cancer nanotechnology.

Nanotechnology offers the potential for new approaches to detecting, treating, and preventing cancer. To determine the current status of the cancer nanotechnology field and the optimal path forward, the National Cancer Institute's Alliance for Nanotechnology in Cancer held three strategic workshops, covering the areas of in vitro diagnostics and prevention, therapy and post-treatment, and in vivo diagnosis and imaging. At each of these meetings, a wide range of experts from academia, industry, the nonprofit sector, and the U.S. government discussed opportunities in the field of cancer nanotechnology and barriers to its implementation.

A hybrid nanosensor for TNT vapor detection.

Real-time detection of trace chemicals, such as explosives, in a complex environment containing various interferents has been a difficult challenge. We describe here a hybrid nanosensor based on the electrochemical reduction of TNT and the interaction of the reduction products with conducting polymer nanojunctions in an ionic liquid. The sensor simultaneously measures the electrochemical current from the reduction of TNT and the conductance change of the polymer nanojunction caused from the reduction product. The hybrid detection mechanism, together with the unique selective preconcentration capability of the ionic liquid, provides a selective, fast, and sensitive detection of TNT. The sensor, in its current form, is capable of detecting parts-per-trillion level TNT in the presence of various interferents within a few minutes.

Charge transport in mesoscopic conducting polymer wires.

In an attempt to reconcile transport in aniline oligomers with that observed in bulk polyaniline, we constructed meso-scale (60 nm) molecular junctions bridged by polyanion-stabilized polyaniline (PANI) strands. Junctions were characterized by their conductance versus electrochemical potential (G-E) and current versus voltage (I-V) characteristics, In contrast to bulk polyaniline, sharp peaks were seen in the G-E data, and these gave rise to negative differential resistance in the I-V curves, behavior much like that observed in aniline oligomers. The width of the conductance peaks increased with the amount of polymer deposited in the junction. In contrast to oligomers, the peaks in the meso-scale devices displayed a large hysteresis. The absolute conductance of the junctions is far too high to be consistent with transport along isolated chains, suggesting that a fundamental charge carrying unit is something morphologically more complex than a single polymer molecule.

Electrical detection of hepatitis C virus RNA on single wall carbon nanotube-field effect transistors.

We report the unambiguous detection of a sequence of Hepatitis C Virus (HCV) at concentrations down to the fractional pM range using Single Wall Carbon Nanotube (SWNT) Field Effect Transistor (FET) devices functionalized with Peptide Nucleic Acid (PNA).

Tuning the chemical selectivity of SWNT-FETs for detection of heavy-metal ions.

A method to functionalize single-walled carbon nanotubes (SWNTs) in a field-effect transistor (FET) device for the selective detection of heavy-metal ions is presented. In this method, peptide-modified polymers were electrochemically deposited onto SWNTs and the selective detection of metal ions was demonstrated by choosing appropriate peptide sequences. The signal transduction mechanism of the peptide-modified SWNT-FETs has also been studied.

Electrochemical gate-controlled conductance of single oligo(phenylene ethynylene)s.

We have studied electron transport properties of unsubstituted oligo(phenylene ethynylene) (OPE) (1) and nitro-substituted OPE (2) covalently bound to two gold electrodes. The conductance values of single 1 and 2 are approximately 13 and approximately 6 nS, respectively. In addition to a decrease in the conductance, the presence of the nitro moiety leads to asymmetric I-V characteristics and a negative differential resistance-like (NDR-like) behavior. We have altered the nitro-substituted OPE by electrochemically reducing the nitro group and by varying the pH of the electrolyte. The conductance decreases linearly with the electron-withdrawing capability (i.e., Hammett substituent values) of the corresponding reduced species. In contrast, the conductance of 1 is independent of the pH and the electrode potential.

A bond-fluctuation mechanism for stochastic switching in wired molecules.

Stochastic on-off conductivity switching observed in phenylene-ethynylene oligomers has been explained in terms of changes in ring conformations, or electron localization, or both. We report the observation of stochastic on-off switching in the simplest of wired molecules: octanedithiol, decanedithiol, and dodecanedithiol bonded on an Au(111) surface. Stochastic switching was observed even when a top gold contact was pressed on by a conducting atomic force microscope tip at constant force. The rate of switching increased substantially at 60 degrees C, a temperature at which these films are commonly annealed. Because such switching in alkanethiols is unlikely to be caused by internal molecular electronic changes and cannot be fully accounted for by breaking of the top contact, we argue that the cause is the well-known mobility of molecules tethered to gold via a thiol linkage.