Purpose: While Monte Carlo particle transport has proven useful in many areas (treatment head design, dose calculation, shielding design, and imaging studies) and has been particularly important for proton therapy (due to the conformal dose distributions and a finite beam range in the patient), the available general purpose Monte Carlo codes in proton therapy have been overly complex for most clinical medical physicists. The learning process has large costs not only in time but also in reliability. To address this issue, we developed an innovative proton Monte Carlo platform and tested the tool in a variety of proton therapy applications. Methods: Our approach was to take one of the already-established general purpose Monte Carlo codes and wrap and extend it to create a specialized user-friendly tool for proton therapy. The resulting tool, TOol for PArticle Simulation (TOPAS), should make Monte Carlo simulation more readily available for research and clinical physicists. TOPAS can model a passive scattering or scanning beam treatment head, model a patient geometry based on computed tomography (CT) images, score dose, fluence, etc., save and restart a phase space, provides advanced graphics, and is fully four-dimensional (4D) to handle variations in beam delivery and patient geometry during treatment. A custom-designed TOPAS parameter control system was placed at the heart of the code to meet requirements for ease of use, reliability, and repeatability without sacrificing flexibility.Results: We built and tested the TOPAS code. We have shown that the TOPAS parameter system provides easy yet flexible control over all key simulation areas such as geometry setup, particle source setup, scoring setup, etc. Through design consistency, we have insured that user experience gained in configuring one component, scorer or filter applies equally well to configuring any other component, scorer or filter. We have incorporated key lessons from safety management, proactively removing possible sources of user error such as line-ordering mistakes. We have modeled proton therapy treatment examples including the UCSF eye treatment head, the MGH stereotactic alignment in radiosurgery treatment head and the MGH gantry treatment heads in passive scattering and scanning modes, and we have demonstrated dose calculation based on patient-specific CT data. Initial validation results show agreement with measured data and demonstrate the capabilities of TOPAS in simulating beam delivery in 3D and 4D. Conclusions: We have demonstrated TOPAS accuracy and usability in a variety of proton therapy setups. As we are preparing to make this tool freely available for researchers in medical physics, we anticipate widespread use of this tool in the growing proton therapy community.

Gap junctions represent a ubiquitous and integral part of multicellular organisms, providing the only conduit for direct exchange of nutrients, messengers and ions between neighboring cells. However, at the molecular level we have limited knowledge of their endogenous permeants and selectivity features. By probing the accessibility of systematically substituted cysteine residues to thiol blockers (a technique called SCAM), we have identified the pore-lining residues of a gap junction channel composed of Cx32. Analysis of 45 sites in perfused Xenopus oocyte pairs defined M3 as the major pore-lining helix, with M2 (open state) or M1 (closed state) also contributing to the wider cytoplasmic opening of the channel. Additional mapping of a close association between M3 and M4 allowed the helices of the low resolution map (Unger et al., 1999. Science. 283:1176–1180) to be tentatively assigned to the connexin transmembrane domains. Contrary to previous conceptions of the gap junction channel, the residues lining the pore are largely hydrophobic. This indicates that the selective permeabilities of this unique channel class may result from novel mechanisms, including complex van der Waals interactions of permeants with the pore wall, rather than mechanisms involving fixed charges or chelation chemistry as reported for other ion channels.

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

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