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PubMed1988

Plasma membrane proton pump inhibition and stalk cell differentiation in Dictyostelium discoideum.

The choice of the stalk cell differentiation pathway in Dictyostelium is promoted by an endogenous substance, DIF-1, which is 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone. It is also favoured by weak acids and two inhibitors of the plasma membrane proton pumps of fungi and plants, diethylstilbestrol (DES) and zearalenone, and antagonised by ammonia and other weak bases, which promote spore differentiation. These observations led to the proposal that the choice of differentiation pathway is regulated by intracellular pH. They also prompted the conjecture that DIF-1 itself is a plasma membrane proton pump inhibitor. We report here experiments showing that DIF-1 is not a plasma membrane proton pump inhibitor. We demonstrate that diethylstilbestrol and zearalenone do inhibit the plasma membrane proton pump of Dictyostelium and we show that there is an excellent qualitative and quantitative correlation between the inhibitory activity of these agents, and of a number of other substances, and their ability to divert differentiation from the spore to the stalk pathway. We conclude that inhibition of the plasma membrane proton pump does shift the choice of differentiation pathway in Dictyostelium towards the stalk pathway, but that DIF does not act by this route, and we propose a model for the actions of DIF and plasma membrane proton pump inhibitors in which the differentiation pathway is controlled by the pH of intracellular vesicles rather than by intracellular pH itself. The model invokes a DIF- and proton-activated vesicular chloride channel whose opening permits acidification of the vesicles and lowers cytosolic Ca++ concentration.

Adenosine Triphosphatases↗
PubMed1987

Protein-structural heterogeneity in a non-allosteric monomeric insect hemoglobin monitored by proton magnetic resonance spectroscopy.

Proton NMR has revealed two modes of structural heterogeneity in the monomeric hemoglobin I of Chironomus thummi thummi, CTT I; rotational disorder caused by a 180 degree rotation of the heme about the alpha, gamma-meso axis (primary heterogeneity), which varies for each preparation or reconstitution of this hemoglobin, and a 'silent' amino acid replacement [Thr/Ala exchange in position 98(FG4)] in the vicinity of the heme group, which is invariant under all experimental conditions. The heme rotational disorder (primary heterogeneity) can be removed by reconstitution of CTT I with the symmetrical protoheme III. The secondary splitting is not affected; the ratio of intensities of the two types of resonance remains constant. The 8-methyl and 3-methyl and one of the alpha-vinyl proton resonances for the major heme rotational component and the 5-methyl and 1-methyl and one of the alpha-vinyl proton resonances for the minor heme rotational component have been identified and assigned by reconstitution with deuterium-labeled heme. Decoupling experiments have been employed to assign vinyl beta protons in cis and trans position to the respective vinyl alpha protons. Hyperfine shifts for the heme protons exhibited no pH influence above pH 6, in accord with the lack of the alkaline Bohr effect. Below pH 6, pH effects are most strongly reflected by the 8-methyl and 5-methyl proton resonances possibly reflecting titration of the propionate groups.

Amino Acid Sequence↗
PubMed1990

Analysis of the control of respiration rate, phosphorylation rate, proton leak rate and protonmotive force in isolated mitochondria using the 'top-down' approach of metabolic control theory.

The rate of respiration of isolated mitochondria was set at different values by addition of either oligomycin or an ADP-regenerating system (glucose and different amounts of hexokinase). We measured the relationship between respiration rate and membrane potential as respiration was titrated by the addition of malonate under each condition. We used the flux control summation and connectivity theorems and the branching theorem of metabolic control theory to calculate the control over respiration rate exerted by the respiratory chain (and associated reactions), phosphorylating system (and associated reactions) and proton leak at each respiration rate. The analysis also yielded the flux control coefficients of these three reactions over phosphorylation rate and proton leak rate and their concentration control coefficients over protonmotive force. We found that respiration rate was controlled largely by the proton leak under non-phosphorylating conditions, by the phosphorylating system at intermediate rates and by both the phosphorylating system and the respiratory chain in state 3. The rate of phosphorylation was controlled largely by the phosphorylating system itself in state 4 and at intermediate rates, while state 3 control was shared between the phosphorylating system and the respiratory chain; the proton leak had insignificant control. In all states the phosphorylating system had large negative control over the proton leak; the chain and the proton leak both had large positive control coefficients. The protonmotive force was controlled by the chain and by the phosphorylating system; the proton leak had little control.

Adenosine Diphosphate↗
PubMed1994

NMR spectroscopy of exchangeable protons of glucoamylase and of complexes with inhibitors in the 9-15-ppm range.

1H-NMR spectra have been recorded for glucoamylases I and II from Aspergillus awamori var. X100 and from A. niger in the 9-15-ppm region. At least 17 distinct peaks, many of them arising from single protons, are observed. These are designated A-Q, A being the furthest downfield. At least 9 of these are lost rapidly by exchange when the enzyme is placed in D2O. Peaks A, B, E and H undergo distinct shifts with pH change in the pH region 3-7. Several others undergo smaller shifts. Small differences are also seen between the enzymes from the two different sources. Binding of the pseudotetrasaccharide inhibitor acarbose leads to a 0.50-ppm downfield shift of peak B, other smaller changes, and retention of two additional protons in D2O. delta-D-gluconolactone induces shifts in peaks E, H, and L. The slow substrate maltitol causes peak A to broaden and shift, peaks J and K to shift and a new or greatly shifted resonance to appear at 15.4 ppm. It disappears as the maltitol is hydrolyzed. Treatment with iodoacetamide or diethyl pyrocarbonate leads to disappearance of peak D at 12.3 ppm. When this peak was irradiated strong nuclear Overhauser effects (NOE) were observed at 8.01 ppm and 7.22 ppm, positions expected for the C epsilon 1 and C delta 2 protons of an uncharged imidazole ring. We identify D as arising from the N epsilon 2 proton of His254 which is uncharged except at the lowest pH values. Other NOE and two-dimensional NOE spectra have provided additional information. Three mutant forms of the A. niger enzyme, in which tryptophan residues have been replaced by phenylalanine, have been examined. Because of shifts induced by changes in ring current and other environmental effects it is hard to make a direct identification of the resonances from the replaced indole NH protons. However, on the basis of a distinct NOE between peaks E and H we have identified these resonances as arising from the indole NH protons of Trp52 and Trp120. Other possible assignments are considered. The NMR spectra of the glucoamylases I, which have a starch binding domain of about 104 residues at the carboxyl terminus, show four sharp resonances in the 9.7-10.6-ppm range that are not present in the glucoamylases II, which lack this domain. These resonances no doubt represent the four indole NH ring protons from Trp543, Trp562, Trp590 and Trp615. Three of these are very sharp suggesting a high mobility of this domain.

Aspergillus↗
PubMed1994

The mechanism of iron release from transferrin. Slow-proton-transfer-induced loss of nitrilotriacetatoiron(III) complex in acidic media.

The role of protonation of amino acid ligands involved in iron release from human serum transferrin, previously saturated with nitrilotriacetatoiron(III) complex, has been elucidated in acidic media. Iron loss occurs first from the N-terminal site at pH < 6 and is followed at pH < 4 by iron release from the C-terminal iron-binding site. Nitrilotriacetatoiron(III) release from the N-terminal site is controlled by the slow protonation of the mixed protein/nitrilotriacetatoiron(III) complex; the second-order rate constant was k3a = 9.95 +/- 0.35 x 10(4) M-1.s-1. Protonation of an amino acid ligand in the C-terminal site leads to a new protein-site-C-loaded mixed complex with dissociation constant K4 = 0.300 +/- 0.025 mM. Nitrilotriacetatoiron(III) release is the result of mixed complex dissociation and the slow rate-limiting protonation of the iron-free protein with a proton dissociation constant K5a = 0.100 +/- 0.010 mM and a second-order rate constant k5a = 4.20 +/- 0.40 x 10(3) M-1.s-1. The mechanism of iron uptake and release seems to imply that slow proton transfers can induce complex formation between iron and the amino acid ligands of each of the protein iron-binding sites. These slow proton transfers may be controlled by the change of conformation of the binding sites upon iron loss.

Binding Sites↗
PubMed2004

Investigation of the contribution of histidine 119 to the conduction of protons through human Nox2.

The conduction of protons through human Nox2 has previously been shown to be dependent upon His115. Alignment of sequences for both animal and plant Nox proteins indicated that histidines 115 and 119 are both highly conserved, while His111 was conserved among animal homologues of Nox1-4. To investigate the possible role that these histidine residues might play in the conduction of protons through Nox2, we have introduced both paired and single mutations into these histidine residues. Each construct was used to generate a CHO cell line in which the expression of the mutated Nox2 was assessed. Nox2 was expressed in each of the CHO cell lines generated, however, the level of expression of H111/115L in CHO cells was lower and that of H111L very much reduced, compared to that of wild-type Nox2. The arachidonic acid activated proton flux was absent in the CHO cell lines expressing the mutations of H111/115L, H111/119L or H115/119L, compared to that observed for wild-type Nox2. Similarly only a small efflux of protons was observed from CHO cells expressing either H119L or H111L. In all cases the expected proton flux was elicited through the addition of the protonophore, carbonyl cyanide m-chlorophenylhydrazone. Conclusions regarding the role of His111 in the conduction of protons cannot be drawn due to the reduced expression. We can, however, conclude that His119, in addition to His115, is required for the conduction of protons through Nox2. His119 has been identified as a highly conserved residue for which no function has previously been proposed.

Amino Acid Sequence↗
PubMed2006

Proton pump inhibitors and Helicobacter pylori gastritis: friends or foes?

H. pylori gastritis and gastric acid closely interact. In H. pylori-positive patients, profound acid suppressive therapy induces a corpus-predominant pangastritis, which is associated with accelerated corpus gland loss and development of atrophic gastritis. Both corpus-predominant and atrophic gastritis have been associated with an increased risk of development of gastric cancer. H. pylori eradication leads to resolution of gastritis and may induce partial regression of pre-existent gland loss. H. pylori eradication does not aggravate GERD nor does it impair the efficacy of proton pump inhibitor maintenance therapy for this condition. This is the background of the advise within the European guidelines for the management of H. pylori infection to offer an H. pylori test and treat policy to patients who require proton pump inhibitor maintenance therapy for GERD. As such a policy fully reverses H. pylori pangastritis even in patients who have been treated for years with proton pump inhibitors, there is no need to eradicate H. pylori before the start of proton pump inhibitors. In fact, the somewhat slower initial response of H. pylori-negative GERD patients to proton pump inhibitor therapy and the fact that many GERD patients will only require short-term therapy suggests to first start the proton pump inhibitor, and only test and treat when maintenance therapy needs to be prescribed. Such considerations prevent the persistent presence of active corpus-predominant gastritis in proton pump inhibitor-treated reflux patients without impairing the clinical efficacy of treatment.

Gastritis↗
PubMed1991

Protons activate a cation conductance in a sub-population of rat dorsal root ganglion neurones.

1. The responses of adult and neonatal rat dorsal root ganglion (DRG) neurones to buffered acidic solutions were studied with both voltage clamp and radioactive ion flux techniques. Electrophysiological experiments were made on acutely isolated neurones and ion flux experiments were made on cells that had been in culture for 3-6 days. 2. Acid solutions of pH < 6.2 evoked a sustained, slowly inactivating inward current in neurones voltage clamped at negative holding potentials. The size of the current increased with increasing proton concentrations. This response was restricted to a sub-population (approximately 45%) of adult and neonatal rat DRG neurones and was distinct from a rapidly activating and inactivating proton-induced inward sodium current that was also found in DRG neurones. 3. The proton-activated sustained current was due to an increase in cation conductance that allowed K+, Cs+ and Na+ to pass with PK/PNa = 1.32 and PCs/PNa = 1.12. 4. Radioactive ion efflux experiments made on neonatal rat cultured DRG neurones showed that protons also increased the permeability to both [14C]guanidinium and 86Rb+ ions. The half-maximal increase in efflux rate for 86Rb+ occurred at pH 5.8. Acid solution also stimulated the efflux of 86Rb+ in cultures of adult rat neurones. 5. Cells that showed a late, sustained proton-activated current also responded to capsaicin. In addition, no proton-activated fluxes of either [14C]guanidinium or 86Rb+ ions were observed in cultures of DRG neurones that had been treated with high concentrations of capsaicin (10 microM) to kill the capsaicin-sensitive neurones. Thus this proton-activated current is restricted largely, if not exclusively, to capsaicin-sensitive peripheral sensory neurones.

Animals↗
PubMed1995

Modification by protons of frog skeletal muscle KATP channels: effects on ion conduction and nucleotide inhibition.

1. The molecular mechanisms underlying pH regulation of skeletal muscle ATP-sensitive K+ (KATP) channels were studied using the patch clamp technique in the inside-out configuration. Two effects of intracellular protons were studied in detail: the decrease in magnitude of single-channel currents and the increase in open probability (Po) of nucleotide-inhibited channels. 2. The pH dependence of inward unit currents under different ionic conditions was in poor agreement with either a direct block of the pore by protons or an indirect proton-induced conformational change, but was compatible with the protonation of surface charges located near the cytoplasmic entrance of the pore. This latter electrostatic mechanism was modelled using Gouy-Chapman-Stern theory, which predicted the data accurately with a surface charge density of about 0.1 negative elementary charges per square nanometre and a pK (pH value for 50% effect) value for protonation of these charges of 6.25. The same mechanism, i.e. neutralization of negative surface charges by cation binding, could also account for the previously reported reduction of inward unit currents by Mg2+. 3. Intracellular alkalization did not affect Po of the KATP channels. Acidification increased Po. In the presence of 0.1 mM ATP (no Mg2+), the channel activation vs. pH relationship could be fitted with a sigmoid curve with a Hill coefficient slightly above 2 and a pK value of 6. This latter value was dependent on the ATP concentration, decreasing from 6.3 in 30 microM ATP to 5.3 in 1 microM ATP. 4. Conversely, the channel inhibition vs. ATP concentration curve was shifted to the right when the pH was lowered. At pH 7.1, the ATP concentration causing half-maximal inhibition was about 10 microM. At pH 5.4, it was about 400 microM. The Hill coefficient values remained slightly below 2. Similar effects were observed when ADP was used as the inhibitory nucleotide. 5. These results confirm that a reciprocal competitive link exists between proton and nucleotide binding sites. Quantitatively, they are in full agreement with a steady-state model of a KATP channel possessing four identical protonation sites (microscopic pK, 6) allosterically connected to the channel open state and two identical nucleotide sites (microscopic ATP dissociation constant, approximately 30 microM) connected to the closed state.

Adenosine Triphosphate↗
PubMed2006

Isoform-dependent interaction of voltage-gated sodium channels with protons.

Protons are potent physiological modifiers of voltage-gated Na(+) channels, shifting the voltage range of channel gating and reducing current magnitude (pK(a) approximately 6). We recently showed that proton block of the skeletal muscle isoform (Na(V)1.4) resulted from protonation of the four superficial carboxylates in the outer vestibule of the channel. We concluded that the large local negative electrostatic field shifted the outer vestibule carboxylate pK(a) into the physiological range. However, block was not complete; the best-fit titration curves yielded an acid pH asymptote of 10-15%, suggesting that the selectivity filter carboxylates may not be protonated. Using HEK 293 cells stably expressing different isoforms, each with varying channel density, we demonstrate that a pH-independent current is found in Na(V)1.4, but not in the cardiac isoform (Na(V)1.5). Mutational studies showed that absence of the pH-independent current in Na(V)1.5 could be ascribed to the cysteine in domain I, just above the selectivity filter aspartate (Cys373). We suggest that this cysteine can be protonated in acid solution to produce a positive charge that blocks the pore. Competition between protons and Na(+) did not exist for Na(+) concentrations between 1 and 140 mm. The residual current in acid solution, when the cysteine is absent, confirms that over the range of pH values that can be achieved physiologically, the selectivity filter carboxylates are not protonated. The pH-independent current helps to protect activation of skeletal muscle during the acidosis that occurs during exercise.

Acidosis↗
PubMed2001

A systematic Monte Carlo study of secondary electron fluence perturbation in clinical proton beams (70-250 MeV) for cylindrical and spherical ion chambers.

Current dosimetry protocols for clinical protons do not take into account any secondary electron fluence perturbation in ion chambers. In this work, we performed a systematic study of secondary electron fluence perturbation factors for spherical and cylindrical ion chambers in proton beams (70-250 MeV). The electron fluence perturbation factor, pe, was calculated using Monte Carlo transport of protons and secondary electrons. The influence of proton energy, cavity wall material (graphite, water, A150, PMMA, polystyrene), cavity radius, cavity wall thickness and positioning depth in water is studied. The influence of inelastic nuclear proton interactions is briefly discussed. It was found that pe depends on wall material; the largest values for pe were obtained for ion chambers with A150 walls (pe=1.009), the smallest values for graphite walls. The perturbation factor was found to be largely independent of proton energy. A slight decrease of pe with cavity radius was obtained, especially for low energy protons. The wall thickness was found to have no effect on pe in the range studied (0.025-0.1 cm). The depth of the cavity in a water phantom was also found to have an insignificant effect on pe. Based on the results in the paper for spherical and cylindrical ion chambers, a method to calculate pe for a thimble ion chamber is presented. The results presented in this paper for cylindrical and spherical ion chambers are in contradiction to the calculated electron fluence perturbation factors for planar ion chambers in the paper by Casnati et al.

Electrons↗
PubMed2002

Relative effectiveness of polyacrylamide gel dosimeters applied to proton beams: Fourier transform Raman observations and track structure calculations.

The feasibility of using polyacrylamide gel (PAG) to characterize a clinically relevant 74 MeV proton beam has been considered. Fourier transform Raman spectroscopy has been used to measure the response (i.e., consumption of monomer) of PAG exposed to the central and end portions of a spread out Bragg peak (SOBP), i.e., in two regions with measurable difference in proton linear energy transfer (LET). The response curve in each region was compared with a typical 6 MV x-ray irradiated gel response curve, thus arriving at a gel "relative effectiveness" (RE) in each of the two regions. In addition, the theory of track structure, which is typically used to calculate a detector RE, is shown to give reasonable agreement when compared with the experimental results. Both experimental and track structure results indicate a decrease in gel response when irradiated with protons, as compared with the x-ray response. In addition, both sets of results indicate a variation in gel response between the mid and end SOBP regions, thus illuminating the dependence of gel response to proton LET. The physical phenomenon causing a lower proton versus x-ray gel response may be understood by considering the track structure calculations, which indicate that gel radiosensitive elements close to the track of a proton (i.e., within 1.5 x 10(-6) cm) are saturated. This saturation is due to the high delta-ray doses deposited in these regions. The track calculations are extended to other situations (e.g., raw BP, different gel compositions) where experimental determination of RE is difficult or time consuming. Results again indicate a gel response dependent on position in the depth dose curve (i.e., LET). Overall, this study illuminates the difficulty in using polyacrylamide gel to extract quantitative dose maps when exposed to proton radiation.

Acrylic Resins↗
PubMed2002

Particle in cell simulation of laser-accelerated proton beams for radiation therapy.

In this article we present the results of particle in cell (PIC) simulations of laser plasma interaction for proton acceleration for radiation therapy treatments. We show that under optimal interaction conditions protons can be accelerated up to relativistic energies of 300 MeV by a petawatt laser field. The proton acceleration is due to the dragging Coulomb force arising from charge separation induced by the ponderomotive pressure (light pressure) of high-intensity laser. The proton energy and phase space distribution functions obtained from the PIC simulations are used in the calculations of dose distributions using the GEANT Monte Carlo simulation code. Because of the broad energy and angular spectra of the protons, a compact particle selection and beam collimation system will be needed to generate small beams of polyenergetic protons for intensity modulated proton therapy.

Computer Simulation↗
PubMed2005

Density resolution of proton computed tomography.

Conformal proton radiation therapy requires accurate prediction of the Bragg peak position. Protons may be more suitable than conventional x-rays for this task since the relative electron density distribution can be measured directly with proton computed tomography (CT). However, proton CT has its own limitations, which need to be carefully studied before this technique can be introduced into routine clinical practice. In this work, we have used analytical relationships as well as the Monte Carlo simulation tool GEANT4 to study the principal resolution limits of proton CT. The noise level observed in proton CT images of a cylindrical water phantom with embedded tissue-equivalent density inhomogeneities, which were generated based on GEANT4 simulations, compared well with predictions based on Tschalar's theory of energy loss straggling. The relationship between phantom thickness, initial energy, and the relative electron density resolution was systematically investigated to estimate the proton dose needed to obtain a given density resolution. We show that a reasonable density resolution can be achieved with a relatively small dose, which is comparable to or even lower than that of x-ray CT.

Algorithms↗
PubMed2006

Characterization of moderator assembly dimension for accelerator boron neutron capture therapy of brain tumors using 7Li(p, n) neutrons at proton energy of 2.5 MeV.

The characteristics of moderator assembly dimension are investigated for the usage of 7Li(p,n) neutrons by 2.5 MeV protons in boron newtron capture therapy (BNCT) of brain tumors in the present study. The indexes checked are treatable protocol depth (TPD), which is the greatest depth of the region satisfying the dose requirements in BNCT protocol, proton current necessary to complete BNCT by 1 h irradiation, and the heat flux deposited in the Li target which should be removed. Assumed materials are D2O for moderator, and mixture of polyethylene and LiF with 50 wt % for collimator. Dose distributions have been computed with MCNP 4B and 4C codes. Consequently, realized TPD does not show a monotonical tendency for the Li target diameter. However, the necessary proton current and heat flux in the Li target decreases as the Li target diameter increases, while this trend reverses at around 10 cm of the Li target diameter for the necessary proton current in the condition of this study. As to the moderator diameter, TPD does not exhibit an apparent dependence. On the other hand, necessary proton current and heat flux decrease as the moderator diameter increases, and this tendency saturates at around 60 cm of the moderator diameter in this study. As to the collimator, increase in inner diameter is suitable from the viewpoint of increasing TPD and decreasing necessary proton current and heat flux, while these indexes do not show apparent difference for collimator inner diameters over 14 cm for the parameters treated here. The practical viewpoint in selecting the parameters of moderator assembly dimension is to increase TPD, within the technically possible condition of accelerated proton current and heat removal from the Li target. In this process, the values for which the resultant characteristics mentioned above saturate or reverse would be important factors.

Boron Neutron Capture Therapy↗
PubMed2006

Neutron scattered dose equivalent to a fetus from proton radiotherapy of the mother.

Scattered neutron dose equivalent to a representative point for a fetus is evaluated in an anthropomorphic phantom of the mother undergoing proton radiotherapy. The effect on scattered neutron dose equivalent to the fetus of changing the incident proton beam energy, aperture size, beam location, and air gap between the beam delivery snout and skin was studied for both a small field snout and a large field snout. Measurements of the fetus scattered neutron dose equivalent were made by placing a neutron bubble detector 10 cm below the umbilicus of an anthropomorphic Rando phantom enhanced by a wax bolus to simulate a second trimester pregnancy. The neutron dose equivalent in milliSieverts (mSv) per proton treatment Gray increased with incident proton energy and decreased with aperture size, distance of the fetus representative point from the field edge, and increasing air gap. Neutron dose equivalent to the fetus varied from 0.025 to 0.450 mSv per proton Gray for the small field snout and from 0.097 to 0.871 mSv per proton Gray for the large field snout. There is likely to be no excess risk to the fetus of severe mental retardation for a typical proton treatment of 80 Gray to the mother since the scattered neutron dose to the fetus of 69.7 mSv is well below the lower confidence limit for the threshold of 300 mGy observed for the occurrence of severe mental retardation in prenatally exposed Japanese atomic bomb survivors. However, based on the linear no threshold hypothesis, and this same typical treatment for the mother, the excess risk to the fetus of radiation induced cancer death in the first 10 years of life is 17.4 per 10,000 children.

Female↗
PubMed2006

A fourier analysis on the maximum acceptable grid size for discrete proton beam dose calculation.

We developed an analytical method for determining the maximum acceptable grid size for discrete dose calculation in proton therapy treatment plan optimization, so that the accuracy of the optimized dose distribution is guaranteed in the phase of dose sampling and the superfluous computational work is avoided. The accuracy of dose sampling was judged by the criterion that the continuous dose distribution could be reconstructed from the discrete dose within a 2% error limit. To keep the error caused by the discrete dose sampling under a 2% limit, the dose grid size cannot exceed a maximum acceptable value. The method was based on Fourier analysis and the Shannon-Nyquist sampling theorem as an extension of our previous analysis for photon beam intensity modulated radiation therapy [J. F. Dempsey, H. E. Romeijn, J. G. Li, D. A. Low, and J. R. Palta, Med. Phys. 32, 380-388 (2005)]. The proton beam model used for the analysis was a near monoenergetic (of width about 1% the incident energy) and monodirectional infinitesimal (nonintegrated) pencil beam in water medium. By monodirection, we mean that the proton particles are in the same direction before entering the water medium and the various scattering prior to entrance to water is not taken into account. In intensity modulated proton therapy, the elementary intensity modulation entity for proton therapy is either an infinitesimal or finite sized beamlet. Since a finite sized beamlet is the superposition of infinitesimal pencil beams, the result of the maximum acceptable grid size obtained with infinitesimal pencil beam also applies to finite sized beamlet. The analytic Bragg curve function proposed by Bortfeld [T. Bortfeld, Med. Phys. 24, 2024-2033 (1997)] was employed. The lateral profile was approximated by a depth dependent Gaussian distribution. The model included the spreads of the Bragg peak and the lateral profiles due to multiple Coulomb scattering. The dependence of the maximum acceptable dose grid size on the orientation of the beam with respect to the dose grid was also investigated. The maximum acceptable dose grid size depends on the gradient of dose profile and in turn the range of proton beam. In the case that only the phantom scattering was considered and that the beam was aligned with the dose grid, grid sizes from 0.4 to 6.8 mm were required for proton beams with ranges from 2 to 30 cm for 2% error limit at the Bragg peak point. A near linear relation between the maximum acceptable grid size and beam range was observed. For this analysis model, the resolution requirement was not significantly related to the orientation of the beam with respect to the grid.

Algorithms↗
PubMed1996

kQ factors for ionization chamber dosimetry in clinical proton beams.

We discuss a formalism for clinical proton beam dosimetry based on the use of ionization chamber absorbed dose-to-water calibration and beam quality correction factors. A quantity kQ, the beam quality correction factor, is defined which corrects the absorbed dose-to-water calibration factor ND,w in a reference beam of quality Q0 to that in a user's beam of quality Q1. This study of proton beam quality correction factors used 60Co (kQ gamma) and proton (kQp) reference beams. The kQ gamma factors were measured using combined water calorimetry and ionometry for PTW and Capintec-Farmer-type ionization chambers, and were computed from standard dosimetry protocols. Agreement between measured and calculated kQ gamma values for both chambers was found within 1.2% in the plateau region for a monoenergetic 250-MeV beam and within 1.8% at the spread-out Bragg peak for a 155-MeV range-modulated beam. Comparison of absorbed doses to water determined in the range-modulated 155-MeV beam was performed with the PTW chamber using three calibration methods: Ngas calibration (AAPM Report 16), ND,w,gamma calibration in a 60Co beam in conjunction with a kQ gamma factor, and ND,w,p calibration in a proton beam in conjunction with a kQp factor. Absorbed doses to water obtained with the three methods agreed within 2% when ionization chamber dosimetry data were analyzed using the proton W-value for air from the AAPM Report 16 and the ICRU 49 proton stopping powers. The use of the proton-calibrated reference ionization chamber, in conjunction with the beam quality correction factor kQp, significantly reduced the systematic uncertainty of the absorbed dose determination.

Biophysical Phenomena↗