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J McDonough

Publications and source records attributed to J McDonough.

At least 19 recordsLinked to original sources
PubMed2001

Comparative treatment planning between proton and X-ray therapy in pancreatic cancer.

With the utilization of new biologic agents and experimental chemotherapy in the treatment of pancreatic cancer, the issue of local-regional control will become increasingly important. This study was undertaken to determine the feasibility of dose escalation using proton therapy, as compared to conventional 3-dimensional conformal radiation, by minimizing the dose to normal tissues. The photon treatment plans of 4 patients with unresectable pancreatic cancer treated on a biologic therapy trial were utilized. Each patient was treated using a 3- or 4-field photon plan with 45 Gy to the clinical target volume (CTV), followed by a boost of 14.4 Gy to the gross target volume (GTV). Using a Helax treatment planning system, proton plans were generated to encompass the same CTV and GTV to the same prescribed dose. Dose-volume histograms (DVHs) were generated for the GTV, CTV, spinal cord, liver, and right and left kidneys. Each DVH was compared between the photon and proton plans. Proton plans utilized either a 2- or 3-field technique. Available energies included 130 or 180 MeV. Range modulators and bolus were used as needed to conform to the target volume. With the CTV and GTV receiving the same dose from the proton and photon plans, all individual proton plans were superior to the photon plans in reduction of normal tissue dose. For the 4 patients, the average dose reduction to 50% of the organ at risk was 78% to spinal cord (p = 0.003), 73% to left kidney (p = 0.025), 43% to right kidney (p = 0.059), and 55% to liver (p = 0.061). These comparative treatment plans show proton therapy results in significant reductions of dose to normal tissue compared to conventional photons while treating the same target volumes. This allows for the design of dose-escalation protocols using protons in combination with new biologic therapies and chemotherapy.

Adenocarcinoma↗
PubMed2001

Oral delivery of biologically active parathyroid hormone.

PURPOSE: Parathyroid hormone (PTH), the only drug known to stimulate bone formation. is a peptide therapeutic indicated in the treatment of osteoporosis. Unfortunately, PTH is only effective when dosed by injection because it has no oral bioavailability. Herein we report the oral absorption of PTH in rats and monkeys facilitated by the novel delivery agent, N-[8-(2-hydroxy-4-methoxy)bensoyl]amino caprylic acid (4-MOAC). METHODS: 4-MOAC was selected from a group of 100 delivery agents based on in vitro chromotography studies and in vivo screening studies in rats. The PTH/4-MOAC combination was then tested in monkeys. The interaction of 4-MOAC and PTH was evaluated by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Monkeys were administered an aqueous solution containing 4-MOAC and PTH and mean peak serum PTH concentrations of about 3000 pg/mL were obtained. The relative bioavailability of oral PTH was 2.1% relative to subcutaneous administration. The biological activity of the orally-delivered PTH was further evaluated in a rat model of osteoporosis. These studies showed that the bone formed following oral PTH/4-MOAC administration was comparable to that formed following PTH injections. The 4-MOAC mediated absorption of PTH is hypothesized to be the result of a noncovalent interaction between 4-MOAC and PTH. The preliminary evaluation of this interaction by NMR is described. CONCLUSIONS: 4-MOAC facilitates the absorption of PTH following oral administration to both rats and monkeys. The orally-absorbed PTH is biologically active as demonstrated in a rat model of osteoporosis.

Administration, Oral↗
PubMed2000

Regulation of transcription in the neuronal nicotinic receptor subunit gene cluster by a neuron-selective enhancer and ETS domain factors.

Expression of neurotransmitter receptors encoded by the nicotinic acetylcholine receptor (nAchR) subunit gene cluster depends on coexpression of the beta4, alpha3, and alpha5 subunits in certain kinds of neurons. One way in which coexpression might be achieved is through the regulation of promoters in the cluster by neuron-selective enhancers. The beta43' enhancer is located between the beta4 and alpha3 promoters and it directs cell type-specific expression in cell lines. It is not known, however, whether beta43' is active in neurons. Therefore, we assayed beta43' in dissociated rat sympathetic ganglia cultures, which contain nAchR-positive neurons as well as nAchR-negative non-neuronal cells. Reporters controlled by the alpha3 promoter and beta43' were expressed in a neuron-selective manner; greater than 90% and up to 100% of luciferase expression was detected in neurons. Neuron selectivity was maintained when beta43' was placed next to ubiquitously active viral promoters. In contrast, replacing beta43' with the SV40 enhancer eliminated neuron selectivity. The enhancer is composed of at least two separate but functionally interdependent elements, each of which interacts with a different type of ETS domain factor. These findings support a model in which beta43' controls neuronal expression of one or more genes in the cluster through interactions with a combination of ETS factors.

Animals↗
PubMed2000

Transcriptional control of the neuronal nicotinic acetylcholine receptor gene cluster by the beta43' enhancer, Sp1, SCIP and ETS transcription factors.

Receptors assembled from the products of a neuronal beta4alpha3alpha5 NAChR gene cluster depend on these genes being coordinately regulated in particular populations of neurons. Little is known, however, about the transcriptional mechanisms that are likely to underlie their co-expression in correct neuronal cell types. We have identified several regulatory elements and transcription factors that influence transcription of the alpha3 and beta4 genes. The promoters of these genes appear to contain a common cis element that binds Sp1 transcription factors. They can be activated by the POU-domain factor SCIP and activation does not require SCIP binding sites. Between these two promoters is a cell type specific enhancer called beta43'. This enhancer has little activity in non-neuronal cells and is preferentially active in particular populations of central neurons. The clustered genes are potential targets of ETS factors as the ETS domain factor, Pet-1 can activate beta43'-dependent transcription. The neuron-selective properties of beta43' and its location suggest that it is a component of the cis regulatory information required to control expression of the beta4 and alpha3 genes in specific populations of neurons.

Animals↗
PubMed2000

Improved branching ratio measurement for the decay K(0)(L) --> &mgr;(+)&mgr;(-)

We report results from Experiment 871, performed at the BNL AGS, of a measurement of the branching ratio K(0)(L)-->&mgr;(+)&mgr;(-) with respect to the CP-violating mode K(0)(L)-->pi(+)pi(-). This experiment detected over 6200 candidate &mgr;(+)&mgr;(-) events, a factor of 6 more than that seen in all previous measurements combined. The resulting branching ratio gamma(K(0)(L)-->&mgr;(+)&mgr;(-))/gamma(K(0)(L)-->pi(+)pi(-)) = (3. 474+/-0.057)x10(-6) leads to a branching fraction B(K(0)(L)-->&mgr;(+)&mgr;(-)) = (7.18+/-0.17)x10(-9), which is consistent with the current world average, and reduces the uncertainty in this decay mode by a factor of 3.

Journal Article↗
PubMed2000

Determining clinical photon beam spectra from measured depth dose with the Cimmino algorithm.

A method to determine the spectrum of a clinical photon beam from measured depth-dose data is described. At shallow depths, where the range of Compton-generated electrons increases rapidly with photon energy, the depth dose provides the information to discriminate the spectral contributions. To minimize the influence of contaminating electrons, small (6 x 6 cm2) fields were used. The measured depth dose is represented as a linear combination of basis functions, namely the depth doses of monoenergetic photon beams derived by Monte Carlo simulations. The weights of the basis functions were obtained with the Cimmino feasibility algorithm, which examines in each iteration the discrepancy between predicted and measured depth dose. For 6 and 15 MV photon beams of a clinical accelerator, the depth dose obtained from the derived spectral weights was within about 1% of the measured depth dose at all depths. Because the problem is ill conditioned, solutions for the spectrum can fluctuate with energy. Physically realistic smooth spectra for these photon beams appeared when a small margin (about +/- 1%) was attributed to the measured depth dose. The maximum energy of both derived spectra agreed with the measured energy of the electrons striking the target to within 1 MeV. The use of a feasibility method on minimally relaxed constraints provides realistic spectra quickly and interactively.

Algorithms↗
PubMed1999

Comparing two methods for calculating phantom scatter.

Two methods are compared for calculating the field-size dependence of the phantom scatter component of dose for x-ray beams. One model sums three Gaussian distributions; the other model is a two-parameter function. With a measurement of the beam quality as input to determine parameters, both models accurately reproduce the relative phantom scatter. However, there are important differences between the models. For all beam energies, the two-parameter model characterizes the absolute phantom scatter as a function of depth and field size, while, also for all beam energies, the six-parameter Gaussian model characterizes the relative phantom scatter at a single depth of 10 cm. For small field sizes, the phantom scatter calculated from the two-parameter model agrees with Monte Carlo calculations better than the Gaussian model. In the Gaussian model, the parameters can be obtained for beam energies between 60Co and 25 MV by linear interpolation based on the measured beam quality. In the two-parameter model, and for energies above 4 MV, the parameters can be obtained using linear functions of the dose-weighted average linear attenuation coefficient, which is related to beam quality.

Calibration↗
PubMed1999

Determination of scatter factor parameters and electron disequilibrium for monoenergetic photon beams.

The tissue-phantom-ratio (TPR) is expressed as the product of the phantom scatter factor (SF), an electron disequilibrium factor, and an attenuation factor, equal to the zero-area TPR. The scatter factor, as a function of depth d and field size s, has been described by two parameters a and w, SF(d,s) = 1 + asd/(ws + d). We have determined the parameters a and w for 20 monoenergetic photon beams between 1 and 20 MeV. Pencil-beam energy-deposition kernels were obtained using Monte Carlo simulations. The kernels were used to calculate broad-beam depth-dose data, which were converted to TPR and fitted to the equation above using an iterative search over a-w space. The parameter a is nearly equal to the attenuation coefficient for all energies while the parameter w increases with energy. The resulting a and w compare favorably to values determined for clinical photon beams, as a function of the measured attenuation coefficient. With the scatter factor determined, we isolated the electron disequilibrium factor for each monoenergetic beam. It can be characterized as a quadratic function of the depth. The coefficients of the quadratic function can be related to the range of the most energetic secondary electron produced.

Computer Simulation↗
PubMed1998

The effect of independent collimator misalignment on the dosimetry of abutted half-beam blocked fields for the treatment of head and neck cancer.

BACKGROUND AND PURPOSE: Independent collimation conveniently allows for the junctioning of abutting fields with non-diverging beam edges. When this technique is used at the junction of multiple fields, e.g. lateral and low anterior fields in three-field head and neck set-ups, there should be a dosimetric match with no overdose or underdose at the matchline. We set out to evaluate the actual dosimetry at the central match plane. MATERIALS AND METHODS: Independent jaws were used to mimic two half-beam blocked fields abutting at the central axis. X-Ray verification film was exposed in a water-equivalent phantom and the dose at the matchline was evaluated with laser densitometry. Collimators were then programmed to force a gap or overlap of the radiation fields to evaluate the effect of jaw misalignment within the tolerance of the manufacturer's specification. Diode measurements of the field edges were also performed. Four beam energies from four different linear accelerators were evaluated. RESULTS: Small systematic inhomogeneities were found along the matchline in all linear accelerators tested. The maximum dose on the central axis varied linearly with small programmed jaw misalignments. For a gap or overlap of 2 mm between the jaws, the matchline dose increased or decreased by 30-40%. The region of overdose or underdose around the matchline is 3-4 mm wide. The discrepancy between the width of jaw separation and the width of the region of altered dose is explained by a penumbra effect. CONCLUSION: We recommend that independent jaw alignment be evaluated routinely and provide a simple method to estimate dose inhomogeneity at the match plane. If there is a field gap or overlap resulting in a clinically significant change in dosimetry, jaw misalignment should be corrected. If it cannot be corrected, part of the benefit of asymmetric collimation is lost and other methods of field junctioning may have to be considered. We routinely use a small block over the spinal cord at the mono-isocenter set-up plane for three-field head and neck treatments to prevent an overdose.

Head and Neck Neoplasms↗
PubMed1998

Extraction of the photon spectra from measured beam parameters.

Knowledge of the photon spectrum of a radiotherapy beam is often needed for three-dimensional (3-D) dose calculations using Monte Carlo methods and/or algorithms employing energy deposition kernels. Direct measurement of the x-ray energy fluence spectrum is not feasible for the high-energy photon beams used clinically. In this paper, the spectrum is extracted from basic beam data that are readily obtained for a clinical beam. We describe the photon spectrum using just two parameters. One parameter, which determines the high-energy part of the spectrum, is obtained using the measured dose in the buildup region for a small field, where electron contamination of the beam can be neglected. The other parameter is extracted from the photon beam attenuation in water. The results compare favorably to spectra generated from Monte Carlo simulations.

Algorithms↗
PubMed1997

beta43': An enhancer displaying neural-restricted activity is located in the 3'-untranslated exon of the rat nicotinic acetylcholine receptor beta4 gene.

Members of a neuronal nicotinic acetylcholine receptor subunit gene cluster ordered beta4, alpha3, alpha5 in the vertebrate genome are expressed in highly restricted patterns in the PNS and CNS. Nothing is known, however, about the regulatory elements that control transcription of these genes in selected neuronal cell populations. We report here a novel enhancer, designated beta43', that is positioned in the beta4 3'-untranslated exon. It is composed of two nearly identical 37 bp direct repeats that are separated by 6 bp. Multimerization of the enhancer upstream of the alpha3 minimal promoter results in synergistic activation. Analysis in different cell types, including three neural lines and primary keratinocytes, shows that beta43' is preferentially active in the neural line PC12, which expresses all members of the cluster. Mobility shift assays reveal a cell-type-specific complex, which forms with the first repeat of the enhancer and PC12 extracts. Complexes co-migrating with the PC12 cell complex are not detected with extracts from other lines, which suggests that PC12 cells contain a differentially expressed factor that may be important for the restricted activity of beta43'. The cell-type-specific activity of the beta43' enhancer suggests that it is important for regulating restricted expression patterns of one or more clustered neuronal acetylcholine receptor genes. Its location within the beta4 gene may be a selective pressure for maintaining tight linkage of clustered neuronal nAchR genes.

Animals↗
PubMed1997

Elements between the protein-coding regions of the adjacent beta 4 and alpha 3 acetylcholine receptor genes direct neuron-specific expression in the central nervous system.

The expression patterns of three clustered neuronal nicotinic acetylcholine receptor (nAchR) subunit genes ordered beta 4, alpha 3, and alpha 5 overlap extensively in the peripheral nervous system (PNS) but only partially in the central nervous system (CNS). We have begun to investigate cell type-specific cis elements regulating these genes by analyzing in both cell culture and transgenic mice, a 2.8-kb fragment (-2732/+47) containing the alpha 3 promoter region, the beta 4/alpha 3 intergenic region, and a portion of the beta 4 3'-untranslated exon. The -2732/+47 fragment is preferentially active in PC12 cells relative to nonneural cell lines. Deletion analysis revealed a cell type-specific positive transcriptional element positioned in the beta 4 3'-untranslated exon. The positive element is likely to be an enhancer and not a second alpha 3 promoter, because no alpha 3 exons are present in this region. Having shown in cell culture that cell-type specific cis elements are positioned between the beta 4 and alpha 3 coding regions, we investigated the activity of -2732/+47 in vivo. Transgenic mice were generated, which carry the lacZ gene fused downstream of -2732/+47. Expression of the lacZ transgene is restricted to neurons of the CNS; no expression was detected in the PNS or in nonneural tissues. LacZ-positive cells were detected virtually exclusively in a subset of CNS nuclei that transcribe the endogenous alpha 3 gene. Some overlap was seen with the beta 4 gene, but nearly none with the alpha 5 gene. Our results demonstrate that cis elements positioned between the alpha 3 and beta 4 coding regions are important for establishing part of the restricted CNS patterns of beta 4, alpha 3, and alpha 5 gene transcription.

Animals↗
PubMed1994

Characterization of an acetylcholine receptor alpha 3 gene promoter and its activation by the POU domain factor SCIP/Tst-1.

Genes encoding neuronal nicotinic acetylcholine receptors exhibit restricted patterns of expression in the nervous system. We are interested in elucidating the molecular mechanisms responsible for establishing these patterns of expression. This paper presents the characterization of regulatory elements upstream of the neuronal nicotinic acetylcholine receptor alpha 3 gene. We have identified a GC-rich multistart site promoter adjacent to the alpha 3 coding region. Similar alpha 3 start sites were identified in PC12 cells and sympathetic ganglion neurons, suggesting similar control mechanisms in the clonal line and peripheral neurons. The start site region lacks TATA-like sequences but does contain initiator-like sequences. We show, in transient transfection assays, that the POU domain transcription factor, SCIP/Tst-1, specifically activates alpha 3 in a neural context. Other POU domain factors tested only weakly activated or repressed alpha 3. Unexpectedly, we found that alpha 3 basal activity and SCIP/Tst-1 activation of alpha 3 is not dependent on the SCIP/Tst-1 binding sites found upstream of the gene. In addition, mutations in the SCIP/Tst-1 coding region that prevent the factor from binding to DNA with high affinity do not obliterate alpha 3 activation. These results lead us to propose that alpha 3 activation by SCIP/Tst-1 is achieved via protein-protein interactions between SCIP/Tst-1 and a specific complement of transcription factors that act directly on the promoter.

Animals↗