Biomedical subjects

L Xing

Publications and source records attributed to L Xing.

At least 19 recordsLinked to original sources

PubMed1999

Synchronizing dynamic multileaf collimators for producing two-dimensional intensity-modulated fields with minimum beam delivery time.

PURPOSE: Leaf motion synchronization of dynamic multileaf collimators (DMLC) for intensity-modulated radiotherapy (IMRT) is important in improving dose distribution and reducing "tongue-and-groove" effects for a prescribed intensity profile. Leaf synchronization could also be used in transforming a one-dimensional leaf-setting algorithm into a two-dimensional leaf-setting algorithm. In this work, we aim to develop a generalized leaf synchronization method for delivering IMRT with the minimized beam delivery time and the optimized subfield variations for a leaf-setting sequence. METHODS AND MATERIALS: With the leaf synchronization procedure, all active MLC leaf pairs start and finish off a leaf sequence simultaneously. In this work, the MLC leaf pairs were synchronized under the condition that the resulting leaf sequence produces the desired intensity profile with the minimum beam delivery time. The parameter of the leaf synchronization function was determined through the least-square minimization of the area variations of all subfields within a leaf sequence. The leaf synchronization and optimization procedure were applied and analyzed for clinical relevant intensity profiles for treating the head-and-neck cancer patients using IMRT. RESULTS: The total monitor units and the optimized beam delivery time of generating a two-dimensional intensity profile was proven through this work to be the global minimum of all leaf-setting sequences including the unsynchronized leaf-setting sequences. The optimized parameter for subfield variations of the synchronized leaf trajectories was found to be dependent on individual intensity profiles. For all our studied cases, the unsynchronized leaf trajectories always have significantly larger subfield variations than the synchronized leaf trajectories. CONCLUSION: It is important and also feasible to synchronize and optimize dynamic MLC leaf motions while still keeping the total beam delivery time minimum for delivering arbitrary two-dimensional intensity-modulated fields.

Algorithms↗

PubMed1999

Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus.

A cDNA encoding the human guanylate binding protein-1 (hGBP-1) was expressed in HeLa cells using a constitutive expression vector. Stably transfected clones expressing hGBP-1 exhibited resistance to the cytopathic effect mediated by both vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) and produced less viral progeny than control cells following infection with these viruses. To study the role hGBP-1 plays in the IFN-mediated antiviral effect, cells were stably transfected with a construct expressing antisense RNA for hGBP-1. VSV infection of IFN-alpha-treated antisense RNA-expressing cells produced an amount of virus comparable to that produced in the parental cell line, while EMCV infection of the IFN-alpha-treated transfected cells and VSV and EMCV infection of the IFN-gamma-treated transfected cells produced far more virus than was produced in the parental cell line. These results demonstrate that GBP-1 mediates an antiviral effect against VSV and EMCV and plays a role in the IFN-mediated antiviral response against these viruses.

DNA-Binding Proteins↗

PubMed1999

Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand.

Among members of the tumor necrosis factor receptor (TNFR) superfamily, 4-1BB, CD27, and glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) share a striking homology in the cytoplasmic domain. Here we report the identification of a new member, activation-inducible TNFR family member (AITR), which belongs to this subfamily, and its ligand. The receptor is expressed in lymph node and peripheral blood leukocytes, and its expression is up-regulated in human peripheral mononuclear cells mainly after stimulation with anti-CD3/CD28 monoclonal antibodies or phorbol 12-myristate 13-acetate/ionomycin. AITR associates with TRAF1 (TNF receptor-associated factor 1), TRAF2, and TRAF3, and induces nuclear factor (NF)-kappaB activation via TRAF2. The ligand for AITR (AITRL) was found to be an undescribed member of the TNF family, which is expressed in endothelial cells. Thus, AITR and AITRL seem to be important for interactions between activated T lymphocytes and endothelial cells.

Amino Acid Sequence↗

PubMed1999

Identification and characterization of immunoreactive calcitonin gene-related peptide from lymphocytes of the rat.

There is accumulating evidence that the immune system can produce neuropeptides. In the light of these facts, we obtained direct evidences to prove that T lymphocytes also synthesize and secrete calcitonin gene-related peptide (CGRP), a neuropeptide localized within primary sensory nerves. By using CGRP specific RIA, CGRP-like immunoreactivity (LI) was found in the extracts of rat lymphocytes from thymus and mesenteric lymph node. The intracellular concentration of lymphocyte-derived CGRP-LI of rat thymus and mesenteric lymph node was 745+/-39 and 447+/-33 fg/10(6) cells, respectively. CGRP-LI in lymphocytes was shown to co-elute with synthetic rat CGRP and sensory neuron-derived CGRP by reverse-phase HPLC. In addition, the CGRP-LI located in the T lymphocytes was also shown by immunocytochemical method examined by electron microscopy. The CGRP mRNA detected by RT-PCR was also present in these lymphocytes and was also identified to be the same one in sensory neurons. These data suggest that CGRP is synthesized and secreted in T lymphocytes of both thymus and lymph node in the rat, and this is identified to be the same one in neuronal tissue. Lymphocyte-derived CGRP may act in an autocrine/paracrine mode and play an important role in certain physiological and pathophysiological conditions.

Animals↗

PubMed1999

Dental abnormalities associated with failure of tooth eruption in src knockout and op/op mice.

c-src knockout and op/op mice develop osteopetrosis as a result of defective osteoclast function and osteoclast formation, respectively. The mutant mice can be distinguished readily from their wild-type littermates around 10-12 days after birth because their incisors do not erupt, but the morphology of their teeth and surrounding bone has not been reported previously in detail. Histologic examination of jaws of src-mutant mice reveals unerupted, abnormal incisors within their bony crypts. The tooth roots are distorted by foci of haphazard proliferation of odontogenic epithelium associated with primitive tooth structures that strongly resemble the tumor-like lesions in humans, known as odontomas. The crowns of the incisors are fused to the adjacent bone, and the developing periodontal ligament is disordered and hypocellular. Osteoclasts are present in the bone surrounding the distorted teeth, but as in other bones in these mice they lack ruffled borders and thus do not resorb effectively. Similar odontogenic proliferation is present around unerupted incisors in op/op mice which form very few osteoclasts, but the amount is significantly less than in src mutant mice. Molars fail to erupt in both types of mutant mice, but they are not accompanied by aberrant odontogenic proliferation. These findings and previous reports of similar abnormalities in jaws from op/op rats suggest that failure of incisor eruption and associated proliferation of odontogenic epithelium in osteopetrotic rodents are a direct result of defective osteoclastic bone resorption.

Animals↗

PubMed1999

Functional implications of genetic interactions between genes encoding small GTPases involved in vesicular transport in yeast.

Ras-related, guanine nucleotide-binding proteins of the Ypt/Rab family play a key role at defined steps in vesicular transport, both in yeast and in mammalian cells. In yeast, Ypt1p has an essential function late in endoplasmic reticulum (ER) to Golgi transport, and the redundant Ypt31/Ypt32 GTPases have been proposed to act in transport through and/or from the Golgi. Here we report that mutant alleles of YPT31 and YPT32, whose gene products have a reduced affinity for GTP, are able to suppress the dominant lethal phenotype of YPT1(N121I). Co-expression of YPT1(N121I) and the suppressor YPT31(N126I) allow essentially undisturbed secretory transport in the absence of the respective wild-type GTPases. Such mutant cells massively overaccumulate 60-100 nm vesicles and are heat sensitive. It appears likely that the mutant GTPases, which are defective in nucleotide binding, compete for the binding of common interacting protein(s). These and other genetic interactions between YPT1, YPT31/32, ARF1 and SEC4 described here strongly support the view that Ypt31p and Ypt32p have a central, Golgi-associated function in anterograde or retrograde transport.

Biological Transport↗

PubMed1999

Required and nonessential functions of nuclear factor-kappa B in bone cells.

Nuclear factor-kappa B (NF-kappaB) is a set of five polypeptide transcription factors, called p50, p52, p65 (also called Rel A), Rel B, and c-Rel, which regulate the expression of a variety of genes involved in immune and inflammatory responses. They were originally named because they were considered essential regulators of B cell kappa light chain expression. More recent studies indicate that NF-kappaB proteins are involved in the regulation of a variety of other cell functions, including cell proliferation, responses to stress, and apoptosis. NF-kappaB heterodimers reside in the cytoplasm of cells bound to inhibitory proteins, the two commonest of which are IkappaBalpha and IkappaBbeta, which prevent NF-kappaB from entering the nucleus. When cells are stimulated, IkappaB is phosphorylated by specific IkappaB kinases and subsequently is ubiquitinated and degraded in proteosomes. This allows NF-kappaB to translocate to the nucleus to regulate the expression of a growing list of genes, including the proinflammatory cytokines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor. IL-1 and tumor necrosis factor in turn also regulate the expression of NF-kappaB. Thus, once activated, NF-kappaB may be involved in upregulatory loops, which can amplify the effects of the initiating stimulus. Because these proinflammatory cytokines have been implicated in the pathogenesis of estrogen deficiency and inflammation-related bone loss, it is likely that NF-kappaB has a significant role in the increased generation and function of osteoclasts in these circumstances. However, an unexpected and essential role of NF-kappaB in the formation of osteoclasts during development was discovered recently after the generation of knockout mice, which lack the expression of the p50 and p52 subunits. This paper will describe recent studies that reveal an essential role for NF-kappaB signaling in the generation of osteoclasts and that suggest that NF-kappaB may also play a key central role in the activation and survival of osteoclasts in conditions in which osteoclastogenesis is upregulated.

Animals↗

PubMed1999

Comparison of estrogen receptor alpha and beta subtypes based on comparative molecular field analysis (CoMFA).

A substantial body of evidence indicates that both humans and wildlife suffer adverse health effects from exposure to environmental chemicals that are capable of interacting with the endocrine system. The recent cloning of the estrogen receptor beta subtype (ER-beta) suggests that the selective effects of estrogenic compounds may arise in part by the control of different subsets of estrogen-responsive promoters by the two ER subtypes, ER-alpha and ER-beta. In order to identify the structural prerequisites for ligand-ER binding and to discriminate ER-alpha and ER-beta in terms of their ligand-binding specificities, Comparative Molecular Field Analysis (CoMFA) was employed to construct a three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) model on a data set of 31 structurally-diverse compounds for which competitive binding affinities have been measured against both ER-alpha and ER-beta. Structural alignment of the molecules in CoMFA was achieved by maximizing overlap of their steric and electrostatic fields using the Steric and Electrostatic ALignment (SEAL) algorithm. The final CoMFA models, generated by correlating the calculated 3D steric and electrostatic fields with the experimentally observed binding affinities using partial least-squares (PLS) regression, exhibited excellent self-consistency (r2 > 0.99) as well as high internal predictive ability (q2 > 0.65) based on cross-validation. CoMFA-predicted values of RBA for a test set of compounds outside of the training set were consistent with experimental observations. These CoMFA models can serve as guides for the rational design of ER ligands that possess preferential binding affinities for either ER-alpha or ER-beta. These models can also prove useful in risk assessment programs to identify real or suspected EDCs.

Algorithms↗

PubMed1999

Optimization of importance factors in inverse planning.

Inverse treatment planning starts with a treatment objective and obtains the solution by optimizing an objective function. The clinical objectives are usually multifaceted and potentially incompatible with one another. A set of importance factors is often incorporated in the objective function to parametrize trade-off strategies and to prioritize the dose conformality in different anatomical structures. Whereas the general formalism remains the same, different sets of importance factors characterize plans of obviously different flavour and thus critically determine the final plan. Up to now, the determination of these parameters has been a 'guessing' game based on empirical knowledge because the final dose distribution depends on the parameters in a complex and implicit way. The influence of these parameters is not known until the plan optimization is completed. In order to compromise properly the conflicting requirements of the target and sensitive structures, the parameters are usually adjusted through a trial-and-error process. In this paper, a method to estimate these parameters computationally is proposed and an iterative computer algorithm is described to determine these parameters numerically. The treatment plan selection is done in two steps. First, a set of importance factors are chosen and the corresponding beam parameters (e.g. beam profiles) are optimized under the guidance of a quadratic objective function using an iterative algorithm reported earlier. The 'optimal' plan is then evaluated by an additional scoring function. The importance factors in the objective function are accordingly adjusted to improve the ranking of the plan. For every change in the importance factors, the beam parameters need to be re-optimized. This process continues in an iterative fashion until the scoring function is saturated. The algorithm was applied to two clinical cases and the results demonstrated that it has the potential to improve significantly the existing method of inverse planning. It was noticed that near the final solution the plan became insensitive to small variations of the importance factors.

Algorithms↗

PubMed1999

Dosimetric verification of a commercial inverse treatment planning system.

A commercial three-dimensional (3D) inverse treatment planning system, Corvus (Nomos Corporation, Sewickley, PA), was recently made available. This paper reports our preliminary results and experience with commissioning this system for clinical implementation. This system uses a simulated annealing inverse planning algorithm to calculate intensity-modulated fields. The intensity-modulated fields are divided into beam profiles that can be delivered by means of a sequence of leaf settings by a multileaf collimator (MLC). The treatments are delivered using a computer-controlled MLC. To test the dose calculation algorithm used by the Corvus software, the dose distributions for single rectangularly shaped fields were compared with water phantom scan data. The dose distributions predicted to be delivered by multiple fields were measured using an ion chamber that could be positioned in a rotatable cylindrical water phantom. Integrated charge collected by the ion chamber was used to check the absolute dose of single- and multifield intensity modulated treatments at various spatial points. The measured and predicted doses were found to agree to within 4% at all measurement points. Another set of measurements used a cubic polystyrene phantom with radiographic film to record the radiation dose distribution. The films were calibrated and scanned to yield two-dimensional isodose distributions. Finally, a beam imaging system (BIS) was used to measure the intensity-modulated x-ray beam patterns in the beam's-eye view. The BIS-measured images were then compared with a theoretical calculation based on the MLC leaf sequence files to verify that the treatment would be executed accurately and without machine faults. Excellent correlation (correlation coefficients > or = 0.96) was found for all cases. Treatment plans generated using intensity-modulated beams appear to be suitable for treatment of irregularly shaped tumours adjacent to critical structures. The results indicated that the system has potential for clinical radiation treatment planning and delivery and may in the future reduce treatment complexity.

Algorithms↗

PubMed1999

VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo.

A novel member of the tumor necrosis factor (TNF) family has been identified from the human umbilical vein endothelial cell cDNA library, named vascular endothelial growth inhibitor (VEGI). The VEGI gene was mapped to human chromosome 9q32. The cDNA for VEGI encodes a protein of 174 amino acid residues with the characteristics of a type II transmembrane protein. Its amino acid sequence is 20-30% identical to other members of the TNF family. Unlike other members of the TNF family, VEGI is expressed predominantly in endothelial cells. Local production of a secreted form of VEGI via gene transfer caused complete suppression of the growth of MC-38 murine colon cancers in syngeneic C57BL/6 mice. Histological examination showed marked reduction of vascularization in MC-38 tumors that expressed soluble but not membrane-bound VEGI or were transfected with control vector. The conditioned media from soluble VEGI-expressing cells showed marked inhibitory effect on in vitro proliferation of adult bovine aortic endothelial cells. Our data suggest that VEGI is a novel angiogenesis inhibitor of the TNF family and functions in part by directly inhibiting endothelial cell proliferation. The results further suggest that VEGI maybe highly valuable toward angiogenesis-based cancer therapy.

Amino Acid Sequence↗

PubMed1999

Physical characteristics of a miniature multileaf collimator.

A preliminary study of the physical characteristics of a miniature multileaf collimator (mMLC) used with 4 MV x rays is reported. The mMLC attached to the accessory mount of a class C or D Varian linear accelerator (Varian Oncology Systems, Palo Alto, CA) with a source to aperture distance of 65 cm. The field penumbra using the small leaves was found to be consistent with the anticipated field penumbra using photon jaws at the same source to aperture distance as the mMLC. The percentage depth dose values of square fields were found to be consistent with the fields collimated with the upper and lower jaws. Output factors for the very small fields were found to vary rapidly. Circular fields could be produced with depth dose characteristics similar to those produced using conical tertiary collimators, commonly used for radiosurgery, but with a broader penumbra.

Dose-Response Relationship, Radiation↗

PubMed1999

Theoretical considerations of monitor unit calculations for intensity modulated beam treatment planning.

A treatment planning system to compute intensity modulated radiotherapy (IMRT) treatments using inverse planning was investigated. The system was designed to optimize the intensity patterns required to treat a specified target volume with specified normal structure constraints. A beam model that uses the convolution of pencil beams was used to compute the dose distributions. A multileaf collimator leaf-setting sequence intended to produce the intensity pattern was computed along with the monitor units required to deliver each of a number of fixed-gantry modulated fields. Computer calculations are commonly verified using an independent manual procedure. It is difficult to calculate treatment delivery monitor units for this variant of IMRT using manual methods. Since manual calculations are not feasible, it is important both to understand and to verify the calculation of treatment monitor units by the planning system algorithm. A formal analysis was made of the dose calculation model and the monitor unit calculation embedded in the algorithm. Experimental verification of the dose delivered by plans computed with the methodology demonstrated an agreement of better than 4% between the dose model and measurements.

Algorithms↗

PubMed1999

Recent advances in bone biology provide insight into the pathogenesis of bone diseases.

Bone is modeled during embryonic development by endochondral and membranous ossification and is continuously remodeled thereafter under the influence of local and systemic factors to provide structural support and assist in calcium homeostasis. Recent studies of knockout and transgenic mice have increased understanding of the regulation of bone modeling during development and of remodeling of mature bone and have shed new light on the pathogenesis of a number of bone disorders. For example, fibroblast growth factor receptor-3, parathyroid hormone-related protein, and tartrate-resistant acid phosphatase affect the function of chondrocytes during endochondral ossification (the latter two by regulating their life spans and thus growth plate thickness and bone length). Some ubiquitously expressed genes seem unexpectedly to have unique functions that are largely confined to bone cells: M-CSF, C-Fos, PU.1, and NF-kappaB are required for osteoclast formation, whereas c-Src and Mitf (microphthalmia transcription factor) are required for osteoclast activity after the cells have formed. Knockout of these genes results in osteopetrosis, a disorder characterized by persistence in marrow cavities of unresorbed osteocartilaginous matrix and, as in some affected humans, by increased mortality. Some proteins seem to act as negative regulators of bone cell function, for example osteoprotegerin (a soluble TNF receptor) in osteoclasts; osteocalcin, bone sialoprotein, and 5-lipoxygenase in osteoblasts. Regulation of osteoclast life span may be an important mechanism by which estrogen and bisphosphonates prevent bone loss in conditions characterized by increased bone resorption, such as postmenopausal osteoporosis. The unique requirement of bone cells for certain gene products raises the possibility that these cells may have specific responses to inhibitory or stimulatory agents, and that signaling molecules in these response pathways could be specific targets for novel therapies to treat or prevent common bone diseases.

Animals↗

PubMed1998

LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer.

LIGHT is a new member of tumor necrosis factor (TNF) cytokine family derived from an activated T cell cDNA library. LIGHT mRNA is highly expressed in splenocytes, activated PBL, CD8(+) tumor infiltrating lymphocytes, granulocytes, and monocytes but not in the thymus and the tumor cells examined. Introduction of LIGHT cDNA into MDA-MB-231 human breast carcinoma caused complete tumor suppression in vivo. Histological examination showed marked neutrophil infiltration and necrosis in LIGHT expressing but not in the parental or the Neo-transfected MDA-MB-231 tumors. Interferon gamma (IFNgamma) dramatically enhances LIGHT-mediated apoptosis. LIGHT protein triggers apoptosis of various tumor cells expressing both lymphotoxin beta receptor (LTbetaR) and TR2/HVEM receptors, and its cytotoxicity can be blocked specifically by addition of a LTbetaR-Fc or a TR2/HVEM-Fc fusion protein. However, LIGHT was not cytolytic to the tumor cells that express only the LTbetaR or the TR2/HVEM or hematopoietic cells examined that express only the TR2/HVEM, such as PBL, Jurkat cells, or CD8(+) TIL cells. In contrast, treatment of the activated PBL with LIGHT resulted in release of IFNgamma. Our data suggest that LIGHT triggers distinct biological responses based on the expression patterns of its receptors on the target cells. Thus, LIGHT may play a role in the immune modulation and have a potential value in cancer therapy.

Apoptosis↗

PubMed1998

A test of the background selection hypothesis based on nucleotide data from Drosophila ananassae.

We estimated DNA sequence variation within and between four populations of Drosophila ananassae at Om(1D) and vermilion (v) by using single-strand conformation polymorphism analysis and direct DNA sequencing. Om(1D) is located on the X chromosome in a region with a normal recombination rate; v is in a region of low recombination. In each population, levels of nucleotide diversity at v are reduced 10- to 25-fold relative to those at Om(1D). Divergence between D. ananassae and its sibling species D. pallidosa, however, is comparable for both loci. This lack of correlation between levels of polymorphism and divergence led to the rejection of a constant-rate, neutral model. To distinguish among alternative models, we propose a test of the background selection hypothesis based on the observed pattern of differentiation between populations. Although the degree of differentiation (measured by FST) among all pairs of subpopulations is similar at Om(1D), we found substantial differences at v. The two northern populations from Burma and Nepal are very homogeneous, whereas comparisons between northern and southern populations (e.g., between Nepal and middle India) produced large FST values. A coalescent-based simulation of the background selection model (in a geographically structured species with a finite number of demes) showed that the observed homogeneity among the northern populations is inconsistent with the background selection hypothesis. Instead, it may have been caused by a recent hitchhiking event that was limited to the northern species range.

Animals↗

PubMed1998

An optimized leaf-setting algorithm for beam intensity modulation using dynamic multileaf collimators.

A leaf-setting algorithm is developed for generating arbitrary beam intensity profiles in discrete levels using dynamic multileaf collimators (DMLCs). The algorithm starts with the algebraic expression for the area under the beam profile. It is shown that the coefficients in this expression can be transformed into the specifications for the leaf-setting sequence. It is proven that the algorithm optimizes beam delivery time and total monitor units for the DMLC leaf setting for intensity modulated radiotherapy (IMRT). The algorithm is demonstrated to be applicable to both the 'step-and-shoot' and 'dynamic' type of beam delivery. The graphical interpretation and numerical implementation scheme of the algorithm is illustrated using a simplified example.

Algorithms↗

PubMed1998

Fast iterative algorithms for three-dimensional inverse treatment planning.

Three types of iterative algorithms, algebraic inverse treatment planning (AITP), simultaneous iterative inverse treatment planning (SIITP), and iterative least-square inverse treatment planning (ILSITP), differentiated according to their updating sequences, were generalized to three dimension with true beam geometry and dose model. A rapid ray-tracing approach was developed to optimize the primary beam components. Instead of recalculating the dose matrix at each iteration, the dose distribution was generated by scaling up or down the dose matrix elements of the previous iteration. This significantly increased the calculation speed. The iterative algorithms started with an initial intensity profile for each beam, specified by a two-dimensional pixel beam map of M elements. The calculation volume was divided into N voxels, and the calculation was done by repeatedly comparing the calculated and desired doses and adjusting the values of the beam map elements to minimize an objective function. In AITP, the iteration is performed voxel by voxel. For each voxel, the dose discrepancy was evaluated and the contributing pencil beams were updated. In ILSITP and SIITP, the iteration proceeded pencil beam by pencil beam instead of voxel by voxel. In all cases, the iteration procedure was repeated until the best possible dose distribution was achieved. The algorithms were applied to two examples and the results showed that the iterative techniques were able to produce superior isodose distributions.

Algorithms↗