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L Chin

Publications and source records attributed to L Chin.

At least 19 recordsLinked to original sources
PubMed2001

A technique for optimization of digitally reconstructed radiographs of the chest in virtual simulation.

INTRODUCTION: Virtual simulation (VS) of radiotherapy uses CT data. Digitally reconstructed radiographs (DRRs) are a critical element of this process, and the quality of these images is frequently suboptimal. We present techniques to improve DRR quality for clinical purposes. The results of two approaches to DRR optimization are presented. METHODS AND MATERIALS: One approach to DRR optimization is to use traditional radiographs as a guide and to adjust the algorithm parameters based on image and objective contrast to produce images that more closely resemble traditional radiographs (Method 1). Another approach is to focus on the visibility of specific anatomic structures. Using this method, two DRR images are optimized manually by interactively adjusting reconstruction parameters, then they are combined into a single composite image (Method 2). DRRs for the chest region, generated using both methods, were evaluated by clinical staff based on usability for treatment verification and field definition. RESULTS: Using Method 1, the resulting DRRs more closely resembled traditional radiographs. This technique allows DRR quality to be improved with little user interaction. These DRRs are generally adequate for clinical use, but not optimal for sites such as the chest. Images generated using Method 2 were considered clinically superior in terms of visibility of specific anatomic structures. These images also compare well with traditional radiographs, although they show an increased contrast level between bone and lower density structures. CONCLUSION: Both Methods 1 and 2 can be used to improve DRR quality for clinical purposes. For the chest region, the additional effort required by Method 2 to achieve a more detailed image appears justified.

Algorithms↗
PubMed2001

Changes in dielectric properties of ex vivo bovine liver at 915 MHz during heating.

We have developed a coaxial measurement system for determining the time and temperature dependence of the dielectric properties of bovine liver at 915 MHz during heating. Our data suggest that changes in dielectric properties due to heating are dominated by the relaxation response of two tissue components: tissue water and proteins. At temperatures above 60 degrees C, the effects of these two components contribute to increases of up to 100% and 5% in the values of conductivity and permittivity respectively. Changes due to tissue water content were found to be reversible with temperature, while changes due to protein denaturation were found to be permanent. The temperature coefficients for reversible changes were found to be 1.82 +/- 0.28% degrees C(-1) and -0.130 +/- (5.9 x 10(-2))% degrees C(-1) for conductivity and permittivity respectively. The critical temperatures and activation energies leading to irreversible changes in conductivity and permittivity were determined using Arrhenius analysis. Frequency factors of (1.14 +/- 0.27) x 10(43) s(-1) and (1.95 +/- 0.49) x 10(36) s(-1) were determined for permittivity and conductivity respectively. The activation energies were calculated to be 70.7 +/- 15.8 kcal mol(-1) for permittivity and 60.1 +/- 14.0 kcal mol(-1) for conductivity.

Animals↗
PubMed2000

Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.

Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. Among the many factors that may contribute to this species variance are differences in telomere length and regulation. Telomeres comprise the nucleoprotein complexes that cap the ends of eukaryotic chromosomes and are maintained by the reverse transcriptase, telomerase. In human cells, insufficient levels of telomerase lead to telomere attrition with cell division in culture and possibly with ageing and tumorigenesis in vivo. In contrast, critical reduction in telomere length is not observed in the mouse owing to promiscuous telomerase expression and long telomeres. Here we provide evidence that telomere attrition in ageing telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex non-reciprocal translocations--a classical cytogenetic feature of human carcinomas. Our data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers.

Adenocarcinoma↗
PubMed2000

Reduction of cardiac volume in left-breast treatment fields by respiratory maneuvers: a CT study.

PURPOSE: A previous study of healthy female volunteers suggested that deep inspiratory breath holding can reduce the cardiac volume in the treatment portals for left-breast cancer treatment. The reduction of irradiated cardiac volume may be important considering the reported late cardiac morbidity and mortality and the frequent coexistent use of potentially cardiotoxic chemotherapy in breast cancer patients. In the present study, we evaluated the heart volume in the fields and, thus, the true benefit of this respiratory maneuver in breast cancer patients undergoing CT simulation. MATERIALS AND METHODS: Fifteen patients (median age, 53) were studied. For each patient, CT scans were performed both when the patient breathed normally (quiet respiration) and when the patient held her breath after a deep inspiration. Tangential fields were planned using the same medial, lateral, superior, and inferior borders on skin for the normal breathing and the breath-holding configurations. The cardiac and left-lung volumes within the tangential fields were calculated for both breathing configurations. Multiple scan series were performed for the breath-holding configuration to provide a more accurate delineation of the cardiac tissue and to study the reproducibility of the patient's position between different cycles of deep inspiration. RESULTS: None of the patients had difficulty holding her breath for 20 s. The cardiac volume in the field was reduced (-86 +/- 24%; p < 0.001) when patients held their breath after a deep inspiration compared to when breathing normally. For 7 patients (47%), deep inspiration moved the heart completely out of the radiation fields. The expansion of the lung tissue due to deep inspiration also increased the absolute lung volume in the tangential fields (183 cm(3) vs 97 cm(3), p < 0.001). However, the fractional volume of the left lung in the field was essentially unchanged. For all but 1 patient, the maximum difference between the external body contours from different breath holding cycles was 5 mm and occurred at the lateral aspect of the breast. At the medial aspect, as indicated by the position of the midline marker, the variations were well within the currently accepted tolerance for patient positioning during tangential treatment. CONCLUSIONS: Deep-inspiration breath holding substantially reduces cardiac volume in the tangential fields for left-sided breast cancer treatment. The variation between patient positions at different cycles of breath holding was found to be reasonably small. Therefore, it appears feasible to reduce cardiac radiation by treating patients with intratreatment minifractions lasting 10-15 s while patients hold their breath.

Aged↗
PubMed2000

Flipping the oncogene switch: illumination of tumor maintenance and regression.

The genetic construction of cancer-prone mice, combined with the capacity to control transgene expression in vivo, provides new opportunities to study the role of oncogenes in the maintenance of fully formed tumors. These inducible cancer models provide a means to dissect how specific oncogenic signals influence host-tumor symbiosis, to validate the importance of a given oncogenic lesion in established advanced tumors, and to predict the biological response and adaptations to therapies targeted to that cancer-causing genetic alteration.

Animals↗
PubMed2000

An inducible melanoma model implicates a role for RAS in tumor maintenance and angiogenesis.

The established tumor is maintained through complex and poorly understood host-tumor interactions guiding processes such as angiogenesis. The numerous and diverse genetic alterations that accompany tumor genesis raises questions as to whether experimental cancer-promoting mutations remain relevant to tumor maintenance. Utilizing a new doxycycline-inducible H-RASV12G INK4a null mouse melanoma model, we have shown that melanoma genesis and maintenance are strictly dependent upon H-RASV12G expression. Withdrawal of doxycycline and H-RASV12G down-regulation resulted in clinical and histological regression of primary and explanted tumors. Moreover, the initial stages of regression were highlighted by dramatic activation of apoptosis in the tumor cells as well as host-derived endothelial cells. These data provide genetic evidence that H-RASV12G plays a critical role in tumor maintenance and tumor angiogenesis.

Animals↗
PubMed2000

Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation.

Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associated with rampant genetic instability and loss of cellular viability and renewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the 'capture' or de novo synthesis of telomere repeats at double-stranded breaks and by the capacity of yeast telomeres to serve as repositories of essential components of the DNA repair machinery, particularly those involved in non-homologous end-joining (NHEJ). Here we used the telomerase-deficient mouse, null for the essential telomerase RNA gene (Terc), to assess the role of telomerase and telomere function on the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc-/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. Our findings establish a intimate relationship between functionally intact telomeres and the genomic, cellular and organismal response to ionizing radiation.

Animals↗
PubMed1999

Essential role for oncogenic Ras in tumour maintenance.

Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.

Animals↗
PubMed1999

Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse.

Maintenance of telomere length is predicted to be essential for bypass of senescence and crisis checkpoints in cancer cells. The impact of telomere dysfunction on tumorigenesis was assessed in successive generations of mice doubly null for the telomerase RNA (mTR) and the INK4a tumor suppressor genes. Significant reductions in tumor formation in vivo and oncogenic potential in vitro were observed in late generations of telomerase deficiency, coincident with severe telomere shortening and associated dysfunction. Reintroduction of mTR into cells significantly restored the oncogenic potential, indicating telomerase activation is a cooperating event in the malignant transformation of cells containing critically short telomeres. The results described here demonstrate that loss of telomere function in a cancer-prone mouse model possessing intact DNA damage responses impairs, but does not prevent, tumor formation.

Animals↗
PubMed1999

p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis.

Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.

Animals↗
PubMed1999

Differential effects of the widely expressed dMax splice variant of Max on E-box vs initiator element-mediated regulation by c-Myc.

dMax, a naturally occurring splice variant of the Myc binding protein Max, lacks the DNA binding basic region and helix 1 of the Helix-Loop-Helix domain; dMax interacts with c-Myc in vitro and in vivo, and inhibits E-box Myc site driven transcription in transient transfection assays. Here we have investigated the expression, function and interactions of dMax. RT/PCR analyses detected dmax mRNA in multiple tissues of the developing, newborn and adult mouse. Functionally, dMax reduced the ability of c-Myc to cooperate with the progression factor A-Myb to promote S phase entry of quiescent smooth muscle cells. In contrast, dMax failed to ablate inhibition of initiator element (Inr)-mediated transcription by c-Myc in Jurkat T cells. In in vitro protein:protein association assays, dMax interacted with c-Myc, N-Myc, L-Myc, Mad1, Mxi1, Mad3 and Mad4, but not with itself or wild-type Max. These interactions required an intact leucine zipper. Inhibition of E-box-mediated transactivation by induction of dMax overexpression resulted in apoptosis of WEHI 231 B cells. Thus, dMax is a widely expressed, naturally occurring protein, with the capacity to bind most members of the Myc/Max superfamily; dMax has little effect on Inr-mediated repression by c-Myc, but can significantly decrease E-box-mediated events promoting proliferation and cell survival.

Animals↗
PubMed1999

Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation.

The telomerase reverse transcriptase component (TERT) is not expressed in most primary somatic human cells and tissues, but is upregulated in the majority of immortalized cell lines and tumors. Here, we identify the c-Myc transcription factor as a direct mediator of telomerase activation in primary human fibroblasts through its ability to specifically induce TERT gene expression. Through the use of a hormone inducible form of c-Myc (c-Myc-ER), we demonstrate that Myc-induced activation of the hTERT promoter requires an evolutionarily conserved E-box and that c-Myc-ER-induced accumulation of hTERT mRNA takes place in the absence of de novo protein synthesis. These findings demonstrate that the TERT gene is a direct transcriptional target of c-Myc. Since telomerase activation frequently correlates with immortalization and telomerase functions to stabilize telomers in cycling cells, we tested whether Myc-induced activation of TERT gene expression represents an important mechanism through which c-Myc acts to immortalize cells. Employing the rat embryo fibroblast cooperation assay, we show that TERT is unable to substitute for c-Myc in the transformation of primary rodent fibroblasts, suggesting that the transforming activities of Myc extend beyond its ability to activate TERT gene expression and hence telomerase activity.

Animals↗
PubMed1999

Virtual light field projection for CT-simulation.

We report a method to project a virtual light field over the patient during CT-simulations of external beam radiotherapy. It can be used to perform all the tasks associated with the physical light field of a conventional simulator. The system consists of a three-dimensional sonic digitizer interfacing with a window-based software on a personal computer. The digitizer can provide the three-dimensional coordinates of any point in space accessible by the digitizer probe. When these coordinates are transformed into the beam's eye view, the position of the digitized point relative to the beam can readily be displayed. Thus, the system establishes a virtual light field in space, which can be "seen" only by the digitizer probe. For any digitized point, the system can immediately show, by the beam's eye view display, whether the point is inside the field, outside of the field, or on the field border. Moreover, this virtual field projection allows one to evaluate external target coverage (or external normal tissue sparing) conveniently and interactively. By simply digitizing the concerned area and viewing its position in the beam's eye view display, one can immediately assess the coverage and if necessary, modify the treatment field accordingly. The system also provides an efficient and essential procedure in CT-simulations for marking treatment portals on the patient. By cruising the digitizer probe on the patient's skin surface under visual and audio guidances, one can promptly find the projection of the field center, field corners, etc., on the patient. Measurements have been performed to study the accuracy of the GP-12 sonic digitizer using rigid phantoms. Based on the measured data, the overall accuracy of the portal localization system is estimated to be +/-2 mm. The system has been in clinical use for our CT simulator.

Calibration↗
PubMed1999

Involvement of the Ink4a gene (p16 and p19arf) in murine tumorigenesis.

The INK4A and INK4B genes map to 9p21, with the INK4A gene encoding two products, p16 and p19ARF. Many neoplasms in which INK4A and INK4B genes are altered show deletions involving both genes. Mice carrying a targeted Ink4a deletion develop tumors at an early age. In the present study we examined the genetic alterations affecting the remaining Ink4a allele and the Ink4b gene in tumors arising in heterozygous Ink4a mice. We identified deletion of the remaining Ink4a allele in 7 of 18 (39%) tumors. We also observed deletion of the exon 1beta in 3 cases, one of them presenting this deletion as a unique alteration. In conclusion, the deletion of the remaining Ink4a allele was the alteration most frequently observed, representing the inactivation of two proteins capable of arresting the cell cycle through different pathways that involve the tumor suppressors pRB and p53.

Animals↗