World records in obstetrics and gynaecology.
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Biomedical subjects
L Chin
Publications and source records attributed to L Chin.
Common and contrasting genomic profiles among the major human lung cancer subtypes.
Lung cancer is the leading cause of cancer mortality worldwide. With the recent success of molecularly targeted therapies in this disease, a detailed knowledge of the spectrum of genetic lesions in lung cancer represents a critical step in the development of additional effective agents. An integrated high-resolution survey of regional amplifications and deletions and gene expression profiling of non-small-cell lung cancers (NSCLC) identified 93 focal high-confidence copy number alterations (CNAs), with 21 spanning less than 0.5 Mb with a median of five genes. Most CNAs were novel and included high-amplitude amplification and homozygous deletion events. Pathogenic relevance of these genomic alterations was further reinforced by their recurrence and overlap with focal alterations of other tumor types. Additionally, the comparison of the genomic profiles of the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC), showed an almost complete overlap with the exception of one amplified region on chromosome 3, specific for SCC. Among the few genes overexpressed within this amplicon was p63, a known regulator of squamous cell differentiation. These findings suggest that the AC and SCC subtypes may arise from a common cell of origin and they are driven to their distinct phenotypic end points by altered expression of a limited number of key genes such as p63.
Adenocarcinoma↗
Changes in the dielectric properties of rat prostate ex vivo at 915 MHz during heating.
Changes in the tissue dielectric properties at 915 MHz of rat prostate tissue due to heating at temperatures in the range 45-75 degrees C were measured. The changes were found to be reversible with temperature and independent of the time of heating. The dielectric properties at 23 +/- 1 degrees C were measured as epsilon' = 62.8 +/- 2.7 and sigma = 1.17 +/- 0.07 S/m, while the linear temperature coefficients for reversible changes were 1.10 +/- 0.11%/ degree C for conductivity and -0.31 +/- 0.05% /degree C for relative permittivity. These properties and their temperature coefficients can be utilized in microwave treatment planning programmes to provide insight into the effects of dielectric changes that arise during microwave thermal therapy of prostate cancer.
Animals↗
Propylthiouracil and carbimazole associated-antineutrophil cytoplasmic antibodies (ANCA) in patients with Graves' disease.
OBJECTIVE: Propylthiouracil treatment of Graves' disease has been postulated to provoke antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aimed to investigate whether carbimazole therapy was also associated with increased risk of ANCA. DESIGN: The occurrence of ANCA and the relationship to thionamide treatment was investigated in a cross-sectional study in a consecutive series of 407 patients' with Graves' disease, 200 with Hashimoto's thyroiditis and 649 normal euthyroid subjects. MEASUREMENTS: ANCA was measured by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) for proteinase 3 and myeloperoxidase-ANCA. RESULTS: The prevalence of ANCA, as measured by IIF, was increased in the Graves' disease cohort (19.9%) compared with euthyroid controls (4.6%; P < 0.001). The prevalence of MPO-ANCA (measured by ELISA) was also increased in Graves' disease (P = 0.019). ANCA prevalence was more strongly associated with propylthiouracil treatment than carbimazole (P = 0.0265), although risk of ANCA was also higher in Graves' patients treated with carbimazole than controls (RR 2.2, P < 0.0001). ANCA positivity was not increased in patients with Hashimoto's thyroiditis. CONCLUSION: This study revealed a high prevalence of ANCA in treated patients with Graves' disease but not in those with Hashimoto's thyroiditis. Furthermore, within the Graves' disease population, ANCA development was associated with propylthiouracil usage to a greater extent than carbimazole. These findings suggest that the altered immune environment associated with autoimmune thyroid disease is not sufficient to develop ANCA but treatment with thionamides is important in promoting ANCA development.
Adult↗
A dosimetric comparison of two multileaf collimator designs.
We present the results of measurements designed to compare two different multileaf collimator (MLC) designs using a novel evaluation technique. The MLC designs evaluated were: a "single-focused" MLC (SF-MLC) mounted below the jaws, and a "double-focused" MLC, which is a complete replacement for the lower jaws. The ability of each MLC to conform isodose lines to a prescribed field edge (PFE) was evaluated using film dosimetry. Circular fields, centered on axis and off axis, were used because they produce a range of "angles of approach" between the MLC leaves and the PFE. They also have the advantage that for an ideal field shaping system the resulting isodoses are concentric perfect circles, a well-defined basis for evaluation. The amplitude of the oscillations of the 50% isodose line about the PFE and the penumbra width as determined by the 20%, 80%, and 90% isodose lines was examined. We observe that the 50% isodose line oscillates around the PFE with greater amplitude for SF-MLC. We attribute this, at least in part, to the rounded ends of the SF-MLC leaves. However, the SF-MLC has a noticeably sharper penumbra, which we attribute to its position further from the source. We conclude that these results are relevant for accurate dosimetric modeling of these devices.
Equipment Design↗
Induction of melanoma in murine macrophage inflammatory protein 2 transgenic mice heterozygous for inhibitor of kinase/alternate reading frame.
The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma are poorly understood, attributable in large part to the different genetic alterations accompanying tumorigenesis. Inhibitor of kinase 4a (INK4a) is often inactivated in families with hereditary melanoma. Loss of INK4a/alternate reading frame (ARF) in mice is associated with increased incidence of other tumors such as lymphoma and fibrosarcoma. However, the incidence of melanoma in INK4a/ARF-deficient mice is very low. Our previous studies have revealed that the CXC chemokine, CXCL1, is overexpressed in human malignant melanoma cells and is linked to transformation of immortalized murine melanocytes. To study the direct role of CXCL1 on the genesis of primary melanoma lesions, transgenic mouse lines were established that express the murine homologue of CXCL1, murine macrophage inflammatory protein 2 (MIP-2), under the transcriptional control of the tyrosinase promoter/enhancer (Tyr-MIP-2) in the mice that were deficient or not deficient for INK4a/ARF. Strong MIP-2 immunoreactivity was associated with pigmented melanocytes in the hyperproliferative hair follicles in the Tyr-MIP-2 transgenic mice, and the level of MIP-2 expression was similar in both INK4a/ARF heterozygous or wild-type mice. After treatment of mice with 7,12-dimethylbenz(a)anthracene, cutaneous melanomas formed in 12% (17/145) of the Tyr-MIP-2 transgene-positive mice, whereas only 2% (3/146) of the Tyr-MIP-2 transgene-negative mice developed melanoma. When melanocytes cultured from MIP-2 transgenic mice null for INK4a/ARF were transplanted into nude mice, melanoma formation occurred in 83% (10/12) of the cases with a latency period of 3 months. However, no melanoma lesions arose in nude mice injected with INK4a/ARF -/- melanocytes, which did not express the MIP-2 transgene. Our results demonstrate that constitutive expression of MIP-2 in INK4a/ARF-deficient melanocytes facilitates formation of malignant melanoma.
Animals↗
Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome.
Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and key regulator of both physiologic and pathologic (e.g., tumor) angiogenesis. In the course of studies designed to assess the ability of constitutive VEGF to block tumor regression in an inducible RAS melanoma model, mice implanted with VEGF-expressing tumors sustained high morbidity and mortality that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome characterized by massive sinusoidal dilation and endothelial cell proliferation and apoptosis. Systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-induced liver pathology and prolonged survival were achieved by surgical excision of VEGF-secreting tumor or by systemic administration of a potent VEGF antagonist (VEGF-TRAP(R1R2)), thus defining a paraneoplastic syndrome caused by excessive VEGF activity. Moreover, this VEGF-induced syndrome resembles peliosis hepatis, a rare human condition that is encountered in the setting of advanced malignancies, high-dose androgen therapy, and Bartonella henselae infection. Thus, our findings in the mouse have suggested an etiologic role for VEGF in this disease and may lead to diagnostic and therapeutic options for this debilitating condition in humans.
Animals↗
Telomere dysfunction alters the chemotherapeutic profile of transformed cells.
Telomerase inhibition has been touted as a novel cancer-selective therapeutic goal based on the observation of high telomerase levels in most cancers and the importance of telomere maintenance in long-term cellular growth and survival. Here, the impact of telomere dysfunction on chemotherapeutic responses was assessed in normal and neoplastic cells derived from telomerase RNA null (mTERC(-/-)) mice. Telomere dysfunction, rather than telomerase per se, was found to be the principal determinant governing chemosensitivity specifically to agents that induced double-stranded DNA breaks (DSB). Enhanced chemosensitivity in telomere dysfunctional cells was linked to therapy-induced fragmentation and multichromosomal fusions, whereas telomerase reconstitution restored genomic integrity and chemoresistance. Loss of p53 function muted the cytotoxic effects of DSB-inducing agents in cells with telomere dysfunction. Together, these results point to the combined use of DSB-inducing agents and telomere maintenance inhibition as an effective anticancer therapeutic approach particularly in cells with intact p53-dependent checkpoint responses.
Animals↗
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↗
Genetic dissection of melanoma pathways in the mouse.
The frequent loss of the INK4a/ARF locus, encoding for both p16(INK4a)and p19(ARF)in human melanoma, raises the question as to which INK4a/ARF gene product functions to suppress melanoma-genesis in vivo. Studies in the mouse have shown that activated RAS mutation can cooperate with INK4a(Delta 2/3)deficiency (null for both p16(INK4a)and p19(ARF)) to promote development of melanoma, and these melanomas retain wild-type p53. Given the functional link between p19(ARF)and p53, we have now shown that activated RAS can also cooperate with p53 deficiency to produce melanoma in the mouse. Moreover, genome-wide analysis of RAS-induced p53 mutant melanomas reveals alterations of key components governing RB-regulated G1/S transition, such as c-Myc. These experimental findings suggest that both RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.
Animals↗
Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions.
Although nonhomologous end-joining (NHEJ) deficiency has been shown to accelerate lymphoma formation in mice, its role in suppressing tumors in cells that do not undergo V(D)J recombination is unclear. Utilizing a tumor-prone mouse strain (ink4a/arf(-/-)), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis. We demonstrate that lig4 heterozygosity promotes the development of soft-tissue sarcomas that possess clonal amplifications, deletions, and translocations. That these genomic alterations are relevant in tumorigenesis is supported by the finding of frequent mdm2 amplification, a known oncogene in human sarcoma. Together, these findings support the view that loss of a single lig4 allele results in NHEJ activity being sufficiently reduced to engender chromosomal aberrations that drive non-lymphoid tumorigenesis.
Animals↗
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↗
Telomere dysfunction triggers developmentally regulated germ cell apoptosis.
Telomere dysfunction results in fertility defects in a number of organisms. Although data from fission yeast and Caenorhabditis elegans suggests that telomere dysfunction manifests itself primarily as defects in proper meiotic chromosome segregation, it is unclear how mammalian telomere dysfunction results in germ cell death. To investigate the specific effects of telomere dysfunction on mammalian germ cell development, we examined the meiotic progression and germ cell apoptosis in late generation telomerase null mice. Our results indicate that chromosome asynapsis and missegregation are not the cause of infertility in mice with shortened telomeres. Rather, telomere dysfunction is recognized at the onset of meiosis, and cells with telomeric defects are removed from the germ cell precursor pool. This germ cell telomere surveillance may be an important mechanism to protect against the transmission of dysfunctional telomeres and chromosomal abnormalities.
Animals↗
Disruption of the Cockayne syndrome B gene impairs spontaneous tumorigenesis in cancer-predisposed Ink4a/ARF knockout mice.
Cells isolated from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair, which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS group A (CSA) or group B (CSB) do not exhibit an increased spontaneous or UV-induced cancer rate. In order to investigate the effect of CSB deficiency on spontaneous carcinogenesis, we crossed CSB(-/-) mice with cancer-prone mice lacking the p16(Ink4a)/p19(ARF) tumor suppressor locus. CSB(-/-) mice are sensitive to UV-induced skin cancer but show no increased rate of spontaneous cancer. CSB(-/-) Ink4a/ARF(-/-) mice developed 60% fewer tumors than Ink4a/ARF(-/-) animals and demonstrated a longer tumor-free latency time (260 versus 150 days). Moreover, CSB(-/-) Ink4a/ARF(-/-) mouse embryo fibroblasts (MEFs) exhibited a lower colony formation rate after low-density seeding, a lower rate of H-Ras-induced transformation, slower proliferation, and a lower mRNA synthesis rate than Ink4a/ARF(-/-) MEFs. CSB(-/-) Ink4a/ARF(-/-) MEFs were also more sensitive to UV-induced p53 induction and UV-induced apoptosis than were Ink4a/ARF(-/-) MEFs. In order to investigate whether the apparent antineoplastic effect of CSB gene disruption was caused by sensitization to genotoxin-induced (p53-mediated) apoptosis or by p53-independent sequelae, we also generated p53(-/-) and CSB(-/-) p53(-/-) MEFs. The CSB(-/-) p53(-/-) MEFs demonstrated lower colony formation efficiency, a lower proliferation rate, a lower mRNA synthesis rate, and a higher rate of UV-induced cell death than p53(-/-) MEFs. Collectively, these results indicate that the antineoplastic effect of CSB gene disruption is at least partially p53 independent; it may result from impaired transcription or from apoptosis secondary to environmental or endogenous DNA damage.
Age Factors↗
Dual inactivation of RB and p53 pathways in RAS-induced melanomas.
The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a(Delta2/3) deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RAS(V12G), Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate with p53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising in INK4a(Delta2/3-/-) mice, and whether tumor-associated mutations emerge in the p16(INK4a)-RB pathway in such melanomas. Here, we report that p53 inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on the INK4a(Delta2/3) null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G(1)/S transition, including c-Myc, cyclin D1, cdc25a, and p21(CIP1). Consistent with the profile of c-Myc dysregulation, the reintroduction of p16(INK4a) profoundly reduced the growth of Tyr-RAS INK4a(Delta2/3-/-) tumor cells but had no effect on tumor cells derived from Tyr-RAS p53(-/-) melanomas. Together, these data validate a role for p53 inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.
Animals↗
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↗
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↗
Animal models of melanoma: recent advances and future prospects.
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Animals↗