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Biomedical subjects

I Ding

Publications and source records attributed to I Ding.

At least 19 recordsLinked to original sources
PubMed2004

Overexpression of VEGF121, but not VEGF165 or FGF-1, improves oxygenation in MCF-7 breast tumours.

Vascular endothelial growth factor (VEGF) is an intensively studied molecule that has significant potential, both in stimulating angiogenesis and as a target for antiangiogenic approaches. We utilised MCF-7 breast cancer cells transfected with either of two of the major VEGF isoforms, VEGF(121) or VEGF(165), or fibroblast growth factor-1 (FGF-1) to distinguish the effects of these factors on tumour growth, vascular function, and oxygen delivery. While each transfectant demonstrated substantially increased tumorigenicity and growth rate compared to vector controls, only VEGF(121) produced a combination of significantly reduced total and perfused vessel spacing, as well as a corresponding reduction in overall tumour hypoxia. Such pathophysiological effects are of potential importance, since antiangiogenic agents designed to block VEGF isoforms could in turn result in the development of therapeutically unfavourable environments. If antiangiogenic agents are also combined with conventional therapies such as irradiation or chemotherapy, microregional deficiencies in oxygenation could play a key role in ultimate therapeutic success.

Angiogenesis Inhibitors↗
PubMed2003

[Rare cause of a chest pain].

HISTORY AND ADMISSION FINDINGS: A 42-year-old woman was admitted because of a newly perceived pain localized in the ventral part of the fifth left rib. The physical examination was normal except for a palpable nodular thyroid and pain on palpation of this rib. The patient history contained a serious car accident and severe cigarette abuse. DIAGNOSTIC PROCEDURES: The chest x-ray in "bone technique" showed an osteolysis in the fifth left rib, which was confirmed by computer tomography and bone scan. The high resolution CT scan of the lung revealed a discrete interstitial reticular pattern with minor cystic alterations without lymph node enlargement. DIAGNOSIS, THERAPY AND CLINICAL COURSE: Transbronchial biopsy, bronchoalveolar lavage and a malignancy screening did not lead to a diagnosis. Therefore, the patient was submitted to partial rib resection and open lung biopsy. Histological examination revealed a Langerhans cell histiocytosis. The initial therapeutic approach was a strict smoking cessation. CONCLUSION: The differential diagnosis of a lytic bone lesion in a heavy smoker should include Langerhans cell histiocytosis. On smoking cessation a remission of the disease may be achieved.

Adult↗
PubMed2003

Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers.

The antioxidant glutathione (GSH) is increased in the epithelial lining fluid (ELF) of chronic smokers. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), also known as gamma-glutamylcysteine synthetase, consisting of a heavy, catalytic (GCLC) and a light, modulatory (GCLM) subunit. To determine the contribution of bronchoalveolar lavage (BAL) cells to GSH levels in ELF, BAL was performed in eight smokers and eight never-smokers. Intra- and extracellular total glutathione (GSHt) levels and GCL subunit expression were assessed. GSHt was increased in ELF from smokers (1,090.1 +/- 163.0 microM versus 559.2 +/- 48.2 microM). GSHt content of BAL cells (nmol x mg protein(-1)) was decreased in smokers without differences reaching statistical significance (8.0 +/- 1.4 versus 12.4 +/- 2.6). GCLM expression was also reduced in smokers (0.6 +/- 0.1 versus 2.8 +/- 0.4) and correlated with intracellular GSHt content. There was no significant difference in GCLC expression and in differential cell counts in BAL fluid. The authors conclude that smoking does increase glutathione levels in the epithelial lining fluid but not intracellular levels in bronchoalveolar lavage cells. The data suggest that the intracellular glutathione concentration of bronchoalveolar lavage cells (predominately alveolar macrophages) is regulated by the modulatory glutamate-cysteine ligase subunit rather than the catalytic subunit.

Adult↗
PubMed2002

Zonal image analysis of tumour vascular perfusion, hypoxia, and necrosis.

A number of laboratories are utilising both hypoxia and perfusion markers to spatially quantify tumour oxygenation and vascular distributions, and scientists are increasingly turning to automated image analysis methods to quantify such interrelationships. In these studies, the presence of regions of necrosis in the immunohistochemical sections remains a potentially significant source of error. In the present work, frozen MCa-4 mammary tumour sections were used to obtain a series of corresponding image montages. Total vessels were identified using CD31 staining, perfused vessels by DiOC(7) staining, hypoxia by EF5/Cy3 uptake, and necrosis by haematoxylin and eosin staining. Our goal was to utilise image analysis techniques to spatially quantitate hypoxic marker binding as a function of distance from the nearest blood vessel. Several refinements to previous imaging methods are described: (1) hypoxia marker images are quantified in terms of their intensity levels, thus providing an analysis of the gradients in hypoxia with increasing distances from blood vessels, (2) zonal imaging masks are derived, which permit spatial sampling of images at precisely defined distances from blood vessels, as well as the omission of necrotic artifacts, (3) thresholding techniques are applied to omit holes in the tissue sections, and (4) distance mapping is utilised to define vascular spacing.

Animals↗
PubMed2001

Intratumoral administration of endostatin plasmid inhibits vascular growth and perfusion in MCa-4 murine mammary carcinomas.

Endostatin, a fragment of the COOH-terminal domain of mouse collagen XVIII is a recently demonstrated endogenous inhibitor of tumor angiogenesis and endothelial cell growth. Antiangiogenic therapy with endostatin in animals requires multiple and prolonged administration of the protein. Gene therapy could provide an alternative approach to continuous local delivery of this antiangiogenic factor in vivo. Established MCa-4 murine mammary carcinomas, grown in immunodeficient mice, were treated with intratumoral injection of endostatin plasmid at 7-day intervals. At the time of sacrifice, 14 days after the first injection, endostatin-treated tumor weights were 51% of controls (P < 0.01). Tumor growth inhibition was accompanied by a marked reduction in total vascular density. Specifically, computerized image analysis showed a 18-21% increase in the median distances between tumor cells and both the nearest anatomical (CD31-stained) vessel [48.1 +/- 3.8 versus 38.3 +/- 1.6 microm (P < 0.05)] and the nearest tumor-specific (CD105-stained) vessel [48.5 +/- 1.5 versus 39.8 +/- 1.5 microm (P < 0.01)]. An increased apoptotic index of tumor cells in endostatin-treated tumors [3.2 +/- 0.5% versus 1.9 +/- 0.3% (P < 0.05)] was observed in conjunction with a significant decrease in tumor perfused vessels (DiOC7 staining), and an increase in tumor cell hypoxia (EF5 staining). Hypoxia resulting from endostatin therapy most likely caused a compensatory increase of in situ vascular endothelial growth factor (VEGF) and VEGF receptor mRNA expression. Increased immunoreactivity of endostatin staining in endostatin-treated tumors was also associated with an increased thrombospondin-1 staining [1.12 +/- 0.16 versus 2.44 +/- 0.35]. Our data suggest that intratumoral delivery of the endostatin gene efficiently suppresses murine mammary carcinoma growth and support the potential utility of the endostatin gene for cancer therapy.

Animals↗
PubMed2001

Rapid differentiation of five common alpha-thalassemia genotypes by polymerase chain reaction.

The alpha-thalassemias are common genetic disorders that arise from reduced synthesis of the alpha-globin chains. At present, large-scale carrier screening and clinically valuable antenatal detection programs have not been established for the congenital disorder alpha-thalassemia (alpha-thal). We have developed a simple nonradioactive polymerase chain reaction (PCR) approach that can detect and differentiate several common alpha-globin gene deletional alpha-thals regardless of the break points. When three primer sets were used--two gene-specific sets for the alpha1- and alpha2-globin genes and one set for the beta-actin gene (serving as an internal control)--PCR products from genomic DNA were simultaneously amplified and analyzed after coamplification and gel electrophoresis. The number of alpha-globin genes present in the subjects was determined by the intensity of alpha1 and alpha2 bands normalized with that of beta-actin when using densitometry. Our results demonstrate that five common genotypes of deletional alpha-thal are differentiated by the ratios of alpha1/beta-actin and alpha2/beta-actin. We also examined the feasibility of coupling this allele-specific amplification to a color-complementary assay. This easy and reproducible PCR assay is suitable for identifying alpha-thal carriers in screenings of large populations and improving genetic counseling.

Actins↗
PubMed2001

Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells.

Tumor growth and metastasis are critically dependent on the formation of new blood vessels. The present study found that extracellular matrix protein 1 (ECM1), a newly described secretory glycoprotein, promotes angiogenesis. This was initially suggested by in situ hybridization studies of mouse embryos indicating that the ECM1 message was associated with blood vessels and its expression pattern was similar to that of flk-1, a recognized marker for endothelium. More direct evidence for the role of ECM1 in angiogenesis was provided by the fact that highly purified recombinant ECM1 stimulated the proliferation of cultured endothelial cells and promoted blood vessel formation in the chorioallantoic membrane of chicken embryos. Immunohistochemical staining with specific antibodies indicated that ECM1 was expressed by the human breast cancer cell lines MDA-435 and LCC15, both of which are highly tumorigenic. In addition, staining of tissue sections from patients with breast cancer revealed that ECM1 was present in a significant proportion of primary and secondary tumors. Collectively, the results of this study suggest that ECM1 possesses angiogenic properties that may promote tumor progression.

Angiogenesis Inducing Agents↗
PubMed2001

Characterization of the effects of antiangiogenic agents on tumor pathophysiology.

A variety of strategies have been proposed to control tumor growth and metastasis by inhibiting tumor angiogenesis. To optimally combine such antiangiogenic approaches with conventional therapy, improved methods are needed to characterize the underlying pathophysiologic changes. The objective of the current work was to demonstrate the utility of a combination of recently developed immunohistochemical and image analysis techniques in quantitating changes in tumor vasculature and hypoxia. Murine MCa-35 mammary carcinomas were frozen after administration of two COX-2 inhibitors: meloxicam and celecoxib (Celebrex). Total blood vessels were visualized using anti-CD31 staining, perfused vessels by intravenous injection of DiOC7, and tumor hypoxia by EF5 uptake. Although both agents produced similar reductions in tumor volume compared with untreated tumors, varied effects on tumor vasculature and hypoxia were noted. Meloxicam reduced total vessel numbers significantly, whereas celecoxib had no effect. Both drugs substantially increased perfused vessel densities. Although mean hypoxic marker uptake was unchanged from matched controls, intratumor EF5 heterogeneities were significantly different between drugs. The results suggest that COX-2 inhibitors can have varying effects on tumor pathophysiology. Successful use of these drugs to enhance radiation response will likely require optimization of drug choice, dose schedule, and direct physiologic monitoring.

Angiogenesis Inhibitors↗
PubMed2001

Keratinocyte growth factors radioprotect bowel and bone marrow but not KHT sarcoma.

Various members of the fibroblast growth factor (FGF) family of proteins have been shown to protect against acute and late radiation damage of normal tissues. Protection of the small bowel, for example, occurs via both increased proliferation and reduced apoptosis. Other beneficial effects of FGFs include promotion of bone growth, pneumonitis prevention, and apoptosis suppression of endothelium in vivo and in vitro after irradiation. This protection against radiation requires only low and infrequent doses of FGFs. Two newly identified members of the FGF family, FGF7 and FGF10, have effects similar to many of the other FGF family proteins, but with more specificity for normal epithelial structures. For this reason, they have also been named keratinocyte growth factors one and two (KGF1 and KGF2, respectively). We therefore examined the potential utility of KGFs for radioprotection of the bone marrow and small bowel and examined safety issues concerning their adverse effects on KHT sarcoma. The results suggest that KGFs could be safely used to prevent radiation toxicity of the abdomen or pelvis and may in fact improve tumor response to radiation.

Animals↗
PubMed1999

Biochemical and functional analysis of mice deficient in expression of the CD45-associated phosphoprotein LPAP.

The role of the CD45-associated phosphoprotein (LPAP / CD45-AP) during an immune response remains unclear. To understand better the function of LPAP we generated LPAP-deficient mice by disrupting exon 2 of the LPAP gene. LPAP-null mice were healthy and did not show gross abnormalities compared to their wild-type littermates. However, immunofluorescence analysis of T and B lymphocytes revealed a reduced expression of CD45, which did not affect a particular subpopulation. In contrast to a recent report (Matsuda et al., J. Exp. Med. 1998. 187: 1863 - 1870) we neither observed significant alterations of the assembly of the CD45 / lck-complex nor of polyclonal T-cell responses. However, lymphnodes from LPAP-null mice showed increased cellularity, which could indicate that expression of LPAP might be required to prevent expansion of lymphocytes in particular lymphatic organs rather than potentiating immune responses.

Animals↗
PubMed1999

Circulating basic fibroblast growth factor declines during Cy/TBI bone marrow transplantation.

Basic fibroblast growth factor (bFGF) inhibits radiation-induced apoptosis, and radioprotects haematopoietic, cartilage growth plate, pulmonary and gastrointestinal tissues. Conversely, chronic overexpression of bFGF may promote fibrosis. We measured the endogenous circulating bFGF in blood of patients undergoing conditioning TBI. Twenty-six patients with haematopoietic malignancies were conditioned with cyclophosphamide/TBI for allogeneic BMT. Daily blood samples were collected each morning prior to, during, and for several days after TBI. bFGF levels in plasma of normal volunteers are 0.8-26 pg/ml. bFGF was below detectability in 22%, 30% and 45% of patients pre-TBI, during TBI or post-TBI respectively. Mean circulating plasma levels of bFGF decreased from a median of 52 pg/ml pre-TBI to 26 pg/ml during TBI, and to 5 pg/ml post-TBI. Among the 26 patients, 13 had more than one non-detectable plasma bFGF level, an additional five had at least one non-detectable level, and only eight patients had detectable levels in all daily samples. Naturally high levels of bFGF were observed in some patients undergoing fractionated TBI. In contrast, as many as 79% of patients had low bFGF levels in one or more samples. The impact of endogenous bFGF on the tolerance of normal tissues to irradiation is unknown, and warrants further study.

Adult↗
PubMed1999

Thrombopoietin has a differentiative effect on late-stage human erythropoiesis.

To further explore the mechanism of the effect of thrombopoietin (TPO) on erythropoiesis, we used a two-phase culture system to investigate the effect of TPO on late-stage human erythroid lineage differentiation. In serum-free suspension and semisolid cultures of human peripheral blood derived erythroid progenitors, TPO alone did not produce benzidine-positive cells. However, in serum-containing culture, TPO alone stimulated erythroid cell proliferation and differentiation, demonstrated by erythroid colony formation, production of benzidine-positive cells and haemoglobin (Hb) synthesis. Monoclonal anti-human erythropoietin antibody and anti-human erythropoietin receptor antibody completely abrogated the erythroid differentiative ability of TPO in the serum-containing systems. This implied that binding of EPO and EPO-R was essential for erythropoiesis and the resultant signal transduction may be augmented by the signals emanating from TPO-c-Mpl interaction. Experiment of withdrawal of TPO further demonstrated the involvement of TPO in late-stage erythropoiesis. RT-PCR results showed that there was EPO-R but not c-Mpl expression on developing erythroblasts induced by TPO in serum-containing system. Our results establish that TPO affects not only the proliferation of erythroid progenitors but also the differentiation of erythroid progenitors to mature erythroid cells.

Cell Differentiation↗
PubMed1998

Radiation-induced changes in bone perfusion and angiogenesis.

PURPOSE: To determine whether blood flow of bone is altered by limb irradiation and whether bFGF, an angiogenic cytokine, might alleviate any flow or growth abnormality resulting from 30 Gy single fraction irradiation. METHODS AND MATERIALS: C3H mice received whole right hind limb radiation at doses of 0 to 30 Gy. Additional groups received 30 Gy, and then beginning 1 or 5 weeks later received intravenous bFGF at a dose of 6 microg/mouse, twice a week for 4 weeks. Serial X-ray films were taken to measure the tibias. At 33 weeks, laser Doppler flow (LDF) measurements were made of both limbs. Cytokine measurements were made using ELISA and RNase protection. RESULTS: Bone growth was reduced following radiation in a dose dependent manner. bFGF improved bone growth after radiation even when begun 5 weeks after radiation, however, we detected no significant improvement in LDF of the irradiated bone or periosteum. Muscle tissue surrounding bone of the irradiated leg showed no increase in isoforms of TGFbeta, TNF, or IFN. There was also no difference in the circulating plasma TGFbeta1 in irradiated mice. In contrast, LDF increased significantly as a function of radiation dose in the nonirradiated tibia. Systemic delivery of bFGF appears to further enhance the increase in flow seen in the nonirradiated limb. CONCLUSION: Radiation induces a chronic antiangiogenic effect contributing to reduced limb growth. At 33 weeks the antiangiogenesis was not associated with local soft tissue elevations of TNF, IFN, or TGFbeta. Radiation toxicity to bone is alleviated by bFGF therapy suggesting that powerful locally-acting antiangiogenic mechanisms are involved. We postulate that the increased LDF of the contralateral tibia is due to circulating angiogenesis factors that are elevated to compensate for the radiation-induced antiangiogenesis.

Animals↗
PubMed1998

Hyperbaric oxygen and basic fibroblast growth factor promote growth of irradiated bone.

PURPOSE: The goal of the current experiment is to test for protective effect of hyperbaric oxygen (HBO) and basic fibroblast growth factor (bFGF) on bone growth. METHODS AND MATERIALS: Control C3H mice received hind leg irradiation at 0, 10, 20, or 30 Gy. HBO-treated groups received radiation 1, 5, or 9 weeks before beginning HBO. The remaining groups began bFGF +/- HBO 1 or 5 weeks after 30 Gy. HBO treatments were given 5 days per week for 4 weeks at 2 ATA for 3 h/day. bFGF was given intravenously at 6 microg twice a week for 4 weeks. RESULTS: HBO improved bone growth after radiation in the 10 and 20 Gy groups. At 18 weeks control tibia length discrepancy is 0.0, 4.2, 8.2, and 10.7% after 0, 10, 20, and 30 Gy, respectively. HBO beginning in week 1, 5, or 9 following 10 Gy decreased these discrepancies to 2.0% (p < 0.05), 1.8% (p < 0.05), and 2.4% (p < 0.05), respectively. After 20 Gy, HBO decreased these discrepancies to 7.0% (p = ns), 4.9% (p < 0.05), and 3.6% (p < 0.05), respectively. At 30 Gy, HBO alone had no effect on bone shortening. bFGF improved tibia length discrepancy with or without HBO. At 18 weeks length discrepancies were 6.5% (p < 0.05) and 7.3 (p < 0.05), and after bFGF alone were 6.8% (p < 0.05) and 7.3% (p < 0.05) for treatment beginning in week 1 or 5, respectively. Tibial growth at 18 and 33 weeks following radiation were similar. CONCLUSION: Radiation effects on bone growth can be significant reduced by HBO after 10 or 20 Gy, but not after 30 Gy. At 30 Gy bFGF still significantly reduced the degree of bone shortening, but HBO provided no added benefit to bFGF therapy.

Animals↗
PubMed1998

In vivo radioprotective effects of angiogenic growth factors on the small bowel of C3H mice.

This study was undertaken to determine if acidic or basic fibroblast growth factor (FGF1 or FGF2) or vascular endothelial growth factor (VEGF) alters the radiation response of small bowel after total-body irradiation (TBI). Female C3H mice were treated with various doses of angiogenic growth factor administered intravenously 24 h before or 1 h after TBI. Radiation doses ranged from 7 to 18 Gy. End points measured were the number of crypts in three portions of the small bowel, the frequency of apoptosis of crypt cells at various times after TBI, and the LD50/30 (bone marrow syndrome) and LD50/6 (GI syndrome). Fibroblast growth factors alone, without TBI, decreased the number of crypts per circumference significantly. Among the factors tested, FGF2 caused the greatest decline in baseline crypt number. Despite this decrease in the baseline crypt number, after irradiation the number of surviving crypts was greater in animals treated with growth factor. The greatest radioprotection occurred at intermediate doses of growth factor (6 to 18 pg/mouse). Mice treated with FGF1 and FGF2 had crypt survival curves with a slope that was more shallow than that for saline-treated animals, indicating radiation resistance of crypt stem cells in FGF-treated mice. The LD50/6 was increased by approximately 10% for all treatments with angiogenic growth factors, whether given before or after TBI. Apoptosis of crypt cells was maximum at 4 to 8 h after TBI. The cumulative apoptosis was decreased significantly in animals treated with angiogenic growth factors, and the greatest protection against apoptosis was seen in animals treated with FGF2 prior to TBI. All three angiogenic growth factors tested were radioprotective in small bowel whether given 24 h before or 1 h after irradiation. The mechanism of protection is unlikely to involve proliferation of crypt stem cells, but probably does involve prevention of radiation-induced apoptosis or enhanced repair of DNA damage of crypt cells.

Angiogenesis Inducing Agents↗
PubMed1997

Acidic fibroblast growth factor (FGF1) increases survival and haematopoietic recovery in total body irradiated C3H/HeNCr mice.

Basic fibroblast growth factor is known to stimulate the proliferation of bone marrow stem and/or progenitor cells in vitro and in vivo. We examined a similar cytokine, acidic fibroblast growth factor (FGF1), for its in vivo radiomodifying effects. Female C3H/HeNCr mice were given human recombinant FGF1 intravenously at doses ranging from 1 to 24 micrograms. FGF1 was delivered in two equal doses 24 and 4 h before or 24 h after otherwise lethal total body irradiation (TBI). In vivo FGF1 radioprotection of C3H mice was maximized at a total dose of 12 micrograms/mouse given before TBI. The radiomodification was 1.16 +/- 0.03 (+/- 1 SD) with an increase of LD50/30 from 736 +/- 9 to 854 +/- 16 cGy (P < 0.01). Some retroactive radiomodification was observed even when FGF1 was given 24 h after irradiation (P < 0.05). FGF1 radioprotected mice by improving the repopulation of haematopoietic progenitor cells of bone marrow. The radioprotection was not associated with an increase in S-phase fraction or detectable circulating IL-3, TNF-alpha or GM-CSF, suggesting that other mechanisms of protection were responsible.

Animals↗