Bruce Fenton - Academia.edu (original) (raw)

Papers by Bruce Fenton

The energy and oxygénation status of tumors from two murine sarcoma lines (KHT, RIF-1) and two h... more The energy and oxygénation status of tumors from two murine sarcoma lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI) were assessed using three independent techniques. Tumor energy metabolism was investigated in vivo by "I" nuclear magnetic resonance spectroscopy. After nuclear magnetic resonance measure ments, tumors were frozen in liquid nitrogen to determine the tissue ATP concentration

Advances in experimental medicine and biology, 2003

Since quantitative measurements of tumor vascular function cannot be obtained in human tumors, ap... more Since quantitative measurements of tumor vascular function cannot be obtained in human tumors, appropriate animal tumor models must be utilized. The current studies were undertaken to compare transplantable, murine KHT tumors with primary and 1st generation transplants of spontaneous mammary carcinomas. To evaluate changes in tumor vascular structure and function, immunostaining of total and perfused vascular spacing, and cryospectrophotometric measurement of intravascular HbO2 saturations were utilized. KHT tumors demonstrated a distinct pattern of decreasing oxygenation with increasing distance from the tumor surface, while spontaneous tumors exhibited striking intertumor heterogeneities and a reduced dependence of oxygenation on distance from tumor surface. Anatomical/perfused vessel distributions and functional response were similar between the primary and transplanted tumor models, as was tissue histological appearance, but were quite different from KHT tumors. These results in...

Radiation Research, 2001

The underlying physiological mechanisms leading to tumor reoxygenation after irradiation have eli... more The underlying physiological mechanisms leading to tumor reoxygenation after irradiation have elicited considerable interest, but they remain somewhat unclear. The current study was undertaken to determine the effects of a single dose of 10 Gy gamma radiation on both tumor pathophysiology and radiobiologically hypoxic fraction. Immunohistochemical staining and perfusion markers were used to quantify tumor vasculature, uptake of the hypoxia marker EF5 to assess the distribution of hypoxia, and intravascular HbO(2) measurements to determine oxygen availability. Tumor radiosensitivity was measured by a clonogenic assay. At 24 h postirradiation, oxygen availability increased, perfused vessel numbers decreased, EF5 uptake decreased, and the radiobiologically hypoxic fraction was unchanged. Together, these results demonstrate that tumor hypoxia develops at an increased distance from perfused blood vessels after irradiation, suggesting a decrease in oxygen consumption at 24 h. By 72 h postirradiation, all physiological parameters had returned to the levels in volume-matched, nonirradiated controls. These studies clearly show that single measures of either tumor oxygenation or vascular structure are inadequate for assessing the effects of radiation on tumor clonogenicity. Although such direct measurements have previously proven valuable in predicting tumor response to therapy or oxygen manipulation, a combination of parameters is required to adequately describe the mechanisms underlying these changes after irradiation.

International Journal of Radiation Oncology*Biology*Physics, 2010

Purpose-Acute gastrointestinal syndrome (AGS) due to ionizing radiation (IR) causes death within ... more Purpose-Acute gastrointestinal syndrome (AGS) due to ionizing radiation (IR) causes death within 7 days. Currently, no satisfactory agent exists for mitigation of AGS. A peptide derived from the receptor binding domain of fibroblast growth factor 2 was synthesized (FGF-P) and its mitigation effect on AGS was examined.

International Journal of Cancer, 2001

Clinical trials utilizing strategies to manipulate tumor oxygenation, blood flow and angiogenesis... more Clinical trials utilizing strategies to manipulate tumor oxygenation, blood flow and angiogenesis are under way, although limited quantitative information exists regarding basic tumor pathophysiology. The current study utilized murine KHT fibrosarcomas, spontaneous mammary carcinomas and first-generation spontaneous transplants to examine heterogeneity in vascular structure and function, to relate these changes to the distribution of tumor hypoxia and to determine whether fundamental relationships among the different pathophysiological parameters exist. Three methods were included: (i) immunohistochemical staining of anatomical and perfused blood vessels, (ii) cryospectrophotometric measurement of intravascular oxyhemoglobin saturations and (iii) fluorescent detection of the EF5 hypoxic marker. While a distinct pattern of decreasing oxygenation with increasing distance from the tumor surface was observed for KHT tumors, striking intertumor variability was found in both spontaneous and first-generation transplants, with a reduced dependence on tumor volume. EF5 hypoxic marker uptake was also much more heterogeneous among individual spontaneous and first-generation tumors compared to KHT. Although mammary carcinomas demonstrated fewer anatomical blood vessels than fibrosarcomas, the proportion of perfused vessels was substantially reduced in KHT tumors, especially at larger tumor volumes. Vascular morphology, tissue histological appearance and pathophysiological parameters differed substantially between KHT tumors and both spontaneous and first-generation tumors. Such differences in vascular structure and function are also likely to correlate with altered response to therapies targeted to the vascular system. Finally, spontaneous differentiation status, tumor morphology, vascular configuration and function were well preserved in first-generation transplanted tumors, suggesting a close relationship between vascular development and function in early-generation transplants and spontaneous tumor models.

American Journal of Clinical Oncology, 2003

The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, alone and in combination with radiatio... more The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, alone and in combination with radiation was investigated in vitro and in vivo. Murine mammary tumor line (MCa-35) and human lung carcinoma line (A549) have high and low basal levels of COX-2 protein, respectively. Treatment of both tumor cells with celecoxib alone resulted in a dose- and time-dependent reduction of cell number (clonogenic cell death) and tumor cell growth rate in vitro; however, inhibition of tumor cell growth by celecoxib was not correlated with the reduction of COX-2 protein in tumor cells. Although both tumor cell types had similar DNA damage after celecoxib treatment, significant induction of tumor cell apoptosis was only observed in MCa-35. Celecoxib-mediated radiation sensitization also occurred in MCa-35 cells determined by clonogenic assay, in part due to a G2/M arrest at 8 to 24 hours after treatment. The tumor growth inhibitory effects of celecoxib were also studied in vivo. It was found that celecoxib inhibited both tumor growth after intragastric administration of celecoxib (5 daily doses of 50 mg/kg). Combined with a single 30-Gy dose of radiation, celecoxib resulted in additive effects on A549 tumors. Celecoxib-treated A549 tumors had marginal reduction of total and perfused blood vessels compared with untreated controls. Reduction of tumor angiogenic cytokine and growth factor mRNA was associated with decreased perfused vessels. Finally, reduction of vascular endothelial growth factor protein after celecoxib was also observed in both tumor lines by Western blot. Our results indicate that the selective inhibition of COX-2 combined with radiation has potential application in radiotherapy, and celecoxib-mediated antitumor effects may act through different mechanisms including direct inhibition of tumor cell proliferation, alteration of tumor cell cycle, and antiangiogenesis.

Toxicological Sciences, 2015

Perinatal environmental exposures are potentially important contributors to the increase in autoi... more Perinatal environmental exposures are potentially important contributors to the increase in autoimmune diseases. Yet, the mechanisms by which these exposures increase self-reactive immune responses later in life are poorly understood. Autoimmune diseases require CD4(+) T cells for initiation, progression, and/or clinical symptoms; thus, developmental exposures that cause durable changes in CD4(+) T cells may play a role. Early life activation of the aryl hydrocarbon receptor (AHR) causes persistent changes in the response of CD4(+) T cells to infection later in life, but whether CD4(+) T cells are affected by developmental exposure in the context of an autoimmune disease is unknown. Gnaq(+/-) mice develop symptoms of autoimmune disease similar to those measured clinically, and therefore can be used to evaluate gene-environment interactions during development on disease progression. Herein, we examined the effect of AHR activation in utero and via lactation, or solely via lactation, on disease onset and severity in adult Gnaq(+/-) offspring. Developmental activation of the AHR accelerated disease in Gnaq(+/-) mice, and this correlates with increases in effector CD4(+) T cell populations. Increased symptom onset and cellular changes due to early life AHR activation were more evident in female Gnaq(+/-) mice compared to males. These observations suggest that developmental AHR activation by pollutants, and other exogenous ligands, may increase the likelihood that genetically predisposed individuals will develop clinical symptoms of autoimmune disease later in life.

Alteration of the phenotype of breast cancers from estrogen-dependent to estrogen-independent gro... more Alteration of the phenotype of breast cancers from estrogen-dependent to estrogen-independent growth often leads to the failure of antiestrogenic tumor therapies. We report that overexpression of vascular endothelial growth factor (VEGF) by estrogen-dependent MCF-7 breast cancer cells could abolish estrogen-dependent tumor growth in ovariectomized mice. In the absence of estrogen, MCF-7 VEGF-expressing tumors with in- creased vessel density showed growth

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2005

Ultrasound induced blood stasis has been observed for a long time, but to date most experimental ... more Ultrasound induced blood stasis has been observed for a long time, but to date most experimental observations have been in vitro. In this paper we discuss a possible diagnostic use for this previously undesirable effect of ultrasound - tumor detection in vivo. We demonstrate that, using optical spectroscopy, effects of ultrasound can be used to differentiate tumor from non-tumor in murine tissue. Finally, we propose a novel diagnostic algorithm that quantitatively differentiates tumor from non-tumor with maximum specificity 0.83, maximum sensitivity 0.79, and area under ROC curve 0.90.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2005

Ultrasound-induced blood stasis has been observed for more than thirty years. Most of the literat... more Ultrasound-induced blood stasis has been observed for more than thirty years. Most of the literature has been focused on the health risks associated with this phenomenon and methods employed to prevent stasis from occurring during ultrasound imaging. To date, experimental observations have been either in vitro or invasive. The current work demonstrates ultrasound- induced blood stasis in murine tumor and nontumor tissue, observed through noninvasive measurements of optical spectroscopy, and discusses possible diagnostic uses for this previously undesirable effect of ultrasound.

Advances in experimental medicine and biology, 2007

The biological and physiological effects of exogenous FGF 1 and VEGF were measured using the KHT ... more The biological and physiological effects of exogenous FGF 1 and VEGF were measured using the KHT murine fibrosarcoma tumor model. Tumor-bearing C3H mice were treated intratumorally with either one or six daily doses of 6 microg/mouse FGF1, VEGF, or saline. Tumors were excised 24 hrs after the final injection. Compared to controls, only FGF1 treatment significantly increased tumor weight and size, and only in the 6 dose group. Both FGF1 and VEGF administration (6 dose) decreased tumor cell hypoxia as detected by EF5 uptake: 85% +/- 5% for FGF1 and 82% +/- 6% for VEGF versus 100% +/- 6% for controls. Decreased tumor cell EF5 staining, however, was not associated with changes in numbers of structural or angiogenic vessels. DiOC7 staining showed a slight decrease in perfused vessel numbers in tumors treated with daily VEGF. Intratumoral injections of FGF1 or VEGF also slightly decreased the tumor tissue chemokine MCP-1, interleukins (IL-1beta, IL-6, and IL-18) mRNA expression, and incre...

Advances in experimental medicine and biology, 2003

Cancer research, Jan 15, 2001

Endostatin, a fragment of the COOH-terminal domain of mouse collagen XVIII is a recently demonstr... more 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 <...

Advances in Experimental Medicine and Biology, 2003

Advances in Experimental Medicine and Biology, 2007

Endostatin, a fragment of the C-terminal domain of mouse collagen XVIII, is a recently demonstrat... more Endostatin, a fragment of the C-terminal domain of mouse collagen XVIII, is a recently demonstrated endogenous inhibitor of tumor angiogenesis. Although endostatin can be detected in blood and urine of tumor-bearing as well as normal mice, the exact localization of the endogenous protein and its related peptides in tumor tissues is unknown. We used immunohistochemistry and immunoblotting to identify endostatin tissue location and staining patterns in tumor, as well as to determine the differences in the levels of endostatin expression between tumor cells (in vitro) and tumor tissues (in vivo). Using a specific polyclonal antibody against murine endostatin, we quantitatively determined the levels of endostatin in five murine mammary tumors and the KHT sarcoma by Western blotting. The staining patterns for this protein in tumor sections were examined histologically by immunohistochemistry. Our results show that: (1) Endogenous endostatin and its related peptides are widely distributed in all in vivo tumor types tested, but not in most of the cultured tumor cell lines. (2) Endogenous endostatin stained most tumor stromal components, including vessel walls, basement membranes, extracellular spaces, and tumor cells. (3) Staining patterns and localization of endostatin and thrombospondin-1 were similar in these tumor sections.

Radiotherapy and Oncology, 2004

Background and purpose: The primary objectives of this study were to address two major questions.... more Background and purpose: The primary objectives of this study were to address two major questions. (1) Does VEGF receptor-2 antibody (DC101) produce detrimental effects on tumor vascular function and oxygenation that could compromise adjuvant therapies? (2) Is pathophysiological response to such antiangiogenic strategies different in transplanted versus primary spontaneous tumors?

Pfl�gers Archiv European Journal of Physiology, 1985

To quantify the interdependence of capillary leukocyte plugging and microvascular hemodynamics, e... more To quantify the interdependence of capillary leukocyte plugging and microvascular hemodynamics, experimental measurements were made of the time required for lymphocytes and granulocytes to enter a micropipette. Using standard micropipette deformation techniques, entrance times were found to be a function of both cell diameter and pipette diameter, with no significant dependence on aspiration pressure over the differential pressure range of 200-400 Pa. Experimental results were combined with a computer network model to describe changes in red cell distribution and flow rate resulting from the delayed entrance of leukocytes (WBC) into capillaries. The network model is based on geometrical measurements from the capillary bed of a hamster cremaster muscle (Sarelius et al. 1981) and utilizes previous work describing: 1. preferential cell distribution at a bifurcation, 2. increased apparent viscosity due to the presence of red and white cells, and 3. increased velocities of red and white cells relative to blood. Red and white cell positions within the network were computed at discrete time increments, and WBC plugging was simulated by a temporary cessation of flow in vessels of smaller diameter than the white cell. In contrast with previous studies, the increased viscosity due to the presence of WBCs was found to have an insignificant effect on overall network flow rate. Instead, a major flow reduction occurs only when capillaries are plugged by the white cells. At normal physiological concentrations (1,000 RBC/WBC), time-averaged overall network flow is reduced by 4.4%, based on averaged experimentally measured entrance times, and up to 14.8% if maximal entrance times are used.(ABSTRACT TRUNCATED AT 250 WORDS)

International Journal of Radiation Oncology*Biology*Physics, 2002

International Journal of Radiation Oncology*Biology*Physics, 1995

Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to d... more Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to direct measures of tumor oxygenation such as HbO2 saturations, tumor pO2 levels, or hypoxic cell labeling. Although correlations have been found within tumor lines, no overall relationships were seen across tumor lines. The current objective was to examine the effect on HF of changes in the fractions of the oxygenated and anoxic tumor cells that remain clonogenic. A mathematical model was developed that relates the HF to direct measures of tumor oxygenation. The primary assumptions were that: (a) the tumor is divided into distinct compartments of either fully oxygenated or fully anoxic cells, and (b) the survival of the oxygenated cells is negligible compared to that of the anoxic cells. Based on these assumptions, the HF is plotted as a function of the fractions of clonogenic or nonclonogenic, and oxygenated or anoxic cells. If all cells are clonogenic, then the HF equals the fraction of anoxic cells. If a higher fraction of anoxic than oxygenated cells are nonclonogenic, then the HF will be overestimated by the fraction of the tumor measured to be anoxic using direct measuring techniques. If a higher fraction of the oxygenated than anoxic cells are nonclonogenic, the HF will be underestimated by the fraction of anoxic cells. Correlations between the HF and direct measures of tumor oxygenation have been described within tumor lines evaluated under different physiological condition. However, such relationships can be totally unpredictable between different tumors if the fraction of the anoxic cells that is clonogenic varies substantially. Clearly, if tumor anoxia cannot be detected using direct measures, this is an accurate indication that the tumor is well oxygenated. When tumor anoxia is present, however, the conclusions are ambiguous. Even when a small fraction of the tumor is measured as anoxic, direct measures of tumor oxygenation may not be representative of the HF if a substantial proportion of nonclonogenic cells is present.

The energy and oxygénation status of tumors from two murine sarcoma lines (KHT, RIF-1) and two h... more The energy and oxygénation status of tumors from two murine sarcoma lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI) were assessed using three independent techniques. Tumor energy metabolism was investigated in vivo by "I" nuclear magnetic resonance spectroscopy. After nuclear magnetic resonance measure ments, tumors were frozen in liquid nitrogen to determine the tissue ATP concentration

Advances in experimental medicine and biology, 2003

Since quantitative measurements of tumor vascular function cannot be obtained in human tumors, ap... more Since quantitative measurements of tumor vascular function cannot be obtained in human tumors, appropriate animal tumor models must be utilized. The current studies were undertaken to compare transplantable, murine KHT tumors with primary and 1st generation transplants of spontaneous mammary carcinomas. To evaluate changes in tumor vascular structure and function, immunostaining of total and perfused vascular spacing, and cryospectrophotometric measurement of intravascular HbO2 saturations were utilized. KHT tumors demonstrated a distinct pattern of decreasing oxygenation with increasing distance from the tumor surface, while spontaneous tumors exhibited striking intertumor heterogeneities and a reduced dependence of oxygenation on distance from tumor surface. Anatomical/perfused vessel distributions and functional response were similar between the primary and transplanted tumor models, as was tissue histological appearance, but were quite different from KHT tumors. These results in...

Radiation Research, 2001

The underlying physiological mechanisms leading to tumor reoxygenation after irradiation have eli... more The underlying physiological mechanisms leading to tumor reoxygenation after irradiation have elicited considerable interest, but they remain somewhat unclear. The current study was undertaken to determine the effects of a single dose of 10 Gy gamma radiation on both tumor pathophysiology and radiobiologically hypoxic fraction. Immunohistochemical staining and perfusion markers were used to quantify tumor vasculature, uptake of the hypoxia marker EF5 to assess the distribution of hypoxia, and intravascular HbO(2) measurements to determine oxygen availability. Tumor radiosensitivity was measured by a clonogenic assay. At 24 h postirradiation, oxygen availability increased, perfused vessel numbers decreased, EF5 uptake decreased, and the radiobiologically hypoxic fraction was unchanged. Together, these results demonstrate that tumor hypoxia develops at an increased distance from perfused blood vessels after irradiation, suggesting a decrease in oxygen consumption at 24 h. By 72 h postirradiation, all physiological parameters had returned to the levels in volume-matched, nonirradiated controls. These studies clearly show that single measures of either tumor oxygenation or vascular structure are inadequate for assessing the effects of radiation on tumor clonogenicity. Although such direct measurements have previously proven valuable in predicting tumor response to therapy or oxygen manipulation, a combination of parameters is required to adequately describe the mechanisms underlying these changes after irradiation.

International Journal of Radiation Oncology*Biology*Physics, 2010

Purpose-Acute gastrointestinal syndrome (AGS) due to ionizing radiation (IR) causes death within ... more Purpose-Acute gastrointestinal syndrome (AGS) due to ionizing radiation (IR) causes death within 7 days. Currently, no satisfactory agent exists for mitigation of AGS. A peptide derived from the receptor binding domain of fibroblast growth factor 2 was synthesized (FGF-P) and its mitigation effect on AGS was examined.

International Journal of Cancer, 2001

Clinical trials utilizing strategies to manipulate tumor oxygenation, blood flow and angiogenesis... more Clinical trials utilizing strategies to manipulate tumor oxygenation, blood flow and angiogenesis are under way, although limited quantitative information exists regarding basic tumor pathophysiology. The current study utilized murine KHT fibrosarcomas, spontaneous mammary carcinomas and first-generation spontaneous transplants to examine heterogeneity in vascular structure and function, to relate these changes to the distribution of tumor hypoxia and to determine whether fundamental relationships among the different pathophysiological parameters exist. Three methods were included: (i) immunohistochemical staining of anatomical and perfused blood vessels, (ii) cryospectrophotometric measurement of intravascular oxyhemoglobin saturations and (iii) fluorescent detection of the EF5 hypoxic marker. While a distinct pattern of decreasing oxygenation with increasing distance from the tumor surface was observed for KHT tumors, striking intertumor variability was found in both spontaneous and first-generation transplants, with a reduced dependence on tumor volume. EF5 hypoxic marker uptake was also much more heterogeneous among individual spontaneous and first-generation tumors compared to KHT. Although mammary carcinomas demonstrated fewer anatomical blood vessels than fibrosarcomas, the proportion of perfused vessels was substantially reduced in KHT tumors, especially at larger tumor volumes. Vascular morphology, tissue histological appearance and pathophysiological parameters differed substantially between KHT tumors and both spontaneous and first-generation tumors. Such differences in vascular structure and function are also likely to correlate with altered response to therapies targeted to the vascular system. Finally, spontaneous differentiation status, tumor morphology, vascular configuration and function were well preserved in first-generation transplanted tumors, suggesting a close relationship between vascular development and function in early-generation transplants and spontaneous tumor models.

American Journal of Clinical Oncology, 2003

The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, alone and in combination with radiatio... more The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, alone and in combination with radiation was investigated in vitro and in vivo. Murine mammary tumor line (MCa-35) and human lung carcinoma line (A549) have high and low basal levels of COX-2 protein, respectively. Treatment of both tumor cells with celecoxib alone resulted in a dose- and time-dependent reduction of cell number (clonogenic cell death) and tumor cell growth rate in vitro; however, inhibition of tumor cell growth by celecoxib was not correlated with the reduction of COX-2 protein in tumor cells. Although both tumor cell types had similar DNA damage after celecoxib treatment, significant induction of tumor cell apoptosis was only observed in MCa-35. Celecoxib-mediated radiation sensitization also occurred in MCa-35 cells determined by clonogenic assay, in part due to a G2/M arrest at 8 to 24 hours after treatment. The tumor growth inhibitory effects of celecoxib were also studied in vivo. It was found that celecoxib inhibited both tumor growth after intragastric administration of celecoxib (5 daily doses of 50 mg/kg). Combined with a single 30-Gy dose of radiation, celecoxib resulted in additive effects on A549 tumors. Celecoxib-treated A549 tumors had marginal reduction of total and perfused blood vessels compared with untreated controls. Reduction of tumor angiogenic cytokine and growth factor mRNA was associated with decreased perfused vessels. Finally, reduction of vascular endothelial growth factor protein after celecoxib was also observed in both tumor lines by Western blot. Our results indicate that the selective inhibition of COX-2 combined with radiation has potential application in radiotherapy, and celecoxib-mediated antitumor effects may act through different mechanisms including direct inhibition of tumor cell proliferation, alteration of tumor cell cycle, and antiangiogenesis.

Toxicological Sciences, 2015

Perinatal environmental exposures are potentially important contributors to the increase in autoi... more Perinatal environmental exposures are potentially important contributors to the increase in autoimmune diseases. Yet, the mechanisms by which these exposures increase self-reactive immune responses later in life are poorly understood. Autoimmune diseases require CD4(+) T cells for initiation, progression, and/or clinical symptoms; thus, developmental exposures that cause durable changes in CD4(+) T cells may play a role. Early life activation of the aryl hydrocarbon receptor (AHR) causes persistent changes in the response of CD4(+) T cells to infection later in life, but whether CD4(+) T cells are affected by developmental exposure in the context of an autoimmune disease is unknown. Gnaq(+/-) mice develop symptoms of autoimmune disease similar to those measured clinically, and therefore can be used to evaluate gene-environment interactions during development on disease progression. Herein, we examined the effect of AHR activation in utero and via lactation, or solely via lactation, on disease onset and severity in adult Gnaq(+/-) offspring. Developmental activation of the AHR accelerated disease in Gnaq(+/-) mice, and this correlates with increases in effector CD4(+) T cell populations. Increased symptom onset and cellular changes due to early life AHR activation were more evident in female Gnaq(+/-) mice compared to males. These observations suggest that developmental AHR activation by pollutants, and other exogenous ligands, may increase the likelihood that genetically predisposed individuals will develop clinical symptoms of autoimmune disease later in life.

Alteration of the phenotype of breast cancers from estrogen-dependent to estrogen-independent gro... more Alteration of the phenotype of breast cancers from estrogen-dependent to estrogen-independent growth often leads to the failure of antiestrogenic tumor therapies. We report that overexpression of vascular endothelial growth factor (VEGF) by estrogen-dependent MCF-7 breast cancer cells could abolish estrogen-dependent tumor growth in ovariectomized mice. In the absence of estrogen, MCF-7 VEGF-expressing tumors with in- creased vessel density showed growth

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2005

Ultrasound induced blood stasis has been observed for a long time, but to date most experimental ... more Ultrasound induced blood stasis has been observed for a long time, but to date most experimental observations have been in vitro. In this paper we discuss a possible diagnostic use for this previously undesirable effect of ultrasound - tumor detection in vivo. We demonstrate that, using optical spectroscopy, effects of ultrasound can be used to differentiate tumor from non-tumor in murine tissue. Finally, we propose a novel diagnostic algorithm that quantitatively differentiates tumor from non-tumor with maximum specificity 0.83, maximum sensitivity 0.79, and area under ROC curve 0.90.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2005

Ultrasound-induced blood stasis has been observed for more than thirty years. Most of the literat... more Ultrasound-induced blood stasis has been observed for more than thirty years. Most of the literature has been focused on the health risks associated with this phenomenon and methods employed to prevent stasis from occurring during ultrasound imaging. To date, experimental observations have been either in vitro or invasive. The current work demonstrates ultrasound- induced blood stasis in murine tumor and nontumor tissue, observed through noninvasive measurements of optical spectroscopy, and discusses possible diagnostic uses for this previously undesirable effect of ultrasound.

Advances in experimental medicine and biology, 2007

The biological and physiological effects of exogenous FGF 1 and VEGF were measured using the KHT ... more The biological and physiological effects of exogenous FGF 1 and VEGF were measured using the KHT murine fibrosarcoma tumor model. Tumor-bearing C3H mice were treated intratumorally with either one or six daily doses of 6 microg/mouse FGF1, VEGF, or saline. Tumors were excised 24 hrs after the final injection. Compared to controls, only FGF1 treatment significantly increased tumor weight and size, and only in the 6 dose group. Both FGF1 and VEGF administration (6 dose) decreased tumor cell hypoxia as detected by EF5 uptake: 85% +/- 5% for FGF1 and 82% +/- 6% for VEGF versus 100% +/- 6% for controls. Decreased tumor cell EF5 staining, however, was not associated with changes in numbers of structural or angiogenic vessels. DiOC7 staining showed a slight decrease in perfused vessel numbers in tumors treated with daily VEGF. Intratumoral injections of FGF1 or VEGF also slightly decreased the tumor tissue chemokine MCP-1, interleukins (IL-1beta, IL-6, and IL-18) mRNA expression, and incre...

Advances in experimental medicine and biology, 2003

Cancer research, Jan 15, 2001

Endostatin, a fragment of the COOH-terminal domain of mouse collagen XVIII is a recently demonstr... more 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 <...

Advances in Experimental Medicine and Biology, 2003

Advances in Experimental Medicine and Biology, 2007

Endostatin, a fragment of the C-terminal domain of mouse collagen XVIII, is a recently demonstrat... more Endostatin, a fragment of the C-terminal domain of mouse collagen XVIII, is a recently demonstrated endogenous inhibitor of tumor angiogenesis. Although endostatin can be detected in blood and urine of tumor-bearing as well as normal mice, the exact localization of the endogenous protein and its related peptides in tumor tissues is unknown. We used immunohistochemistry and immunoblotting to identify endostatin tissue location and staining patterns in tumor, as well as to determine the differences in the levels of endostatin expression between tumor cells (in vitro) and tumor tissues (in vivo). Using a specific polyclonal antibody against murine endostatin, we quantitatively determined the levels of endostatin in five murine mammary tumors and the KHT sarcoma by Western blotting. The staining patterns for this protein in tumor sections were examined histologically by immunohistochemistry. Our results show that: (1) Endogenous endostatin and its related peptides are widely distributed in all in vivo tumor types tested, but not in most of the cultured tumor cell lines. (2) Endogenous endostatin stained most tumor stromal components, including vessel walls, basement membranes, extracellular spaces, and tumor cells. (3) Staining patterns and localization of endostatin and thrombospondin-1 were similar in these tumor sections.

Radiotherapy and Oncology, 2004

Background and purpose: The primary objectives of this study were to address two major questions.... more Background and purpose: The primary objectives of this study were to address two major questions. (1) Does VEGF receptor-2 antibody (DC101) produce detrimental effects on tumor vascular function and oxygenation that could compromise adjuvant therapies? (2) Is pathophysiological response to such antiangiogenic strategies different in transplanted versus primary spontaneous tumors?

Pfl�gers Archiv European Journal of Physiology, 1985

To quantify the interdependence of capillary leukocyte plugging and microvascular hemodynamics, e... more To quantify the interdependence of capillary leukocyte plugging and microvascular hemodynamics, experimental measurements were made of the time required for lymphocytes and granulocytes to enter a micropipette. Using standard micropipette deformation techniques, entrance times were found to be a function of both cell diameter and pipette diameter, with no significant dependence on aspiration pressure over the differential pressure range of 200-400 Pa. Experimental results were combined with a computer network model to describe changes in red cell distribution and flow rate resulting from the delayed entrance of leukocytes (WBC) into capillaries. The network model is based on geometrical measurements from the capillary bed of a hamster cremaster muscle (Sarelius et al. 1981) and utilizes previous work describing: 1. preferential cell distribution at a bifurcation, 2. increased apparent viscosity due to the presence of red and white cells, and 3. increased velocities of red and white cells relative to blood. Red and white cell positions within the network were computed at discrete time increments, and WBC plugging was simulated by a temporary cessation of flow in vessels of smaller diameter than the white cell. In contrast with previous studies, the increased viscosity due to the presence of WBCs was found to have an insignificant effect on overall network flow rate. Instead, a major flow reduction occurs only when capillaries are plugged by the white cells. At normal physiological concentrations (1,000 RBC/WBC), time-averaged overall network flow is reduced by 4.4%, based on averaged experimentally measured entrance times, and up to 14.8% if maximal entrance times are used.(ABSTRACT TRUNCATED AT 250 WORDS)

International Journal of Radiation Oncology*Biology*Physics, 2002

International Journal of Radiation Oncology*Biology*Physics, 1995

Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to d... more Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to direct measures of tumor oxygenation such as HbO2 saturations, tumor pO2 levels, or hypoxic cell labeling. Although correlations have been found within tumor lines, no overall relationships were seen across tumor lines. The current objective was to examine the effect on HF of changes in the fractions of the oxygenated and anoxic tumor cells that remain clonogenic. A mathematical model was developed that relates the HF to direct measures of tumor oxygenation. The primary assumptions were that: (a) the tumor is divided into distinct compartments of either fully oxygenated or fully anoxic cells, and (b) the survival of the oxygenated cells is negligible compared to that of the anoxic cells. Based on these assumptions, the HF is plotted as a function of the fractions of clonogenic or nonclonogenic, and oxygenated or anoxic cells. If all cells are clonogenic, then the HF equals the fraction of anoxic cells. If a higher fraction of anoxic than oxygenated cells are nonclonogenic, then the HF will be overestimated by the fraction of the tumor measured to be anoxic using direct measuring techniques. If a higher fraction of the oxygenated than anoxic cells are nonclonogenic, the HF will be underestimated by the fraction of anoxic cells. Correlations between the HF and direct measures of tumor oxygenation have been described within tumor lines evaluated under different physiological condition. However, such relationships can be totally unpredictable between different tumors if the fraction of the anoxic cells that is clonogenic varies substantially. Clearly, if tumor anoxia cannot be detected using direct measures, this is an accurate indication that the tumor is well oxygenated. When tumor anoxia is present, however, the conclusions are ambiguous. Even when a small fraction of the tumor is measured as anoxic, direct measures of tumor oxygenation may not be representative of the HF if a substantial proportion of nonclonogenic cells is present.