Biomedical subjects

B D Ross

Publications and source records attributed to B D Ross.

At least 37 records · Page 2Linked to original sources

PubMed2000

Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ionizing radiation can sensitize breast carcinoma cells to TRAIL-induced apoptosis. This synergistic effect is p53-dependent and may be the result of radiation-induced up-regulation of the TRAIL-receptor DR5. Importantly, TRAIL and ionizing radiation have a synergistic effect in the regression of established breast cancer xenografts. Changes in tumor cellularity and extracellular space were monitored in vivo by diffusion-weighted magnetic resonance imaging (diffusion MRI), a noninvasive technique to produce quantitative images of the apparent mobility of water within a tissue. Increased water mobility was observed in combined TRAIL- and radiation-treated tumors but not in tumors treated with TRAIL or radiation alone. Histological analysis confirmed the loss of cellularity and increased numbers of apoptotic cells in TRAIL- and radiation-treated tumors. Taken together, our results provide support for combining radiation with TRAIL to improve tumor eradication and suggest that efficacy of apoptosis-inducing cancer therapies may be monitored noninvasively, using diffusion MRI.

Animals↗

PubMed2000

Experimental gliosarcoma induces chemokine receptor expression in rat brain.

Macrophage/microglial infiltration is a characteristic feature of brain tumors. The functional role(s) of these cells is complex and could include both trophic and suppressive effects on tumors. Information has recently emerged about the molecular signals that regulate the accumulation and function of monocytes in pathological disorders. Recent data indicate that the chemokine, monocyte chemoattractant protein-1 (MCP-1), a potent monocyte activating and chemotactic factor, is a primary regulator of the macrophage response in brain tumors. We hypothesized that if MCP-1 regulates macrophage/microglial infiltration, then expression of the specific MCP-1 receptor, CCR2, will be induced in peritumoral tissue and/or within brain tumors. Identification of a specific receptor that is preferentially expressed in brain tumors could be important both in terms of tumor biology and as a potential therapeutic target. We used an established experimental gliosarcoma model, induced by intracranial transplantation of cultured 9L cells into adult rat brain, to test this hypothesis. RT-PCR analysis showed high levels of both MCP-1 and CCR2 mRNA and Western blot analysis demonstrated increased CCR2 protein in tumor extracts. Immunocytochemistry showed CCR2 immunoreactive microglia in peritumoral tissue and, unexpectedly, that intrinsic tumor cells, rather than monocytes, were the predominant source of CCR2. These results demonstrate that CCR2 expression is markedly upregulated in this brain tumor model.

Animals↗

PubMed2000

Novel peak assignments of in vivo (13)C MRS in human brain at 1.5 T.

(13)C MRS studies at natural abundance and after intravenous 1-(13)C glucose infusion were performed on a 1.5-T clinical scanner in four subjects. Localization to the occipital cortex was achieved by a surface coil. In natural abundance spectra glucose C(3beta,5beta), myo-inositol, glutamate C(1,2,5), glutamine C(1,2,5), N-acetyl-aspartate C(1-4,C=O), creatine CH(2), CH(3), and C(C=N), taurine C(2,3), bicarbonate HCO(-)(3) were identified. After glucose infusion (13)C enrichment of glucose C(1alpha,1beta), glutamate C(1-4), glutamine C(1-4), aspartate C(2,3), N-acetyl-aspartate C(2,3), lactate C(3), alanine C(3), and HCO(-)(3) were observed. The observation of (13)C enrichment of resonances resonating at >150 ppm is an extension of previously published studies and will provide a more precise determination of metabolic rates and substrate decarboxylation in human brain.

Adult↗

PubMed2000

Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy.

Detection of a therapeutic response early in the course of cancer treatment, before tumor growth delay or regression, is not currently possible in experimental models or clinical medicine. New interim measures of therapeutic response would be particularly useful in the development of cancer chemosensitization gene therapy by facilitating optimization of gene transfer protocols and prodrug dosing schedules. Diffusion MRI is a sensitive technique producing quantitative and noninvasive images of the apparent mobility of water within a tissue. We investigated the utility of diffusion MRI for detecting early changes associated with a refined cytosine deaminase (CD)/5-fluorocytosine (5FC) chemosensitization gene therapy paradigm in orthotopic 9L gliomas stably expressing the recently cloned S. cerevisiae CD gene. Mean tumor diffusion increased 31% within 8 days of initiating 5-FC treatment, preceding tumor growth arrest and regression. Complete regression of the intracranial tumor was observed in four of five treated animals, and recurrent tumor in the remaining animal exhibited water diffusion behavior similar to primary, untreated tumors. These results demonstrate the efficacy of the yCD/5FC strategy for glioma and suggest that increased tumor water diffusion is an indicator of active therapeutic intervention.

Animals↗

PubMed2000

Real or imaginary? Human metabolism through nuclear magnetism.

This account of the beginnings and later applications of the use of nuclear magnetic resonance for noninvasive medical diagnosis was presented at a Symposium held in Oxford, UK, during September 13-15, 2000 to mark the centenary of the birth of Hans Krebs, on August 25, 1900.

Alzheimer Disease↗

PubMed1999

Noninvasive quantitation of cytosine deaminase transgene expression in human tumor xenografts with in vivo magnetic resonance spectroscopy.

Analysis of transgene expression in vivo currently requires destructive and invasive molecular assays of tissue specimens. Noninvasive methodology for assessing the location, magnitude, and duration of transgene expression in vivo will facilitate subject-by-subject correlation of therapeutic outcomes with transgene expression and will be useful in vector development. Cytosine deaminase (CD) is a microbial gene undergoing clinical trials in gene-directed enzyme prodrug gene therapy. We hypothesized that in vivo magnetic resonance spectroscopy could be used to measure CD transgene expression in genetically modified tumors by directly observing the CD-catalyzed conversion of the 5-fluorocytosine (5-FC) prodrug to the chemotherapeutic agent 5-fluorouracil (5-FU). The feasibility of this approach is demonstrated in subcutaneous human colorectal carcinoma xenografts in nude mice by using yeast CD (yCD). A three-compartment model was used to analyze the metabolic fluxes of 5-FC and its metabolites. The rate constants for yCD-catalyzed prodrug conversion (k(1)(app)), 5-FU efflux from the observable tumor volume (k(2)(app)), and formation of cytotoxic fluorinated nucleotides from 5-FU (k(3)(app)) were 0.49 +/- 0.27 min(-1), 0.766 +/- 0.006 min(-1), and 0.0023 +/- 0.0007 min(-1), respectively. The best fits of the 5-FU concentration data assumed first-order kinetics, suggesting that yCD was not saturated in vivo in the presence of measured intratumoral 5-FC concentrations well above the in vitro K(m). These results demonstrate the feasibility of using magnetic resonance spectroscopy to noninvasively monitor therapeutic transgene expression in tumors. This capability provides an approach for measuring gene expression that will be useful in clinical gene therapy trials.

Animals↗

PubMed1999

Enzyme/prodrug therapy for head and neck cancer using a catalytically superior cytosine deaminase.

The use of cytosine deaminase (CD) in conjunction with 5-fluorocytosine (5-FC) has been studied for cancer gene therapy as a means of achieving tumor-specific generation of the toxic metabolite 5-fluorouracil (5-FU). Since 5-FC is frequently used as an antifungal agent, and because it has little or no efficacy as an antibacterial agent, we hypothesized that yeast CD (YCD) might be more efficient at utilizing 5-FC as a substrate and hence be a better choice for a CD/5-FC gene therapy strategy than the typically utilized bacterial CD (BCD). To that end Saccharomyces cerevisiae CD was cloned from yeast genomic DNA and expressed in vitro. Functional analysis of BCD and YCD expressed in COS-1 cells indicated that BCD and YCD both utilized cytosine with equal efficacy; however, 5-FC was an extremely poor substrate for BCD, with an apparent catalytic efficiency 280-fold lower than that observed for YCD. Retroviral infection of tumor cell lines in vitro indicated that the IC50 of 5-FC was 30-fold lower in YCD-infected cultures as compared with cultures infected with BCD retrovirus. In addition, when SCCVII murine squamous cell carcinoma cells were infected in vitro at low rates of infection (< or =10%) there was no significant cytotoxicity toward BCD-expressing cells while there was potent cytotoxicity to both YCD-expressing cells and "bystander cells" even at this low level of expression. Finally, stable BCD- or YCD-expressing SCCVII clones were developed and used in an orthotopic immune-competent model of head and neck cancer. Subsequent treatment with 5-FC followed by monitoring of tumor growth by noninvasive magnetic resonance imaging (MRI) and survival of animals indicated a growth delay during the course of 5-FC treatment for BCD-expressing tumors, which quickly regrew at the end of treatment. In contrast, YCD-expressing tumors exhibited not only a growth delay, which was of longer duration, but also in some cases frank tumor regression and complete cures occurred.

Animals↗

PubMed1999

Creatin' news.

Explore the source record for details and available documents.

Brain↗

PubMed1999

In vivo magnetic resonance spectroscopy of human fetal neural transplants.

To better define the survival and cellular composition of human fetal neurotransplants in vivo, we performed quantitative 1H MRS to determine the concentration of the neuronal amino acid [N-acetylaspartate] within MRI-visible grafts. In all, 71 grafts in 38 patients [24 Parkinson's disease (PD), 14 Huntington's disease (HD)] were examined, as well as 24 untreated PD and HD patients and 13 age-matched normal controls. MRI appearances of edema were present in three out of 71 grafts, the remainder being consistent with histologically identified viable neural transplant tissue. N-acetylaspartate (NAA), creatine, choline, myoinositol and glutamine plus glutamate (Glx) were identified in all post-transplant putamens, with abnormal metabolites, lactate and/or lipid detectable in only three patients. Of 71 grafts, 19 occupied more than 60% of the MRS-examined volume (VOI) (mean 84.2 +/- 3%; range 61-100%). In those, [NAA] was 8.50 +/- 0.99 mM in eight PD spectra and 6.59 +/- 0.81 mM in 11 HD spectra, and was not significantly different from controls. In contrast, transplanted fetal neurones contain less than 0.4 mM of the neuronal amino acid NAA. This suggests that established fetal neurotransplants in the human putamen of both PD and HD patients are populated by adult neurones, axons and dendrites.

Adult↗

PubMed1999

Localized 15N NMR spectroscopy of rat brain by ISIS.

Three-dimensional image-selected in vivo spectroscopy (ISIS), combined with proton-decoupled nuclear-Overhauser-enhanced 15N nuclear magnetic resonance (NMR), was used to localize [15N]metabolites, observed by a head coil, to the brain in rats. In spontaneously breathing anesthetized rats given intravenous [15N]ammonium acetate infusion, brain [5-15N]glutamine was observed in the localized spectrum with a v1/2 of 5 Hz in 19-28 min at 4.7 T, while the signal from blood [15N]urea was eliminated by the localization process. In rats given [15N]leucine infusion, the peak representing predominantly (89%) brain [15N]glutamate was observed, with elimination of the signal from muscle [15N]alanine. In vivo peak areas of the brain [15N]metabolites in the localized spectra were proportional to their concentrations. The advantages and limitations of localization by ISIS using a volume coil with a homogeneous B1 field are compared with those of localization by a surface coil for in vivo 15N NMR study of neurotransmitters in the brain.

Acetates↗

PubMed1999

Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled (31)P MRS in in vivo human brain.

Cerebral phosphorylated metabolites, possibly involved in membrane and myelin sheath metabolism, were measured and quantified using proton-decoupled (31)P ({(1)H}-(31)P) MRS in 32 children and 28 adults. Age-dependent changes were determined for phosphorylethanolamine (PE), phosphorylcholine (PC), glycerophosphorylethanolamine (GPE), glycerophosphorylcholine (GPC), and phosphocreatine (PCr) concentrations. In the neonate, PE dominates the spectrum and decreases with age along with PC, whereas GPE, GPC, and PCr increase in concentration with postnatal age. PE (1.23 +/- 0.13 mM) and GPE (0.57 +/- 0.08 mM) co-resonate with choline in (1)H MRS. Together with PC (0.57 +/- 0.12 mM) and GPC (0. 94 +/- 0.13 mM) these four metabolites accounted for all of the visible (1)H MRS choline in normal adult brain. Children with diseases that affect myelination were found to have abnormal ¿(1)H¿-(31)P MRS. The new quantitative assay may provide novel insights in determining and monitoring normal and abnormal brain maturation noninvasively. Magn Reson Med 42:643-654, 1999.

Adolescent↗

PubMed1999

Activation of neurotransplants in humans.

Clinical studies report symptomatic benefit in most fetal neurotransplantation treated Parkinson's disease patients. The underlying mechanism is incompletely explained. We investigated whether neural connections between host and transplanted tissue are established. Two Parkinson's disease patients with clinically excellent outcome after transplantation were studied with functional magnetic resonance imaging. A repetitive motor task that provided robust stimulation in the contralateral putamen in volunteers activated graft bearing regions of putamen in patients. In response to contralateral motor tasks, activation was recorded consistently in left putamen in patient 1 and in right putamen in patient 2. Functional magnetic resonance imaging suggests that neuronal rewiring contributes to the functioning of neurotransplants in vivo in humans.

Adult↗

PubMed1999

In vivo detection of (15)N-coupled protons in rat brain by ISIS localization and multiple-quantum editing.

Three-dimensional image-selected in vivo spectroscopy (ISIS) was combined with phase-cycled (1)H-(15)N heteronuclear multiple-quantum coherence (HMQC) transfer NMR for localized selective observation of protons J-coupled to (15)N in phantoms and in vivo. The ISIS-HMQC sequence, supplemented by jump-return water suppression, permitted localized selective observation of 2-5 micromol of [(15)N(indole)]tryptophan, a precursor of the neurotransmitter serotonin, through the (15)N-coupled proton in 20-40 min of acquisition in vitro at 4.7 T. In vivo, the amide proton of [5-(15)N]glutamine was selectively observed in the brain of spontaneously breathing (15)NH(4)(+)-infused rats, using a volume probe with homogeneous (1)H and (15)N fields. Signal recovery after three-dimensional localization was 72-82% in phantoms and 59 +/- 4% in vivo. The result demonstrates that localized selective observation of (15)N-coupled protons, with complete cancellation of all other protons except water, can be achieved in spontaneously breathing animals by the ISIS-HMQC sequence. This sequence performs both volume selection and heteronuclear editing through an addition/subtraction scheme and predicts the highest intrinsic sensitivity for detection of (15)N-coupled protons in the selected volume. The advantages and limitations of this method for in vivo application are compared to those of other localized editing techniques currently in use for non-exchanging protons.

Animals↗

PubMed1999

Identification of cerebral acetone by 1H-MRS in patients with epilepsy controlled by ketogenic diet.

Ketogenic diet (KD) is highly effective in controlling epileptic seizures in children. One of the mechanisms postulated, the accumulation of ketone bodies, acetoacetate (AcAc) and/or betahydroxybutyrate (beta-OHB) in the brain, would be detectable by non-invasive proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS was performed in occipital cortical grey matter in 14 epileptics (E); ages 3.8-48.3 years), seven KD and seven without, and 16 healthy age-matched subjects. One E was examined before and after KD. A singlet resonance (sigma = 2.22 ppm), distinct from AcAc (sigma = 2.26 and 3.46 ppm), and identified as acetone was present in all spectra of children on KD (nine spectra in five children; concentration 0.7 +/- 0.2 mM). This resonance was absent from Control and E without diet. AcAc and beta-OHB, which were not detectable in KD brain, were found in urine or blood of all KD. Seizures were well controlled in all E in whom acetone was detected. Two of seven E, both adults, were seizure-free without detectable acetone. Cerebral acetone may contribute to seizure control in KD, but is unlikely to be the sole mechanism.

Acetone↗

PubMed1999

Early castration reduces prostatic carcinogenesis in transgenic mice.

OBJECTIVES: To test the hypothesis that transgenic mouse models of prostate cancer could be useful for testing chemoprevention strategies by evaluating the effects of early castration on prostate carcinogenesis in TRAMP mice. Human prostate cancer, unlike other cancers, requires androgens for oncogenesis yet acquires partial androgen independence in the castrated milieu. This paradigm is the basis for an ongoing clinical trial using selective androgen deprivation for prostate cancer chemoprevention. However, preclinical correlates for hormonal prevention or other chemoprevention strategies of prostate cancer have not previously been demonstrated in autochthonous models of prostate carcinogenesis. METHODS: Magnetic resonance imaging was used to longitudinally measure prostate growth in castrated and noncastrated TRAMP mice, and mice were prospectively examined for the onset of advanced, palpable prostate cancer. Modulation of androgen-responsive oncogene expression, as well as oncogene expression in refractory cancers, was evaluated by Western blot. RESULTS: Early castration significantly reduced prostate tumor growth as measured by magnetic resonance imaging and improved cancer-free survival. Prevention of prostate cancer development in these mice was associated with durable suppression of androgen-responsive oncogene expression (T-antigen expression not detectable by Western blot); prostate cancers refractory to the hormonal prevention strategy demonstrated androgen-independent oncogene expression. CONCLUSIONS: These findings suggest that carcinogenesis related to androgen-responsive oncogene expression can be prevented in some cases by hormonal manipulation and that transgenic TRAMP mice are useful for the preclinical evaluation of hormonal and possibly other strategies of prostate cancer chemoprevention.

Age Factors↗

PubMed1999

Clinical impact of MR spectroscopy when MR imaging is indeterminate for pediatric brain tumors.

OBJECTIVE: We undertook this study to determine if single-voxel proton (hydrogen) MR spectroscopy could have clinical impact on the management of pediatric brain tumors when MR findings were indeterminate. SUBJECTS AND METHODS: Eleven children (mean age, 9 years) being examined for brain tumors underwent MR imaging that revealed indeterminate criteria of enhancement, mass effect, and prolonged T1 and T2 signal. MR spectroscopy was then used to distinguish radiation necrosis from tumor in one patient, differentiate residual tumor from scarring in two patients, document early treatment response in three patients, and discriminate benign from malignant masses in five patients. RESULTS: In 10 of the 11 patients, spectra were successfully acquired. Based on the chemical analysis of the indeterminate area shown on MR imaging, clinical impact was achieved in these 10 patients. Clinical impact included treatment modification in five patients, follow-up studies replacing further treatment in three patients, and tumor characterization in the remaining two patients. Confirmation was by histology in four patients and by follow-up MR imaging and MR spectroscopy for up to 30 months in the remaining six patients. CONCLUSION: When MR imaging is indeterminate in evaluating pediatric brain tumors, MR spectroscopy can provide objective neurochemical information, thereby altering treatment.

Adolescent↗

PubMed1999

Combined radiation and enzyme/prodrug treatment for head and neck cancer in an orthotopic animal model.

In an effort to improve the therapeutic outcome for squamous cell cancer of the head and neck, we have used the enzyme cytosine deaminase (CD) and the prodrug 5-fluorocytosine (5-FC) as a means to deliver the chemotherapeutic agent 5-fluorouracil (5-FU) in a tumor-specific manner and have evaluated the use of this treatment in combination with external-beam radiation. Infection of SCCVII cells in culture with a CD-expressing retrovirus and treatment with 5-FC was cytotoxic depending on the time of treatment and dose of 5-FC. An orthotopic model of squamous cell cancer of the head and neck was used in vivo to study the CD/5-FC system both alone and with concurrent radiation due to the radiosensitizing properties that 5-FU generates in situ. Treated mice were imaged using magnetic resonance imaging (MRI), and their survival was evaluated. Neither 5-FU nor radiation either alone or combined provided a survival advantage. In contrast, 5-FC treatment prolonged survival and decreased tumor burden compared to control animals, but the tumors recurred after the treatment ceased. Finally, combined treatment with concurrent administration of 5-FC and radiation resulted in a synergistic decrease in tumor growth and enhanced survival over treatment with 5-FC or radiation alone.

Animals↗

PubMed1998

Contributions of cell kill and posttreatment tumor growth rates to the repopulation of intracerebral 9L tumors after chemotherapy: an MRI study.

The drought of progress in clinical brain tumor therapy provides an impetus for developing new treatments as well as methods for testing therapeutics in animal models. The inability of traditional assays to simultaneously measure tumor size, location, growth kinetics, and cell kill achieved by a treatment complicates the interpretation of therapy experiments in animal models. To address these issues, tumor volume measurements obtained from serial magnetic resonance images were used to noninvasively estimate cell kill values in individual rats with intracerebral 9L tumors after treatment with 0.5, 1, or 2 x LD10 doses of 1,3-bis(2-chloroethyl)-1-nitrosourea. The calculated cell kill values were consistently lower than those reported using traditional assays. A dose-dependent increase in 9L tumor doubling time after treatment was observed that significantly contributed to the time required for surviving cells to repopulate the tumor mass. This study reveals that increases in animal survival are not exclusively attributable to the fraction of tumor cells killed but rather are a function of the cell kill and repopulation kinetics, both of which vary with treatment dose.

Animals↗