Biomedical subjects

Mary J Lindstrom

Publications and source records attributed to Mary J Lindstrom.

At least 19 recordsLinked to original sources

PubMed2006

Neu-induced retroviral rat mammary carcinogenesis: a novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas.

Clinically relevant animal models of mammary carcinogenesis are crucial for the development and evaluation of new breast cancer chemopreventive agents. The neu-induced retroviral rat mammary carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary carcinomas in intact Wistar-Furth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, approximately 50% of mammary carcinomas can be prevented by tamoxifen treatment. In ovariectomized animals, the mammary carcinomas are hormonally nonresponsive and cannot be prevented by tamoxifen. We evaluated the efficacy of retinoic X receptor-selective retinoids (rexinoids) in this novel model of mammary carcinogenesis. The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas. Dietary LG100268 at 100 mg/kg diet decreased tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats. Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling. The neu-induced retroviral rat mammary carcinogenesis model represents a valuable addition to existing rodent chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive tumors.

Animals↗

PubMed2006

Power and precision grip force control in three-to-five-year-old children: velocity control precedes amplitude control in development.

The aim of this study was to examine the development of underlying motor control strategies in young children by characterizing the changes in performance of a visually guided force regulation task using two different grip formations; a whole-hand power grip (developmentally easier) and a thumb-index finger precision grip (developmentally more advanced). Typically developing preschool children (n=50, 3.0-5.5 years) used precision and power grips to perform a ramp and hold task with their dominant and non-dominant hands. Participants performed five trials with each hand and grip holding the force at 30% of their maximum volitional contraction for 3 s. The data were examined for both age-related and performance-related changes in motor performance. Across ages, children increased in strength, decreased in initial overshoot of the target force level, and decreased in rate of force release. Results of a cluster analysis suggest non-linear changes in the development of force control in preschool children, with a plateau in (or maturation of) velocity measures (rate of force increase and force decrease) earlier than in amplitude-related measures (initial force overshoot and force variability).

Child, Preschool↗

PubMed2005

Responsiveness of human retinoblastoma and neuroblastoma models to a non-calcemic 19-nor Vitamin D analog.

OBJECTIVES: To investigate the effectiveness of 2-methylene-19-nor-(20S)-1alpha-hydroxybishomopregnacalciferol (2MbisP) in inhibiting the growth of retinoblastoma (RB) and neuroblastoma (NB). METHODS: For the RB study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model and the transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 2MbisP or vehicle for 5 weeks. For the NB study, the xenograft athymic mouse/human neuroblastoma cell (SK-N-AS) model was treated with 2MbisP or vehicle for 5 weeks. Tumor size and toxicity were assessed. RESULTS: In the xenograft models of RB and NB, 2MbisP caused statistically significant inhibition of tumor growth. Tumor growth inhibition was also observed in the transgenic RB mice, but did not achieve statistical significance. In all the groups, no biologically significant toxic effects were observed using the following variables: serum calcium levels, degree of kidney calcification, changes in body weight or survival. CONCLUSIONS: In athymic mice, 2MbisP was effective in inhibiting RB and NB growth compared with controls. A lesser effect was seen in the transgenic RB model. 2MbisP did not cause hypercalcemia or a significant increase in mortality. CLINICAL RELEVANCE: 2MbisP should be considered for use in clinical trials of RB and NB.

Animals↗

PubMed2005

Mammary glands of sexually immature rats are more susceptible than those of mature rats to the carcinogenic, lethal, and mutagenic effects of N-nitroso-N-methylurea.

Knowing that the prepubertal period is a time of enhanced susceptibility for radiation-induced human breast cancer, we used the Fischer 344 rat model to explore the age-differential susceptibility of the mammary gland to the carcinogenic, lethal, and mutagenic effects of two structurally diverse chemical carcinogens, N-nitroso-N-methylurea (NMU), and 7,12-dimethylbenz(a)anthracene (DMBA). Mammary carcinoma incidences and multiplicities were significantly greater in immature than mature NMU-treated rats while mammary carcinoma incidences and multiplicities were significantly lower in immature than mature DMBA-treated rats. The survival of mammary clonogens of mature NMU-treated rats in limiting dilution transplantation assays was greater than that of the survival of mammary clonogens of immature NMU-treated rats. No differences were found in the survival of mammary cells from immature and mature rats exposed to DMBA. Although there were no mutation spectra differences, mammary epithelial cells of immature NMU-treated rats had greater mutation frequencies than those of mature NMU-treated rats. Together these results support the hypothesis that the mammary gland of immature rats is more susceptible to the carcinogenic, lethal, and mutagenic effects of alkylating agents represented by NMU in a carcinogen-class-specific manner. Further, the results suggest the importance of mechanistic and epidemiological studies of the susceptibility of the prepubertal breast to specific carcinogens such as alkylating agents.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

Association of automated and human observer lesion detecting ability using phantoms.

A set of tissue-mimicking phantoms containing spherical negative contrast simulated lesions was employed to associate an automated method for determining detectability with human observers. Six alternative methods for computing the lesion signal-to-noise ratio (LSNR) were employed for quantifying automated detecting ability. The six methods differ regarding effective lesion area and whether or not gradients in local mean background echo levels were accounted for. The two-alternative-forced-choice (TAFC) technique was used to associate detecting ability of human observers with LSNR values. Although the six methods gave similar results, one method exhibited the least dependency on lesion diameter and is recommended; that method accounts for gradients in local mean background echo levels and employs an effective sphere area of 2/pi times the projected sphere area. A reasonable LSNR detection threshold value of -2.0 was found to apply for nominal transducer frequencies from 4 through 6 MHz and for lesion diameters from 2 through 5 mm. This result allows rapid human-observer-calibrated automated determination of the depth range of detectability as a function of sphere diameter and contrast.

Humans↗

PubMed2005

Development of vocal tract length during early childhood: a magnetic resonance imaging study.

Speech development in children is predicated partly on the growth and anatomic restructuring of the vocal tract. This study examines the growth pattern of the various hard and soft tissue vocal tract structures as visualized by magnetic resonance imaging (MRI), and assesses their relational growth with vocal tract length (VTL). Measurements on lip thickness, hard- and soft-palate length, tongue length, naso-oro-pharyngeal length, mandibular length and depth, and distance of the hyoid bone and larynx from the posterior nasal spine were used from 63 pediatric cases (ages birth to 6 years and 9 months) and 12 adults. Results indicate (a) ongoing growth of all oral and pharyngeal vocal tract structures with no sexual dimorphism, and a period of accelerated growth between birth and 18 months; (b) vocal tract structure's region (oral/anterior versus pharyngeal/posterior) and orientation (horizontal versus vertical) determine its growth pattern; and (c) the relational growth of the different structures with VTL changes with development-while the increase in VTL throughout development is predominantly due to growth of pharyngeal/posterior structures, VTL is also substantially affected by the growth of oral/anterior structures during the first 18 months of life. Findings provide normative data that can be used for modeling the development of the vocal tract.

Age Factors↗

PubMed2004

Effectiveness of vitamin D analogues in treating large tumors and during prolonged use in murine retinoblastoma models.

OBJECTIVE: To investigate the effectiveness of the vitamin D analogues 1,25-(OH)(2)-16-ene-23-yne vitamin D(3) (16,23-D(3)) and 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting retinoblastoma growth in large tumors in a xenograft model and with prolonged use in a transgenic model. METHODS: For the large-tumor study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model was used. Subcutaneous tumors were allowed to grow to an average volume of 1600 mm(3). Systemic treatment with 1 of the vitamin D analogues or with vehicle (control groups) was carried out for 5 weeks. For the long-term study, transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 1 of the 2 compounds or vehicle (control groups) for up to 15 weeks. Tumor size and signs of toxicity were assessed. RESULTS: In the large-tumor study, tumor volume ratios for the 1alpha-OH-D(2) and 16,23-D(3) groups were significantly lower than those for controls (P<.002). No significant differences in tumor volume were seen between the 1alpha-OH-D(2) and 16,23-D(3) groups (P =.15). In the long-term study, the 1alpha-OH-D(2) group showed significantly smaller tumor size compared with its control (P<.001). No significant difference was seen between the 16,23-D(3) group and its control. Some toxic effects related to hypercalcemia were seen in both studies. CONCLUSIONS: In athymic mice in the large-tumor study, both 1alpha-OH-D(2) and 16,23-D(3) were effective in inhibiting tumor growth compared with controls. In the long-term study, 1alpha-OH-D(2) inhibited tumor growth but 16,23-D(3) did not. Effective doses of both compounds caused hypercalcemia and a significant increase in mortality. Clinical Relevance Use of 1alpha-OH-D(2) inhibited tumor growth in large tumors and with long-term treatment compared with controls. Because of hypercalcemia-related toxic effects seen in the present experiments, in clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that lower serum calcium levels or use of relatively lower doses or skipped doses. The ideal alternative solution would be to identify vitamin D analogues that retain the antineoplastic action without the calcemic activity.

Animals↗

PubMed2004

Effectiveness of 1alpha-hydroxyvitamin D2 in inhibiting tumor growth in a murine transgenic pigmented ocular tumor model.

OBJECTIVE: To study the effectiveness of the vitamin D analogue 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting ocular tumor growth in transgenic "Tyr-Tag" mice that developed pigmented ocular tumors produced with the simian virus 40 T and t antigens under the control of the mouse tyrosinase gene. These animals develop pigmented intraocular tumors primarily from the retinal pigment epithelium that closely resemble the histologic features and growth pattern of human choroidal melanoma. METHODS: A total of 73 Tyr-Tag transgenic mice between 6 and 7 weeks old were randomly assigned by sex and litter to 3 treatment groups to receive 0.05 microg/d, 0.1 microg/d, or 0.2 microg/d of 1alpha-OH-D(2); a control group received vehicle (coconut oil). The drug was administered by oral gavage 5 times a week for 5 weeks. The animals were then euthanized and their eyes were enucleated and processed histologically. Three serial sections from each eye were examined microscopically and the mean tumor area measured using Optimus software version 6.5 (Media Cybernetics LP, Silver Spring, Md). Toxic adverse effects were assessed on the basis of mortality, weight loss, and serum calcium levels. RESULTS: The mean tumor size in the 0.1- microg/d and 0.2- microg/d dose groups was smaller than in the controls (P<.001). No significant difference was seen between the 0.05- microg/d dose group and the control group (P =.64). Survival for the 0.1- microg/d and 0.2- microg/d dose groups was lower than for the controls (95% in the controls vs 85.7% and 73.7%, respectively; P<.01). CONCLUSION: In the Tyr-Tag transgenic mouse, 1alpha-OH-D(2) inhibits pigmented ocular tumor growth at moderate drug levels with relatively low mortality. Clinical Relevance Vitamin D analogues merit further preclinical study in the treatment of ocular melanoma.

Animals↗

PubMed2004

Self modeling with flexible, random time transformations.

Methods for modeling sets of complex curves where the curves must be aligned in time (or in another continuous predictor) fall into the general class of functional data analysis and include self-modeling regression and time-warping procedures. Self-modeling regression (SEMOR), also known as a shape invariant model (SIM), assumes the curves have a common shape, modeled nonparametrically, and curve-specific differences in amplitude and timing, traditionally modeled by linear transformations. When curves contain multiple features that need to be aligned in time, SEMOR may be inadequate since a linear time transformation generally cannot align more than one feature. Time warping procedures focus on timing variability and on finding flexible time warps to align multiple data features. We draw on these methods to develop a SIM that models the time transformations as random, flexible, monotone functions. The model is motivated by speech movement data from the University of Wisconsin X-ray microbeam speech production project and is applied to these data to test the effect of different speaking conditions on the shape and relative timing of movement profiles.

Biomechanical Phenomena↗

PubMed2004

Enhancement of the antiangiogenic activity of interleukin-12 by peptide targeted delivery of the cytokine to alphavbeta3 integrin.

We engineered a fusion protein, mrIL-12vp [mouse recombinant interleukin (IL)-12 linked to vascular peptide], linking the vascular homing peptide CDCRGDCFC (RGD-4C), a ligand for alphavbeta3 integrin, to mrIL-12 to target IL-12 directly to tumor neovasculature. The fusion protein stimulated IFN-gamma production in vitro and in vivo, indicating its biological activity was consistent with mrIL-12. Immunofluorescence techniques showed mrIL-12vp specifically bound to alphavbeta3 integrin-positive cells but not to alphavbeta3 integrin-negative cells. In corneal angiogenesis assays using BALB/c mice treated with either 0.5 microg/mouse/d of mrIL-12vp or mrIL-12 delivered by subcutaneous continuous infusion, mrIL-12vp inhibited corneal neovascularization by 67% compared with only a slight reduction (13%) in angiogenesis in the mrIL-12-treated animals (P = 0.008). IL-12 receptor knockout mice given mrIL-12vp showed a marked decrease in the area of corneal neovascularization compared with mice treated with mrIL-12. These results indicate that mrIL-12vp inhibits angiogenesis through IL-12-dependent and IL-12-independent mechanisms, and its augmented antiangiogenic activity may be due to suppression of endothelial cell signaling pathways by the RGD-4C portion of the fusion protein. Mice injected with NXS2 neuroblastoma cells and treated with mrIL-12vp showed significant suppression of tumor growth compared with mice treated with mrIL-12 (P = 0.03). Mice did not show signs of IL-12 toxicity when treated with mrIL-12vp, although hepatic necrosis was present in mrIL-12-treated mice. Localization of IL-12 to neovasculature significantly enhances the antiangiogenic effect, augments antitumor activity, and decreases toxicity of IL-12, offering a promising strategy for expanding development of IL-12 for treatment of cancer patients.

Angiogenesis Inhibitors↗

PubMed2003

Toxicity and dose-response studies of 1-alpha hydroxyvitamin D2 in LH-beta-tag transgenic mice.

PURPOSE: To determine the effectiveness of a vitamin D analog, 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHbeta-Tag mouse) and to evaluate its toxicity. DESIGN: Experimental study using an animal (LHbeta-Tag transgenic mouse) randomized (controlled) trial. PARTICIPANTS AND CONTROLS: Two hundred seventeen LHbeta-Tag transgene-positive 8- to 10-week-old mice total; 179 drug-treated animals, 38 control animals. METHODS: Mice were fed a vitamin D- and calcium-restricted diet and were randomized to treatment groups receiving control (vehicle), or 0.1, 0.3, 0.5, or 1.0 micro g/day of 1alpha-OH-D(2) via oral gavage 5 times weekly for 5 weeks. Body weight was measured at the start of treatment and twice weekly during treatment. Animals were euthanized on the last day of treatment. The eyes were enucleated, processed histologically, and serially sectioned. Representative sections from the superior, middle, and inferior regions of each globe were examined microscopically and tumor areas were measured using Optimas software. Serum was collected for serum calcium levels. Kidneys were removed for histologic processing and were analyzed microscopically for kidney calcification. MAIN OUTCOME MEASURES: Mean tumor area was measured to determine drug effectiveness. Toxicity was assessed by survival, weight loss over the treatment period, serum calcium, and kidney calcification. RESULTS: The mean tumor size in each 1alpha-OH-D(2) group was smaller than controls (all P values < 0.02): control, 90,248 micro m(2); 0.1 micro g, 31,545 micro m(2); 0.3 micro g, 16,750 micro m(2); 0.5 micro g, 30,245 micro m(2); and 1.0 micro g, 16,049 micro m(2). No dose-dependent response curve was evident. The survival percentage for each group was as follows: control, 97%; 0.1 micro g, 91%; 0.3 micro g, 88%; 0.5 micro g, 70%; and 1.0 micro g, 63%. Mortality was higher in the 0.5- micro g and 1.0- micro g doses (P values < 0.01) compared with other treatment groups and with the control group. Serum calcium levels were significant in all treatment groups compared with controls (all P values < 0.0001). CONCLUSIONS: In the LHbeta-Tag mouse, 1alpha-OH-D(2) inhibits retinoblastoma with no significant increase in mortality in lower doses (0.1-0.3 micro g). 1alpha-OH-D(2) has approval by the Food and Drug Administration as an investigative drug for cancer treatment, and has shown efficacy with low toxicity in adult cancer trials. 1alpha-OH-D(2) meets the criteria for human clinical trials.

Animals↗

PubMed2003

Affinity with Raf is sufficient for Ras to efficiently induce rat mammary carcinomas.

The role of three major Ras downstream effector pathways in the induction of mammary cancer was studied using an in situ mammary ductal gene delivery model. Replication-defective retroviral vectors were used to infect endogenous rat mammary epithelial cells with three individual Ras effector loop mutants, each of which transduces its signal through a different Ras effector pathway (Raf, PI3K or RalGDS). Several groups have used Ras effector loop mutants in cultured cells, clearly characterizing the signaling specificity of each over a wide range of cell lines and conditions. Each of the three Ras effector loop mutations impairs Ras for neoplastic transformation of immortal cell lines in culture. In contrast, when evaluated in vivo by infecting endogenous rat mammary epithelial cells in situ with retroviral vectors, we find that codon 12 mutant activated V12-Ras and all three V12-Ras effector loop mutants individually induce mammary carcinomas. Most notably, a Ras effector loop mutant that lacks affinity with PI3K and RalGDS but retains affinity with Raf (E38-V12-Ras) is relatively similar in potency to V12-Ras for mammary carcinoma induction. Two other Ras effector loop mutants, each lacking affinity with Raf, one retaining affinity with PI3K (C40-V12-Ras), the other with RalGDS (G37-V12-Ras), resulted in much longer tumor latency than E38-V12-Ras and V12-Ras and a reduced carcinoma frequency. Tumor latencies for V12-Ras, E38-V12-Ras, C40-V12-Ras and G37-V12-Ras were 4, 4, 11 and 12 weeks, respectively. We conclude that the Ras-Raf pathway can function independently of the Ras-PI3K and Ras-RalGDS pathways for rapid induction of rat mammary carcinomas, while Ras-PI3K and Ras-RalGDS pathways may also individually induce mammary carcinomas following a long latency.

3T3 Cells↗

PubMed2003

Vitamin D analogues increase p53, p21, and apoptosis in a xenograft model of human retinoblastoma.

PURPOSE: To study the antineoplastic effect of vitamin D analogues in a xenograft model of human retinoblastoma. METHODS: Athymic mice were injected subcutaneously with Y79 cells and treated 5 days a week with either mineral oil (control group) or the vitamin D analogues calcitriol or 1,25-dihydroxy-16-ene-23-yne vitamin D(3) (16,23-D(3)). BrdU was injected 1 hour before death. Animals were killed after 1, 2, 3, or 5 weeks. Paraffin-embedded sections of the tumors were studied for cell proliferation by monitoring for BrdU incorporation and cell death by terminal transferase dUTP-nick end labeling (TUNEL), 3'-overhang ligation, and histology. Sections of the tumors were immunostained for p53 and p21. RESULTS: There was no significant difference in incorporation of BrdU among the three groups, suggesting that cell proliferation is unaffected by vitamin D analogues. TUNEL was increased in tumors treated with vitamin D analogues compared with the control group. This increase was statistically significant for calcitriol in the time frame examined, but not statistically significant for 16,23-D(3). Alternatively, the ratio of proliferation to cell death was significantly different for both calcitriol and 16,23-D(3) compared with control tumors after 3 weeks of treatment. Dying cells contained DNA strand breaks with overhanging nucleotides and nuclear changes characteristic of apoptosis. There was an increase in staining for p53 and p21 in areas associated with cell death in specimens treated with vitamin D analogues. CONCLUSIONS: Vitamin D analogues appear to attenuate retinoblastoma tumor growth in athymic mice by increasing apoptosis. Cell death is associated with the upregulation of both p53 and p21.

Animals↗

PubMed2002

Decreased susceptibility to NMU-induced mammary carcinogenesis in transgenic rats carrying multiple copies of a rat ras gene driven by the rat Harvey ras promoter.

Ras protein over-expression has been observed in human breast cancers although the significance of Ras over-expression in the etiology of breast cancer is unknown and its contribution to breast cancer prognosis is still debated. In this study, the over-expression of both wild-type Harvey and Kirsten Ras proteins as contributors to rat mammary carcinogenesis were examined using a transgenic rat model. Three rat transgenic lines (designated HrHr transgenics) carrying three to six copies of wild-type rat Harvey ras driven by the wild-type rat Harvey ras promoter were produced. In addition, transgenic lines carrying either three or seven copies of the Kirsten ras gene under the same promoter (HrKr) were produced. No pathological changes in the mammary gland were observed in any of the HrHr or HrKr transgenic rat line heterozygotes. Two of the Ras transgenic lines, HrHr (R8) and HrKr (4334), had a significant reduction in NMU-induced rat mammary cancer when compared to their non-transgenic littermates. All five Ras transgenic lines developed fewer carcinomas than their non-transgenic littermates following NMU exposure. The percentage of NMU-induced G35 to A35 activating mutations in the endogenous Harvey ras gene in mammary carcinomas from the HrHr, HrKr transgenic rats and their non-transgenic littermates was similar ( approximately 50%). In contrast, less than 1% of the NMU-induced carcinomas in these Ras transgenic rats had an activating ras mutation in their transgenes. These findings highlight the potential of Ras to function as a modifier gene in repressing mammary carcinogenesis.

Animals↗

PubMed2002

Regions of H- and K-ras that provide organ specificity/potency in mammary cancer induction.

Organ-specific cancers with activated ras oncogenes most often are associated exclusively with only one ras isoform. For example, only H-ras activation is associated with rat mammary cancers. The mechanism underlying this specificity is mostly unknown. We have shown previously that this tissue specificity of Ras isoforms is defined by the Ras protein itself and not by differential gene expression among Ras family members. Here we show that elements in the known domains in the hypervariable region of Ras (amino acids 170-189) interact in part to control this mammary/H-Ras specificity. In addition, these in vivo mammary studies for the first time identify domains in the mostly homologous region of Ras (amino acids 1-169) that strongly influence the oncogenic potency/specificity of H-Ras.

Amino Acid Sequence↗

PubMed2002

Toxicity and dose-response studies of 1alpha-hydroxyvitamin D2 in a retinoblastoma xenograft model.

BACKGROUND: Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D(2) inhibit retinoblastoma growth in the athymic (nude) mouse xenograft (Y-79 cell line) model of retinoblastoma, they can cause severe toxicity. OBJECTIVE: To examine the toxicity of and dose-dependent response for the inhibition of tumor growth for 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), an analogue with reduced systemic toxicity, in the athymic Y-79 mouse model. METHODS: Mice were randomized into treatment and control groups for 5-week toxicity and dose-response studies. Treatment was via oral gavage 5 times per week. Dose-response studies measured tumor inhibition and drug serum levels. Tumor size and body weight were measured weekly together with various criteria for toxicity. Animals were euthanized at the end of the treatment period. Tumors and kidneys were harvested, and serum was analyzed for calcium and drug levels. RESULTS: Doses of 0.1 to 1.2 microg/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-microg and 0.3-microg doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 microg were lower than those observed in studies of calcitriol and vitamin D(2). CONCLUSION: A vitamin D analogue, 1alpha-OH-D(2), inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D(2).

Animals↗

PubMed2002

Tongues and lips without jaws: a comparison of methods for decoupling speech movements.

Speech-related motions of small markers attached to the tongue, lower lip, and lower jaw of 44 normal young adult talkers of American English were analyzed to estimate the relative accuracy of selected methods for decoupling tongue and lip motions from ongoing jaw motion when all movements are originally measured relative to a common reference frame (such as the head). In general, results of the analysis show that a common "simple subtraction" method that ignores pitching rotation of the jaw yields larger errors in positions and speeds of decoupled tongue and lip markers than methods that do not ignore rotation. When the jaw is widely opened, is moving quickly, and/or when any decoupled marker is relatively far from the origin of a local coordinate system fixed to the jaw, positional and speed errors associated with the subtraction method can exceed 5 mm and 25 mm/s, respectively. We propose a simple procedure for estimating the pitching rotation of the jaw that can be applied when pitch cannot be measured. We then show that decoupled motions of tongue and lower lip markers based on estimated jaw rotation involve less error than those derived from any other decoupling method considered. Careful attention to processing methods should yield more accurate inferences about the nature and degree of coordination between speech-related movements of the tongue and lower lip that are decoupled from, and hence independent of, concurrent movements of the lower jaw.

Adult↗

PubMed2002

Vitamin D analogs, a new treatment for retinoblastoma: The first Ellsworth Lecture.

PURPOSE: This lecture honors the memory of Dr. Robert M. Ellsworth, an important figure in the development of current treatments of retinoblastoma (RB), and reviews our studies of vitamin D analogs as treatments for retinoblastoma in two experimental mouse models. We identified vitamin D receptors in retinoblastoma and examined the effectiveness and mechanism of action of these analogs. METHODS: Reverse-transcriptase polymerase chain reaction (RT-PCR) amplification was used to detect vitamin D receptor mRNAs in human and mouse retinoblastomas. The effectiveness and toxicity of vitamin D(2), calcitriol, and synthetic analogs were studied in the athymic/Y-79 xenograft and transgenic mouse models of RB. Dosing was 5X/week for five weeks. Dose-response studies focused on tumor inhibition; toxicity studies investigated survival and serum calcium. The mechanism of action of vitamin D was investigated using terminal transferase dUTP labeling 3'-overhang ligation to measure apoptosis; immunohistochemistry measured p53-dependent gene expression and cell proliferation. RESULT: Vitamin D receptor mRNAs were detectable in Y-79 RB cells, LH beta-Tag tumors, and human RB specimens using RT-PCR. Calcitriol inhibited cell growth in vitro. Calcitriol and vitamin D(2) inhibited in vivo growth in xenograft and transgenic models, but therapeutic levels were toxic due to hypercalcemia. Two analogs, 16,23-D(3) and 1 alpha-OH-D( 2), inhibited tumors in animal models of RB with reduced toxicity. The mechanism of action appears related to increased p53-related gene expression resulting in increased apoptosis. CONCLUSION: 16,23-D(3) and 1 alpha-OH-D(2) are effective in tumor reduction in two mouse models of RB with low toxicity. These results warrant initiating phase 1 and phase 2 clinical studies in children.

Animals↗