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Biomedical subjects

Daniel E Hall

Publications and source records attributed to Daniel E Hall.

At least 19 recordsLinked to original sources
PubMed2006

Vascular targeted nanoparticles for imaging and treatment of brain tumors.

PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.

Angiography↗
PubMed2006

Dynamic imaging of emerging resistance during cancer therapy.

One of the greatest challenges in developing therapeutic regimens is the inability to rapidly and objectively assess tumor response due to treatment. Moreover, tumor response to therapeutic intervention in many cases is transient, and progressive alterations within the tumor may mask the effectiveness of an initially successful therapy. The ability to detect these changes as they occur would allow timely initiation of alternative approaches, maximizing therapeutic outcome. We investigated the ability of diffusion magnetic resonance imaging (MRI) to provide a sensitive measure of tumor response throughout the course of treatment, possibly identifying changes in sensitivity to the therapy. Orthotopic 9L gliomas were subjected to two separate therapeutic regimens, with one group receiving a single 5-day cycle (1omega) of low-dose 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and a second group receiving two cycles at the same dose, bisected with 2 days of rest (2omega). Apparent diffusion coefficient maps were acquired before and throughout treatment to observe changes in water mobility, and these observations were correlated to standard measures of therapeutic response and outcome. Our results showed that diffusion MRI was indeed able to detect the emergence of a drug-resistant tumor subpopulation subsequent to an initially successful cycle of BCNU therapy, leading to minimal gains from a second cycle. These diffusion MRI findings were highly correlated with tumor growth delay, animal survival, and ex vivo growth inhibition assays showing emerging resistance in excised tumors. Overall, this study highlights the ability of diffusion MRI to provide sensitive dynamic assessment of therapy-induced response, allowing early opportunities for optimization of therapeutic protocols.

Animals↗
PubMed2006

Inhibition of vascular endothelial growth factor (VEGF)-A causes a paradoxical increase in tumor blood flow and up-regulation of VEGF-D.

PURPOSE: Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas. EXPERIMENTAL DESIGN: Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated. RESULTS: Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors. CONCLUSION: Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.

Animals↗
PubMed2006

College students' views on gay and lesbian issues: does education make a difference.

Many in academia believe that higher education leads to an increase in tolerance towards individuals who are different. There are some empirical findings to support this premise; however, the impact of higher education on acceptance of homosexuality has not been adequately explored. Gays and lesbians in society face many negative attitudes. Based upon the survey results of 364 students at a Midwestern university, juniors and seniors had statistically significant more positive attitudes towards gays and lesbians than did freshmen and sophomores. Even in multi-variate analysis, upper-level students had more positive views on many of the attitudinal measures.

Adolescent↗
PubMed2006

The functional diffusion map: an imaging biomarker for the early prediction of cancer treatment outcome.

Functional diffusion map (fDM) has been recently reported as an early and quantitative biomarker of clinical brain tumor treatment outcome. This approach spatially maps and quantifies treatment-induced changes in tumor water diffusion values resulting from alterations in cell density/cell membrane function and microenvironment. This current study was designed to evaluate the capability of fDM for preclinical evaluation of dose escalation studies and to determine if these changes were correlated with outcome measures (cell kill and overall survival). Serial T2-weighted were carried out on rodents with orthotopically implanted 9L brain tumors receiving three doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (6.65, 13.3, and 26.6 mg/kg, i.p.). All images were coregistered to baseline T2-weighted images for fDM analysis. Analysis of tumor fDM data on day 4 posttreatment detected dose-dependent changes in tumor diffusion values, which were also found to be spatially dependent. Histologic analysis of treated tumors confirmed spatial changes in cellularity as observed by fDM. Early changes in tumor diffusion values were found to be highly correlative with drug dose and independent biologic outcome measures (cell kill and survival). Therefore, The fDM imaging biomarker for early prediction of treatment efficacy can be used in the drug development process.

Animals↗
PubMed2005

Continuous arterial spin labeling using a train of adiabatic inversion pulses.

PURPOSE: To develop a simple and robust magnetic resonance imaging (MRI) pulse sequence for the quantitative measurement of blood flow in the brain and cerebral tumors that has practical implementation advantages over currently used continuous arterial spin labeling (CASL) schemes. MATERIALS AND METHODS: Presented here is a single-coil protocol that uses a train of hyperbolic secant inversion pulses to produce continuous arterial spin inversion for perfusion weighting of fast spin echo images. Flow maps of normal rat brains and those containing a 9L gliosarcoma orthotopic tumor model conditions were acquired with and without carbogen. RESULTS: The perfusion-weighted images have reduced magnetization transfer signal degradation as compared to the traditional single-coil CASL while avoiding the use of a more complex two-coil CASL technique. Blood flow measurements in tumor and normal brain tissue were consistent with those previously reported by other CASL techniques. Contralateral and normal brain showed increased blood flow with carbogen breathing, while tumor tissue lacked the same CO(2) reactivity. CONCLUSION: This variation of the CASL technique is a quantitative, robust, and practical single-coil method for measuring blood flow. This CASL method does not require specialized radiofrequency coils or amplifiers that are not routinely used for anatomic imaging of the brain, therefore allowing these flow measurements to be easily incorporated into traditional rodent neuroimaging protocols.

Anesthetics, Inhalation↗
PubMed2005

Intratumoral injection of BCNU in ethanol (DTI-015) results in enhanced delivery to tumor--a pharmacokinetic study.

Solvent facilitated perfusion (SFP) has been proposed as a technique to increase the delivery of chemotherapeutic agents to tumors. SFP entails direct injection of the agent into the tumor in a water-miscible organic solvent, and because the solvent moves easily through both aqueous solutions and cellular membranes it drives the penetration of the solubilized anticancer agent throughout the tumor. To test this hypothesis, we compared the pharmacokinetics (PK) of 14C-labeled 1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat gliomas after intravenous (IV) infusion in 90% saline--10% ethanol or direct intratumoral (IT) injection of 14C-BCNU in 100% ethanol (DTI-015). Treatment with DTI-015 yielded a peak radioactive count (Cmax) for the 14C label that was 100-1000 fold higher in the tumor than in all other tissues in addition to a concentration in the tumor that was 100-fold higher than that achieved following IV infusion of 14C-BCNU. Pathologic and auto-radiographic analysis of tissue sections following IT injection of 14C-BCNU in ethanol into either tumor or normal rat brain revealed both an enhanced local volume of distribution and an increased concentration of BCNU delivered to tumor compared to non-tumor bearing brain. To investigate the mechanism behind the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI were performed on 9L tumors before and after treatment and demonstrated a decrease in tumor perfusion following IT injection of DTI-015. Finally, initial PK of patient blood samples following administration of DTI-015 into relapsed high-grade glioma indicated a 20-fold decrease in systemic exposure to BCNU compared to IV infusion of BCNU providing further evidence for the enhanced therapeutic ratio observed for DTI-015.

Animals↗
PubMed2005

Strangers or friends? A proposal for a new spirituality-in-medicine ethic.

We argue that debate regarding whether and how physicians should engage religious concerns has proceeded under inadequate terms. The prevailing paradigm approaches dialogue regarding religion as a form of therapeutic technique, engaged by one stranger, the physician, upon another stranger, the patient. This stranger-technique framework focuses the debate on questions of physicians' competence, threats to patients' autonomy, and neutrality regarding religion, and in so doing, it too greatly circumscribes the scope of physician-patient dialogue. In contrast, we argue that dialogue regarding religion is better approached as a form of philosophical discourse about ultimate human concerns. Such moral discourse is often essential to the patient-physician relationship, and rather than shrinking from such discourse, physicians might engage patients regarding religious concerns guided by an ethic of moral friendship that seeks the patient's good through wisdom, candor, and respect.

Adult↗
PubMed2005

Social versus individual motivation: implications for normative definitions of religious orientation.

The traditional interpretation of "intrinsic" religiousness has fostered an unchallenged assumption that normative and substantive religious motivation is inherently individual and personal. Social motives for religiousness and structured practices have been characterized as "extrinsic" and as lacking in formative significance. We argue that this view is most applicable in American Protestant religions, and hence existing religious motivation scales reflect a distinctly American Protestant view. We then show that social motives and structured ritual practices are, in fact, as normative as individual motivations in several religious traditions. In particular, we describe the social practices and motives normative for Judaism and certain streams of Christianity. We then discuss the potential relevance of this analysis to emotion, collective identity, and moral judgment.

Christianity↗
PubMed2004

Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker.

To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 mul under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.

Animals↗
PubMed2004

In vivo real-time imaging of TGF-beta-induced transcriptional activation of the RANK ligand gene promoter in intraosseous prostate cancer.

BACKGROUND: Current animal models of prostate cancer (CaP) bone metastasis do not allow measurement of either tumor growth in bone over time or activation of gene promoters in intraosseous tumors. To develop these methods, we used bioluminescent imaging (BLI) to determine if expression of receptor activator of NF-kappaB ligand (RANKL), a pro-osteoclastogenic factor that promotes CaP bone metastases, is modulated by the bone matrix protein transforming growth factor-beta (TGF-beta) in vivo. METHODS: C4-2B human CaP cells were treated with TGF-beta in vitro and RANKL mRNA and protein production were measured by polymerase chain reaction (PCR) and ELISA, respectively. Then C4-2B cells stably transfected with the RANKL promoter driving luciferase (lux) were injected intra-tibially into severe combined immundeficient (SCID) mice. Tumors were subjected to BLI every 2 weeks for 6 weeks and serum prostate specific antigen (PSA) was measured using ELISA. Vehicle (V), 1,25 dihydroxyvitamin D (VitD), or TGF-beta was administered to mice with established tumors and BLI to measure RANKL promoter activity was performed. Tumors were then subjected to immunohistochemistry for lux and assayed for RANKL mRNA levels. RESULTS: TGF-beta induced RANKL protein and mRNA expression and activated the RANKL promoter activity in a dose-dependent manner in vitro. BLI demonstrated an increase in intraosseous tumor size over time, which correlated with serum PSA levels. Administration of TGF-beta and VitD to mice with established intraosseous tumors increased lux activity compared to V. Intratibial tumor RANKL mRNA expression paralleled the increased promoter activity. Immunohistochemistry confirmed the presence of lux in the intraosseous tumors. CONCLUSIONS: These results demonstrate the ability to measure intraosseous tumor growth over time and gene promoter activation in an established intraosseous tumor in vivo and also demonstrate that TGF-beta induces activates the RANKL promoter. These results provide a novel method to explore the biology of CaP bone metastases.

Animals↗
PubMed2004

In vivo visualization of aging-associated gene transcription: evidence for free radical theory of aging.

The expression of a variety of proteins is elevated with aging through unknown mechanisms. The free radical theory of aging promulgates that reactive oxygen species (ROS) promote the aging process. However, the mechanisms as to how ROS contribute to the aging process are not clear. We present data here that demonstrate that aging induced ROS promote aging-associated interleukin-6 (IL-6) gene transcription in mice that are transgenic for the murine IL-6 promoter driving a luciferase reporter cDNA. N-acetylcysteine (NAC), an antioxidant, completely reverses the increased endogenous IL-6 promoter activity in the old mice determined by real-time bioluminescence imaging (BLI). We conclude that ability of ROS to act as secondary messengers and induce gene expression may contribute to the aging process.

Acetylcysteine↗
PubMed2004

Can physicians' care be neutral regarding religion?

A recent critique of the growing field of spirituality and medicine suggests that physicians should foster a professional ethic that is deliberately neutral regarding religion. The critique reflects an anxiety that it is almost inherently coercive for physicians to engage their patient's spiritual concerns, and it expresses a parallel admonition to physicians not to impose their values on patients. Although the authors agree that religious coercion is never warranted, they argue that neutrality regarding religion is neither possible nor desirable. They suggest rather that the challenging interface between religion and medicine requires wisdom and character formed by deep self-awareness of the various commitments (religious or otherwise) that shape decisions regarding medical practice, policy, and professional conduct.

Attitude of Health Personnel↗
PubMed2004

Conceptualizing "religion": How language shapes and constrains knowledge in the study of religion and health.

Despite recent advances in the field of religion and health, meaningful findings will increasingly depend on the capacity to conceptualize "religion" properly. To date, scientists' conception of religion has been shaped by the Enlightenment paradigm. However, recent developments in philosophy make the "objectivity" of the Enlightenment paradigm problematic, if not untenable. Contrary to common understanding, the secularism essential to the Enlightenment paradigm does not enjoy any special privilege over religious ways of seeing the world, because both religious and secular worldviews constitute self-referentially complete interpretations of the human condition. If there is no objective frame of reference from which to measure religiousness, then the study of religion and health is fundamentally contingent on the specific languages and contexts in which particular religions find expression. While applying this cultural-linguistic approach to religion would require significant changes in the existing methods for studying religion and health, such changes may generate a deeper understanding of this relationship.

Attitude to Health↗
PubMed2003

A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI.

A novel polyacrylamide superparamagnetic iron oxide nanoparticle platform is described which has been synthetically prepared such that multiple crystals of iron oxide are encapsulated within a single polyacrylamide matrix (PolyAcrylamide Magnetic [PAM] nanoparticles). This formulation provides for an extremely large T2 and T2* relaxivity of between 620 and 1140 sec(-1) mM(-1). Administration of PAM nanoparticles into rats bearing orthotopic 9L gliomas allowed quantitative pharmacokinetic analysis of the uptake of nanoparticles in the vasculature, brain, and glioma. Addition of polyethylene glycol of varying sizes (0.6, 2, and 10 kDa) to the surface of the PAM nanoparticles resulted in an increase in plasma half-life and affected tumor uptake and retention of the nanoparticles as quantified by changes in tissue contrast using MRI. The flexible formulation of these nanoparticles suggests that future modifications could be accomplished allowing for their use as a targeted molecular imaging contrast agent and/or therapeutic platform for multiple indications.

Acrylic Resins↗