Design and testing of a microcontroller that enables alpha particle irradiators to deliver complex dose rate patterns.

There is increasing interest in using alpha particle emitting radionuclides for cancer therapy because of their unique cytotoxic properties which are advantageous for eradicating tumor cells. The high linear energy transfer (LET) of alpha particles produces a correspondingly high density of ionizations along their track. Alpha particle emitting radiopharmaceuticals deposit this energy in tissues over prolonged periods with complex dose rate patterns that depend on the physical half-life of the radionuclide, and the biological uptake and clearance half-times in tumor and normal tissues.

Vitamins A, C, and E May Reduce Intestinal 210Po Levels after Ingestion.

Damage to the gut mucosa is a probable contributory cause of death from ingested Po. Therefore, medical products are needed that can prevent, mitigate, and/or repair gastrointestinal (GI) damage caused by high-LET radiation emitted by Po. The present studies investigated the capacity of a diet highly enriched with vitamins A, C, and E (vitamin ACE) to protect against intestinal mucosal damage indicated by functional reductions in nutrient transport caused by orally ingested Po.

High Levels of Dietary Supplement Vitamins A, C and E are Absorbed in the Small Intestine and Protect Nutrient Transport Against Chronic Gamma Irradiation.

We examined nutrient transport in the intestines of mice exposed to chronic low-LET 137Cs gamma rays. The mice were whole-body irradiated for 3 days at dose rates of 0, 0.13 and 0.

Changes in lognormal shape parameter guide design of patient-specific radiochemotherapy cocktails.

Unlabelled: Uptake of radiopharmaceuticals and chemotherapeutic drugs is nonuniform at the microscopic level. Their distributions are typically lognormal, suggesting that failure in chemotherapy and targeted radionuclide therapy may be attributable, in part, to the characteristics of this biologically ubiquitous distribution. The lognormal problem can be overcome by using cocktails of 2 or more agents, tailored such that at least 1 agent is strongly incorporated by every cell in the target population.

Marked changes in endogenous antioxidant expression precede vitamin A-, C-, and E-protectable, radiation-induced reductions in small intestinal nutrient transport.

Rapidly proliferating epithelial crypt cells of the small intestine are susceptible to radiation-induced oxidative stress, yet there is a dearth of data linking this stress to expression of antioxidant enzymes and to alterations in intestinal nutrient absorption. We previously showed that 5-14 days after acute γ-irradiation, intestinal sugar absorption decreased without change in antioxidant enzyme expression. In the present study, we measured antioxidant mRNA and protein expression in mouse intestines taken at early times postirradiation.

Radiation-induced reductions in transporter mRNA levels parallel reductions in intestinal sugar transport.

More than a century ago, ionizing radiation was observed to damage the radiosensitive small intestine. Although a large number of studies has since shown that radiation reduces rates of intestinal digestion and absorption of nutrients, no study has determined whether radiation affects mRNA expression and dietary regulation of nutrient transporters. Since radiation generates free radicals and disrupts DNA replication, we tested the hypotheses that at doses known to reduce sugar absorption, radiation decreases the mRNA abundance of sugar transporters SGLT1 and GLUT5, prevents substrate regulation of sugar transporter expression, and causes reductions in sugar absorption that can be prevented by consumption of the antioxidant vitamin A, previously shown by us to radioprotect the testes.

Pharmacokinetic analysis of polyamide nucleic-acid-cell penetrating peptide conjugates targeted against HIV-1 transactivation response element.

We have demonstrated that polyamide nucleic acids complementary to the transactivation response (TAR) element of HIV-1 LTR inhibit HIV-1 production when transfected in HIV-1 infected cells. We have further shown that anti-TAR PNA (PNA(TAR)) conjugated with cell-penetrating peptide (CPP) is rapidly taken up by cells and exhibits strong antiviral and anti-HIV-1 virucidal activities. Here, we pharmacokinetically analyzed (125)I-labeled PNA(TAR) conjugated with two CPPs: a 16-mer penetratin derived from antennapedia and a 13-mer Tat peptide derived from HIV-1 Tat.

Lognormal distribution of cellular uptake of radioactivity: statistical analysis of alpha-particle track autoradiography.

Unlabelled: Recently, the distribution of radioactivity among a population of cells labeled with 210Po was shown to be well described by a lognormal (LN) distribution function (J Nucl Med. 2006;47:1049-1058) with the aid of autoradiography. To ascertain the influence of Poisson statistics on the interpretation of the autoradiographic data, the present work reports on a detailed statistical analysis of these earlier data.

Biological response to nonuniform distributions of (210)Po in multicellular clusters.

Radionuclides are distributed nonuniformly in tissue. The present work examined the impact of nonuniformities at the multicellular level on the lethal effects of (210)Po. A three-dimensional (3D) tissue culture model was used wherein V79 cells were labeled with (210)Po-citrate and mixed with unlabeled cells, and multicellular clusters were formed by centrifugation.

Elevated blood lead concentrations and vitamin D deficiency in winter and summer in young urban children.

Background: It is widely recognized that blood lead concentrations are higher in the summer than in winter. Although the effects of some environmental factors such as lead in dust on this phenomenon have been studied, relationships to sunlight-induced vitamin D synthesis have not been adequately investigated. Vitamin D status is influenced by the diet, sunlight exposure, age, skin pigmentation, and other factors, and may modify gastrointestinal lead absorption or release of lead stored in bones into the bloodstream.

Log normal distribution of cellular uptake of radioactivity: implications for biologic responses to radiopharmaceuticals.

Unlabelled: It is widely recognized that radiopharmaceuticals are generally distributed nonuniformly in tissues. Such nonuniformities are observed over the entire range of spatial levels, ranging from organ to subcellular levels. The implications of nonuniform distributions of radioactivity for dosimetry, and ultimately for the biologic response of tissues containing radioactivity, have been investigated extensively.

Modeling multicellular response to nonuniform distributions of radioactivity: differences in cellular response to self-dose and cross-dose.

Radiopharmaceuticals are distributed nonuniformly in tissue. While distributions of radioactivity often appear uniform at the organ level, in fact, microscopic examination reveals that only a fraction of the cells in tissue are labeled. Labeled cells and unlabeled cells often receive different absorbed doses depending on the extent of the nonuniformity and the characteristics of the emitted radiations.

Isolating effects of microscopic nonuniform distributions of (131)I on labeled and unlabeled cells.

Unlabelled: Radiopharmaceuticals are generally distributed nonuniformly in tissue. At the microscopic level, only a fraction of the cells in tissue are labeled. Consequently, the labeled cells receive an absorbed dose from radioactivity within the cell (self-dose) as well as an absorbed dose from radioactivity in surrounding cells (cross-dose).

A multi-port low-fluence alpha-particle irradiator: fabrication, testing and benchmark radiobiological studies.

A new multi-port irradiator, designed to facilitate the study of the effects of low fluences of alpha particles on monolayer cultures, has been developed. The irradiator consists of four individual planar (241)Am alpha-particle sources that are housed inside a helium-filled Lucite chamber. Three of the radioactive sources consist of 20 MBq of (241)Am dioxide foil.

When may a nonuniform distribution of 131I be considered uniform? An experimental basis for multicellular dosimetry.

Unlabelled: To varying degrees, radiopharmaceuticals are distributed nonuniformly in tissue. At a macroscopic level, the radiopharmaceutical may appear to be uniformly distributed throughout the tissue. However, on closer inspection, not all cells in the tissue may be labeled with the radiopharmaceutical.