Mitochondria and cancer: past, present, and future.

The area of mitochondrial genomics has undergone unprecedented growth over the past several years. With the advent of the age of omics, investigations have reached beyond the nucleus to encompass the close biological communication and finely coordinated interactions between mitochondria and their nuclear cell mate. Application of this holistic approach, to all metabolic interactions within the cell, is providing a more complete understanding of the molecular transformation of the cell from normal to malignant behavior, before histopathological indications are evident. In this review the surging momentum in mitochondrial science, as it relates to cancer, is described in three progressive perspectives: (1) Past: the historical contributions to current directions of research; (2) Present: Contemporary findings, results and approaches to mitochondria and cancer, including the role of next generation sequencing and proteomics; (3) FUTURE: Based on the present body of knowledge, the potential assets and benefits of mitochondrial research are projected into the near future.

Real-time polymerase chain reaction analysis of a 3895-bp mitochondrial DNA deletion in epithelial swabs and its use as a quantitative marker for sunlight exposure in human skin.

BACKGROUND: The use of mitochondrial DNA (mtDNA) damage as a reliable and highly sensitive biomarker of ultraviolet (UV) radiation exposure in both the dermis and epidermis has now been well developed by our group and others. We have previously identified a 3895-bp mtDNA deletion which occurred more frequently and to a higher level in usually sun-exposed skin as opposed to occasionally sun-exposed skin. This work focused on older-aged individuals and, in particular, perilesional, histologically normal skin biopsies taken from patients with skin cancer. OBJECTIVES: To develop novel, less-invasive methods of obtaining skin samples (i.e. epidermis) from volunteers covering a much wider age range and larger number of individuals (n = 239). METHODS: The 3895-bp deletion was quantified by a specific real-time polymerase chain reaction assay in normal human epidermis samples taken from three body sites with differing sun exposure. RESULTS: The results show a statistical increase of the level of the 3895-bp deletion with increasing sun exposure in the epidermal swabs of human skin (P < 0·001) and with increasing age of the donor in the needle biopsy samples. CONCLUSIONS: These data suggest that the upper layers of the epidermis are an accessible and reliable site for assessing mtDNA damage caused by UV exposure.

Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay.

Several cancers are characterized by large-scale mtDNA deletions. We previously provided evidence that one of these deletions has potential utility in resolving false from true-negative prostate needle biopsies. This study was to assess the clinical value of this deletion in predicting re-biopsy outcomes. We used a quantitative polymerase chain reaction assay to measure the levels of the deletion in individual negative needle biopsies from 101 patients who had a repeat biopsy within a year with known outcomes. Using an empirically established cycle threshold (Ct) cutoff of 31, and the lowest Ct for each patient as diagnostic of prostate cancer, as well as the histopathologic diagnosis on second biopsy, we calculated the clinical performance of the deletion. The Ct cutoff at 31 gave a sensitivity and specificity of 84 and 54%, respectively, with the area under a receiver-operating characteristics curve of 0.749. The negative predictive value was 91%. The assay was able to predict the presence of a missed tumor in 17 out of 20 men a year before diagnosis. This ancillary test appears to identify men who do not require a repeat biopsy with a high degree of certainty. The results suggest that the majority of men with atypical small acinar proliferation have a concurrent missed tumor and therefore require close monitoring for early detection.

A sex difference in the cortisol response to tail docking and ACTH develops between 1 and 8 weeks of age in lambs.

It is important to understand factors that may influence responses to stress, as these factors may also influence vulnerability to pathologies that can develop when stress responses are excessive or prolonged. It is clear that, in adults, the sex of an individual can influence the cortisol response to stress in a stressor specific manner. Nevertheless, the stage of development at which these sex differences emerge is unknown. We tested the hypothesis that there are sex differences in the cortisol response to tail docking and ACTH in lambs of 1 and 8 weeks of age. We also established cortisol responses in males when tail docking was imposed alone and in combination with castration at these ages. In experiment 1, 1 and 8 week old male and female lambs were subjected to sham handling, tail docking or, in males, a combination of tail docking and castration. In experiment 2, we administered ACTH (1.0 IU/kg) to male and female lambs at 1 and 8 weeks of age. There were significant cortisol responses to all treatments at both ages. Sex differences in the cortisol responses to tail docking and ACTH developed between 1 and 8 weeks of age, with females having greater responses than males. The data suggest that the mechanism for the sex difference in response to tail docking may involve the adrenal glands. At both ages, in males, the cortisol response to the combined treatment of tail docking and castration was significantly greater than that for tail docking alone.

Altered metabolism and mitochondrial genome in prostate cancer.

Mutations in mitochondrial DNA are frequent in cancer and the accompanying mitochondrial dysfunction and altered intermediary metabolism might contribute to, or signal, tumour pathogenesis. The metabolism of human prostate peripheral zone glandular epithelial cells is unique. Compared with many other soft tissues, these glandular epithelial cells accumulate high concentrations of zinc, which inhibits the activity of m-aconitase, an enzyme involved in citrate metabolism through Krebs cycle. This causes Krebs cycle truncation and accumulation of high concentrations of citrate to be secreted in prostatic fluid. The accumulation of zinc also inhibits terminal oxidation. Therefore, these cells exhibit inefficient energy production. In contrast, malignant transformation of the prostate is associated with an early metabolic switch, leading to decreased zinc accumulation and increased citrate oxidation. The efficient energy production in these transformed cells implies increased electron transport chain activity, increased oxygen consumption, and perhaps, excess reactive oxygen species (ROS) production compared with normal prostate epithelial cells. Because ROS have deleterious effects on DNA, proteins, and lipids, the altered intermediary metabolism may be linked with ROS production and accelerated mitochondrial DNA mutations in prostate cancer.

Estimation of internal radiation dose to the adult Asian population from the dietary intakes of two long-lived radionuclides.

Daily dietary intakes of two naturally occurring long-lived radionuclides, 232Th and 238U, were estimated for the adult population living in a number of Asian countries, using highly sensitive analytical methods such as instrumental and radiochemical neutron activation analysis (INAA and RNAA), and inductively coupled plasma mass spectrometry (ICP-MS). The Asian countries that participated in the study were Bangladesh (BGD), China (CPR), India (IND), Japan (JPN), Pakistan (PAK), Philippines (PHI), Republic of Korea (ROK) and Vietnam (VIE). Altogether, these countries represent more than 50% of the world population. The median daily intakes of 232Th ranged between 0.6 and 14.4 mBq, the lowest being for Philippines and the highest for Bangladesh, and daily intakes of 238U ranged between 6.7 and 62.5 mBq, lowest and the highest being for India and China, respectively. The Asian median intakes were obtained as 4.2 mBq for 232Th and 12.7 mBq for 238U. Although the Asian intakes were lower than intakes of 12.3 mBq (3.0 ug) 232Th and 23.6 mBq (1.9 ug) 238U proposed by the International Commission on Radiological Protection (ICRP) for the ICRP Reference Man, they were comparable to the global intake values of 4.6 mBq 232Th and 15.6 mBq 238U proposed by the United Nation Scientific Commission on Effects of Radiation (UNSCEAR). The annual committed effective doses to Asian population from the dietary intake of 232Th and 238U were calculated to be 0.34 and 0.20 microSv, respectively, which are three orders of magnitude lower than the global average annual radiation dose of 2400 microSv to man from the natural radiation sources as proposed by UNSCEAR.

Contents of cesium, iodine, strontium, thorium, and uranium in selected human organs of adult asian population.

Contents of cesium, iodine, strontium, thorium, and uranium in some selected human organs were estimated for adult Asian population using data obtained in four Asian countries: China, India, Philippines, and Republic of Korea, as part of a Coordinated Research Program of the International Atomic Energy Agency on "Ingestion and Organ contents of elements of importance in radiation protection." These countries together represent more than 40% of the world population. Highly sensitive analytical techniques were employed to measure cesium in skeletal muscle, iodine in thyroid, strontium in skeleton, thorium and uranium in skeleton, liver, kidneys, and lungs where, in comparison to other organs, these elements are present in higher concentrations. The organ contents for adult Asian population, when compared with the corresponding data proposed for Reference Man by International Commission on Radiological Protection (ICRP), showed about 40 times lower kidneys content and about 10 times lower skeleton content of uranium. The content of thorium in skeleton for Asian population was also half of the ICRP Reference Man value. Interestingly, organ contents for the other elements such as iodine in thyroid, cesium in skeletal muscle, and strontium in skeleton were comparable for Asian and the Caucasian population (represented by ICRP Reference Man). Organ contents for these elements were also calculated by applying the new ICRP models of these elements to their daily intakes. The comparison of the calculated and measured organ contents showed that despite uncertainties in the organ content values arising due to the inter-country variations in daily dietary intakes, the contents were within a factor of two to three. This observation is significant since human data both on organ contents and ingestion were obtained at environmental level of intakes. The study suggests that currently available ICRP models for these elements are quite realistic.

Dietary intakes of seven elements of importance in radiological protection by asian population: comparison with ICRP data.

Within the framework of a Coordinated Research Project (CRP) organized by the International Atomic Energy Agency, Vienna, the daily dietary intakes of seven elements by adult populations living in nine Asian countries were estimated. The countries that participated in the study were Bangladesh, China, India, Indonesia, Japan, Pakistan, Philippines, South Korea (Republic of Korea, ROK), and Vietnam and together they represented more than half of the world population. The seven elements studied were calcium, cesium, iodine, potassium, strontium, thorium, and uranium. These elements have chemical and biological similarity to some of the radionuclides abundantly encountered during nuclear power production and therefore data on these elements could provide important information on their biokinetic behavior. Analyses of diet samples for these seven elements were carried out using highly sensitive and reliable analytical techniques. One thousand one hundred and sixty analytical determinations were made on two hundred and twenty samples of typical diets consumed in these countries to estimate the daily intakes of these elements by the adult Asian population. The median daily dietary intakes for the adult Asian population were found to be 0.45 g calcium, 7 microg cesium, 90 microg iodine, 1.75 g potassium, 1.65 mg strontium, 1 microg thorium, and 1 microg uranium. When compared with the intakes proposed for ICRP Reference Man by International Commission for Radiological Protection, these intakes were lower by factors of 0.41 for calcium, 0.7 for cesium, 0.45 for iodine, 0.53 for potassium, 0.87 for strontium, 0.33 for thorium, and 0.52 for uranium. The lower daily intakes of calcium, cesium, and iodine by Asian population could be due to significantly lower consumption of milk and milk products, which are rich in these elements. The significantly lower intake of calcium in most of the Asian countries may lead to higher uptake of fission nuclide 90Sr and could result in perhaps higher internal radiation dose. The use of highly sensitive and reliable analytical methods resulted in accurate and lower intake values obtained for thorium and uranium, which suggest that radiation dose from their ingestion at natural background levels is likely to be lower than what may be concluded from ICRP data.

Contribution of calcium and other dietary components to global variations in bone mineral density in young adults.

A research project on comparative international studies of osteoporosis using isotope techniques was organized by the International Atomic Energy Agency (IAEA) with the participation of 12 countries (Brazil, Canada, Chile, China, Croatia, Hungary, Philippines, Russia, Singapore, South Africa, Turkey, and the United Kingdom). Participating centers in 11 countries (all but the UK) made measurements and collected data on men and women aged 15 to 49 years. In addition to studies of bone mineral density (BMD) at the femoral neck and lumbar spine using DEXA, anthropometric, lifestyle, and nutritional data were also collected. The results of the nutritional studies are reviewed in this paper. Overall, about 8% of the observed variability in spine BMD could be attributed to nutritional factors in men and women; in men, no such relationship could be determined. No single nutritional component (not even calcium) stood out as being of particular importance across all participating centers.

Variational principles for describing chemical reactions. Reactivity indices based on the external potential.

In a recent paper [J. Am. Chem. Soc. 2000, 122, 2010], the authors explored variational principles that help one understand chemical reactivity on the basis of the changes in electron density associated with a chemical reaction. Here, similar methods are used to explore the effect changing the external potential has on chemical reactivity. Four new indices are defined: (1) a potential energy surface that results from the second-order truncation of the Taylor series in the external potential about some reference, Upsilon(R(1),R(2),.,R(M)()); (2) the stabilization energy for the equilibrium nuclear geometry (relative to some reference), Xi; (3) the flexibility, or "lability", of the molecule at equilibrium, Lambda; and (4) the proton hardness, Pi, which performs a role in the theory of Brönsted-Lowry acids and bases that is similar to the role of the chemical hardness in the theory of Lewis acids and bases. Applications considered include the orientation of a molecule in an external electric field, molecular association reactions, and reactions between Brönsted-Lowry acids and bases.

Context of maternal lineages in the Greater Southwest.

We present mitochondrial haplogroup characterizations of the prehistoric Anasazi of the United States (US) Southwest. These data are part of a long-term project to characterize ancient Great Basin and US Southwest samples for mitochondrial DNA (mtDNA) diversity. Three restriction site polymorphisms (RSPs) and one length polymorphism identify four common Native American matrilines (A, B, C, and D). The Anasazi (n = 27) are shown to have a moderate frequency of haplogroup A (22%), a high frequency of haplogroup B (56%), and a low frequency of C (15%). Haplogroup D has not yet been detected among the Anasazi. In comparison to modern Native American groups from the US Southwest, the Anasazi are shown to have a distribution of haplogroups similar to the frequency pattern exhibited by modern Pueblo groups. A principal component analysis also clusters the Anasazi with some modern (Pueblo) Southwestern populations, and away from other modern (Athapaskan speaking) Southwestern populations. The Anasazi are also shown to have a significantly different distribution of the four haplogroups as compared to the eastern Great Basin Great Salt Lake Fremont (n = 32), although both groups cluster together in a principal component analysis. The context of our data suggests substantial stability within the US Southwest, even in the face of the serious cultural and biological disruption caused by colonization of the region by European settlers. We conclude that although sample numbers are fairly low, ancient DNA (aDNA) data are useful for assessing long-term populational affinities and for discerning regional population structure.

Information theory, atoms in molecules, and molecular similarity.

Using information theory, it is argued that from among possible definitions of what an atom is when it is in a molecule, a particular one merits special attention. Namely, it is the atom defined by the "stockholders partitioning" of a molecule invented by Hirshfeld [(1977) Theor. Chim. Acta 44, 129]. The theoretical tool used is the minimum entropy deficiency principle (minimum missing information principle) of Kullback and Liebler [(1951) Ann. Math. Stat. 22, 79]. A corresponding analysis is given of the problem of assessing similarity between molecules or pieces of molecules.

Exercise during the childbearing year.

Many women wish to continue to pursue an active lifestyle during pregnancy, while the pregnancy itself may provide the motivation for other more sedentary women to begin an exercise program for the sake of improved health/fitness. Also, female competitive athletes, upon becoming pregnant, may wish to continue sports performance and require careful monitoring to assure maternal-fetal safety. This review is designed to assist the perinatal educator who is in the position to advise the pregnant patient on the risks and benefits of physical activity during the childbearing year and provide suggestions for developing individualized exercise programs.

Acquisition of improved reference values for cesium, iodine, strontium, thorium, and uranium in selected NIST reference materials.

As part of a study on the ingestion and organ content of some trace elements of importance in radiological protection, additional work has been undertaken to acquire improved reference values for cesium, iodine, strontium, thorium, and uranium in four selected reference materials provided by the US National Institute of Standards and Technology. The materials are SRM-1548 Total Diet, SRM-1548a Typical Diet, SRM-1486 Bone Meal, and RM-8414 Bovine Muscle. A coordinated study was undertaken with the help of seven selected laboratories in five countries. Instrumental and radiochemical neutron activation analysis and inductively coupled plasma-mass spectrometry were the analytical main techniques used.

IAEA Internet database of natural matrix reference materials.

The International Atomic Energy Agency maintains a database on internationally available certified reference materials of natural origin. The database was updated in 1998 and prepared for an Internet implementation. A user-friendly structure was created, providing two main pathways for browsing, either according to the matrix classification or the producer's name. The database presently contains over 20,000 values for 480 measurands and 1085 reference materials from 43 different producers. Most of the materials entered contain values for trace and minor elements (66%).

Health-related monitoring and assessment of airborne particulate matter. An overview of recent IAEA programs.

Since 1992, the International Atomic Energy Agency (IAEA) has been promoting studies of air pollution using a standard design of air sampler that provides separation on filters into two size fractions with cutoffs of 2.5 and 10 microns (approximately). These are the size ranges presently considered to have the most important health consequences. Such filter samples are highly amenable to analysis using nuclear and related techniques. After reviewing some of the health effects of airborne particulate matter and current air quality standards and guidelines, this article provides an overview of current and recent IAEA programs in this area, which involve collaborative activities with participants in more than 40 countries.

Biomonitoring of air pollution as exemplified by recent IAEA programs.

Biomonitoring is an appropriate tool for assessing the levels of atmospheric pollution, having several advantages compared with the use of direct measurements of contaminants (e.g., in airborne particulate matter, atmospheric deposition, precipitation), related primarily to the permanent and common occurrence of the chosen organisms in the field, the ease of sampling, and trace element accumulation. Furthermore, biomonitors may provide a measure of integrated exposure over an extended period of time and are present in remote areas and no expensive technical equipment is involved in collecting them. They accumulate contaminants over the exposure time and concentrate them, thus facilitating analytical measurements. Based on large-scale biomonitoring surveys, polluted areas can be identified, and by applying appropriate statistical tools, information can be obtained on the type of pollution sources and on the transboundary transport of atmospheric pollutants. The International Atomic Energy Agency is including the research on biomonitors in its projects on health-related environmental studies. Biomonitoring activities from several coordinated research projects on air pollution are presented, and results from an international workshop are discussed. In addition, activities in supporting improvement quality in the participating laboratories are outlined.

Enhanced transdermal delivery of sex hormones in swine with a novel topical aerosol.

This study investigated the enhanced transdermal delivery of testosterone (Tes) and estradiol (E2) in swine in vivo with novel metered-dose topical aerosols containing the penetration enhancer padimate O (PadO) and predicted the dose deliverable in humans from the calculated drug flux across the skin. Weanling swine were catheterized and castrated under general anaesthesia and used as a conscious hypogonadal model. Tes and E2 (with and without PadO) were applied once, and venous blood samples were taken over 24 h. Tes and E2 plasma levels were determined by radioimmunoassay. After daily topical dosing of Tes for 6 days, the plasma Tes levels were determined and the transdermal flux was calculated by correcting the pseudo steady-state plasma concentration versus time profile with the clearance of an iv dose within the same swine. After a single application of the E2 aerosol over 30 cm2, or the Tes aerosol over 180 cm2, the mean AUC0-24 h when PadO was included in the spray was 14.1- and 2.0-fold greater than control, respectively (p < 0.03). After the sixth application of the Tes spray with PadO, the mean flux (+/-SE, n = 4) across swine skin in vivo was 2.12 +/- 0.35 microg/cm2.h, which gave a predicted flux in humans of 0.95 microg/cm2.h. From these data the expected plasma levels of Tes in hypogonadal men would compare well with the normal diurnal Tes profile in healthy men. These novel topical aerosols are capable of enhanced transdermal delivery of sex hormones in vivo, and they have the potential to deliver clinically relevant doses to humans.

The effects of post-weaning progestagen treatment (Regumate) of early-weaned primiparous sows on subsequent reproductive performance.

This study investigated the effects of feeding the orally active progestagen, altrenogest (Regumate) post-weaning on the subsequent reproductive performance of early weaned sows. Ninety (90) Large White/Landrace first parity sows were randomly assigned to three treatments. Treatment 1 (EW) and treatment 3 (CW) sows were weaned on day 12 and day 24 post-partum, respectively while treatment 2 sows (EW-R) were weaned on day 12 post-partum and received an individual daily dose of 20 mg of Regumate on days 13 to 24 post-partum inclusive. Each sow was mated naturally at least twice at the first post-weaning or post-treatment oestrus and slaughtered on days 25-28 of pregnancy to determine the number of corpora lutea and embryos. Regumate-to-oestrus and weaning-to-oestrus intervals were similar for EW-R and CW sows (6.2 vs. 5.6 days). However, both intervals were significantly shorter (P < 0.01) than the weaning-to-oestrus interval of EW sows (7.3 days). An excellent synchronization of oestrus was achieved with Regumate treatment with 97% of treated sows in oestrus within 7 days of Regumate withdrawal compared with 64% for EW sows (P < 0.01) and 87% for CW sows (P > 0.05). Treatment with Regumate resulted in a significant increase in ovulation rate (16.9 vs. 15.4 and 14.9 for treatments EW-R, EW and CW, respectively; P < 0.05) and a non-significant increase in early embryonic survival (77% vs. 68% vs. 68% for treatments EW-R, EW and CW, respectively; P > 0.05). These results indicate that Regumate feeding is a potential management tool to alleviate the diminished reproductive performance associated with early weaning regimes since it leads to successful control of oestrus, higher ovulation and embryo survival rates and thus a greater potential litter size.