The NAD(+) salvage pathway modulates cancer cell viability via p73.

The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.

Protein quality evaluation of amaranth in adult humans.

This study was carried out to determine the nutritional quality of the protein of amaranth grain submitted to extrusion and popping processes, using cheese protein as reference. For the biological evaluation, the short-term nitrogen balance index method was followed with 12 experimental adult male human subjects. A Latin square series 3 x 3 was used (three periods, three subjects) as an experimental design balanced to minimize residual effects by randomly ordering treatments, columns and rows. The study consisted of three periods of nine days each. The first period started by feeding all subjects a low nitrogen diet, followed by increases of the protein level every two days. The levels were 0.2, 0.4, 0.6/g protein/kg/day, keeping other nutritional elements constant and adequate, including calories, minerals and vitamins. All subjects received all their meals using as a source of protein extruded amaranth, popped amaranth or processed cheese. Water intake was kept at a rate of 0.8-1.0 ml per calories consumed. During the study, the subjects maintained regular physical activity. Amaranthus cruentus was utilized. The extruded amaranth was prepared with the Brady Crop Cooker under conditions previously established in other studies. The popped amaranth was prepared at a 250 degrees C temperature during 15-20 sec. The extruded and popped amaranths were provided as a sweet puree and, as all the other foods conforming the diets of each subject, they were weighed with 0.1 g of accuracy. Diet samples, as well as faeces and urine, were collected daily, which were ordered according to period and level of protein, conforming pools to determine their nitrogen content by the Kjeldahl method. True digestibility results of the protein were 101.4, 89.8 and 85.5% for cheese, extruded amaranth and popped amaranth, respectively. The statistical analysis according to the Tukey test showed that the true digestibility of the protein was the same for the two products of amaranth and different than the digestibility of cheese. Nitrogen balance index values from the equation between nitrogen intake and nitrogen retained, were 0.97, 0.86 and 0.79 for cheese, extruded amaranth and popped amaranth, respectively. The respective values between nitrogen absorbed and nitrogen retained were 0.97, 0.98 and 0.96. The Tukey test indicated that for NI to NR cheese was statistically different for the two amaranth products, which were similar between them. For the relationship NA to NR all values were statistically the same.(ABSTRACT TRUNCATED AT 400 WORDS)

Radionuclide-induced evolution of DNA and the origin of life.

Artesian groundwaters of high radionuclide concentration are ubiquitous and may have provided the large, sustained energy sources that were required to drive the multistage process of DNA and primordial cell evolution. The rapid, early development of the genetic code as well as its degeneracy can be attributed to exceptionally high radiation-induced mutation rates in this unique environment. The ability of double-strand DNA to direct enzymatic repair of radiation damage to single strands contributed importantly to its selective evolution. It is postulated that the polymerization of nucleotides took place at elevated temperatures within alpha-particle tracks of high ion and free-radical density, followed by rapid quenching to ambient conditions. It also is evident that radiation resistance and ploidy were important selection factors in cellular evolution.

A dose-per-pulse monitor for a dual-mode medical accelerator.

On a radiotherapy accelerator, the dose monitoring system is the last level of protection between the patient and the extremely high dose rate which all accelerators are capable of producing. The risk of losing this level of protection is substantially reduced if two or more dose monitoring systems are used which are mechanically and electrically independent in design. This paper describes the installation of an independent radiation monitor in a dual-mode, computer-controlled accelerator with a moveable monitor chamber. The added device is fixed in the beam path, is capable of monitoring each beam pulse, and is capable of terminating irradiation within the pulse repetition period if any measured pulse is unacceptably high.

A flatness and calibration monitor for accelerator photon and electron beams.

A flatness monitor has been built to quickly and accurately check accelerator beam flatness and dose calibration. Consisting of a 7 X 7 ion chamber array, the unit operates in photon beams from 60Co energies to 25 MV and electron beams (scattered or scanned) from 6 MeV to 25 MeV.

alpha-Radiation dose at bronchial bifurcations of smokers from indoor exposure to radon progeny.

Synergistic interactions of indoor radon progeny with the cigarette smoking process have been evaluated experimentally. Smoking enhances the air concentration of submicron particles and attached radon decay products. Fractionation in burning cigarettes gives rise to the association of radon progeny with large particles in mainstream cigarette smoke, which are selectively deposited in "hot spots" at bronchial bifurcations. Because smoke tars are resistant to dissolution in lung fluid, attached radon progeny undergo substantial radioactive decay at bifurcations before clearance. Radon progeny inhaled during normal breathing between cigarettes make an even larger contribution to the alpha-radiation dose at bifurcations. Progressive chemical and radiation damage to the epithelium at bifurcations gives rise to prolonged retention of insoluble 210Pb-enriched smoke particles produced by tobacco trichome combustion. The high incidence of lung cancer in cigarette smokers is attributed to the cumulative alpha-radiation dose at bifurcations from indoor radon and thoron progeny--218Po, 214Po, 212Po, and 212Bi--plus that from 210Po in 210Pb-enriched smoke particles. It is estimated that a carcinogenic alpha-radiation dose of 80-100 rads (1 rad = 0.01 J/kg = 0.01 Gy) is delivered to approximately equal to 10(7) cells (approximately equal to 10(6) cells at individual bifurcations) of most smokers who die of lung cancer.

Polonium-210: lead-210 ratios as an index of residence times of insoluble particles from cigarette smoke in bronchial epithelium.

Lead-210 and its granddaughter polonium-210 are both natural constituents of cigarette smoke, the 210Pb being enriched in insoluble particles derived from sintered tobacco trichome tips. These particles are stripped of the polonium on combustion, and thus the polonium begins growth at the time of inhalation. Polonium-210 is found in bronchial tissues of smokers, and evidence shows that 210Pb is present at these sites in excess of the polonium. On the assumption that all polonium arises from ingrowth from the insoluble particles, one may calculate from the polonium-lead ratio the mean residence time of these particles. The half-life of polonium (138 days) is almost ideal for this purpose, and its alpha radiation makes measurements of very low concentrations possible. This technique is the first available to assess residence time for inhaled particles in the bronchial epithelium, an important datum because of the vulnerability of bronchial tissues to disease. Measurements from three smokers and two non-smokers show that 210Pb from natural aerosols also is concentrated at bronchial bifurcations, but little 210Pb is associated with this soluble lead. This fact makes estimates of residence time in bronchial epithelium of smokers (3-5 months in these preliminary data) likely to be low.

The sulfur cycle.

Even granting our uncertainties about parts of our model of the sulfur cycle, we can draw some conclusions from it: 1) Man is now contributing about one half as much as nature to the total atmospheric burden of sulfur compounds, but by A.D. 2000 he will be contributing about as much, and in the Northern Hemisphere alone he will be more than matching nature. 2) In industrialized regions he is overwhelming natural processes, and the removal processes are slow enough (several days, at least) so that the increased concentration is marked for hundreds to thousands of kilometers downwind. 3) Our main areas of uncertainty, and ones that demand immediate attention because of their importance to the regional air pollution question, are: (i) the rates of conversion of H(2)S and SO(2) to sulfate particles in polluted as well as unpolluted atmospheres; (ii) the efficiency of removal of sulfur compounds by precipitation in polluted air. And for a better understanding of the global model we need to know: (i) the amount of biogenic H(2)S that enters the atmosphere over the continents and coastal areas; (ii) means of distinguishing man-made and biogenic contributions to excess sulfate in air and precipitation; (iii) the volcanic production of sulfur compounds, and their influence on the particle concentration in the stratosphere; (iv) the large-scale atmospheric circulation patterns that exchange air between stratosphere and troposphere (although absolute amounts of sulfate particles involved are small relative to the lower tropospheric burden); (v) the role of the oceans as sources or sinks for SO(2).