Relation between macroscopic and microscopic activation energies in nonequilibrium surface processing.

Realistic Monte Carlo simulations show that the apparent macroscopic activation energy is only partially explained by the expected expression for the average over the microscopic activation energies for surface processing. An additional term accounting for the existence of fluctuations in the fractions of particles has to be taken into account. In all cases considered, the additional term can be accurately estimated by a posteriori analysis of the temperature dependence of the surface densities. In addition, we demonstrate that the relative contribution of the different competing microscopic processes to the macroscopic activation energy can be accurately obtained during the simulations, allowing for the unambiguous identification of the particular surface species which effectively control the process. As an example of the nonequilibrium open interfaces to which the results apply, the case of wet chemical etching of crystalline silicon is considered. The results can be directly applied to surface growth.

[Reversion of cancer and mitochondrial filamentation]. / Reversión del cáncer y filamentación mitocondrial.

It is concisely described the dedication of the author during the last thirty years to the study of the nature, cause and treatment of cancer through the investigation by his group of the energy metabolism of tumors. It is defined the precise responsibility of the author in the discoveries of the second site of control of glycolysis, rotenone tumors, quelamycin and thioproline, filamentous mitochondria, and the technique of cancer reversal by dual strategy.

Carcinogenesis with the insecticide rotenone.

Rotenone is an insecticide which has been used extensively for a long time, and is now widely used in the U.S.A. and other industrialized countries. Rotenone is used mainly as an agricultural insecticide, household garden insecticide and water plant pesticide. Through these uses, rotenone may now be reaching the human male and female in these countries in substantial amounts, carried by fresh or cooked vegetables, consumed fish and drinking water. A review of the existing published reports and unpublished official documents dealing with the capacity of rotenone to induce neoplastic, paraneoplastic and preneoplastic lesions in the rat is presented here. It is strongly suggested that rotenone is carcinogenic to the rat (at doses from 2 to 25 parts per million continuously in food, or from 0.8 to 2.5 mg/kg weight for 1 to 4 months by oral administration), above all, when the rats receive deficient diets, especially those poor in riboflavin. Rotenone carcinogenesis, among other things, seems to exhibit a peculiar dose response pattern, which could be explained by its possible hormonal mechanism of action. Further studies to assess definitively the role of rotenone as a possible environmental carcinogen are proposed as being highly necessary.

Mitochondrial function in myasthenia gravis.

We determined the respiration rate, respiratory control and ADP/O ratios, with different substrates in mitochondria isolated from 2 patients with myasthenia gravis and compared them with normal human muscle. In all cases studied, a severe alteration of the respiratory control with variable derangement of oxidative phosphorylation was found. This abnormality of mitochondrial metabolism was referred to by Luft as 'loosely coupled' and was reported in other neuromuscular diseases. In our opinion this defective oxidative metabolism is nonspecific.

On the irreproducibility of thioproline.

Thioproline was the first inducer of reverse transformation of neoplastic cells to be tested, with encouraging activity, in cancer patients. These results could not be reproduced in two subsequent clinical trials. The possible reason for this irreproducibility could be that, in the first active trials, the patients may have taken other non-cancer-related drugs that, by acting on the cyclic AMP and prostaglandin cascades, could have functioned as positive cooperators on the effect of thioproline. A new clinical trial, with thioproline associated to its cooperators, is proposed in tumors which have no hope of improvement with cytostatics.

Mitochondrial functions in chronic spinal muscular atrophy.

We determined the respiration rate, respiratory control and ADP/O ratios, with different substrates in mitochondria isolated from seven patients with chronic spinal muscular atrophy and compared them with normal human muscle. In all cases studied, a severe alteration of the respiratory control with variable derangement of oxidative phosphorylation was found. Similar findings have been described in other neuromuscular disorders including the so-called "mitochondrial myopathy". We believe that this disturbance of mitochondrial function is non specific and only the hypermetabolic syndrome of Luft could be considered biochemically as a "mitochondrial myopathy", a disorder selectively involving mitochondria of skeletal muscle.

Treatment of cancer by an inducer of reverse transformation.

Thiazolidine-4-carboxylic acid (thioproline, "norgamem") a compound found to act on the cell membrane of tumour cells, causing reverse transformation to normal cells was investigated in patients with advanced cancer. Responses were obtained at several dose levels mainly in epidermoid carcinoma of the head and neck with pulmonary metastases. Histological studies showed involution and transformation into low-grade malignancies and disappearance of evidence of cancer.

Quelamycin: a summary of phase I clinical trials.

Quelamycin is triferric doxorubicin, a metallic derivative of adriamycin which, in experimental studies, has been found to have a better therapeutic index than adriamycin and no cardiotoxicity. In Spain, phase I clinical trials carried out in 96 patients with advanced cancer have shown that the drug has low toxicity and considerable antitumor activity, while it is not cardiotoxic, even at cumulative doses of nearly 3 g.

Early clinical trial with quelamycin.

Quelamycin (triferric doxorubicin) is a derivative of Adriamycin with different pharmacologic properties. Our phase I clinical study of quelamycin includes 37 patients with a wide spectrum of solid tumors. The recommended dose in good-risk patients is 150 mg/m2, given as a 1-hour infusion every 3 weeks. The dose-limiting factor appears to be myelosuppression, especially leukopenia. Other toxic effects include gastrointestinal intolerance and alopecia. Chills and fever are commonly encountered and might be due to an excess of free iron in currently available preparations. Cardiotoxicity could not be properly assessed. An objective antitumor effect was seen in patients with lung, gastric, colon, and ovarian carcinomas as well as osteogenic sarcoma. Further preclinical and clinical studies with an improved pharmaceutic formulation of the drug are highly desirable.

Inhibition of sodium-potassium-activated adenosine 5'-triphosphatase and ion transport by adriamycin.

The antitumor antibiotic Adriamycin is a potent inhibitor of the sodium-potassium-activated adenosine triphosphatase of native heart microsomes. Adriamycin also inhibits potassium transport (although not sodium transport) in slices of kidney cortex. The effects on both the adenosine triphosphatase and ion transport are markedly reduced by Ca2+, probably by chelation of this metal by Adriamycin. These effects could provide a basis for explaining the Adriamycin cardiotoxicity as a digitalis-type toxicity.