Interactions of radiation therapy with common and innovative systemic treatments: Antidiabetic treatments, antihypertensives, lipid-lowering medications, immunosuppressive medications and other radiosensitizing methods.

The invention and approval of innovative anticancer therapies in the last decade have revolutionized oncology treatment. Radiotherapy is one of the three traditional pillars in oncology treatment with surgery and systemic therapies. Some standard-of-care combinations of chemoradiotherapy widened the therapeutic window of radiation, while some other chemotherapies such as gemcitabine caused unacceptable toxicities when combined with radiation in lung cancers. Fast-paced progress are specially focused on immunotherapies, targeted-therapies, anti-angiogenic treatment, DNA repair inhibitors, hormonotherapy and cell cycle inhibitors. New anticancer therapeutic arsenals provided new possibilities of combined oncological treatments. The interactions of the radiotherapy with other systemic treatments, such as non-anticancer immunomodulatory/immunosuppressive medications are sometimes overlooked even though they could offer a real therapeutic benefit. In this review, we summarize the new opportunities and the risks of historical and novel combined therapies with radiation: non-anticancer immunomodulatory/immunosuppressive drugs, systemic reoxygenation, new therapies such as nanoparticles and SMAC mimetics. Key biological mechanisms, pre-clinical and available clinical data will be provided to demonstrate the promising opportunities in the years to come.

[Treatment of primary disease for synchronous metastatic prostate cancer]. / Irradiation de la maladie primitive des cancers de la prostate avec métastases synchrones.

The management of early metastatic prostate cancer is based on systemic treatment by androgen deprivation therapy with or without chemotherapy or next-generation anti-androgen therapies. Local treatment of the prostate was initially used only to alleviate local symptoms. However, local radiotherapy of the prostate has been the subject of retrospective and prospective studies in patients with better prognostic factors, particularly in oligometastatic status. The results of these studies support that prostate radiotherapy can prolong the survival of patients with a low metastatic burden. This article states the biological bases, the main published and future published studies aimed to embed this strategy to optimize therapeutic management.

Sistema de bajo costo y alto rendimiento para bioensayos farmacológicos in vitro de tejido vivo / Low-Cost and High-Throughput System for Pharmacological Bioassays of Living Tissue in vitro

La potencialidad terapéutica de fármacos se averigua mediante estudios bioquímicos y celulares que nos hablan de sus acciones sobre vías de señalización y receptores. Sin embargo, en algunas enfermedades -por ejemplo, enfermedades neurológicas conocidas como "desórdenes del movimiento"-, los bioensayos realizados miden las acciones farmacológicas mediante valoraciones conductuales en modelos animales de las mismas. No se han logrado bioensayos que correlacionen la acción terapéutica de fármacos sobre la actividad del tejido vivo. Se puede medir la actividad de decenas de neuronas mediante imagenología de calcio en tejido vivo. Ciertos parámetros de esta actividad neuronal registrada in vitro reflejan su estado patológico, así como la acción terapéutica de fármacos determinados. No hay un sistema integrado orientado a estos bioensayos, por lo que se combinan diferentes equipos comerciales de manera independiente con costo final de alrededor de 100,000 USD. Presentamos un prototipo de un sistema integral encaminado a realizar este tipo de bioensayos: microscopía de epifluorescencia con calidad suficiente para adquirir y medir cuantitativamente la actividad celular del tejido vivo registrada in vitro pero de costo 10 veces menor -alrededor de 10,000 USD-. Se pueden realizar satisfactoriamente bioensayos funcionales de uso potencial en la industria farmacéutica, investigación y docencia.

The therapeutic potential of drugs is determined by biochemical and cellular studies that inform us about their actions on signaling pathways and receptors. However, in some diseases -for example, neurological diseases such as "movement disorders"-, bioassays measure the pharmacological actions by evaluating behavior in animal models of the diseases. There are no bioassays that correlate drug therapeutic actions on living tissue. The neural activity of several neurons can be measured by using calcium imaging on living tissue. Certain parameters of the recorded neuronal activity in vitro reflect the pathological state and the therapeutic actions of specific drugs. There is no integrated system oriented to these bioassays, so different commercial equipment has to be integrated independently with costs about 100,000 USD. We present a prototype of an integral system aimed to perform bioassays in vitro: epifluorescence microscopy with enough quality for the acquisition and quantitative assessment of cell activity recorded in the living tissue with costs around 10 times less -about 10,000 USD-. It allows successfully functional bioassays of potential use in the pharmaceutical industry, research an education.

Parametric and subject-specific finite element modelling of the lower cervical spine. Influence of geometrical parameters on the motion patterns.

Morphometrical and postural features of the cervical spine are supposed to significantly influence its biomechanical behaviour. However, the effects of these geometrical parameters are quite difficult to evaluate. An original numerical method is proposed in order to automatically generate parametric and subject-specific meshes of the lower cervical spine. Sixteen finite element models have been built from cadaver specimens using low dose biplanar X-rays. All the generated meshes fulfilled the quality criteria. A preliminary evaluation was performed on the C5-C6 functional units using a database of previous experimental tests. The principal and coupled motions were simulated. The responses of the numerical models were within the experimental standard deviation corridors in most cases. Rotation-moment relationships were then compared to assess the influence of geometry on the mechanical response. Geometry was found to play a significant role in the motion patterns.

Hepatic production of apolar aldehydes in rats with carbon tetrachloride-induced cirrhosis.

The aim of this study was to identify apolar aldehydes in liver homogenates from rats with CCl4-induced cirrhosis and, as a corollary, the antioxidant effect of zinc administration. The study was performed in five control rats and in ten cirrhotic rats which were further sub-divided into two groups to receive either a standard diet or one supplemented with zinc. The percentage of hepatic fibrosis, plasma malondialdehyde concentration and alanine aminotransferase activity were measured as well as the following aldehydes: hexanal, octanal, decanal, 2-hexenal, 2-octenal, 2-nonenal, 2,4-heptadienal and 2,4-decadienal. Of the 10 cirrhotic rats, 4 had elevated concentrations of the highly toxic 2,4-dialkenals which coincided with a higher percentage of fibrosis and plasma alanine aminotransferase activity. These aldehydes were not observed in the control group. Zinc administration was associated with a reduction of the hepatic malondialdehyde concentration and an amelioration on the degree of hepatic injury. In conclusion, this study demonstrates the presence of the highly toxic 2,4-dialkenals in hepatic tissue of rats whith CCl4-induced cirrhosis. Results obtained would suggest that these particular aldehydes may be related to the severity of the hepatic injury.

Low plasma vitamin A concentrations in familial combined hyperlipidemia.

As many as 20% of the survivors of acute myocardial infarction present with the heritable form of hyperlipidemia, termed familial combined hyperlipidemia (FCHL). Some of the genes reported to be involved in this disorder, such as those for lipoprotein lipase (LPL) and apolipoprotein (apo) C-III, are controlled by a peroxisome proliferator-activated receptor (PPAR)/retinoic acid receptor X (RXR) regulatory system, which is retinoic acid dependent. If, as we hypothesized, the availability of retinoic acid or its precursor retinol (vitamin A) could be altered in FCHL, this could help explain some aspects of the phenotypic expression of the disease. We therefore measured plasma retinol concentrations in 30 FCHL subjects and 56 controls. Plasma retinol concentrations in FCHL subjects were significantly lower than that of control subjects (1.96 +/- 0.83 mumol/L vs 2.91 +/- 1.23 mumol/L, respectively; P < 0.0001). This novel finding of significantly decreased concentrations of plasma retinol in FCHL relative to control subjects gives support to the hypothesis that vitamin A might be involved in the expression of this disorder.

[Polymorphism (RFLP-PstI) of the apoprotein A-I gene in a healthy population. Its relation to high-density lipoproteins]. / Polimorfismo (RFLP-PstI) del gen de la apoproteína A-I, en población sana. Relación con las lipoproteínas de alta densidad.

BACKGROUND: Some RFLPs for the genes encoding for apoproteins have been associated with dyslipidemia and the predisposition to atherosclerosis. It is of interest to investigate the apo A-I gene in a Mediterranean population, since it is the major protein in HDL. METHODS: We studied the A-I C-III A-IV gene cluster RFLP defined by the endonuclease Pst I in 149 healthy males randomly selected among industrial workers in Tarragona. The mean age was 40 +/- 7 years (range 20 to 62). We analysed cholesterol and triglycerides in plasma and the lipoprotein fractions (VLDL, IDL, LDL and HDL) obtained by ultracentrifugation. The RFLP was determined for the enzyme Pst I in the A-I C-III A-IV gene cluster by the Southern blotting method. RESULTS: The genotype distribution was P1P1 81.9%, P1P2 14.8% and P2P2 3.4% and the allelic frequency was P1 89.3% and P2 10.7%. The plasma cholesterol, triglycerides, apo A-I and apo B did not show significant differences between these groups. The P2P2 subjects had lower HDL-C values (P1P1 1.17 +/- 0.39 mmol/l, P1P2 1.16 +/- 0.28 mmol/l y P2P2 0.89 +/- 0.14 mmol/l; p < 0.01). CONCLUSIONS: The distribution of the genotypes in the Mediterranean population were similar to that observed in the USA and in Europe. P2P2 subjects had decreased HDL cholesterol but the low prevalence of the genotype being very low limits its value as a marker of coronary artery disease risk.

Effectiveness of probucol in reducing plasma low-density lipoprotein cholesterol oxidation in hypercholesterolemia.

Oxidized low-density lipoprotein (LDL) interacts with macrophages to induce intracellular cholesterol ester accumulation and foam cell formation. Probucol is a lipid-lowering drug with a well-known antioxidant action. The thiobarbituric acid (TBA)-reacting substances were measured as an index of plasma and LDL lipid peroxidation in a group of hypercholesterolemic patients compared with a normolipidemic control group. The effect of probucol treatment on plasma and LDL lipid peroxidation in the hypercholesterolemic group was also evaluated. Twenty-five patients (10 men and 15 women) with total cholesterol levels greater than 6.5 mmol/liter were given probucol for 24 weeks. Lipid and apoprotein measurements were obtained at 0, 12 and 24 weeks. TBA-reacting substances were also measured in plasma and the LDL fraction. Twenty-five normolipidemic subjects matched for sex, age and body mass index underwent complete blood analysis for purposes of comparison at week 0. Plasma, LDL and high-density lipoprotein cholesterol, and plasma apoproteins A-I and B significantly decreased after 12 and 24 weeks of probucol treatment. Hypercholesterolemic subjects (men and women) had significantly higher TBA-reacting substances in plasma and LDL than control subjects had (p less than 0.05). The amount of TBA-reacting substances in plasma and LDL showed a very significant decrease after probucol treatment (40 and 44%, respectively, after 24 weeks; p less than 0.05). This reduction was not related to age, sex or body mass index, and was greater than the decrease in lipids. These results support a potential role for probucol as a coadjuvant drug in any lipid-lowering antiatherogenic therapy.

Genetic analysis of total cholesterol and triglycerides in a pedigree of St. Thomas rabbits.

A pedigree consisting of 103 New Zealand White hyperlipidemic and normal rabbits was used in a genetic analysis of total cholesterol and triglyceride levels to test for Mendelian control of hyperlipidemia. The founder male of this pedigree was identified through hypercholesterolemia and evidence suggested vertical transmission of a hypercholesterolemic phenotype in this pedigree, although a combined hyperlipidemia phenotype (elevated cholesterol and triglycerides) also occurred in many descendents of the original founders. Segregation analysis of quantitative measures of total cholesterol and triglycerides in this pedigree was employed to test hypotheses about Mendelian control in the presence of substantial inbreeding. A simple Mendelian model was the best explanation for triglycerides in these animals. This best fitting model was essentially co-dominant with genotypic specific variances, where the heterozygote was hypertriglyceridemic and the mutant homozygote showed even more extreme values. The observed distribution of total cholesterol was also compatible with a mixture of distinct genotypic distributions, but there was evidence of non-Mendelian transmission in this pedigree. The observed hypertriglyceridemia in these animals may reflect an abnormality of very low density lipoprotein metabolism described previously. Further studies will be required to elucidate the genetic control of hypercholesterolemia and the associated combined hyperlipidemia in these rabbits.