Selective use of postoperative neck radiotherapy in oral cavity and oropharynx cancer: a prospective clinical study

Background: In cervical postoperative radiotherapy, the target volume is usually the same as the extension of the previous dissection. We evaluated a protocol of selective irradiation according to the risk estimated for each dissected lymph node level. Methods: Eighty patients with oral/oropharyngeal cancer were included in this prospective clinical study between 2005 and 2008. Patients underwent surgery of the primary tumor and cervical dissection, with identification of positive nodal levels, followed by selective postoperative radiotherapy. Three types of selective nodal clinical target volume (CTV) were defined: CTV0, CTV1, and CTV2, with a subclinical disease risk of < 10%, 10-25%, and 25% and a prescribed radiation dose of < 35 Gy, 50 Gy, and 66-70 Gy, respectively. The localization of node failure was categorized as field, marginal, or outside the irradiated field. Results: A consistent pattern of cervical infiltration was observed in 97% of positive dissections. Lymph node failure occurred within a high-risk irradiated area (CTV1-CTV2) in 12 patients, marginal area (CTV1/CTVO) in 1 patient, and non-irradiated low-risk area (CTV0) in 2 patients. The volume of selective lymph node irradiation was below the standard radiation volume in 33 patients (mean of 118.6 cc per patient). This decrease in irradiated volume was associated with greater treatment compliance and reduced secondary toxicity. The three-year actuarial nodal control rate was 80%. Conclusion: This selective postoperative neck irradiation protocol was associated with a similar failure pattern to that observed after standard neck irradiation and achieved a significant reduction in target volume and secondary toxicity.This work was supported, in part, by Grants-in-Aid for Scientific Research from the Health Andalusian Authority PI-SAS-209/04

Interplay between glucose and palmitate uptake in breast carcinoma in vitro

One of the most studied tumor cells lines in vitro is the breast carcinoma MDA-MB-231 cell line. Several studies have proved its glycolytic profile, namely known as the Warburg effect. Glutamine oxidation is also important for its metabolism. Nevertheless, the use of fatty acids for obtaining energy in these cells is still rising. Palmitic acid is the most common saturated fatty acid, containing sixteen carbons in its structure. However, the use of palmitate for metabolic studies in MDA-MB-231 is not very extended due to its pro-apoptotic effect in this cell line after certain time exposure. Nonetheless, in this work we used palmitate as a metabolic fuel for just 30 minutes in order to see the almost immediate response of the cells to its presence, after a 30 minutes fast period. Our results show that MDA-MB-231 cells are not able of oxidizing palmitate nor producing lactate from it. Simultaneous presence of palmitate with glucose or with glutamine does not affect glucose nor glutamine uptake in these cells. However, we observed that even low concentrations of glucose increase palmitate uptake in MDA-MB-231 after a 30 minutes incubation. Treatment with 5 mM 2-deoxyglucose also for 30 minutes counters this rise, since 2-deoxyglucose diminishes palmitate uptake. Increasing glucose concentration to the same dosis of 2-deoxyglucose leads to a prevalence of the glucose effect on palmitate uptake. The exact role of glucose and glucose derivatives should be further studied in order to know more about palmitate metabolism in this cell line.Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). This communication has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech"

Identification and characterization of new anti-angiogenic compounds from natural sources

The inhibition of angiogenesis has attracted broad attention in the field of pharmacological research, not only for cancer, but for other angiogenesis dependent diseases including ophthalmic, cutaneous and inflammatory diseases, as well as a number of rare diseases. Our research group has characterized multiple new natural bioactive compounds with multitargeted antiangiogenic effects by employing a well-established set of in vitro, in vivo and ex vivo preclinical models of angiogenesis. Most of them have been isolated from plants and terrestrial microorganisms, mainly due to their higher availability and because their therapeutic effects had been previously known in folk traditional medicines. In vitro primary screening includes cell differentiation and toxicity and proliferation assays. Secondary screening involves several experiments to evaluate effects on adhesion, migration, invasion, apoptosis or cell cycle analysis, among others. Additionally, we perform a further molecular characterization analyzing possible signaling pathways that are affected to elucidate their mechanism of action. The characterization is completed with the ex vivo aortic ring assay, and in vivo assays, as CAM and zebrafish assays, to ensure the anti-angiogenic ability. As a fruit of the mentioned screening, a number of compounds with remarkable anti-angiogenic activity have been identified and characterized.Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain)]. This communicaction has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech"

Fasentin, a glucose uptake inhibitor, is also able to inhibit angiogenesis

Es comunicación a congreso en formato pósterThe role of glucose on endothelial cell (EC) metabolism and angiogenesis has been an emerging issue in the last few years. Some inhibitors of glucose metabolism, such as 2-deoxyglucose, have been shown to have anti-angiogenic effects. Fasentin is a poor-studied inhibitor of glucose uptake which modulates GLUT-1 and GLUT-4 transporters in cancer cells. We wanted to test its possible effect on EC glucose uptake, showing a light decrease in HMEC at 100 µM. Lower doses did not affect this characteristic of glucose metabolism. In line with this fact, fasentin at 100 µM totally inhibited tube formation on Matrigel in these cells. This anti-angiogenic effect is not likely to be helped by a pro-apoptotic effect of fasentin but, as proved with additional assays, it could be due to a decrease on the signaling for extracellular matrix degradation. More research would be necessary in order to elucidate its fine regulation on angiogenesis and metabolism.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. [Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). This communicaction has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech"]

Synthesis and biological activity of a new class of antitumor cyclopeptides based on the solomonamides

Solomonamides A (1) and B (2) are novel natural products recently isolated from the marine sponge Theonella swinhoei [1]. Preliminary structural studies revealed an unprecedented cyclic peptide type structure. Interestingly, solomonamide A exhibits anti-inflammatory activity, showing potent reduction (60%) of inflammation at a very low concentration of 100 µg/kg in animal models. However, the scarcity of these compounds from their natural sources has been a drawback for further pharmacological assays. In fact, the anti-inflammatory activity of solomonamide B was not evaluated due to the limited amounts. This difficulty to access large amounts of these compounds makes quite difficult to gain insight into their biological profiles and mechanism of action and justifies the chemical synthesis of this new class of cyclic peptides. As a consequence, the solomonamides have been the subject of several synthetic efforts [2] notably by the Reddy group who has recently reported the first total synthesis of solomonamide B based on a intramolecular Heck reaction, which led to a revision of the initially proposed structure for 2 [3].Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

El análogo de las estrigolactonas GR-24 inhibe la angiogénesis in vitro e in vivo

Muchas fitohormonas han mostrado un gran potencial en la prevención y terapia contra el cáncer. Las estrigolactonas son hormonas vegetales derivadas de los caroteinoides que están implicadas en la inhibición de la ramificación de la raíz y el brote, promover la germinación de plantas parásitas e intervenir en el establecimiento de simbiosis con micorrizas arbusculares. Se ha descrito la capacidad antitumoral de diferentes análogos de estrigolactonas, entre ellos GR-24, frente a diferentes líneas celulares tumorales in vitro y en modelos xenográficos. En este estudio se ha evaluado la capacidad citotóxica y anti-angiogénica de GR-24, tanto in vitro como in vivo. In vitro, GR-24 presenta una IC50 entre 50 y 90 μM en diversas líneas celulares tumorales y endoteliales. Además, afecta a pasos clave del proceso angiogénico, como son la proliferación, diferenciación, migración y capacidad de degradación de la matriz extracelular de células endoteliales, a concentraciones menores que su IC50. En los ensayos in vivo, GR-24 muestra un gran efecto inhibidor sobre la formación de vasos sanguíneos en la membrana corioalantoidea de pollo y sobre la formación de vasos intersegmentales en embriones de Danio rerio. En conjunto, estos resultados sugieren que GR-24 puede ser un nuevo compuesto prometedor en la terapia anti-angiogénica y otras enfermedades dependientes de angiogénesis.[Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain)]. This communicaction has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech"

Antitumor and antiangiogenic potential of solomonamide synthesis intermediates

Es comunicación (formato panel) a congreso internacionalIn this work we developed a new synthetic strategy towards the solomonamides. a novel class of cyclopeptides of marine origin. The described synthetic approach utilized an olefin metathesis reaction to form the [15]-membered ring contained in these natural products. During the synthetic process, a diverse set of analogues was generated and we evaluated their potential antitumor activity in vitro. For this purpose we performed in vitro proliferation assays, determining the IC50 values of the compounds in a panel of tumor cell lines. In addition, we evaluated the possible antiangiogenic effects of these solomonamide analogues by using in vitro endothelial cell differentiation assays. Our results showed that the potential antitumor and antiangiogenic activity of the studied analogues depended on their chemical structure, suggesting that the presence of specific functional groups could be responsible of their biological activity. Further studies are needed to understand the basis of the observed activities in endothelial and tumor cells.Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). This communicaction has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Evaluation of the anti-angiogenic potential of hydroxytyrosol derivatives

Angiogenesis, a process which allows the formation of new vessels from pre-existing ones, is an essential phenomenon for tumor survival since it allows cancer cells to obtain nutrients and oxygen. This explains the increasing interest showed by many groups of research and pharmaceutical companies to find compounds with potential to disrupt at least one of the steps within the angiogenic process. Hydroxytyrosol (3,4-dihydroxyphenyl ethanol) has been identified as the most important health-related phenolic compound of virgin olive oil because of its pleiotropic effects on multiple targets. In 2012, our group identified hydroxytyrosol as an anti-angiogenic compound able to inhibit several key steps in the angiogenic process. In the present study, the potential effects of six hydroxytyrosol derivatives are tested and compared with those exhibited by hydroxytyrosol by making use of several in vitro and in vivo assays. Results indicate that these are candidate new anti-angiogenic compounds with potential utility in anti-tumor and anti-angiogenic therapies.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech [Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain)]. This communication has the support of a travel grant

Comparative aspects of the internal reproductive system of males in species of Melolonthinae, Dynastinae, and Rutelinae (Coleoptera: Scarabaeoidea) from Mexico

The anatomy of the internal male reproductive systems of 12 species of Melolonthinae (Phyllophaga, Chlaenobia, Macrodactylus, Isonychus), six species of Dynastinae (Cyclocephala), and three species of Rutelinae (Paranomala) (Coleoptera, Scarabaeoidea) of Mexico are described. A total of 350 male specimens representing 21 species were collected. From each species, the reproductive systems were obtained by micro-dissection, placed in a liquid fixative, stained, and drawn to scale. The internal genitalia of each species was described and compared among the species examined. The reproductive system of the Melolonthinae species is comprised of two testicles, each with six follicles, two deferent ducts, two accessory glands, two glandular ducts, an ejaculatory duct, and the aedeagus (not described for any of the species examined). The number of testicular follicles per testicle is as reported in different species of other Scarabaeoidea subfamilies. The length of the accessory glands and the ejaculatory duct varies in the species studied. The ejaculatory bulb is present in all of the species of Dynastinae and Rutelinae examined but in only three species of Melolonthinae.Se describió la anatomía del sistema reproductivo interno de los machos en 12 especies de Melolonthinae (Phyllophaga, Chlaenobia, Macrodactylus, Isonychus), seis de Dynastinae (Cyclocephala) y tres de Rutelinae (Paranomala) (Coleoptera, Scarabaeoidea) de México. Se recolectaron un total de 350 ejemplares machos representantes de 21 especies. De cada especie se obtuvieron los sistemas reproductivos por microdisección y fueron colocados en un líquido fijador, después teñidos y dibujados a escala. Se describió la genitalia interna de cada especie y se comparó entre las especies examinadas. El sistema reproductivo de las especies de Melolonthinae consta de dos testículos cada uno con seis folículos, dos conductos deferentes, dos glándulas accesorias, dos conductos glandulares, un conducto eyaculador y el edeago (no descrito en ninguna especie). El número de folículos testiculares por testículo es igual al conocido en diferentes especies de otras subfamilias de Scarabaeoidea. La longitud de las glándulas accesorias y del conducto eyaculador varían dependiendo de cada especie estudiada. Un bulbo eyaculador está presente sólo en tres especies de Melolonthinae y en todas las especies de Dynastinae y Rutelinae examinadas