Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies

Background: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. Objective: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. Design, Setting, and Participants: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArrayH NT Cycler. Outcome Measurements and Statistical Analysis: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. Results and Limitations: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. Conclusion: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.

Childhood cancer and nuclear power plants in Switzerland: a census-based cohort study.

BACKGROUND: Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland. METHODS: We computed person-years at risk for children aged 0-15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5-10 km and 10-15 km from the nearest NPP with children born >15 km away, using Poisson regression models. RESULTS: We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0-4 and 0-15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0-4 and 0-15 year olds were 1.20 (0.60-2.41) and 1.05 (0.60-1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61-1.54) and 0.89 (0.63-1.27). There was no evidence of a dose-response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results. CONCLUSIONS: This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.

Stereotactic body radiotherapy with helical TomoTherapy for medically inoperable early stage primary and second-primary non-small-cell lung neoplasm: 1-year outcome and toxicity analysis.

OBJECTIVE: This study investigated the effectiveness of stereotactic body radiotherapy with helical TomoTherapy (T-SBRT) for treating medically inoperable primary and second-primary early stage non-small-cell lung neoplasm (SPLN) and evaluated whether the movement of organizing pneumonia (OP) within the irradiation field (IF) can be detected via analysis of radiological changes. METHODS: Patients (n = 16) treated for 1 year (2011-12) at our hospital by T-SBRT at a total dose of 60 Gy in five fractions were examined retrospectively. Outcome and toxicity were recorded and were separately described for SPLN. CT scans were reviewed by a single radiologist. RESULTS: Of the 16 patients, 5 (31.3%) had primary lung malignancies, 10 (62.5%) had SPLN, and 1 case (6.3%) had isolated mediastinal metastasis of lung neoplasm. Pathological evidence was obtained for 72.2% of all lesions. The median radiological follow-up was 11 months (10.5 months for SPLN). For all cases, the 6- and 12-month survival rates were 100% and 77.7% (100% and 71.4%, respectively, for SPLN), and the 6- and 12-month locoregional control rates were 100% in all cases. 2 (12.5%) of 16 patients developed grade 3 late transient radiation pneumonitis following steroid therapy and 1 (6.3%) presented asymptomatic infiltrates comparable to OP opacities. CONCLUSION: T-SBRT seems to be safe and effective. ADVANCES IN KNOWLEDGE: Mild OP is likely associated with radiation-induced anomalies in the IF, identification of migrating opacities can help discern relapse of radiation-induced opacities.

Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies

Background: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. Objective: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. Design, Setting, and Participants: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArrayH NT Cycler. Outcome Measurements and Statistical Analysis: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. Results and Limitations: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. Conclusion: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.

Surgery Versus Radiotherapy for Early Oropharyngeal Tumors: a Never-Ending Debate.

OPINION STATEMENT: Therapeutic options for early stage oropharyngeal squamous cell carcinoma (OPSCC) include both surgery and radiotherapy as single treatment modality. Retrospective data reporting on locoregional control and survival rates in early stage OPSCC have shown equivalent efficacy, although no prospective randomized trials are available to confirm these results. Given the assumed comparable oncologic results in both groups, complication rates and functional outcomes associated with each modality play a major role when making treatment decisions. Radiotherapy is used preferentially in many centers because few trials have reported higher complication rates in surgical patients. However, these adverse effects were mainly due to traditional invasive open surgical approaches used for access to the oropharynx. In order to decrease the morbidity of these techniques, transoral surgical (TOS) approaches have been developed progressively. They include transoral laser microsurgery (TLM), transoral robotic surgery (TORS), and conventional transoral techniques. Meta-analysis comparing these new approaches with radiotherapy showed equivalent efficacy in terms of oncologic results. Furthermore, studies reporting on functional outcomes in patients undergoing TOS for OPSCC did not show major long-term functional impairment following treatment. Given the abovementioned statements, it is our practice to treat early stage OPSCC as follows: whenever a single modality treatment seems feasible (T1-2 and N0-1), we advocate TOS resection of the primary tumor associated with selective neck dissection, as indicated. In our opinion, the advantage of this approach relies on the possibility to stratify the risk of disease progression based on the pathological features of the tumor. Depending on the results, adjuvant radiation treatment or chemoradiotherapy can be chosen for high-risk patients. For tumors without adverse features, no adjuvant treatment is given. This approach also allows prevention of potential radiation-induced late complications while keeping radiotherapy as an option for any second primary lesions whenever needed. Definitive radiotherapy is generally reserved for selected patients with specific anatomical location associated with poor functional outcome following surgery, such as tumor of the soft palate, or for patients with severe comorbidities that do not allow surgical treatment.

Cancer testiculaire: un modèle pour optimiser le suivi radiologique [Testicular cancer: a model to optimize the radiological follow-up].

Le cancer testiculaire, bien que peu fréquent, revêt une importance particulière en oncologie ; il représente actuellement un modèle pour optimiser un suivi radiologique tout en essayant de diminuer l'apparition de tumeurs radio-induites.En effet, cette pathologie présente un taux très élevé de survie nécessitant, au vu du jeune âge des patients, des bilans radiologiques à long terme, auxquels pourront être liés des effets secondaires, en particulier les tumeurs secondaires.Afin de diminuer cela, les recommandations de prise en charge ont évolué et les protocoles de radiologie s'améliorent afin d'exposer à moins de rayonnements ionisants pour un résultat identique.Il est donc devenu primordial de maintenir un suivi optimal tout en essayant d'en minimiser la toxicité. Despite being rare cancers, testicular seminoma and non-seminoma play an important role in oncology: they represent a model on how to optimize radiological follow-up, aiming at a lowest possible radiation exposure and secondary cancer risk. Males diagnosed with testicular cancer undergo frequently prolonged follow-up with CT-scans with potential toxic side effects, in particular secondary cancers. To reduce the risks linked to ionizing radiation, precise follow-up protocols have been developed. The number of recommended CT-scanners has been significantly reduced over the last 10 years. The CT scanners have evolved technically and new acquisition protocols have the potential to reduce the radiation exposure further.

Effects of vacancy-type defects in silicon based particle detectors

The semiconductor particle detectors used at CERN experiments are exposed to radiation. Under radiation, the formation of lattice defects is unavoidable. The defects affect the depletion voltage and leakage current of the detectors, and hence affect on the signal-to-noise ratio of the detectors. This shortens the operational lifetime of the detectors. For this reason, the understanding of the formation and the effects of radiation induced defects is crucial for the development of radiation hard detectors. In this work, I have studied the effects of radiation induced defects-mostly vacancy related defects-with a simulation package, Silvaco. Thus, this work essentially concerns the effects of radiation induced defects, and native defects, on leakage currents in particle detectors. Impurity donor atom-vacancy complexes have been proved to cause insignificant increase of leakage current compared with the trivacancy and divacancy-oxygen centres. Native defects and divacancies have proven to cause some of the leakage current, which is relatively small compared with trivacancy and divacancy-oxygen.

Apnea-like suppression of respiratory motion: First evaluation in radiotherapy.

BACKGROUND AND PURPOSE: Compensation for respiratory motion is needed while administering radiotherapy (RT) to tumors that are moving with respiration to reduce the amount of irradiated normal tissues and potentially decrease radiation-induced collateral damages. The purpose of this study was to test a new ventilation system designed to induce apnea-like suppression of respiratory motion and allow long enough breath hold durations to deliver complex RT. MATERIAL AND METHODS: The High Frequency Percussive Ventilation system was initially tested in a series of 10 volunteers and found to be well tolerated, allowing a median breath hold duration of 11.6min (range 3.9-16.5min). An evaluation of this system was subsequently performed in 4 patients eligible for adjuvant breast 3D conformal RT, for lung stereotactic body RT (SBRT), lung volumetric modulated arc therapy (VMAT), and VMAT for palliative pleural metastases. RESULTS: When compared to free breathing (FB) and maximal inspiration (MI) gating, this Percussion Assisted RT (PART) offered favorable dose distribution profiles in 3 out of the 4 patients tested. PART was applied in these 3 patients with good tolerance, without breaks during the "beam on time period" throughout the overall courses of RT. The mean duration of the apnea-like breath hold that was necessary for delivering all the RT fractions was 7.61min (SD=2.3). CONCLUSIONS: This first clinical implementation of PART was found to be feasible, tolerable and offers new opportunities in the field of RT for suppressing respiratory motion.

Antioxidant effect of 4-nerolidylcatechol and α-tocopherol in erythrocyte ghost membranes and phospholipid bilayers

4-Nerolidylcatechol (4-NC) is found in Pothomorphe umbellataroot extracts and is reported to have a topical protective effect against UVB radiation-induced skin damage, toxicity in melanoma cell lines, and antimalarial activity. We report a comparative study of the antioxidant activity of 4-NC and α-tocopherol against lipid peroxidation initiated by two free radical-generating systems: 2,2′-azobis(2-aminopropane) hydrochloride (AAPH) and FeSO4/H2O2, in red blood cell ghost membranes and in egg phosphatidylcholine (PC) vesicles. Lipid peroxidation was monitored by membrane fluidity changes assessed by electron paramagnetic resonance spectroscopy of a spin-labeled lipid and by the formation of thiobarbituric acid-reactive substances. When lipoperoxidation was initiated by the hydroxyl radical in erythrocyte ghost membranes, both 4-NC and α-tocopherol acted in a very efficient manner. However, lower activities were observed when lipoperoxidation was initiated by the peroxyl radical; and, in this case, the protective effect of α-tocopherol was lower than that of 4-NC. In egg PC vesicles, malondialdehyde formation indicated that 4-NC was effective against lipoperoxidation initiated by both AAPH and FeSO4/H2O2, whereas α-tocopherol was less efficient in protecting against lipoperoxidation by AAPH, and behaved as a pro-oxidant for FeSO4/H2O2. The DPPH (2,2-diphenyl-1-picrylhydrazyl) free-radical assay indicated that two free radicals were scavenged per 4-NC molecule, and one free radical was scavenged per α-tocopherol molecule. These data provide new insights into the antioxidant capacity of 4-NC, which may have therapeutic applications for formulations designed to protect the skin from sunlight irradiation.

A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

On the effect of molecular structure and composition on the photofragmentation of biomolecules

The research on the interaction between radiation and biomolecules pro-vides valuable information for both radiobiology and molecular physics. While radiobiology is interested in the damage inflicted on the molecule upon irradiation, molecular physics exploits these studies to obtain infor-mation about the physical properties of the molecule and the quantum me-chanical processes involved in the interaction. This thesis work investigated how a small change in the structure or composition of a biomolecule changes the response of the molecule to ioniz-ing radiation. Altogether eight different biomolecules were studied: nucleo-sides uridine, 5-methyluridine and thymidine; amino acids alanine, cysteine and serine; and halogenated acetic acids chloro- and bromoacetic acids. The effect of ionizing radiation on these molecules was studied on molecular level, investigating the samples in gas phase. Synchrotron radiation of VUV or soft x-ray range was used to ionize sample molecules, and the subsequent fragmentation processes were investigated with ion mass spectroscopy and ion-ion-electron coincidence spectroscopy. The comparison between the three nucleosides revealed that adding or removing a single functional group can affect not only the bonds from which the molecule ruptures upon ionization but also the charge localiza-tion in the formed fragments. Studies on amino acids and halogenated acetic acids indicated that one simple substitution in the molecule can dramatical-ly change the extent of fragmentation. This thesis work also demonstrates that in order to steer the radiation-induced fragmentation of the molecules, it is not always necessary to alter the amount of energy deposited on the molecules but selecting a suitable substitution may suffice.

The Role of MicroRNA Regulation of Cardiac Ion Channel in Arrhythmia

La fibrillation auriculaire (FA) est le trouble du rythme le plus fréquemment observé en pratique clinique. Elle constitue un risque important de morbi-mortalité. Le traitement de la FA reste un défi majeur en lien avec les nombreux effets secondaires associés aux approches thérapeutiques actuelles. Dans ce contexte, une meilleure compréhension des mécanismes sous-jacents à la FA est essentielle pour le développement de nouvelles thérapies offrant un meilleur rapport bénéfice/risque pour les patients. La FA est caractérisée par i) un remodelage électrique délétère associé le plus souvent ii) à un remodelage structurel du myocarde favorisant la récurrence et le maintien de l’arythmie. La diminution de la période réfractaire effective au sein du tissu auriculaire est un élément clef du remodelage électrique. Le remodelage structurel, quant à lui, se manifeste principalement par une fibrose tissulaire qui altère la propagation de l’influx électrique dans les oreillettes. Les mécanismes moléculaires impliqués dans la mise en place de ces deux substrats restent mal connus. Récemment, le rôle des microARNs (miARNs) a été pointé du doigt dans de nombreuses pathologies notamment cardiaques. Dans ce contexte les objectifs principaux de ce travail ont été i) d'acquérir une compréhension approfondie du rôle des miARNs dans la régulation de l’expression des canaux ioniques et ii) de mieux comprendre le rôle de ces molécules dans l’installation d’un substrat favorable a la FA. Nous avons, dans un premier temps, effectué une analyse bio-informatique combinée à des approches expérimentales spécifiques afin d’identifier clairement les miARNs démontrant un fort potentiel de régulation des gènes codant pour l’expression des canaux ioniques cardiaques humains. Nous avons identifié un nombre limité de miARNs cardiaques qui possédaient ces propriétés. Sur la base de ces résultats, nous avons démontré que l’altération de l'expression des canaux ioniques, observée dans diverse maladies cardiaques (par exemple, les cardiomyopathies, l’ischémie myocardique, et la fibrillation auriculaire), peut être soumise à ces miARNs suggérant leur implication dans l’arythmogénèse. La régulation du courant potassique IK1 est un facteur déterminant du remodelage électrique auriculaire associée à la FA. Les mécanismes moléculaires sous-jacents sont peu connus. Nous avons émis l’hypothèse que l'altération de l’expression des miARNs soit corrélée à l’augmentation de l’expression d’IK1 dans la FA. Nous avons constaté que l’expression de miR-26 est réduite dans la FA et qu’elle régule IK1 en modulant l’expression de sa sous-unité Kir2.1. Nous avons démontré que miR-26 est sous la répression transcriptionnelle du facteur nucléaire des lymphocytes T activés (NFAT) et que l’activité accrue de NFATc3/c4, aboutit à une expression réduite de miR-26. En conséquence IK1 augmente lors de la FA. Nous avons enfin démontré que l’interférence in vivo de miR-26 influence la susceptibilité à la FA en régulant IK1, confirmant le rôle prépondérant de miR-26 dans le remodelage auriculaire électrique. La fibrose auriculaire est un constituant majeur du remodelage structurel associé à la FA, impliquant l'activation des fibroblastes et l’influx cellulaire du Ca2 +. Nous avons cherché à déterminer i) si le canal perméable au Ca2+, TRPC3, jouait un rôle dans la fibrose auriculaire en favorisant l'activation des fibroblastes et ii) étudié le rôle potentiel des miARNs dans ce contexte. Nous avons démontré que les canaux TRPC3 favorisent l’influx du Ca2 +, activant la signalisation Ca2 +-dépendante ERK et en conséquence activent la prolifération des fibroblastes. Nous avons également démontré que l’expression du TRPC3 est augmentée dans la FA et que le blocage in vivo de TRPC3 empêche le développement de substrats reliés à la FA. Nous avons par ailleurs validé que miR-26 régule les canaux TRPC3 en diminuant leur expression dans les fibroblastes. Enfin, nous avons montré que l'expression réduite du miR-26 est également due à l’activité augmentée de NFATc3/c4 dans les fibroblastes, expliquant ainsi l’augmentation de TRPC3 lors de la FA, confirmant la contribution de miR-26 dans le processus de remodelage structurel lié à la FA. En conclusion, nos résultats mettent en évidence l'importance des miARNs dans la régulation des canaux ioniques cardiaques. Notamment, miR-26 joue un rôle important dans le remodelage électrique et structurel associé à la FA et ce, en régulant IK1 et l’expression du canal TRPC3. Notre étude démasque ainsi un mécanisme moléculaire de contrôle de la FA innovateur associant des miARNs. miR-26 en particulier représente apres ces travaux une nouvelle cible thérapeutique prometteuse pour traiter la FA.

Synthesis and Characterisation of Thermoplastic Ionomers based on Natural Rubber

Chemically modified novel thermo-reversible zinc sulphonated ionomers based on natural rubber (NR), radiation induced styrene grafted natural rubber (RI-SGNR), and chemically induced styrene grafted natural rubber (CI-SGNR) were synthesized using acetyl sulphate/zinc acetate reagent system. Evidence for the attachment of sulphonate groups has been furnished by FTIR spectra. which was supplanted by FTNMR results. Estimation of the zinc sulphonate group was done using spectroscopic techniques such as XRFS and ICPAES. The TGA results prove improvement in the therrno-oxidative stability of the modified natural rubber. Both DSC and DMTA studies show that the incorporation of the ionic groups affect the thermal transition of the base polymer. Retention of the improved physical properties of the novel ionomers even after three repeated cycles of mastication and molding at 120 degree C may be considered as the evidence for the reprocessabiJity of the ionomer. Effect of both particulate (carbon black. silica & zinc stearate) and fibrous fillers (nylon & glass) on the properties of the radiation induced styrene grafted natural rubber ionomer has been evaluated. Incorporation of HAF carbon black results in maximum improvement in physical properties. Silica reinforces the backbone chain and weakens the ionic associations. Zinc stearate plays the dual role of reinforcement and ptasticization. The nylon and glass filled lonorner compounds show good improvement in the physical properties in comparison with the neat ionomer. Dispersion and adhesion of the fillers in the ionomer matrix has been amply supported by their SEM micrographs. Microwave probing of the electrical behavior of the 26.5 ZnSRISGNR ionomer reveals that the maximum relative complex conductivity and the complex permittivity appear at the frequency of 2.6 GHz. The complex conductivity of the base polymer increases from 1.8x 10.12 S/cm to 3.3xlO·4 S/cm. Influence of fillers on the dielectric constant and conductivity of the new ionic thermoplastic elastomer has been studied. The ionomer I nylon compound shows the highest microwave conductivity. Use of the 26.5 ZnS-RISGNR ionomer as a compatibilizer for obtaining the technologically compatible blends from the immiscible SBR/NBR system has been verified. The heat fugitive ionic cross-linked natural rubber may be, therefore, useful as an alternative to vulcanized rubber and thermoplastic elastomer

Design and fabrication of a photothermal spectrometer and investigations of multilayer thin films"

In this work we present the results of our attempt to build a compact photothermal spectrometer capable of both manual and automated mode of operation.The salient features of the system include the ability to analyse thin film, powder and polymer samples. The tool has been in use to investigate thermal, optical and transport properties. Binary and ternary semiconducting thin films were analysed for their thermal diffusivities. The system could perform thickness measurements nondestructively. Ion implanted semiconductors are widely studied for the effect of radiation induced defects. We could perform nondestructive imaging of defects using our spectrometer.The results reported in his thesis on the above in addition to studies on In2S3 and transparent conducting oxide ZnO have been achieved with this spectrometer. Various polymer samples have been easily analysed for their thermal diffusivities. The technique provided ease of analysis not achieved with conventional techniques like TGA and DSC. Industrial application of the tool has also been proved by analyzing defects of welded joints and adhesion of paints. Indigenization of the expensive lock-in-amplifier and automation has been the significant achievement in the course of this dissertation. We are on our way to prove the noise rejection capabilities of our PC LIA.

Efecto de la hipoxia-reoxigenación y las radiaciones ionizantes en la captación de glucosa en líneas tumorales de seno y colon cocultivadas con células endoteliales.

La captación de glucosa y su conversión en lactato juega un papel fundamental en el metabolismo tumoral, independientemente de la concentración de oxígeno presente en el tejido (efecto Warburg). Sin embrago, dicha captación varía de un tipo tumoral a otro, y dentro del mismo tumor, situación que podría depender de las características microambientales tumorales (fluctuaciones de oxígeno, presencia de otros tipos celulares) y de factores estresores asociados a los tratamientos. Se estudió el efecto de la hipoxia-reoxigenación (HR) y las radiaciones ionizantes (RI) sobre la captación de glucosa, en cultivos de líneas tumorales MCF-7 y HT-29, cultivadas de forma aislada o en cocultivo con la línea celular EAhy296. Se encontró que la captación de glucosa en HR es diferente para lo descrito en condiciones de hipoxia permanente y que es modificada en el cocultivo. Se identificaron poblaciones celulares dentro de la misma línea celular, de alta y baja captación de glucosa, lo que implicaría una simbiosis metabólica de la célula como respuesta adaptativa a las condiciones tumorales. Se evaluó la expresión de NRF2 y la translocación nuclear de NRF2 y HIF1a, como vías de respuesta a estrés celular e hipoxia. La translocación nuclear de las proteínas evaluadas explicaría el comportamiento metabólico de las células tumorales de seno, pero no de colon, por lo cual deben existir otras vías metabólicas implicadas. Las diferencias en el comportamiento de las células tumorales en HR en relación con hipoxia permitirá realizar planeaciones dosimétricas más dinámicas, que reevalúen las condiciones de oxigenación tumoral constantemente.