Applications of metrological techniques for clinical implementation of dosimetry and radiobiology in molecular radiotherapy

Molecular radiotherapy (MRT) is a fast developing and promising treatment for metastasised neuroendocrine tumours. Efficacy of MRT is based on the capability to selectively "deliver" radiation to tumour cells, minimizing administered dose to normal tissues. Outcome of MRT depends on the individual patient characteristics. For that reason, personalized treatment planning is important to improve outcomes of therapy. Dosimetry plays a key role in this setting, as it is the main physical quantity related to radiation effects on cells. Dosimetry in MRT consists in a complex series of procedures ranging from imaging quantification to dose calculation. This doctoral thesis focused on several aspects concerning the clinical implementation of absorbed dose calculations in MRT. Accuracy of SPECT/CT quantification was assessed in order to determine the optimal reconstruction parameters. A model of PVE correction was developed in order to improve the activity quantification in small volume, such us lesions in clinical patterns. Advanced dosimetric methods were compared with the aim of defining the most accurate modality, applicable in clinical routine. Also, for the first time on a large number of clinical cases, the overall uncertainty of tumour dose calculation was assessed. As part of the MRTDosimetry project, protocols for calibration of SPECT/CT systems and implementation of dosimetry were drawn up in order to provide standard guidelines to the clinics offering MRT. To estimate the risk of experiencing radio-toxicity side effects and the chance of inducing damage on neoplastic cells is crucial for patient selection and treatment planning. In this thesis, the NTCP and TCP models were derived based on clinical data as help to clinicians to decide the pharmaceutical dosage in relation to the therapy control and the limitation of damage to healthy tissues. Moreover, a model for tumour response prediction based on Machine Learning analysis was developed.

Genetic structure of Gymnures (genus Hylomys; Erinaceidae) on continental islands of Southeast Asia: Historical effects of fragmentation

Eustatic sea level changes during Pleistocene climatic fluctuations produced several cycles of connection-isolation among continental islands of the Sunda shelf. To explore the potential effects of these fluctuations, we reconstructed a model of the vicariant events that separated these islands, based on bathymetric information. Among many possible scenarios, two opposite phylogenetic patterns of evolution were predicted for terrestrial organisms living in this region: one is based on the classical allopatric speciation mode of evolution, while the other is the outcome of a sequential dispersal colonization of the archipelago. We tested the applicability of these predictions with an analysis of sequence variation of the cytochrome b gene from several taxa of Hylomys. They were sampled throughout SE-Asia and the Sunda islands. High levels of haplotype differentiation characterize the different island taxa. Such levels of differentiation support the existence of several allopatric species, as was suggested by previous allozyme and morphological data. Also in accordance with previous results, the occurrence of two sympatric species from Sumatra is suggested by their strongly divergent haplotypes. One species, Hylomys suillus maxi, is found both on Sumatra and in Peninsular Malaysia, while the other, H. parvus, is endemic to Sumatra. Its closest relative is H. suillus dorsalis from Borneo. Phylogenetic reconstructions also demonstrate the existence of a Sundaic clade composed of all island taxa, as opposed to those from the continent. Although there is no statistical support for either proposed biogeographic model of evolution, we argue that the sequential dispersal scenario is more appropriate to describe the genetic variation found among the Hylomys taxa. However, despite strong differentiation among island haplotypes, the cladistic relationships between some island taxa could not be resolved. We argue that this is evidence of a rapid radiation, suggesting that the separation of the islands may have been perceived as a simultaneous event rather than as a succession of vicariant events. Furthermore, the estimates of divergence times between the haplotypes of these taxa suggest that this radiation may actually have predated the climatic fluctuations of the Pleistocene. Further refinement of the initial palaeogeographic models of evolution are therefore needed to account for these results.

Modulation of radiation-induced genetic damage by HCMV: A glioma case-control study

Human cytomegalovirus (HCMV) infection occurs early in life and leads to life-long viral persistence. An association between HCMV infection and malignant gliomas has been reported suggesting that HCMV may play a role in glioma pathogenesis. The reported effects of HCMV on cells suggest that it could facilitate accrual of genotoxic damage. We therefore tested the hypothesis that HCMV infection modifies the sensitivity of cells to genetic damage from environmental insults such as γ-irradiation. Peripheral blood lymphocytes from 110 glioma patients and 100 controls were used to measure the level of both chromosome damage and cell death as endpoints for genetic instability. For each study participant, the extent of baseline, HCMV-, γ-radiation- and both – induced genetic instability was evaluated. Radiation induced a significant increase in aberration frequency over baseline in both cases and controls. Similarly, HCMV induced a significant increase in aberration frequency regardless of the disease status. Interestingly, HCMV induced damage was either equal or higher than that induced by radiation. Infected with HCMV prior to challenge with γ-radiation demonstrated a significant increase in the aberration frequency as compared to baseline, radiation- or HCMV-treated cells. With regards to apoptosis, cases showed a lower percentage of induction following in vitro exposure to γ-radiation and/or HCMV infection. The level of apoptosis was inversely related to the amount of chromosome damage in the cases, but not in the controls. These data indicate that, HCMV infection enhances the sensitivity of PBLs to γ-radiation-induced genetic damage.^

The effects of ionizing radiation on the reproductive capacity of adult Penaeus (Marsupenaeus) japonicus (Bate)

The reproductive capacity of adult Penaeus (Marsupenaeus) japonicus (Bate) was assessed after exposure to ionizing gamma radiation from a cobalt-60 source. Males and females were each exposed to 0, 10 and 20 Gray (Gy) of ionizing radiation (IR) and reciprocally crossed to give nine mating combinations. Fecundity and hatch rate of resulting spawnings were used as measures of reproductive capacity. IR significantly (P

Optimizing the radiation pattern of smart antennas using genetic algorithms

This work is directed towards optimizing the radiation pattern of smart antennas using genetic algorithms. The structure of the smart antennas based on Space Division Multiple Access (SDMA) is proposed. It is composed of adaptive antennas, each of which has adjustable weight elements for amplitudes and phases of signals. The corresponding radiation pattern formula available for the utilization of numerical optimization techniques is deduced. Genetic algorithms are applied to search the best phase-amplitude weights or phase-only weights with which the optimal radiation pattern can be achieved. ^ One highlight of this work is the proposed optimal radiation pattern concept and its implementation by genetic algorithms. The results show that genetic algorithms are effective for the true Signal-Interference-Ratio (SIR) design of smart antennas. This means that not only nulls can be put in the directions of the interfering signals but also simultaneously main lobes can be formed in the directions of the desired signals. The optimal radiation pattern of a smart antenna possessing SDMA ability has been achieved. ^ The second highlight is on the weight search by genetic algorithms for the optimal radiation pattern design of antennas having more than one interfering signal. The regular criterion for determining which chromosome should be kept for the next step iteration is modified so as to improve the performance of the genetic algorithm iteration. The results show that the modified criterion can speed up and guarantee the iteration to be convergent. ^ In addition, the comparison between phase-amplitude perturbations and phase-only perturbations for the radiation pattern design of smart antennas are carried out. The effects of parameters used by the genetic algorithm on the optimal radiation pattern design are investigated. Valuable results are obtained. ^

Update On Ultraviolet A And B Radiation Generated By The Sun And Artificial Lamps And Their Effects On Skin.

Solar radiation, especially ultraviolet A (UVA) and ultraviolet B (UVB), can cause damage to the human body, and exposure to the radiation may vary according to the geographical location, time of year and other factors. The effects of UVA and UVB radiation on organisms range from erythema formation, through tanning and reduced synthesis of macromolecules such as collagen and elastin, to carcinogenic DNA mutations. Some studies suggest that, in addition to the radiation emitted by the sun, artificial sources of radiation, such as commercial lamps, can also generate small amounts of UVA and UVB radiation. Depending on the source intensity and on the distance from the source, this radiation can be harmful to photosensitive individuals. In healthy subjects, the evidence on the danger of this radiation is still far from conclusive.

Non-additive genetic effects on weights and performance of a Brazilian Bos taurus x Bos indicus beef composite

The aim of the present study was to evaluate the heterosis effects on weaning weight at 205 days (WW, N = 146,464), yearling weight at 390 days (YW, N = 69,315) and weight gain from weaning to yearling (WG, N = 59,307) in composite beef cattle. The fixed models were: RM, which included contemporary groups, class of age of dam, outcrossing percentages for direct and maternal effects, and additive direct and maternal ( AM) breed effects; R, RM model, minus AM breed effects, and H, RM model, minus additive breed effects. The estimates for W205 were in general positive (P < 0.01). The R and H models resulted in similar estimates, but they were very different from the ones estimated by the RM model. For W390, the R and H models resulted in general positive estimates (P < 0.05). For WG, the RM model resulted in general significant heterosis effects (P < 0.05). It can be concluded that the RM model seems to supply estimates of better quality (P < 0.01).

Gene Expression Profiles in Radiation Workers Occupationally Exposed to Ionizing Radiation

Ionizing radiation OR) imposes risks to human health and the environment. IR at low doses and low (lose rates has the potency to initiate carcinogenesis. Genotoxic environmental agents such as IR trigger a cascade of signal transduction pathways for cellular protection. In this study, using cDNA microarray technique, we monitored the gene expression profiles in lymphocytes derived from radiation-ex posed individuals (radiation workers). Physical dosimetry records on these patients indicated that the absorbed dose ranged from 0.696 to 39.088 mSv. Gene expression analysis revealed statistically significant transcriptional changes in a total of 78 genes (21 up-regulated and 57 clown-regulated) involved in several biological processes such as ubiquitin cycle (UHRF2 and PIAS1), DNA repair (LIG3, XPA, ERCC5, RAD52, DCLRE1C), cell cycle regulation/proliferation (RHOA, CABLES2, TGFB2, IL16), and stress response (GSTP1, PPP2R5A, DUSP22). Some of the genes that showed altered expression profiles in this study call be used as biomarkers for monitoring the chronic low level exposure in humans. Additionally, alterations in gene expression patterns observed in chronically exposed radiation workers reinforces the need for defining the effective radiation dose that causes immediate genetic damage as well as the long-term effects on genomic instability, including cancer.