Helical tomotherapy for the treatment of anal canal cancer: a dosimetric comparison with 3D conformal radiotherapy.

AIMS AND BACKGROUND: The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC. METHODS AND STUDY DESIGN: Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared. RESULTS: The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p<0.0001). HT plans resulted in better sparing of OARs (p<0.0001). CONCLUSIONS: HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity.

Controle da maturação de caqui 'Fuyu' com aplicação de aminoetoxivinilglicina e 1-metilciclopropeno

O armazenamento de caquis é uma ferramenta importante na manutenção da qualidade e no prolongamento da oferta do fruto após a colheita. O objetivo deste trabalho foi avaliar o efeito da aplicação de AVG em pré-colheita, e do 1-MCP, em pré e pós-armazenamento, sobre a manutenção da qualidade pós-colheita e seu efeito na incidência de distúrbios em caquis 'Fuyu' armazenados em atmosfera controlada a -0,5 ºC e transferidos a condição de ambiente (20 ºC) por 6 dias. Os tratamentos foram: [1] controle; [2] aplicação de AVG (123 g ha-1); [3] aplicação de 1-MCP (1,0 µL L-1) em pré-armazenamento; [4] aplicação de AVG e 1-MCP em pré-armazenamento; [5] aplicação de 1-MCP em pós-armazenamento; [6] aplicação de AVG e 1-MCP em pós-armazenamento. Os frutos foram avaliados quanto à qualidade na ocasião da colheita, visando à caracterização do lote e, após quatro meses de armazenamento a -0,5 ºC e mais seis dias a 20 ºC, quanto à firmeza da polpa, pH, coloração da casca, índices de amaciamento e de escurecimento, teores de sólidos solúveis e de acidez titulável, respiração, produção de etileno, além da atividade da enzima ACC oxidase. Os resultados indicaram que a aplicação de 1-MCP em pré ou em pós-armazenamento foi eficiente em conter o amaciamento da polpa de caquis 'Fuyu' previamente armazenados em atmosfera controlada a -0,5 ºC e mantidos a 20 ºC por seis dias. Todavia, o uso deste fitorregulador em pré-armazenamento ocasionou maior escurecimento da epiderme. O uso de AVG em pré-colheita não retardou a maturação de caquis 'Fuyu' armazenados na mesma condição.

Virtual milgram : empathic concern or personal distress? Evidence from functional MRI and dispositional measures

One motive for behaving as the agent of another"s aggression appears to be anchored in as yet unelucidated mechanisms of obedience to authority. In a recent partial replication of Milgram"s obedience paradigm within an immersive virtual environment, participants administered pain to a female virtual human and observed her suffering. Whether the participants" response to the latter was more akin to other-oriented empathic concern for her well-being or to a self-oriented aversive state of personal distress in response to her distress is unclear. Using the stimuli from that study, this event-related fMRI-based study analysed brain activity during observation of the victim in pain versus not in pain. This contrast revealed activation in pre-defi ned brain areas known to be involved in affective processing but not in those commonly associated with affect sharing (e.g., ACC and insula). We then examined whether different dimensions of dispositional empathy predict activity within the same pre-defi ned brain regions: While personal distress and fantasy (i.e., tendency to transpose oneself into fi ctional situations and characters) predicted brain activity, empathic concern and perspective taking predicted no change in neuronal response associated with pain observation. These exploratory fi ndings suggest that there is a distinct pattern of brain activity associated with observing the pain-related behaviour of the victim within the context of this social dilemma, that this observation evoked a self-oriented aversive state of personal distress, and that the objective"reality" of pain is of secondary importance for this response. These fi ndings provide a starting point for experimentally more rigorous investigation of obedience.

Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and effect of perineuronal net loss.

Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in β band) in slices of the mouse anterior cingulate cortex (ACC). We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets (PNNs) enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia (SZ) patients who display prefrontal anomalies of both the dopaminergic system and the PNNs.

Free Fatty Acids Impair FGF21 Action in HepG2 Cells.

BACKGROUND/AIMS: Fibroblast growth factor 21 (FGF21) is a key mediator of glucose and lipid metabolism. However, the beneficial effects of exogenous FGF21 administration are attenuated in obese animals and humans with elevated levels of circulating free fatty acids (FFA). METHODS: We investigated in vitro how FFA impact FGF21 effects on hepatic lipid metabolism. RESULTS: In the absence of FFA, FGF21 reduced lipogenesis and increased lipid oxidation in HepG2 cells. Inhibition of lipogenesis was associated with a down regulation of SREBP-1c, FAS and SCD1. The lipid-lowering effect was associated with AMPK and ACC phosphorylation, and up regulation of CPT-1α expression. Further, FGF21 treatment reduced TNFα gene expression, suggesting a beneficial action of FGF21 on inflammation. In contrast, the addition of FFA abolished the positive effects of FGF21 on lipid metabolism. CONCLUSION: In the absence of FFA, FGF21 improves lipid metabolism in HepG2 cells and reduces the inflammatory cytokine TNFα. However, under high levels of FFA, FGF21 action on lipid metabolism and TNFα gene expression is impaired. Therefore, FFA impair FGF21 action in HepG2 cells potentially through TNFα.

Estudio piloto de la relación entre el aumento de la velocidad de onda del pulso en arteria carótida común medida por resonancia magnética y los factores de riesgo vasculares clásicos en sujetos con sospecha de lesión cerebrovascular isquémica

Arterial stiffness assessed by carotid-femoral pulse wave velocity (cfPWV) measurement is now well accepted as an independent predictor of vascular mortality and morbidity. However, the value of cfPWV has been considered to be limited for risk classification in patients with several vascular risk factors. Magnetic resonance (MR) allows measurement of PWV between two points, though to date mainly used to study the aorta. To assess the common carotid artery pulse wave velocity by magnetic resonance, determine their association with classical vascular risk factors and ischemic brain injury burden in patients with suspected ischemic cerebrovascular disease

Sonata 9 (Mesto)

Digitoitu 20. 8. 2008.

Ectonucleotidase activities in Sertoli cells from immature rats

Sertoli cells have been shown to be targets for extracellular purines such as ATP and adenosine. These purines evoke responses in Sertoli cells through two subtypes of purinoreceptors, P2Y2 and P A1. The signals to purinoreceptors are usually terminated by the action of ectonucleotidases. To demonstrate these enzymatic activities, we cultured rat Sertoli cells for four days and then used them for different assays. ATP, ADP and AMP hydrolysis was estimated by measuring the Pi released using a colorimetric method. Adenosine deaminase activity (EC 3.5.4.4) was determined by HPLC. The cells were not disrupted after 40 min of incubation and the enzymatic activities were considered to be ectocellularly localized. ATP and ADP hydrolysis was markedly increased by the addition of divalent cations to the reaction medium. A competition plot demonstrated that only one enzymatic site is responsible for the hydrolysis of ATP and ADP. This result indicates that the enzyme that acts on the degradation of tri- and diphosphate nucleosides on the surface of Sertoli cells is a true ATP diphosphohydrolase (EC 3.6.1.5) (specific activities of 113 ± 6 and 21 ± 2 nmol Pi mg-1 min-1 for ATP and ADP, respectively). The ecto-5'-nucleotidase (EC 3.1.3.5) and ectoadenosine deaminase activities (specific activities of 32 ± 2 nmol Pi mg-1 min-1 for AMP and 1.52 ± 0.13 nmol adenosine mg-1 min-1, respectively) were shown to be able to terminate the effects of purines and may be relevant for the physiological control of extracellular levels of nucleotides and nucleosides inside the seminiferous tubules.

Axonal pathfinding mechanisms at the cortical midline and in the development of the corpus callosum

The corpus callosum is a large fiber tract that connects neurons in the right and left cerebral hemispheres. Agenesis of the corpus callosum (ACC) is associated with a large number of human syndromes but little is known about why ACC occurs. In most cases of ACC, callosal axons are able to grow toward the midline but are unable to cross it, continuing to grow into large swirls of axons known as Probst bundles. This phenotype suggests that in some cases ACC may be due to defects in axonal guidance at the midline. General guidance mechanisms that influence the development of axons include chemoattraction and chemorepulsion, presented by either membrane-bound or diffusible molecules. These molecules are not only expressed by the final target but by intermediate targets along the pathway, and by pioneering axons that act as guides for later arriving axons. Midline glial populations are important intermediate targets for commissural axons in the spinal cord and brain, including the corpus callosum. The role of midline glial populations and pioneering axons in the formation of the corpus callosum are discussed. Finally the differential guidance of the ipsilaterally projecting perforating pathway and the contralaterally projecting corpus callosum is addressed. Development of the corpus callosum involves the coordination of a number of different guidance mechanisms and the probable involvement of a large number of molecules.

Expression of beclin 1 in primary salivary adenoid cystic carcinoma and its relation to Bcl-2 and p53 and prognosis

Beclin 1 plays a critical role in autophagy and functions as a haploinsufficient tumor suppressor. The expression and prognostic significance of beclin 1 in head and neck adenoid cystic carcinoma (ACC) are largely unexplored. Therefore, we investigated the expression of beclin 1, Bcl-2, and p53 in head and neck ACC tissue. Tissue samples from 35 cases (15 females, 20 males) of head and neck ACC were utilized for immunohistochemistry. Beclin 1 expression was observed in 32 cases (91.4%) and considered to be high in 15 cases (42.9%) and low in 20 cases (57.1%). Beclin 1 expression was significantly correlated with a histological growth pattern (P=0.046) and histological grade (P=0.037). Beclin 1 expression was inversely correlated with Bcl-2 expression (P=0.013) and significantly associated with overall survival (P=0.006). Bcl-2 and p53 expression were observed in 21 cases (60.0%) and 16 cases (45.7%). Bcl-2 expression was significantly correlated with perineural invasion (P=0.041) and not associated with overall survival (P=0.053). p53 expression was directly correlated with beclin 1 expression (P=0.044). Our results indicated that beclin 1 may be a novel, promising prognostic factor for clinical outcome in head and neck ACC patients and may play a part in the development of head and neck ACC by interacting with Bcl-2 and p53.

Effects of 5-aza-2′deoxycytidine on RECK gene expression and tumor invasion in salivary adenoid cystic carcinoma

Reversion-inducing cysteine-rich protein with kazal motifs (RECK), a novel tumor suppressor gene that negatively regulates matrix metalloproteinases (MMPs), is expressed in various normal human tissues but downregulated in several types of human tumors. The molecular mechanism for this downregulation and its biological significance in salivary adenoid cystic carcinoma (SACC) are unclear. In the present study, we investigated the effects of a DNA methyltransferase (DNMT) inhibitor, 5-aza-2′deoxycytidine (5-aza-dC), on the methylation status of the RECK gene and tumor invasion in SACC cell lines. Methylation-specific PCR (MSP), Western blot analysis, and quantitative real-time PCR were used to investigate the methylation status of the RECK gene and expression of RECK mRNA and protein in SACC cell lines. The invasive ability of SACC cells was examined by the Transwell migration assay. Promoter methylation was only found in the ACC-M cell line. Treatment of ACC-M cells with 5-aza-dC partially reversed the hypermethylation status of the RECK gene and significantly enhanced the expression of mRNA and protein, and 5-aza-dC significantly suppressed ACC-M cell invasive ability. Our findings showed that 5-aza-dC inhibited cancer cell invasion through the reversal of RECKgene hypermethylation, which might be a promising chemotherapy approach in SACC treatment.

Ciclo de maturação e produção de etileno de tomates (Lycopersicon esculentum, Mill.) transgênicos

Objetivou-se estudar o comportamento fisiológico de frutos de tomateiro (Lycopersicon esculentum, Mill.), da cv. Kadá, transformados geneticamente, via Agrobacterium tumefaciens, com o clone de DNA pMEL1, em orientação antisenso, e de frutos desta mesma cultivar, não transformados. O estudo fisiológico foi realizado avaliando-se a duração do ciclo de maturação dos frutos, amadurecidos na planta e após a colheita no estádio verde-maduro, e sua produção de etileno. Os frutos transformados amadurecidos na planta tiveram um ciclo total médio de 27 dias, enquanto os amadurecidos após a colheita, tiveram este intervalo prolongado a 50 dias. Ao contrário, os tomates não transformados apresentaram um ciclo de maturação mais acelerado quando colhidos no estádio verde-maduro, em relação aos frutos amadurecidos nas plantas. Os valores foram, em média, de 20 e 30 dias, respectivamente. Estes resultados estão correlacionados com as variações na produção de etileno observada nos dois genótipos. Frutos não transformados produziram, em média, 10,46 nL de etileno.g-1.h-1, enquanto os transgênicos tiveram sua produção de etileno diminuída para 0,13 nL.g-1.h-1. Pode-se concluir, então, que a redução da produção de etileno, verificada nos tomates transformados, é necessária, mas não é suficiente para prolongar o ciclo de maturação e aumentar a durabilidade dos frutos. Para que isto ocorra, é necessário que se proceda à colheita dos tomates no estádio verde-maduro.

Bebida mista com propriedade estimulante à base de água de coco e suco de caju clarificado

Na indústria de bebidas, uma alternativa para acrescentar valor nutricional ou simplesmente desenvolver novos sabores é a mistura de diferentes sucos de frutas na formulação de bebidas mistas. Este trabalho teve como objetivo o desenvolvimento de uma bebida à base de água de coco e suco de caju clarificado (cajuína), com adição de cafeína, conferindo-lhe propriedades estimulantes. Foram avaliadas cinco formulações, com diferentes proporções de cajuína, tendo sido padronizados previamente o pH, teor de sólidos solúveis e cafeína. As formulações foram submetidas à caracterização físico-química (pH, sólidos solúveis, acidez, açúcares redutores, não redutores e totais e vitamina C), análises microbiológicas e avaliação sensorial de aceitação (atributos de cor, sabor, avaliação global e intenção de compra). Todas as formulações em estudo apresentaram boa aceitação sensorial, não havendo diferença entre as médias dos atributos avaliados. Na intenção de compra, a formulação mais aceita foi ACC 20 (20% de cajuína e 80% de água de coco). A incorporação de vitamina C na bebida através da adição da cajuína foi mais evidente até a formulação ACC 20. Os resultados indicaram que a formulação ACC 20 foi a mais viável para elaboração da bebida mista. Todas as formulações apresentaram padrões microbiológicos satisfatórios.

Cortical and autonomic modulation of attentional control /

Whereas the role of the anterior cingulate cortex (ACC) in cognitive control has received considerable attention, much less work has been done on the role of the ACC in autonomic regulation. Its connections through the vagus nerve to the sinoatrial node of the heart are thought to exert modulatory control over cardiovascular arousal. Therefore, ACC is not only responsible for the implementation of cognitive control, but also for the dynamic regulation of cardiovascular activity that characterizes healthy heart rate and adaptive behaviour. However, cognitive control and autonomic regulation are rarely examined together. Moreover, those studies that have examined the role of phasic vagal cardiac control in conjunction with cognitive performance have produced mixed results, finding relations for specific age groups and types of tasks but not consistently. So, while autonomic regulatory control appears to support effective cognitive performance under some conditions, it is not presently clear just what factors contribute to these relations. The goal of the present study was, therefore, to examine the relations between autonomic arousal, neural responsivity, and cognitive performance in the context of a task that required ACC support. Participants completed a primary inhibitory control task with a working memory load embedded. Pre-test cardiovascular measures were obtained, and ontask ERPs associated with response control (N2/P3) and error-related processes (ERN/Pe) were analyzed. Results indicated that response inhibition was unrelated to phasic vagal cardiac control, as indexed by respiratory sinus arrhythmia (RSA). However, higher resting RSA was associated with larger ERN ampUtude for the highest working memory load condition. This finding suggests that those individuals with greater autonomic regulatory control exhibited more robust ACC error-related responses on the most challenging task condition. On the other hand, exploratory analyses with rate pressure product (RPP), a measure of sympathetic arousal, indicated that higher pre-test RPP (i.e., more sympathetic influence) was associated with more errors on "catch" NoGo trials, i.e., NoGo trials that simultaneously followed other NoGo trials, and consequently, reqviired enhanced response control. Higher pre-test RPP was also associated with smaller amplitude ERNs for all three working memory loads and smaller ampUtude P3s for the low and medium working memory load conditions. Thus, higher pretest sympathetic arousal was associated with poorer performance on more demanding "catch" NoGo trials and less robust ACC-related electrocortical responses. The findings firom the present study highlight tiie interdependence of electrocortical and cardiovascular processes. While higher pre-test parasympathetic control seemed to relate to more robust ACC error-related responses, higher pre-test sympathetic arousal resulted in poorer inhibitory control performance and smaller ACC-generated electrocortical responses. Furthermore, these results provide a base from which to explore the relation between ACC and neuro/cardiac responses in older adults who may display greater variance due to the vulnerabihty of these systems to the normal aging process.

Electrophysiological correlates of performance monitoring in middle and late adolescence

The ability to monitor and evaluate the consequences of ongoing behaviors and coordinate behavioral adjustments seems to rely on networks including the anterior cingulate cortex (ACC) and phasic changes in dopamine activity. Activity (and presumably functional maturation) of the ACC may be indirectly measured using the error-related negativity (ERN), an event-related potential (ERP) component that is hypothesized to reflect activity of the automatic response monitoring system. To date, no studies have examined the measurement reliability of the ERN as a trait-like measure of response monitoring, its development in mid- and late- adolescence as well as its relation to risk-taking and empathic ability, two traits linked to dopaminergic and ACC activity. Utilizing a large sample of 15- and 18-year-old males, the present study examined the test-retest reliability of the ERN, age-related changes in the ERN and other components of the ERP associated with error monitoring (the Pe and CRN), and the relations of the error-related ERP components to personality traits of risk propensity and empathy. Results indicated good test-retest reliability of the ERN providing important validation of the ERN as a stable and possibly trait-like electrophysiological correlate of performance monitoring. Ofthe three components, only the ERN was of greater amplitude for the older adolescents suggesting that its ACC network is functionally late to mature, due to either structural or neurochemical changes with age. Finally, the ERN was smaller for those with high risk propensity and low empathy, while other components associated with error monitoring were not, which suggests that poor ACe function may be associated with the desire to engage in risky behaviors and the ERN may be influenced by the extent of individuals' concern with the outcome of events.