Oncogene advance online publication

Inadvertent mammalian tissue exposures to low doses of ionizing radiation (IR) after radiation accidents, remediation of radioactive-contaminated areas, space travel or a dirty bomb represent an interesting trauma to an organism. Possible low-dose IR-induced bystander effects could impact our evaluation of human health effects, as cells within tissue are not equally damaged after doses of IR p10 cGy. To understand tissue responses after low IR doses, we generated a reporter system using the human clusterin promoter fused to firefly luciferase (hCLUp-Luc). Secretory clusterin (sCLU), an extracellular molecular chaperone, induced by low doses of cytotoxic agents, clears cell debris. Low-dose IR (X2 cGy) exposure induced hCLUp-Luc activity with peak levels at 96 h, consistent with endogenous sCLU levels. As doses increased (X1 Gy), sCLU induction amplitudes increased and time-to-peak response decreased. sCLU expression was stimulated by insulin-like growth factor-1, but suppressed by p53. Responses in transgenic hCLUp-Luc reporter mice after low IR doses showed that specific tissues (that is, colon, spleen, mammary, thymus and bone marrow) of female mice induced hCLUp-Luc activity more than male mice after whole body (X10 cGy) irradiation. Tissue-specific, non-linear dose-and time-responses of hCLUp-Luc and endogenous sCLU levels were noted. Colon maintained homeostatic balance after 10 cGy. Bone marrow responded with delayed, but prolonged and elevated expression. Intraperitoneal administration of a-transforming growth factor (TGF)b1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling by activated TGFb1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGFb1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGFb1 signaling and most likely promotes wound healing

Residual γH2AX foci as an indication of lethal DNA lesions

<p>Abstract</p> <p>Background</p> <p>Evidence suggests that tumor cells exposed to some DNA damaging agents are more likely to die if they retain microscopically visible γH2AX foci that are known to mark sites of double-strand breaks. This appears to be true even after exposure to the alkylating agent MNNG that does not cause direct double-strand breaks but does produce γH2AX foci when damaged DNA undergoes replication.</p> <p>Methods</p> <p>To examine this predictive ability further, SiHa human cervical carcinoma cells were exposed to 8 DNA damaging drugs (camptothecin, cisplatin, doxorubicin, etoposide, hydrogen peroxide, MNNG, temozolomide, and tirapazamine) and the fraction of cells that retained γH2AX foci 24 hours after a 30 or 60 min treatment was compared with the fraction of cells that lost clonogenicity. To determine if cells with residual repair foci are the cells that die, SiHa cervical cancer cells were stably transfected with a RAD51-GFP construct and live cell analysis was used to follow the fate of irradiated cells with RAD51-GFP foci.</p> <p>Results</p> <p>For all drugs regardless of their mechanism of interaction with DNA, close to a 1:1 correlation was observed between clonogenic surviving fraction and the fraction of cells that retained γH2AX foci 24 hours after treatment. Initial studies established that the fraction of cells that retained RAD51 foci after irradiation was similar to the fraction of cells that retained γH2AX foci and subsequently lost clonogenicity. Tracking individual irradiated live cells confirmed that SiHa cells with RAD51-GFP foci 24 hours after irradiation were more likely to die.</p> <p>Conclusion</p> <p>Retention of DNA damage-induced γH2AX foci appears to be indicative of lethal DNA damage so that it may be possible to predict tumor cell killing by a wide variety of DNA damaging agents simply by scoring the fraction of cells that retain γH2AX foci.</p

К ВОПРОСУ ВЫБОРА ТАКТИКИ ЛЕЧЕНИЯ ПРИ МЕТАСТАТИЧЕСКОМ КОЛОРЕКТАЛЬНОМ РАКЕ

Treatment outcomes of 176 colorectal cancer patients with liver metastases were retrospectivelly analyzed. There were 86 men and 90 women in the age range 28 to 84 years. Multiple metastasis was detected in 79.5 % of patients and solitary metastasis in 20.5 % of patients. Cytoreductive surgery was performed in 30.7 % of patients and palliative surgery in 57.9 %. Surgical treatment was not performed in 5.1% of patients. The median survival time of patients after symptomatic surgeries was 10.8 months (1.5-26 months). Cytoreductive surgery increased the median survival time by more than 2 months (13 months, 2–44 months). Thus, radical surgery for colorectal cancer patients with liver metastases is justified by the increase in the median survival time of the patients.Проведен ретроспективный анализ результатов лечения 176 больных колоректальным раком с метастатическим поражением печени, в возрасте от 28 до 84 лет, в том числе 86 мужчин и 90 женщин. Множественное метастатическое поражение выявлено у 79,5 %, солитарное – у 20,5 % пациентов. Циторедуктивные операции выполнены у 30,7 % больных, паллиативные – у 57,9 %, у 5,1 % пациентов оперативное лечение не проводилось. Продолжительность жизни пациентов после симптоматических операций составила в среднем 10,8 мес (1,5–26 мес). Выполнение циторедуктивной операции увеличивает медиану жизни более чем на два месяца – до 13 мес (2–44 мес). Таким образом, целесообразность проведения радикальных оперативных вмешательств у пациентов с колоректальным раком и метастазами в печень подтверждается увеличением средней продолжительности жизни пациентов

СОЛИДНО-ПСЕВДОПАПИЛЛЯРНАЯ ОПУХОЛЬ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ У МОЛОДОЙ ЖЕНЩИНЫ: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Treatment outcomes of soloid-pseudopapillar tumor of the pancreas in a young woman have been presented. Soloid-pseudopapillar tumor of the pancreas is a rare neoplasm. As a rule, it is detected by chance during routine screening US examinations. Diagnosis is frequently delayed and tumor size at presentation is frequently large. In case of systic pancreatic lesion, soloid-pseudopapillar tumor should be considered in the diagnosis. As a low-grade malignancy, the tumor seldom recurs and metastasizes.Представлен результат лечения молодой пациентки с солидно- псевдопапиллярной опухолью поджелудочной железы. Данная опухоль является чрезвычайно редкой и, как правило, выявляется случайно во время профилактических осмотров либо когда опухоль становится больших размеров. Наличие кистозного образования на поджелудочной железе следует рассматривать в том числе и с позиции возможности выявления солидно-псевдопапиллярной опухоли. Прогноз заболевания благоприятный, рецидивы редки

Fondements scientifiques de l’utilisation du modèle linéaire sans seuil (LNT) aux faibles doses et débits de dose en radioprotection

Le modèle linéaire sans seuil (LNT) a été introduit dans le système de radioprotection il y a environ 60 ans, mais ce modèle et son utilisation en radioprotection sont encore débattus aujourd'hui. Cet article résume les résultats en radiobiologie et en épidémiologie accumulés au cours de la dernière décennie sur les effets d’une exposition aux rayonnements ionisants à faible Transfert d’Energie Linéique (TEL) et discute de leur impact sur l'utilisation du modèle LNT dans l'évaluation des risques de cancer par rayonnement à faibles doses. Les connaissances acquises au cours des 10 dernières années, tant en radiobiologie qu'en épidémiologie, ont renforcé les fondements scientifiques sur les risques de cancer à faibles doses. En radiobiologie, bien que certains mécanismes ne soient pas linéaires avec la dose, les premiers stades de la cancérogenèse composés d'événements mutationnels, qui jouent un rôle clé dans la cancérogenèse, montrent des réponses linéaires à des doses aussi faibles que 10 mGy. L'impact des mécanismes non mutationnels sur le risque de cancer associé aux rayonnements à faibles doses est actuellement difficile à évaluer. En épidémiologie, les résultats montrent un excès de risques de cancer à des niveaux de dose de 100 mGy ou moins. Bien que certains résultats récents indiquent des relations non linéaires avec la dose pour certains types de cancers, le modèle LNT ne surestime pas substantiellement globalement les risques à faibles doses. Les résultats actuels, en radiobiologie ou en épidémiologie, ne démontrent pas l'existence d'un seuil de dose en dessous duquel le risque de cancer associé aux rayonnements serait nul. Des incertitudes persistent mais un tel seuil de dose, s'il existe, ne pourrait être supérieur à quelques dizaines de mGy. L'IRSN considère que les connaissances scientifiques actuellement disponibles ne remettent pas en cause l'utilisation du modèle LNT pour l'évaluation des risques de cancers radio-induits en appui au système de radioprotection. L'utilisation de ce modèle semble raisonnable d'un point de vue scientifique, et aucune autre relation dose-réponse ne semble plus adaptée ou justifiée à des fins de radioprotection

ЗАСТОСУВАННЯ МЕТОДІВ ІДЕНТИФІКАЦІЇ ДЛЯ ОЦІНКИ ПАРАМЕТРІВ ВИГИН НИХ КОЛИВАНЬ КУЗОВІВ ВАГОНІВ

The description of the developed method of vibration tests with the subsequent data processing is given.Дано описание метода виброиспытаний с последующей обработкой данных.Даний опис методу вібровипробувань з подальшою обробкою даних