Use of aequorin-based indicators for monitoring Ca2+ in acidic organelles

Over the last years, there is accumulating evidence that acidic organelles can accumulate and release Ca2+ upon cell activation. Hence, reliable recording of Ca2+ dynamics in these compartments is essential for understanding the physiopathological aspects of acidic organelles. Genetically encoded Ca2+ indicators (GECIs) are valuable tools to monitor Ca2+ in specific locations, although their use in acidic compartments is challenging due to the pH sensitivity of most available fluorescent GECIs. By contrast, bioluminescent GECIs have a combination of features (marginal pH sensitivity, low background, no phototoxicity, no photobleaching, high dynamic range and tunable affinity) that render them advantageous to achieve an enhanced signal-to-noise ratio in acidic compartments. This article reviews the use of bioluminescent aequorin-based GECIs targeted to acidic compartments. A need for more measurements in highly acidic compartments is identified

Prolactin receptor does not correlate with oestrogen and progesterone receptors in primary breast cancer and lacks prognostic significance. Ten year results of the Naples adjuvant (GUN) study.

The correlation between prolactin (PRLR) and oestrogen (ER) or progesterone receptors (PgR) in breast cancer and a possible prognostic significance of PRLR at 10 year follow-up have been investigated in the Naples (GUN) adjuvant trial. A total of 308 pre- and post-menopausal patients with early breast cancer, who entered the trial from 1 February 1978 to 31 December 1983, received randomly Tamoxifen (TM), 30 mg per die for 2 years, or no therapy. PRLR status was known in 229 (74.3%) patients. Values of specific binding less than 1% were considered negative. PRLR was positive in 75/229 (32.8%). ER was assayed in 210/229 (91.7%) patients and PgR in 188/229 (82.1%). No significant correlation, by the Spearman test, was found between PRLR and ER or PgR, while ER status was highly interrelated with PgR status. By the Cox model no evidence of an independent prognostic role of PRLR on disease-free survival (DFS) was observed, nor an interaction between PRLR and adjuvant treatment with TM was found

A predictive index of axillary nodal involvement in operable breast cancer.

We investigated the association between pathological characteristics of primary breast cancer and degree of axillary nodal involvement and obtained a predictive index of the latter from the former. In 2076 cases, 17 histological features, including primary tumour and local invasion variables, were recorded. The whole sample was randomly split in a training (75% of cases) and a test sample. Simple and multiple correspondence analysis were used to select the variables to enter in a multinomial logit model to build an index predictive of the degree of nodal involvement. The response variable was axillary nodal status coded in four classes (N0, N1-3, N4-9, N > or = 10). The predictive index was then evaluated by testing goodness-of-fit and classification accuracy. Covariates significantly associated with nodal status were tumour size (P < 0.0001), tumour type (P < 0.0001), type of border (P = 0.048), multicentricity (P = 0.003), invasion of lymphatic and blood vessels (P < 0.0001) and nipple invasion (P = 0.006). Goodness-of-fit was validated by high concordance between observed and expected number of cases in each decile of predicted probability in both training and test samples. Classification accuracy analysis showed that true node-positive cases were well recognised (84.5%), but there was no clear distinction among the classes of node-positive cases. However, 10 year survival analysis showed a superimposible prognostic behaviour between predicted and observed nodal classes. Moreover, misclassified node-negative patients (i.e. those who are predicted positive) showed an outcome closer to patients with 1-3 metastatic nodes than to node-negative ones. In conclusion, the index cannot completely substitute for axillary node information, but it is a predictor of prognosis as accurate as nodal involvement and identifies a subgroup of node-negative patients with unfavourable prognosis

Thromboelastographic profiles as a tool for thrombotic risk in digestive tract cancer

Background: Quantification of the magnitude of thrombotic risk associated with malignancy and with anti-cancer therapy is indispensable to use anticoagulant drugs which selectively interfere with haemostatic mechanisms protecting patients from venous thromboembolism (VTE) and probably from tumor progression. However, none of activation coagulation markers has any predictive value for the occurrence of the thrombotic events in one individual patient. Current clotting methods can’t reveal the overall dynamic clot formation; in contrast thromboelastographic methods specifically assess overall coagulation kinetics and its strength in whole blood. Aim: Objective of study was to evaluate if the activation of coagulation as eventually revealed by ROTEM® thromboelastometry could assess an hypercoagulable state in surgical neoplastic patients. Patients and Methods: Fifty consecutive patients with carcinoma of the digestive tract in preoperative period (23 M, 27 F aging 61.5 (45–79 years) and 147 healthy subjects (71 M, 76 F) were studied. A recent thromboelastometric method based on thrombelastography after Hartert was employed. Measurements were performed on ROTEM Coagulation Analyzer. The continuous coagulation data from 50 min course were transformed into dynamic velocity profiles of WB clot formation. Results: Standard parameters (CT, CFT, MCF) of cancer patients were similar to controls. CT (in cancer patients): females 50 s (38.3–58.7), males 50 s (42–71.2) vs 51 s (42–59), p = 0.1210 / 53 s (42–74.8), p = 0.1975 (in controls). CFT (in cancer patients): females 72 s (32- 92.4), males 80 s (50.2- 128.7) vs 78 s (62–100), p = 0.0128 / 80 s (59–124.4), p = 0.9384 (in controls). MCF (in cancer patients): females 70 mm (59.9–82.5), males 63 mm (56–73.7) vs 69 mm (59–95.8), p = 0.9911 / 69 mm (53.6–90), p = 0.0135 (in controls). Females showed a higher MaxVel when compared to males. The MaxVel was increased in cancer patients: females 19 mm /100 s (14.3–49.5) males 18 mm / 100 s (11–27) vs 15 mm 100 s (11.8–22), p < 0.001 / 13 mm / 100 s (10–21.8), p < 0.001 in controls .The t-MaxVel was shortened in cancer patients: females 65 s (48.6–112.8), males 81 s (50.1–135.9) vs 115 s (56.8–166), p <0.001 / 115 s (59.8–180.8), p = 0.0002 in controls. The AUC was increased in cancer patients: females 6451 mm 100 (5511–8148), males 5984 mm 100 (5119-6899) vs 5778 mm 100 (4998–6655), p < 0.001 / 5662 mm 100 (4704–6385), p = 0.0105. Conclusion: Unlike other assays measuring variations in a single component during coagulation, the thrombelastographic method records a profile of real-time continuous WB clot formation, and may provide extensive informations on haemostasis in neoplastic patients before surgery.Предпосылки исследования количественная оценка риска тромбоза, связанного со злокачественными заболеваниями и противоопухолевой терапией, обязательно включает в себя применение средств-антикоагулянтов, защищающих больного от развития венозной тромбоэмболии (VTE)и возможно п рогрессии заболевания . Тем не менее ни один из маркеров ак- тивации коагуляции не имеет прогностической ценности с точки зрения возможности возникновения тромбоза у каждого отдельно взятого пациента. Современные мето ды оценки свертывания крови не отража ют образование тромба винамике ; наоборот, метод тромбо эластографии дает возможность специфически оценить кинетику свертывания крови целом . Цель: определить, в какой мере активность коагуляции, определяемой методом тромбоэ ластометрии, отражает состояние гиперсвертываемости крови у больных онкологического профиля после хирургического вмешательства. Пациенты и м ды: обследованы 50 больных раком пищ еваритель ного тракта в дооп ерационный п ериод (27 женщин, 23 му жчины, средний возраст 61,5 года (45–79 лет) и 147 здоровых доноров (71 мужчина, 76 женщин). Применяли метод тромбоэластометрии , основанный на тромбоэластографии Гартерта, с использованием анализатора коагуляциифирмыROTEM. Текущие д анные о свертывании за 50 мин измерений представили в виде динамичных профилей вязкости при образовании сгустка крови. Результаты: стандартные параметры (перио д коагуляции (CT), перио д образования сгу стка (CFT), максимал ь ная п лот- ность сгустка (MCF)) больных онкологического п рофиля близки к контроль ным . CT у больных онкологического п рофиля составлял: у женщин — 50 с (38,3–58,7), у му жчин 50 (42–71,2) vs 51 (42–59), p = 0,1210/53 ( 42–74,8 ), p = 0,1975 в контрольной группе . CFT у таких пациентов составлял : у женщин — 72 ( 32–92,4 м жчин – 80 с (50,2–128,7) vs 78 (62–100), p = 0,0128 80 (59–124,4), p = 0,9384 в контрол ьной группе . MCF у больных онкологического п составлял: у женщин — 70 мм (59,9–82,5), у мужчин — 63 мм (56–73,7) vs 69 мм (59–95,8), p = 0,9911 / 69 мм (53,6–90), p = 0,0135 в контрол ьной группе. У женщинпоказатели вязкости крови MaxVel были выше, чем у му жчин . Показатели MaxVel повышены у таких пациентов : у женщин — 19 мм/100 с (14,3–49,5) у му жчин — 18 мм/100 (11–27 ) vs 15 мм / 100 (11,8–22), p < 0,001 / 13 мм / 100 с (10–21,8), p <0,001 в контрол ьной группе. ь t-MaxVel понижен у больных онкологического профиля: у женщин – 65 с (48,6–112,8) , у мужчин – 81 с (50,1–135,9) vs 115 с (56,8–166), p < 0,001 / 115 с (59,8–180,8), p = 0,0002 в контрольной группе. Показатель AUC у повышен у женщин — 6451 мм 100 (5511–8148), у мужчин — 5984 мм 100 (5119–6899) vs 5778 мм 100 (4998–6655), p < 0,001 / 5662 мм 100 (4704–6385), p = 0.0105. Выводы в отличие от других мето дов, измеря ющих вариации отдельных комп онентов системы крови, метод тромбо эластографии отражает текущийп рофиль образования сгу сткав режиме реаль ного времени является информативным споссобом оценки состояния гемостаза у онкологических больных

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management

HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence

Mechanical behavior of asphalt mixtures containing silica gels as warm additives

This paper presents the results of a study of some compounds capable of absorbing water into their structure (silica gel), as potential foaming binders. Asphalt mixtures were manufactured at different manufacturing and compaction temperatures, using four different silica gels. Static and dynamic tests were carried out to determine their behavior in asphalt mixtures. The results were compared with those obtained using hot-mix asphalt and warm-mix asphalt manufactured with zeolite. The lab results showed a similar behavior of asphalt mixtures containing either silica gel or zeolite.The research presented herein was sponsored by the Research Office of Universidad de La Frontera (DIUFRO) under the project number DI15-0089

Comparing nuclear power trajectories in Germany and the UK: from ‘regimes' to ‘democracies’ in sociotechnical transitions and Discontinuities

This paper focuses on arguably the single most striking contrast in contemporary major energy politics in Europe (and even the developed world as a whole): the starkly differing civil nuclear policies of Germany and the UK. Germany is seeking entirely to phase out nuclear power by 2022. Yet the UK advocates a ‘nuclear renaissance’, promoting the most ambitious new nuclear construction programme in Western Europe.Here,this paper poses a simple yet quite fundamental question: what are the particular divergent conditions most strongly implicated in the contrasting developments in these two countries. With nuclear playing such an iconic role in historical discussions over technological continuity and transformation, answering this may assist in wider understandings of sociotechnical incumbency and discontinuity in the burgeoning field of‘sustainability transitions’. To this end, an ‘abductive’ approach is taken: deploying nine potentially relevant criteria for understanding the different directions pursued in Germany and the UK. Together constituted by 30 parameters spanning literatures related to socio-technical regimes in general as well as nuclear technology in particular, the criteria are divided into those that are ‘internal’ and ‘external’ to the ‘focal regime configuration’ of nuclear power and associated ‘challenger technologies’ like renewables. It is ‘internal’ criteria that are emphasised in conventional sociotechnical regime theory, with ‘external’ criteria relatively less well explored. Asking under each criterion whether attempted discontinuation of nuclear power would be more likely in Germany or the UK, a clear picture emerges. ‘Internal’ criteria suggest attempted nuclear discontinuation should be more likely in the UK than in Germany– the reverse of what is occurring. ‘External’ criteria are more aligned with observed dynamics –especially those relating to military nuclear commitments and broader ‘qualities of democracy’. Despite many differences of framing concerning exactly what constitutes ‘democracy’, a rich political science literature on this point is unanimous in characterising Germany more positively than the UK. Although based only on a single case,a potentially important question is nonetheless raised as to whether sociotechnical regime theory might usefully give greater attention to the general importance of various aspects of democracy in constituting conditions for significant technological discontinuities and transformations. If so, the policy implications are significant. A number of important areas are identified for future research, including the roles of diverse understandings and specific aspects of democracy and the particular relevance of military nuclear commitments– whose under-discussion in civil nuclear policy literatures raises its own questions of democratic accountability

Past, present and future of adjuvant HIPEC in patients at high risk for colorectal peritoneal metastases

EDITORIA

Parametric POMDPs for planning in continuous state spaces

This thesis is concerned with planning and acting under uncertainty in partially-observable continuous domains. In particular, it focusses on the problem of mobile robot navigation given a known map. The dominant paradigm for robot localisation is to use Bayesian estimation to maintain a probability distribution over possible robot poses. In contrast, control algorithms often base their decisions on the assumption that a single state, such as the mode of this distribution, is correct. In scenarios involving significant uncertainty, this can lead to serious control errors. It is generally agreed that the reliability of navigation in uncertain environments would be greatly improved by the ability to consider the entire distribution when acting, rather than the single most likely state. The framework adopted in this thesis for modelling navigation problems mathematically is the Partially Observable Markov Decision Process (POMDP). An exact solution to a POMDP problem provides the optimal balance between reward-seeking behaviour and information-seeking behaviour, in the presence of sensor and actuation noise. Unfortunately, previous exact and approximate solution methods have had difficulty scaling to real applications. The contribution of this thesis is the formulation of an approach to planning in the space of continuous parameterised approximations to probability distributions. Theoretical and practical results are presented which show that, when compared with similar methods from the literature, this approach is capable of scaling to larger and more realistic problems. In order to apply the solution algorithm to real-world problems, a number of novel improvements are proposed. Specifically, Monte Carlo methods are employed to estimate distributions over future parameterised beliefs, improving planning accuracy without a loss of efficiency. Conditional independence assumptions are exploited to simplify the problem, reducing computational requirements. Scalability is further increased by focussing computation on likely beliefs, using metric indexing structures for efficient function approximation. Local online planning is incorporated to assist global offline planning, allowing the precision of the latter to be decreased without adversely affecting solution quality. Finally, the algorithm is implemented and demonstrated during real-time control of a mobile robot in a challenging navigation task. We argue that this task is substantially more challenging and realistic than previous problems to which POMDP solution methods have been applied. Results show that POMDP planning, which considers the evolution of the entire probability distribution over robot poses, produces significantly more robust behaviour when compared with a heuristic planner which considers only the most likely states and outcomes