Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2

<p>Abstract</p> <p>Background</p> <p>The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses.</p> <p>Methods</p> <p>Subjects with stage II (≥ 6 +LN), III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact.</p> <p>Results</p> <p>All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up.</p> <p>Conclusion</p> <p>Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00005956</p

Simply imagining sunshine, lollipops and rainbows will not budge the bias: The role of ambiguity in interpretive bias modification

Imagery-based interpretive bias modification (CBM-I) involves repeatedly imagining scenarios that are initially ambiguous before being resolved as either positive or negative in the last word/s. While the presence of such ambiguity is assumed to be important to achieve change in selective interpretation, it is also possible that the act of repeatedly imagining positive or negative events could produce such change in the absence of ambiguity. The present study sought to examine whether the ambiguity in imagery-based CBM-I is necessary to elicit change in interpretive bias, or, if the emotional content of the imagined scenarios is sufficient to produce such change. An imagery-based CBM-I task was delivered to participants in one of four conditions, where the valence of imagined scenarios were either positive or negative, and the ambiguity of the scenario was either present (until the last word/s) or the ambiguity was absent (emotional valence was evident from the start). Results indicate that only those who received scenarios in which the ambiguity was present acquired an interpretive bias consistent with the emotional valence of the scenarios, suggesting that the act of imagining positive or negative events will only influence patterns of interpretation when the emotional ambiguity is a consistent feature

New prioritized value iteration for Markov decision processes

The problem of solving large Markov decision processes accurately and quickly is challenging. Since the computational effort incurred is considerable, current research focuses on finding superior acceleration techniques. For instance, the convergence properties of current solution methods depend, to a great extent, on the order of backup operations. On one hand, algorithms such as topological sorting are able to find good orderings but their overhead is usually high. On the other hand, shortest path methods, such as Dijkstra's algorithm which is based on priority queues, have been applied successfully to the solution of deterministic shortest-path Markov decision processes. Here, we propose an improved value iteration algorithm based on Dijkstra's algorithm for solving shortest path Markov decision processes. The experimental results on a stochastic shortest-path problem show the feasibility of our approach. © Springer Science+Business Media B.V. 2011.García Hernández, MDG.; Ruiz Pinales, J.; Onaindia De La Rivaherrera, E.; Aviña Cervantes, JG.; Ledesma Orozco, S.; Alvarado Mendez, E.; Reyes Ballesteros, A. (2012). New prioritized value iteration for Markov decision processes. Artificial Intelligence Review. 37(2):157-167. doi:10.1007/s10462-011-9224-zS157167372Agrawal S, Roth D (2002) Learning a sparse representation for object detection. In: Proceedings of the 7th European conference on computer vision. Copenhagen, Denmark, pp 1–15Bellman RE (1954) The theory of dynamic programming. Bull Amer Math Soc 60: 503–516Bellman RE (1957) Dynamic programming. Princeton University Press, New JerseyBertsekas DP (1995) Dynamic programming and optimal control. Athena Scientific, MassachusettsBhuma K, Goldsmith J (2003) Bidirectional LAO* algorithm. In: Proceedings of indian international conferences on artificial intelligence. p 980–992Blackwell D (1965) Discounted dynamic programming. Ann Math Stat 36: 226–235Bonet B, Geffner H (2003a) Faster heuristic search algorithms for planning with uncertainty and full feedback. In: Proceedings of the 18th international joint conference on artificial intelligence. Morgan Kaufmann, Acapulco, México, pp 1233–1238Bonet B, Geffner H (2003b) Labeled RTDP: improving the convergence of real-time dynamic programming. In: Proceedings of the international conference on automated planning and scheduling. Trento, Italy, pp 12–21Bonet B, Geffner H (2006) Learning depth-first search: a unified approach to heuristic search in deterministic and non-deterministic settings and its application to MDP. In: Proceedings of the 16th international conference on automated planning and scheduling. Cumbria, UKBoutilier C, Dean T, Hanks S (1999) Decision-theoretic planning: structural assumptions and computational leverage. J Artif Intell Res 11: 1–94Chang I, Soo H (2007) Simulation-based algorithms for Markov decision processes Communications and control engineering. Springer, LondonDai P, Goldsmith J (2007a) Faster dynamic programming for Markov decision processes. Technical report. Doctoral consortium, department of computer science and engineering. University of WashingtonDai P, Goldsmith J (2007b) Topological value iteration algorithm for Markov decision processes. In: Proceedings of the 20th international joint conference on artificial intelligence. Hyderabad, India, pp 1860–1865Dai P, Hansen EA (2007c) Prioritizing bellman backups without a priority queue. In: Proceedings of the 17th international conference on automated planning and scheduling, association for the advancement of artificial intelligence. Rhode Island, USA, pp 113–119Dibangoye JS, Chaib-draa B, Mouaddib A (2008) A Novel prioritization technique for solving Markov decision processes. In: Proceedings of the 21st international FLAIRS (The Florida Artificial Intelligence Research Society) conference, association for the advancement of artificial intelligence. Florida, USAFerguson D, Stentz A (2004) Focused propagation of MDPs for path planning. In: Proceedings of the 16th IEEE international conference on tools with artificial intelligence. pp 310–317Hansen EA, Zilberstein S (2001) LAO: a heuristic search algorithm that finds solutions with loops. Artif Intell 129: 35–62Hinderer K, Waldmann KH (2003) The critical discount factor for finite Markovian decision processes with an absorbing set. Math Methods Oper Res 57: 1–19Li L (2009) A unifying framework for computational reinforcement learning theory. PhD Thesis. The state university of New Jersey, New Brunswick. NJLittman ML, Dean TL, Kaelbling LP (1995) On the complexity of solving Markov decision problems.In: Proceedings of the 11th international conference on uncertainty in artificial intelligence. Montreal, Quebec pp 394–402McMahan HB, Gordon G (2005a) Fast exact planning in Markov decision processes. In: Proceedings of the 15th international conference on automated planning and scheduling. Monterey, CA, USAMcMahan HB, Gordon G (2005b) Generalizing Dijkstra’s algorithm and gaussian elimination for solving MDPs. Technical report, Carnegie Mellon University, PittsburghMeuleau N, Brafman R, Benazera E (2006) Stochastic over-subscription planning using hierarchies of MDPs. In: Proceedings of the 16th international conference on automated planning and scheduling. Cumbria, UK, pp 121–130Moore A, Atkeson C (1993) Prioritized sweeping: reinforcement learning with less data and less real time. Mach Learn 13: 103–130Puterman ML (1994) Markov decision processes. Wiley Editors, New YorkPuterman ML (2005) Markov decision processes. Wiley Inter Science Editors, New YorkRussell S (2005) Artificial intelligence: a modern approach. Making complex decisions (Ch-17), 2nd edn. Pearson Prentice Hill Ed., USAShani G, Brafman R, Shimony S (2008) Prioritizing point-based POMDP solvers. IEEE Trans Syst Man Cybern 38(6): 1592–1605Sniedovich M (2006) Dijkstra’s algorithm revisited: the dynamic programming connexion. Control Cybern 35: 599–620Sniedovich M (2010) Dynamic programming: foundations and principles, 2nd edn. Pure and Applied Mathematics Series, UKTijms HC (2003) A first course in stochastic models. Discrete-time Markov decision processes (Ch-6). Wiley Editors, UKVanderbei RJ (1996) Optimal sailing strategies. Statistics and operations research program, University of Princeton, USA ( http://www.orfe.princeton.edu/~rvdb/sail/sail.html )Vanderbei RJ (2008) Linear programming: foundations and extensions, 3rd edn. Springer, New YorkWingate D, Seppi KD (2005) Prioritization methods for accelerating MDP solvers. J Mach Learn Res 6: 851–88

Mycoprotein ingestion stimulates protein synthesis rates to a greater extent than milk protein in rested and exercised skeletal muscle of healthy young men: a randomized controlled trial.

This is the author accepted manuscript. The final version is available from American Society for Nutrition via the DOI in this record.BACKGROUND: Mycoprotein is a fungal-derived sustainable protein-rich food source, and its ingestion results in systemic amino acid and leucine concentrations similar to that following milk protein ingestion. OBJECTIVE: We assessed the mixed skeletal muscle protein synthetic response to the ingestion of a single bolus of mycoprotein compared with a leucine-matched bolus of milk protein, in rested and exercised muscle of resistance-trained young men. METHODS: Twenty resistance-trained healthy young males (age: 22 ± 1 y, body mass: 82 ± 2 kg, BMI: 25 ± 1 kg·m-2) took part in a randomized, double-blind, parallel-group study. Participants received primed, continuous infusions of L-[ring-2H5]phenylalanine and ingested either 31 g (26.2 g protein: 2.5 g leucine) milk protein (MILK) or 70 g (31.5 g protein: 2.5 g leucine) mycoprotein (MYCO) following a bout of unilateral resistance-type exercise (contralateral leg acting as resting control). Blood and m. vastus lateralis muscle samples were collected before exercise and protein ingestion, and following a 4-h postprandial period to assess mixed muscle fractional protein synthetic rates (FSRs) and myocellular signaling in response to the protein beverages in resting and exercised muscle. RESULTS: Mixed muscle FSRs increased following MILK ingestion (from 0.036 ± 0.008 to 0.052 ± 0.006%·h-1 in rested, and 0.035 ± 0.008 to 0.056 ± 0.005%·h-1 in exercised muscle; P <0.01) but to a greater extent following MYCO ingestion (from 0.025 ± 0.006 to 0.057 ± 0.004%·h-1 in rested, and 0.024 ± 0.007 to 0.072 ± 0.005%·h-1 in exercised muscle; P <0.0001) (treatment × time interaction effect; P <0.05). Postprandial FSRs trended to be greater in MYCO compared with MILK (0.065 ± 0.004 compared with 0.054 ± 0.004%·h-1, respectively; P = 0.093) and the postprandial rise in FSRs was greater in MYCO compared with MILK (Delta 0.040 ± 0.006 compared with Delta 0.018 ± 0.005%·h-1, respectively; P <0.01). CONCLUSIONS: The ingestion of a single bolus of mycoprotein stimulates resting and postexercise muscle protein synthesis rates, and to a greater extent than a leucine-matched bolus of milk protein, in resistance-trained young men. This trial was registered at clinicaltrials.gov as 660065600.Quorn Food

Vegan and omnivorous high protein diets support comparable daily myofibrillar protein synthesis rates and skeletal muscle hypertrophy in young adults.

This is the final version. Available from Elsevier via the DOI in this record.Data availability: Data described in the manuscript may be made available upon request, pending application.BACKGROUND: It remains unclear whether non-animal-derived dietary protein sources (and therefore vegan diets) can support resistance training-induced skeletal muscle remodeling to the same extent as animal-derived protein sources. METHODS: In Phase 1, 16 healthy young adults (m = 8, f = 8; age: 23 ± 1 y; BMI: 23 ± 1 kg/m2) completed a 3-d dietary intervention (high protein, 1.8 g·kg bm-1·d-1) where protein was derived from omnivorous (OMNI1; n = 8) or exclusively non-animal (VEG1; n = 8) sources, alongside daily unilateral leg resistance exercise. Resting and exercised daily myofibrillar protein synthesis (MyoPS) rates were assessed using deuterium oxide. In Phase 2, 22 healthy young adults (m = 11, f = 11; age: 24 ± 1 y; BMI: 23 ± 0 kg/m2) completed a 10 wk, high-volume (5 d/wk), progressive resistance exercise program while consuming an omnivorous (OMNI2; n = 12) or non-animal-derived (VEG2; n = 10) high-protein diet (∼2 g·kg bm-1·d-1). Muscle fiber cross-sectional area (CSA), whole-body lean mass (via DXA), thigh muscle volume (via MRI), muscle strength, and muscle function were determined pre, after 2 and 5 wk, and postintervention. OBJECTIVES: To investigate whether a high-protein, mycoprotein-rich, non-animal-derived diet can support resistance training-induced skeletal muscle remodeling to the same extent as an isonitrogenous omnivorous diet. RESULTS: Daily MyoPS rates were ∼12% higher in the exercised than in the rested leg (2.46 ± 0.27%·d-1 compared with 2.20 ± 0.33%·d-1 and 2.62 ± 0.56%·d-1 compared with 2.36 ± 0.53%·d-1 in OMNI1 and VEG1, respectively; P 0.05). Resistance training increased lean mass in both groups by a similar magnitude (OMNI2 2.6 ± 1.1 kg, VEG2 3.1 ± 2.5 kg; P > 0.05). Likewise, training comparably increased thigh muscle volume (OMNI2 8.3 ± 3.6%, VEG2 8.3 ± 4.1%; P > 0.05), and muscle fiber CSA (OMNI2 33 ± 24%, VEG2 32 ± 48%; P > 0.05). Both groups increased strength (1 repetition maximum) of multiple muscle groups, to comparable degrees. CONCLUSIONS: Omnivorous and vegan diets can support comparable rested and exercised daily MyoPS rates in healthy young adults consuming a high-protein diet. This translates to similar skeletal muscle adaptive responses during prolonged high-volume resistance training, irrespective of dietary protein provenance. This trial was registered at clinicaltrials.gov as NCT03572127.Marlow Foods Ltd

Education can improve the negative perception of a threatened long-lived scavenging bird, the Andean condor

Human-wildlife conflicts currently represent one of the main conservation problems for wildlife species around the world. Vultures have serious conservation concerns, many of which are related to people's adverse perception about them due to the belief that they prey on livestock. Our aim was to assess local perception and the factors influencing people's perception of the largest scavenging bird in South America, the Andean condor. For this, we interviewed 112 people from Valle Fértil, San Juan province, a rural area of central west Argentina. Overall, people in the area mostly have an elementary education, and their most important activity is livestock rearing. The results showed that, in general, most people perceive the Andean condor as an injurious species and, in fact, some people recognize that they still kill condors. We identified two major factors that affect this perception, the education level of villagers and their relationship with livestock ranching. Our study suggests that conservation of condors and other similar scavengers depends on education programs designed to change the negative perception people have about them. Such programs should be particularly focused on ranchers since they are the ones who have the worst perception of these scavengers. We suggest that highlighting the central ecological role of scavengers and recovering their cultural value would be fundamental to reverse their persecution and their negative perception by people.Fil: Cailly Arnulphi, Verónica Beatríz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Lambertucci, Sergio Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Borghi, Carlos Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; Argentin

Modifiers of short-term effects of ozone on mortality in eastern Massachusetts - A case-crossover analysis at individual level

<p>Abstract</p> <p>Background</p> <p>Substantial epidemiological studies demonstrate associations between exposure to ambient ozone and mortality. A few studies simply examine the modification of this ozone effect by individual characteristics and socioeconomic status, but socioeconomic status was usually coded at the city level.</p> <p>Methods</p> <p>This study used a case-crossover design to examine whether impacts of ozone on mortality were modified by socioeconomic status coded at the tract or characteristics at an individual level in eastern Massachusetts, US for a period May-September, 1995-2002, with a total of 157,197 non-accident deaths aging 35 years or older. We used moving averages of maximal 8-hour concentrations of ozone monitored at 8 stationary stations as personal exposure.</p> <p>Results</p> <p>A 10 ppb increase in the four-day moving average of maximal 8-hour ozone was associated with 1.68% (95% confidence interval (CI): 0.51%, 2.87%), 1.96% (95% CI: -1.83%, 5.90%), 8.28% (95% CI: 0.66%, 16.48%), 0.44% (95% CI: -1.45%, 2.37%), -0.83% (95% CI: -2.94%, 1.32%), -1.09% (95% CI: -4.27%, 2.19%) and 6.5% (95% CI: 1.74%, 11.49%) changes in all natural deaths, respiratory disorders, diabetes, cardiovascular diseases, heart diseases, acute myocardial infarction and stroke, respectively. We did not find any evidence that the associations were significantly modified by socioeconomic status or individual characteristics although small differences of estimates across subpopulations were demonstrated.</p> <p>Conclusions</p> <p>Exposure to ozone was associated with specific cause mortality in Eastern Massachusetts during May-September, 1995-2002. There was no evidence that effects of ozone on mortality were significantly modified by socioeconomic status and individual characteristics.</p

Postmenopausal hormones and sleep quality in the elderly: a population based study

<p>Abstract</p> <p>Background</p> <p>Sleep disturbance and insomnia are commonly reported by postmenopausal women. However, the relationship between hormone therapy (HT) and sleep disturbances in postmenopausal community-dwelling adults is understudied. Using data from the multicenter Study of Osteoporotic Fractures (SOF), we tested the relationship between HT and sleep-wake estimated from actigraphy.</p> <p>Methods</p> <p>Sleep-wake was ascertained by wrist actigraphy in 3,123 women aged 84 ± 4 years (range 77-99) from the Study of Osteoporotic Fractures (SOF). This sample represents 30% of the original SOF study and 64% of participants seen at this visit. Data were collected for a mean of 4 consecutive 24-hour periods. Sleep parameters measured objectively included total sleep time, sleep efficiency (SE), sleep latency, wake after sleep onset (WASO), and nap time. All analyses were adjusted for potential confounders (age, clinic site, race, BMI, cognitive function, physical activity, depression, anxiety, education, marital status, age at menopause, alcohol use, prior hysterectomy, and medical conditions).</p> <p>Results</p> <p>Actigraphy measurements were available for 424 current, 1,289 past, and 1,410 never users of HT. Women currently using HT had a shorter WASO time (76 vs. 82 minutes, P = 0.03) and fewer long-wake (≥ 5 minutes) episodes (6.5 vs. 7.1, P = 0.004) than never users. Past HT users had longer total sleep time than never users (413 vs. 403 minutes, P = 0.002). Women who never used HT had elevated odds of SE <70% (OR,1.37;95%CI,0.98-1.92) and significantly higher odds of WASO ≥ 90 minutes (OR,1.37;95%CI,1.02-1.83) and ≥ 8 long-wake episodes (OR,1.58;95%CI,1.18-2.12) when compared to current HT users.</p> <p>Conclusions</p> <p>Postmenopausal women currently using HT had improved sleep quality for two out of five objective measures: shorter WASO and fewer long-wake episodes. The mechanism behind these associations is not clear. For postmenopausal women, starting HT use should be considered carefully in balance with other risks since the vascular side-effects of hormone replacement may exceed its beneficial effects on sleep.</p

Genetic aspects of dental disorders

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.This paper reviews past and present applications of quantitative and molecular genetics to dental disorders. Examples are given relating to craniofacial development (including malocclusion), oral supporting tissues (including periodontal diseases) and dental hard tissues (including defects of enamel and dentine as well as dental caries). Future developments and applications to clinical dentistry are discussed. Early investigations confirmed genetic bases to dental caries, periodontal diseases and malocclusion, but research findings have had little impact on clinical practice. The complex multifactorial aetiologies of these conditions, together with methodological problems, have limited progress until recently. Present studies are clarifying previously unrecognized genetic and phenotypic heterogeneities and attempting to unravel the complex interactions between genes and environment by applying new statistical modelling approaches to twin and family data. linkage studies using highly polymorphic DNA markers are providing a means of locating candidate genes, including quantitative trait loci (QTL). In future, as knowledge increases: it should be possible to implement preventive strategies for those genetically-predisposed individuals who are identified-predisposed individuals who are identified to be at risk.Grant C. Townsend, Michael J. Aldred and P. Mark Bartol

Study of Leishmania pathogenesis in mice : experimental considerations

Although leishmaniases are endemic in 98 countries, they are still considered neglected tropical diseases. Leishmaniases are characterized by the emergence of new virulent and asymptomatic strains of Leishmania spp. and, as a consequence, by a very diverse clinical spectrum. To fight more efficiently these parasites, the mechanisms of host defense and of parasite virulence need to be thoroughly investigated. To this aim, animal models are widely used. However, the results obtained with these models are influenced by several experimental parameters, such as the mouse genetic background, parasite genotype, inoculation route/infection site, parasite dose and phlebotome saliva. In this review, we propose an update on their influence in the two main clinical forms of the disease: cutaneous and visceral leishmaniases