Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Functionally distinct contributions of the anterior and posterior putamen during sublexical and lexical reading.

Previous studies have investigated orthographic-to-phonological mapping during reading by comparing brain activation for (1) reading words to object naming, or (2) reading pseudowords (e.g., "phume") to words (e.g., "plume"). Here we combined both approaches to provide new insights into the underlying neural mechanisms. In fMRI data from 25 healthy adult readers, we first identified activation that was greater for reading words and pseudowords relative to picture and color naming. The most significant effect was observed in the left putamen, extending to both anterior and posterior borders. Second, consistent with previous studies, we show that both the anterior and posterior putamen are involved in articulating speech with greater activation during our overt speech production tasks (reading, repetition, object naming, and color naming) than silent one-back-matching on the same stimuli. Third, we compared putamen activation for words versus pseudowords during overt reading and auditory repetition. This revealed that the anterior putamen was most activated by reading pseudowords, whereas the posterior putamen was most activated by words irrespective of whether the task was reading words or auditory word repetition. The pseudoword effect in the anterior putamen is consistent with prior studies that associated this region with the initiation of novel sequences of movements. In contrast, the heightened word response in the posterior putamen is consistent with other studies that associated this region with "memory guided movement." Our results illustrate how the functional dissociation between the anterior and posterior putamen supports sublexical and lexical processing during reading

Vaccination with DNA plasmids expressing Gn coupled to C3d or alphavirus replicons expressing Gn protects mice against rift valley fever virus

Background: Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent. Methodology/Principal Findings: We developed two potential vaccines, DNA plasmids and alphavirus replicons, expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d. Each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into naïve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12. Conclusion/Significance: These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use. © 2010 Bhardwaj et al

The level set method for the two-sided eigenproblem

We consider the max-plus analogue of the eigenproblem for matrix pencils Ax=lambda Bx. We show that the spectrum of (A,B) (i.e., the set of possible values of lambda), which is a finite union of intervals, can be computed in pseudo-polynomial number of operations, by a (pseudo-polynomial) number of calls to an oracle that computes the value of a mean payoff game. The proof relies on the introduction of a spectral function, which we interpret in terms of the least Chebyshev distance between Ax and lambda Bx. The spectrum is obtained as the zero level set of this function.Comment: 34 pages, 4 figures. Changes with respect to the previous version: we explain relation to mean-payoff games and discrete event systems, and show that the reconstruction of spectrum is pseudopolynomia

Access to interpreting services in England: secondary analysis of national data

Background: Overcoming language barriers to health care is a global challenge. There is great linguistic diversity in the major cities in the UK with more than 300 languages, excluding dialects, spoken by children in London alone. However, there is dearth of data on the number of non-English speakers for planning effective interpreting services. The aim was to estimate the number of people requiring language support amongst the minority ethnic communities in England. Methods: Secondary analysis of national representative sample of subjects recruited to the Health Surveys for England 1999 and 2004. Results: 298,432 individuals from the four main minority ethnic communities (Indian, Pakistani, Bangladeshi and Chinese) who may be unable to communicate effectively with a health professional. This represents 2,520,885 general practice consultations per year where interpreting services might be required. Conclusion: Effective interpreting services are required to improve access and health outcomes of non-English speakers and thereby facilitate a reduction in health inequalities

Sensory-to-motor integration during auditory repetition: a combined fMRI and lesion study.

The aim of this paper was to investigate the neurological underpinnings of auditory-to-motor translation during auditory repetition of unfamiliar pseudowords. We tested two different hypotheses. First we used functional magnetic resonance imaging in 25 healthy subjects to determine whether a functionally defined area in the left temporo-parietal junction (TPJ), referred to as Sylvian-parietal-temporal region (Spt), reflected the demands on auditory-to-motor integration during the repetition of pseudowords relative to a semantically mediated nonverbal sound-naming task. The experiment also allowed us to test alternative accounts of Spt function, namely that Spt is involved in subvocal articulation or auditory processing that can be driven either bottom-up or top-down. The results did not provide convincing evidence that activation increased in either Spt or any other cortical area when non-semantic auditory inputs were being translated into motor outputs. Instead, the results were most consistent with Spt responding to bottom up or top down auditory processing, independent of the demands on auditory-to-motor integration. Second, we investigated the lesion sites in eight patients who had selective difficulties repeating heard words but with preserved word comprehension, picture naming and verbal fluency (i.e., conduction aphasia). All eight patients had white-matter tract damage in the vicinity of the arcuate fasciculus and only one of the eight patients had additional damage to the Spt region, defined functionally in our fMRI data. Our results are therefore most consistent with the neurological tradition that emphasizes the importance of the arcuate fasciculus in the non-semantic integration of auditory and motor speech processing

A study on text-score disagreement in online reviews

In this paper, we focus on online reviews and employ artificial intelligence tools, taken from the cognitive computing field, to help understanding the relationships between the textual part of the review and the assigned numerical score. We move from the intuitions that 1) a set of textual reviews expressing different sentiments may feature the same score (and vice-versa); and 2) detecting and analyzing the mismatches between the review content and the actual score may benefit both service providers and consumers, by highlighting specific factors of satisfaction (and dissatisfaction) in texts. To prove the intuitions, we adopt sentiment analysis techniques and we concentrate on hotel reviews, to find polarity mismatches therein. In particular, we first train a text classifier with a set of annotated hotel reviews, taken from the Booking website. Then, we analyze a large dataset, with around 160k hotel reviews collected from Tripadvisor, with the aim of detecting a polarity mismatch, indicating if the textual content of the review is in line, or not, with the associated score. Using well established artificial intelligence techniques and analyzing in depth the reviews featuring a mismatch between the text polarity and the score, we find that -on a scale of five stars- those reviews ranked with middle scores include a mixture of positive and negative aspects. The approach proposed here, beside acting as a polarity detector, provides an effective selection of reviews -on an initial very large dataset- that may allow both consumers and providers to focus directly on the review subset featuring a text/score disagreement, which conveniently convey to the user a summary of positive and negative features of the review target.Comment: This is the accepted version of the paper. The final version will be published in the Journal of Cognitive Computation, available at Springer via http://dx.doi.org/10.1007/s12559-017-9496-

Sprint interval and sprint continuous training increases circulating CD34+ cells and cardio-respiratory fitness in young healthy women

The improvement of vascular health in the exercising limb can be attained by sprint interval training (SIT). However, the effects on systemic vascular function and on circulating angiogenic cells (CACs) which may contribute to endothelial repair have not been investigated. Additionally, a comparison between SIT and sprint continuous training (SCT) which is less time committing has not been made

Sunscreens - Which and what for?

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel