Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies

The British Lexicon Project: Lexical decision data for 28,730 monosyllabic and disyllabic English words

We present a new database of lexical decision times for English words and nonwords, for which two groups of British participants each responded to 14,365 monosyllabic and disyllabic words and the same number of nonwords for a total duration of 16 h (divided over multiple sessions). This database, called the British Lexicon Project (BLP), fills an important gap between the Dutch Lexicon Project (DLP; Keuleers, Diependaele, & Brysbaert, Frontiers in Language Sciences. Psychology, 1, 174, 2010) and the English Lexicon Project (ELP; Balota et al., 2007), because it applies the repeated measures design of the DLP to the English language. The high correlation between the BLP and ELP data indicates that a high percentage of variance in lexical decision data sets is systematic variance, rather than noise, and that the results of megastudies are rather robust with respect to the selection and presentation of the stimuli. Because of its design, the BLP makes the same analyses possible as the DLP, offering researchers with a new interesting data set of word-processing times for mixed effects analyses and mathematical modeling. The BLP data are available at http://crr.ugent.be/blp and as Electronic Supplementary Materials

Formation of left-handed helices by C2′-fluorinated nucleic acids under physiological salt conditions

Recent findings in cell biology have rekindled interest in Z-DNA, the left-handed helical form of DNA. We report here that two minimally modified nucleosides, 2'F-araC and 2'F-riboG, induce the formation of the Z-form under low ionic strength. We show that oligomers entirely made of these two nucleosides exclusively produce left-handed duplexes that bind to the Zα domain of ADAR1. The effect of the two nucleotides is so dramatic that Z-form duplexes are the only species observed in 10 mM sodium phosphate buffer and neutral pH, and no B-form is observed at any temperature. Hence, in contrast to other studies reporting formation of Z/B-form equilibria by a preference for purine glycosidic angles in syn, our NMR and computational work revealed that sequential 2'F…H2N and intramolecular 3'H…N3' interactions stabilize the left-handed helix. The equilibrium between B- and Z- forms is slow in the 19F NMR time scale (≥ms), and each conformation exhibited unprecedented chemical shift differences in the 19F signals. This observation led to a reliable estimation of the relative population of B and Z species and enabled us to monitor B-Z transitions under different conditions. The unique features of 2'F-modified DNA should thus be a valuable addition to existing techniques for specific detection of new Z-binding proteins and ligands

Is there an orthographic boost for ambiguous words during their processing?

The present study explores the issue of why ambiguous words are recognized faster than unambiguous ones during word recognition. To this end we contrasted two different hypotheses: the semantic feedback hypothesis (Hino and Lupker in J Exp Psychol Hum Percept Perform 22:1331-1356, 1996. https://doi.org/10.1037/0096-1523.22.6.1331 ), and the hypothesis proposed by Borowsky and Masson (J Exp Psychol Learn Mem Cognit 22:63-85, 1996. https://doi.org/10.1037/0278-7393.22.1.63 ). Although both hypotheses agree that ambiguous words benefit during recognition in that they engage more semantic activation, they disagree as to whether or not this greater semantic activation feeds back to the orthographic level, hence speeding up the orthographic coding of ambiguous words. Participants were presented with ambiguous and unambiguous words in two tasks, a lexical decision task (LDT) and a two-alternative forced-choice task (2AFC). We found differences between ambiguous and unambiguous words in both the LDT and the 2AFC tasks. These results suggest that the orthographic coding of ambiguous words is boosted during word processing. This finding lends support to the semantic feedback hypothesis.This research was funded by the Spanish Ministry of Economy and Competitiveness (PSI2015-63525-P) and by the Research Promotion Program of the Universitat Rovira i Virgili (2016PFR-URV-B2-37). This has also been partially supported by the FCT (Foundation for Science and Technology) through the state budget with Reference IF/00784/2013/CP1158/CT0013. The first author also holds a grant from the Universitat Rovira i Virgili (2015PMF-PIPF-16)

Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Funding Cancer Research UK, Medical Research Council

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment