Miracle-dz/UniFAR-FTUs huggingface dataset:
Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study

Abstract Background Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
Reaching the Limits of Reciprocity in Favor Exchange: The Effects of Generous, Stingy, and Matched Favor Giving on Social Status

Group members gain social status via giving favors to others, but why and when they do so remain unclear in the literature. Building on social exchange theory and social status literature, we identify three types of favor giving among group members (generous, stingy, and matched) and propose that an affective mechanism (i.e., gratitude) and a cognitive mechanism (i.e., perceived competence) underlie the relationship between favor giving and status attainment. Specifically, generous/stingy favor giving has a linear relationship with status attainment through both gratitude and perceived competence, whereas matched favor giving has a curvilinear relationship with status attainment only through perceived competence. An experimental study and a field study lend support to our propositions. Our study complements the literature by offering a complete picture of how three types of favor giving among group members shape their social status in different ways.
High-temperature Creep Resistance in Rare-earth-doped, Fine-grained Al_2O_3

High-temperature creep in undoped Al_2O_3 and La_2O_3- or Y_2O_3- or Lu_2O_3-doped Al_2O_3 with a grain size of about 1 µm is examined in uniaxial compression testing at temperatures between 1150 and 1350 °C. The high-temperature creep resistance in Al_2O_3 is highly improved by the rare-earth oxide doping in the level of 0.045 mol %, and the creep rate is suppressed in the order La_2O_3 <Y_2O_3 <Lu_2O_3. Rare-earth ions in each doped Al_2O_3 are found to segregate in Al_2O_3 grain boundaries without forming amorphous phase or second-phase particles. The activation energy for creep in undoped Al_2O_3 is estimated to be 410 kJ/mol, while it is about 800 kJ/mol in the three rare-earth oxide-doped Al_2O_3. The grain boundary diffusivity must be highly reduced by the segregation of the dopant cation in Al_2O_3 grain boundaries.
Effects of a pretarget distractor on saccade reaction times across space and time in monkeys and humans

Previous studies have shown that the influence of a behaviorally irrelevant distractor on saccade reaction times (SRTs) varies depending on the temporal and spatial relationship between the distractor and the saccade target. We measured distractor influence on SRTs to a subsequently presented target, varying the spatial location and the timing between the distractor and the target. The distractor appeared at one of four equally eccentric locations, followed by a target (either 50 ms or 200 ms after) at one of 136 different locations encompassing an area of 20° square. We extensively tested two humans and two monkeys on this task to determine interspecies similarities and differences, since monkey neurophysiology is often used to interpret human behavioral findings. Results were similar across species; for the short interval (50 ms), SRTs were shortest to a target presented close to or at the distractor location and increased primarily as a function of the distance from the distractor. There was also an effect of distractor-target direction and visual field. For the long interval (200 ms) the results were inverted; SRTs were longest for short distances between the distractor and target and decreased as a function of distance from distractor. Both SRT patterns were well captured by a two-dimensional dynamic field model with short-distance excitation and long-distance inhibition, based upon known functional connectivity found in the superior colliculus that includes wide-spread excitation and inhibition. Based on these findings, we posit that the different time-dependent patterns of distractor-related SRTs can emerge from the same underlying neuronal mechanisms common to both species.
Different Determinants of Ventilatory Inefficiency at Different Stages of Reduced Ejection Fraction Chronic Heart Failure Natural History

Background It is not known whether determinants of ventilation (VE)/volume of exhaled carbon dioxide (VCO 2) slope during incremental exercise may differ at different stages of reduced ejection fraction chronic heart failure natural history. Methods and Results VE/VCO 2 slope was fitted up to lowest VE/VCO 2 ratio, that is, a proxy of the VE/perfusion ratio devoid of nonmetabolic stimuli to ventilatory drive. VE/VCO 2 slope tertiles were generated from our database (<27.5 [tertile 1], ≥27.5 to <32.0 [tertile 2], and ≥32.0 [tertile 3]), and 147 chronic heart failure patients with repeated tests yielding VE/VCO 2 slopes in 2 different tertiles were selected. Determinants of VE/VCO 2 slope changes across tertile pairs 1 versus 2, 2 versus 3, and 1 versus 3 were assessed by exploring changes in VE and VCO 2 at lowest VE/VCO 2 and those in VE/work rate (W) and VCO 2/W slope. Resting and peak cardiac output (CO) were calculated as VO 2/estimated arteriovenous O2 difference and the CO/W slope analyzed. Notwithstanding a progressively lower W with increasing tertile, VE at lowest VE/VCO 2 and VE/W slope were significantly higher in tertiles 2 and 3 versus tertile 1. Conversely, VCO 2 at lowest VE/VCO 2 and CO/W slope significantly decreased across tertiles, whereas VCO 2/W slope did not. Difference (Δ) in VE/W slope between tertiles accounted for 71% of ΔVE/VCO 2 slope variance, with ΔVCO 2/W slope explaining an additional 26% (model r=0.99; r 2=0.97; P<0.0001). Similar results were obtained substituting ΔVCO 2/W slope with ΔCO/W slope. Conclusions Ventilatory overactivation is the predominant cause of VE/VCO 2 slope increase at initial stages of chronic heart failure, whereas hemodynamic impairment plays an additional role at more‐advanced pathophysiological stages.
Parkinson’s disease: Impact of clinical and cognitive aspects on quality of life

Parkinson’s disease (PD) is a chronic disease manifested principally by motor signs and symptoms, but with frequent neuropsychological alterations. Objectives To study the relationship between clinical and cognitive aspects and the perception of quality of life (QOL) in PD patients. Methods Twenty consecutive patients (13 men) with idiopathic PD (mean age: 64.5y), mean disease time of 7.8 years and at stages 1-3 according to the modified Hoehn and Yahr staging scale (HYS), all outpatients from the Neurology Department of the Celso Pierro General and Maternity Hospital (PUC-Campinas), were analyzed. The following were applied: a clinical-neurological assessment, the Mini-Mental State Examination (MMSE), standard neuropsychological battery of the CERAD (Consortium to Establish a Registry for Alzheimer’s Disease), Hamilton Depression Rating Scale (HAM-D) and a QOL questionnaire (Parkinson’s Disease Questionnaire - PDQ-39). Statistical analysis was carried out at a significance level of p<0.05. Results On the PDQ-39 under the sections total, mobility and activities of daily living, and the items motor compromise (HYS) and language of the MMSE were predictors of worse QOL. Verbal fluency was a factor for emotional well-being on the PDQ-39, whereas higher scores for HAM-D and worse performance on the item attention and calculation of the MMSE were associated with worse QOL in the social support section. Total score on the MMSE and educational level were QOL factors in cognition. Conclusions The findings of the present study suggest that clinical, cognitive, motor or other depression-related factors contribute differently to the domains of QOL.
The application of enhanced virtual environments for co-located childhood movement disorder rehabilitation

In this paper we discuss potential benefits and future directions in virtual reality rehabilitation for co-located motor training in children with developmental movement disorders. We discuss the potential for co-located VR to promote participation using cooperative virtual environments, facilitate social learning, and quantify levels of social interaction. We pay particular attention to the capacity of co-located systems to enhance levels of participation and the psychosocial outcomes of VR therapy. Finally, we offer directions for future research.
Technological Progress, Mobility, and Growth

This paper analyses the relationship between technological progress earnings inequality the transmission of inequality across generations and economic growth. The analysis demonstrates that the interplay between technological progress and two components that determine individual earnings - parental specific human capital and individual ability - governs the evolutionary patterns of wage inequality intergenerational earnings mobility the pace of technological progress and economic growth. In periods of major technological inventions the ability effect is the dominating factor and earnings inequality rises. The decline in the relative importance of initial parental conditions (i.e. the driving force behind the persistence of inequality) enhances mobility and generates a larger concentration of individuals with high levels of ability and human capital in technologically advanced sectors stimulating further technological progress and future economic growth. In periods of technological innovations however once existing technologies become more accessible the parental specific human capital effect is the dominating factor mobility is diminished and inequality declines but becomes more persistent. The reduction in the concentration of human capital in technologically advanced sectors diminishes the likelihood of major technological breakthroughs and slows down future economic growth. User friendliness therefore becomes unfriendly to future economic growth. (authors)
Multiscale Characterization of Geotextile-Reinforced Granular Soil

Geosynthetic-reinforced soils are heterogeneous and discontinuous geomaterials that can be designed with great flexibility. For environmental and economical reasons, the application of geosynthetic reinforcements in the construction of infrastructures is becoming prevalent, along with the increase of the diversity in reinforcement forms, e.g. discrete fiber, planar layer, cellular encasement, to name a few. Despite high improvement on the stiffness and strength, the interactions between granular particles and geosynthetic inclusions complicate the stress history, deformation pattern and fabric characteristics in the reinforced soils, posing formidable challenges to the predictive models of geosynthetic-reinforced soils. Considering the ‘discrete’ nature of granular soils, this thesis aims to obtain a better understanding of the behavior of geosynthetic-reinforced granular soil via multiscale characterization and modeling of soil–geosynthetic interactions, and thence develop analytical solutions for this complex geomaterial for practical usage. The Discrete Element Method (DEM) is utilized to provide a cross-scale interpretation of the micromechanics in the granular soil with different forms of geosynthetic reinforcement. The sequential data assimilation based on recursive Bayesian estimation is employed to calibrate the mesoscale response of the DEM models of Toyoura sand. With the assumptions derived from the newly obtained understanding, a close-form elastoplastic solution is proposed for geotextile-wrapped soil under compression. In order to solve general soil–geosynthetic interaction problems, the concurrent multiscale modeling strategy is incorporated into the hierarchical multiscale framework based on a coupled finite element method (FEM)/DEM approach, avoiding both the scale limitation of DEM models and the continuum-based constitutive models of a great complexity for geosynthetic-reinforced soils.
Daidzein exerts anticancer activity towards SKOV3 human ovarian cancer cells by inducing apoptosis and cell cycle arrest, and inhibiting the Raf/MEK/ERK cascade

Ovarian cancer is the main cause of gynecological cancer‑associated mortality around the world. Despite initial responses to chemotherapy, frequent relapse occurs. Daidzein is an important flavonoid and has been shown to exhibit a diversity of pharmacological properties, including antimicrobial and anticancer activities. However, information on the anticancer activity of daidzein against ovarian cancer remains limited. Therefore, the present study evaluated the anticancer activity of daidzein against a panel of human ovarian cancer cell lines and one normal ovarian cell line (Moody). The results revealed that daidzein exhibited potent anticancer activity against SKVO3 cells with a half‑maximal inhibitory concentration (IC50) of 20 µM. However, it exhibited comparatively lower activity against normal ovarian Moody cells, which had an IC50 of 100 µM. Daidzein induced morphological changes in SKOV3 cells and mitochondrial apoptosis, as evident from DAPI, AO/EB and Annexin V/propidium iodide staining. This was associated with the upregulation of B‑cell lymphoma 2‑associated X protein, cytochrome c, cleaved caspase‑3 and ‑9, and cleaved poly (ADP‑ribose) polymerase. Daidzein also triggered G2/M cell arrest through the downregulation of pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1. The effect of daidzein on the migration of SKOV3 cells was also determined, the results of which indicated that daidzein inhibited cell migration in a concentration‑dependent manner and was coupled with concomitant decrease in the expression of matrix metalloproteinase (MMP)‑2 and ‑9. Additionally, daidzein‑inhibited cell growth was simultaneous with suppression of the expression of phosphorylated mitogen‑activated protein kinase kinase and phosphorylated extracellular signal‑regulated kinase. The present study also examined whether daidzein exerts similar activity against SKOV3 cells in nude mouse xenograft models and it was revealed that daidzein considerably reduced the tumorigenesis in vivo, indicative of the potential for daidzein as a lead molecule in the development of ovarian cancer chemotherapy.
Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016

A novel mcr colistin resistance gene was identified in a strain of Salmonella enterica, monophasic variant of serovar Typhimurium (4,5,12:i:- ), isolated from a pig at slaughter in Italy in 2013, and in Escherichia coli strains collected during routine diagnostic of post-weaning diarrhoea in pigs from Spain and Belgium in 2015 and 2016. Immediate implementation of mcr-screening including this novel gene variant is required for Salmonella and E. coli from humans and food-producing animals in Europe.
Abstractive Cross-Language Summarization via Translation Model Enhanced Predicate Argument Structure Fusing

Cross-language multidocument summarization is the task to generate a summary in a target language (e.g., Chinese) from a collection of documents in a different source language (e.g., English). Previous methods such as the extractive and compressive algorithms focus only on single sentence selection and compression, which cannot make full use of the similar sentences containing complementary information. Furthermore, the translation model knowledge is not fully explored in previous approaches. To address these two problems, we propose in this paper an abstractive cross-language summarization framework. First, the source language documents are translated into target language with a machine translation system. Then, the method constructs a pool of bilingual concepts and facts represented by the bilingual elements of the source-side predicate-argument structures (PAS) and their target-side counterparts. Finally, new summary sentences are produced by fusing bilingual PAS elements with the integer linear programming algorithm to maximize both of the salience and translation quality of the PAS elements. The experimental results on English-to-Chinese cross-language summarization demonstrate that our proposed method outperforms the state-of-the-art extractive systems in both automatic and manual evaluations.
Light-weight implementation options for curve-based cryptography: HECC is also ready for RFID

In this paper we describe a low footprint implementation of HyperElliptic Curve Cryptography (HECC) for RFID tags. This HECC processor supports divisor multiplication on a hyperelliptic curve defined over GF(2<sup>83</sup>). We propose a Unified GF(2<sup>m</sup>) Multiplier/Inverter (UMI) which is smaller than ALUs with separated multipliers and inverters. With the UMI divisor multiplications using affine coordinates can be efficiently supported. Since affine coordinates require less registers thanprojective coordinates, the size of register file is also reduced. We choose hyperelliptic curves defined with the h(x) = x and f(x) = x<sup>5</sup> + f<inf>3</inf>x<sup>3</sup> + x<sup>2</sup> + f<inf>0</inf>. The HECC processor, synthesized with 130 nm standard cell library, uses 14.5 kGates. It consumes 13.4 μW when running at 300 kHz. One divisor multiplication takes 450 ms, which makes our solution a feasible option for light-weight applications.
Over-expression of mitochondrial creatine kinase in the murine heart improves functional recovery and protects against injury following ischaemia–reperfusion

Abstract Aims Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of ATP at times of high demand. We hypothesized that elevating MtCK would be beneficial in ischaemia–reperfusion (I/R) injury. Methods and results Mice were created over-expressing the sarcomeric MtCK gene with αMHC promoter at the Rosa26 locus (MtCK-OE) and compared with wild-type (WT) littermates. MtCK activity was 27% higher than WT, with no change in other CK isoenzymes or creatine levels. Electron microscopy confirmed normal mitochondrial cell density and mitochondrial localization of transgenic protein. Respiration in isolated mitochondria was unaltered and metabolomic analysis by 1 H-NMR suggests that cellular metabolism was not grossly affected by transgene expression. There were no significant differences in cardiac structure or function under baseline conditions by cine-MRI or LV haemodynamics. In Langendorff-perfused hearts subjected to 20 min ischaemia and 30 min reperfusion, MtCK-OE exhibited less ischaemic contracture, and improved functional recovery (Rate pressure product 58% above WT; P < 0.001). These hearts had reduced myocardial infarct size, which was confirmed in vivo: 55 ± 4% in WT vs. 29 ± 4% in MtCK-OE; P < 0.0001). Isolated cardiomyocytes from MtCK-OE hearts exhibited delayed opening of the mitochondrial permeability transition pore (mPTP) compared to WT, which was confirmed by reduced mitochondrial swelling in response to calcium. There was no detectable change in the structural integrity of the mitochondrial membrane. Conclusions Modest elevation of MtCK activity in the heart does not adversely affect cellular metabolism, mitochondrial or in vivo cardiac function, but modifies mPTP opening to protect against I/R injury and improve functional recovery. Our findings support MtCK as a prime therapeutic target in myocardial ischaemia.
Recent cross-modal statistical learning influences visual perceptual selection

Incoming sensory signals are often ambiguous and consistent with multiple perceptual interpretations. Information from one sensory modality can help to resolve ambiguity in another modality, but the mechanisms by which multisensory associations come to influence the contents of conscious perception are unclear. We asked whether and how novel statistical information about the coupling between sounds and images influences the early stages of awareness of visual stimuli. We exposed subjects to consistent, arbitrary pairings of sounds and images and then measured the impact of this recent passive statistical learning on subjects' initial conscious perception of a stimulus by employing binocular rivalry, a phenomenon in which incompatible images presented separately to the two eyes result in a perceptual alternation between the two images. On each trial of the rivalry test, subjects were presented with a pair of rivalrous images (one of which had been consistently paired with a specific sound during exposure while the other had not) and an accompanying sound. We found that, at the onset of binocular rivalry, an image was significantly more likely to be perceived, and was perceived for a longer duration, when it was presented with its paired sound than when presented with other sounds. Our results indicate that recently acquired multisensory information helps resolve sensory ambiguity, and they demonstrate that statistical learning is a fast, flexible mechanism that facilitates this process.