julilili42/papers huggingface dataset:
Relationship of response and survival in patients with relapsed and refractory multiple myeloma treated with pomalidomide plus low-dose dexamethasone in the MM-003 trial randomized phase III trial (NIMBUS)
2016-05-13

Relapsed/refractory multiple myeloma (RRMM) patients have poor overall survival (OS). Pomalidomide plus low-dose dexamethasone (POM + LoDEX) significantly extends OS in RRMM vs. high-dose dexamethasone. Survival of patients with stable disease (SD) was compared to patients with progressive disease (PD) or ≥ partial response (≥PR) at cycles (C) 3, 5, and 7. Among 302 patients randomized to POM + LoDEX, at C3 19.2% achieved ≥ PR, 38.4% SD, and 14.6% PD. Patients with SD at C3 (17.4%) and C5 (13.6%) showed improved responses at C7. Median OS from randomization by response at C3 was 22.4 months for ≥ PR (n = 58, HR 0.66; 95% CI 0.40-1.08, p = 0.0976 vs. SD), 16.2 months for SD (n = 116), and 6.3 months for PD (n = 44, HR 3.43; 95% CI 2.23-5.27, p < 0.0001 vs. SD). Similar patterns were observed for C5 and C7. Results show that POM + LoDEX should be a standard treatment after lenalidomide and bortezomib, including in SD patients.
Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab
2016-05-17

Abstract Purpose: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. Experimental Design: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan–Meier analysis and Cox regression were applied for survival analysis. Results: Relative eosinophil count (REC) ≥1.5%, relative lymphocyte count (RLC) ≥17.5%, ≤2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n = 177) and the confirmation (n = 182) cohort and had independent positive impact (all P &amp;lt; 0.001). Their independent role was subsequently confirmed in the validation cohort (n = 257; all P &amp;lt; 0.01). The number of favorable factors was strongly associated with prognosis. One-year OS probabilities of 83.9% versus 14.7% and response rates of 58.3% versus 3.3% were observed in patients with four of four compared to those with none of four favorable baseline factors present, respectively. Conclusions: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. Clin Cancer Res; 22(22); 5487–96. ©2016 AACR.
Neurofilament light chain in FTD is elevated not only in cerebrospinal fluid, but also in serum
2016-05-17

Frontotemporal dementia (FTD) is a devastating neurodegenerative disorder for which readily available biomarkers are needed to monitor disease progression and response to future therapies. Neurofilament light chain (NfL), a cytoskeletal protein, is elevated in the cerebrospinal fluid (CSF) of patients with FTD, correlating with disease severity.1 ,2 As CSF sampling is more invasive than venepuncture and requires higher subject compliance, we tested the hypothesis that NfL levels in FTD are elevated not only in CSF, but also in serum. NfL levels in FTD were also compared with those in amyotrophic lateral sclerosis (ALS).3 CSF and serum samples of a consecutive series of 41 FTD, 25 ALS and 46 healthy control subjects were collected from 2009 until 2014 (see online supplement 1: Methodological and statistical details, see online supplement 2: Subject characteristics). Only participants with normal CSF white cell counts (cell count 600 pg/mL, Innotest ELISA, Innogenetics, Belgium) were included. CSF and serum NfL concentrations were measured by a previously established electrochemiluminescence immunoassay.4 CSF levels of total tau (h-tau) were determined by a commercial ELISA (Innogenetics). ### Supplementary data [jnnp-2015-312972supp.pdf] NfL levels in CSF differed significantly between FTD, ALS and control subjects (F (2, 109)=88.36, p<0.001, one-way analysis of variance (ANOVA), calculated for log-transformed levels, figure 1A), also if corrected for age (F (2, 108)=88.66, p<0.001). Both patients with FTD (2557 pg/mL (median); 1760–3167, (IQR)) and patients with ALS (6658 pg/mL; (4205–10438)) showed significantly higher CSF NfL levels than controls (981 pg/mL; (777–1374)). NfL levels in ALS were significantly higher than in FTD (all p<0.001, two-sided Student's t tests, Bonferroni-corrected, effect sizes: FTD vs controls r=0.65, ALS vs controls r=0.85, ALS vs FTD r=0.59). Figure 1 (A) and (B) neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and serum of frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and ...
Smart RFID label with a printed multisensor platform for environmental monitoring
2016-05-17

This work reports on the design, fabrication and characterization of an inkjet-printed multisensing platform on flexible polymeric substrates integrated into a printed semi-passive high frequency radio frequency identification (HF RFID) smart label. The printed platform was integrated after fabrication to the main RFID carrier, which contained an NFC RFID chip, a microprocessor, a readout frontend and a screen-printed circuitry and antenna. The multisensing platform has channels for capacitive vapor detection (i.e. humidity), two channels for resistive-based vapor detection (i.e. ammonia) with heating capability, and one resistive channel for temperature detection (RTD). Amodular approach was employed where the sensing platform was integrated to the base RFID label carrier using foil-tofoil integration techniques compatible with large area fabrication. Besides wireless communication, the semi-passive label possesses data logging and the possibility of measuring all the sensors simultaneously through a direct readout circuitry. In addition to individual sensor characterization, the full functionality of the smart label was successfully demonstrated by measuring different temperature, humidity and ammonia levels.
Membranous CD24 drives the epithelial phenotype of pancreatic cancer
2016-05-17

Surface CD24 has previously been described, together with CD44 and ESA, for the characterization of putative cancer stem cells in pancreatic ductal adenocarcinoma (PDAC), the most fatal of all solid tumors. CD24 has a variety of biological functions including the regulation of invasiveness and cell proliferation, depending on the tumor entity and subcellular localization. Genetically engineered mouse models (GEMM) expressing oncogenic KrasG12D recapitulate the human disease and develop PDAC. In this study we investigate the function of CD24 using GEMM of endogenous PDAC and a model of cerulein-induced acute pancreatitis. We found that (i) CD24 expression was upregulated in murine and human PDAC and during acute pancreatitis (ii) CD24 was expressed exclusively in differentiated PDAC, whereas CD24 absence was associated with undifferentiated tumors and (iii) membranous CD24 expression determines tumor subpopulations with an epithelial phenotype in grafted models. In addition, we show that CD24 protein is stabilized in response to WNT activation and that overexpression of CD24 in pancreatic cancer cells upregulated β-catenin expression augmenting an epithelial, non-metastatic signature. Our results support a positive feedback model according to which (i) WNT activation and subsequent β-catenin dephosphorylation stabilize CD24 protein expression, and (ii) sustained CD24 expression upregulates β-catenin expression. Eventually, membranous CD24 augments the epithelial phenotype of pancreatic tumors. Thus we link the WNT/β-catenin pathway with the regulation of CD24 in the context of PDAC differentiation.
Clinical outcome and paravalvular leakage of the new balloon‐expandable Edwards Sapien 3 valve in comparison to its predecessor model (Edwards Sapien XT) in patients undergoing transfemoral aortic valve replacement
2016-05-17

Objectives The aim of this study was to compare the 30‐day procedural, clinical and echocardiographic outcome of the new balloon‐expandable Edwards Sapien 3 (ES3) valve with the Edwards Sapien XT (ESXT). Background : Post‐implant paravalvular leaks (PVL) after transfemoral aortic valve replacement (TAVR) resulting in residual aortic regurgitation (AR) are a major limitation for long term outcome. New TAVR‐devices have to eliminate this problem. Methods Transfemoral TAVR was performed in 209 consecutive intermediate‐high‐risk surgical patients (pts) with symptomatic aortic stenosis (ESXT n = 102, ES3 n = 107). Transthoracic echocardiography (TTE) and 3‐dimensional computed tomography were used for valve size selection. Primary endpoint of the study was none/trace AR derived by TTE 30‐days after TAVR. Results All pts underwent successfully TAVR with a combined device success of 100/102 (99%) in ESXT and 107/107 (100%) in ES3 pts. Fluoroscopy time (ESXT 11.8 ± 0.5 min vs. ES3 10.0 ± 0.5 min, P = 0.003) and contrast (ESXT 188.9 ± 5.6 mL vs. ES3 170.4 ± 4.7 mL, P = 0.04) were significantly lower in ES3 patients. 30‐day clinical events did not differ. Transvalvular mean pressure gradients were significantly reduced to 7.4 ± 0.8 mmHg after ESXT and to 10.1± 0.4 mmHg after ES3 implantation. After 30 days none/trace AR was found in 34.3% ( n = 35) of all ESXT pts in contrast to 89.7% ( n = 96) of all ES3 patients. Moderate‐to‐severe AR was found rarely (ESXT 2.9% vs. ES3 0%, P = 0.073). Conclusions Although there was no significant difference in 30 day mortality, the newer ES3 valve reduced significantly residual paravalvular leakage. © 2016 Wiley Periodicals, Inc.
On the Centenary of Emanuel Gil‐Av, Former Professor of the Weizmann Institute of Science and Pioneer of Enantioselective Chromatography
2016-05-17

Abstract Emanuel Gil‐Av (Zimkin) was born in 1916 and passed away in 1996. The introduction of chemical selectivity into the chromatographic separation process constitutes his main scientific contribution. This approach culminated in the first enantiomeric separation of racemic amino acids by gas chromatography on an optically active chiral stationary phase in 1966, together with Binyamin Feibush and Rosita Charles‐Sigler. Thus the year 2016 marks an important date to remember and to appreciate the invaluable achievements of Gil‐Av in the realm of chirality carried out at the Weizmann Institute of Science, Israel.
Erratum to: The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells
2016-05-17

After publication of this work [1], we noted that we inadvertently missed to include research funding organisations that supported this work. Missing research funding was supplemented in the acknowledgements.
SIMULATING THE FORMATION OF MASSIVE PROTOSTARS. I. RADIATIVE FEEDBACK AND ACCRETION DISKS
2016-05-18

ABSTRACT We present radiation hydrodynamic simulations of collapsing protostellar cores with initial masses of 30, 100, and 200 M ⊙ . We follow their gravitational collapse and the formation of a massive protostar and protostellar accretion disk. We employ a new hybrid radiative feedback method blending raytracing techniques with flux-limited diffusion for a more accurate treatment of the temperature and radiative force. In each case, the disk that forms becomes Toomre-unstable and develops spiral arms. This occurs between 0.35 and 0.55 freefall times and is accompanied by an increase in the accretion rate by a factor of 2–10. Although the disk becomes unstable, no other stars are formed. In the case of our 100 and 200 M ⊙ simulations, the star becomes highly super-Eddington and begins to drive bipolar outflow cavities that expand outwards. These radiatively driven bubbles appear stable, and appear to be channeling gas back onto the protostellar accretion disk. Accretion proceeds strongly through the disk. After 81.4 kyr of evolution, our 30 M ⊙ simulation shows a star with a mass of 5.48 M ⊙ and a disk of mass 3.3 M ⊙ , while our 100 M ⊙ simulation forms a 28.8 M ⊙ mass star with a 15.8 M ⊙ disk over the course of 41.6 kyr, and our 200 M ⊙ simulation forms a 43.7 M ⊙ star with an 18 M ⊙ disk in 21.9 kyr. In the absence of magnetic fields or other forms of feedback, the masses of the stars in our simulation do not appear to be limited by their own luminosities.
Role of secondary metabolites in the interaction betweenPseudomonas fluorescensand soil microorganisms under iron-limited conditions
2016-05-18

Microorganisms can be versatile in their interactions with each other, being variously beneficial, neutral or antagonistic in their effect. Although this versatility has been observed among many microorganisms and in many environments, little is known regarding the mechanisms leading to these changes in behavior. In the present work, we analyzed the mechanism by which the soil bacterium Pseudomonas fluorescens BBc6R8 shifts from stimulating the growth of the ectomycorrhizal fungus Laccaria bicolor S238N to killing the fungus. We show that among the three secondary metabolites produced by the bacterial strain-the siderophores enantio-pyochelin and pyoverdine, and the biosurfactant viscosin-the siderophores are mainly responsible for the antagonistic activity of the bacterium under iron-limited conditions. While the bacterial strain continues to produce beneficial factors, their effects are overridden by the action of their siderophores. This antagonistic activity of the strain P. fluorescens BBC6R8 in iron-depleted environments is not restricted to its influence on L. bicolor, since it was also seen to inhibit the growth of the actinomycete Streptomyces ambofaciens ATCC23877. We show that the strain P. fluorescens BBc6R8 uses different strategies to acquire iron, depending on certain biotic and abiotic factors.
VARIABILITY IN SECOND LANGUAGE LEARNING
2016-05-18

Second language learning outcomes are highly variable, due to a variety of factors, including individual differences, exposure conditions, and linguistic complexity. However, exactly how these factors interact to influence language learning is unknown. This article examines the relationship between these three variables in language learners. Native English speakers were exposed to an artificial language containing three sentence patterns of varying linguistic complexity. They were randomly assigned to two groups—incidental and instructed—designed to promote the acquisition of implicit and explicit knowledge, respectively. Learning was assessed with a grammaticality judgment task, and subjective measures of awareness were used to measure whether exposure had resulted in implicit or explicit knowledge. Participants also completed cognitive tests. Awareness measures demonstrated that learners in the incidental group relied more on implicit knowledge, whereas learners in the instructed group relied more on explicit knowledge. Overall, exposure condition was the most significant predictor of performance on the grammaticality judgment task, with learners in the instructed group outperforming those in the incidental group. Performance on a procedural learning task accounted for additional variance. When outcomes were analyzed according to linguistic complexity, exposure condition was the most significant predictor for two syntactic patterns, but it was not a predictor for the most complex sentence group; instead, procedural learning ability was.
Next-Generation Therapeutics: mRNA as a Novel Therapeutic Option for Single-Gene Disorders
2016-05-18

In single-gene disorders, such as α1-antitrypsin deficiency (AATD), hemophilia B (clotting factor IX deficiency), and lecithin-cholesterol acyltransferase deficiency (LCATD), a gene mutation causes missing or dysfunctional protein synthesis, which in turn can lead to serious complications for the patient affected. Furthermore, single-gene disorders are associated with severe, early-onset conditions and necessitate expensive lifelong care. Today, therapeutic treatment options remain limited, cost-intensive, or ineffective. Therefore, the novel mRNA-based therapeutic strategy for the treatment of single-gene disorders, which is based on the induction of de novo synthesis of the functional proteins, has extraordinary potential. After the delivery of the specific mRNA to the target cells, the desired protein is expressed by the cells’ own translational machinery, and hence, a fully functional protein replaces the defective or missing protein. mRNA therapy provides an innovative, highly promising, and inexpensive therapeutic approach and will thus lead to new advances in the treatment of single-gene disorders.
Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives
2016-05-18

The Journal of Cancer Metastasis and Treatment is an open access journal focused on cancer metastasis and treatment, including the occurrence, development, progression, metastasis, and treatment of oncologic disease. It covers basic, translational and clinical research related to cancer cell biology, genomics, precision medicine, oncology internal medicine, radiotherapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neurooncology, etc.
Sebacinales – one thousand and one interactions with land plants
2016-05-19

Summary Root endophytism and mycorrhizal associations are complex derived traits in fungi that shape plant physiology. Sebacinales (Agaricomycetes, Basidiomycota) display highly diverse interactions with plants. Although early‐diverging Sebacinales lineages are root endophytes and/or have saprotrophic abilities, several more derived clades harbour obligate biotrophs forming mycorrhizal associations. Sebacinales thus display transitions from saprotrophy to endophytism and to mycorrhizal nutrition within one fungal order. This review discusses the genomic traits possibly associated with these transitions. We also show how molecular ecology revealed the hyperdiversity of Sebacinales and their evolutionary diversification into two sister families: Sebacinaceae encompasses mainly ectomycorrhizal and early‐diverging saprotrophic species; the second family includes endophytes and lineages that repeatedly evolved ericoid, orchid and ectomycorrhizal abilities. We propose the name Serendipitaceae for this family and, within it, we transfer to the genus Serendipita the endophytic cultivable species Piriformospora indica and P. williamsii . Such cultivable Serendipitaceae species provide excellent models for root endophytism, especially because of available genomes, genetic tractability, and broad host plant range including important crop plants and the model plant Arabidopsis thaliana . We review insights gained with endophytic Serendipitaceae species into the molecular mechanisms of endophytism and of beneficial effects on host plants, including enhanced resistance to abiotic and pathogen stress. Contents Summary 20 I. Introduction 21 II. Phylogeny and systematics of Sebacinales 21 III. Ecology and diversity of Sebacinales interactions with plants 23 IV. Endophytism in Serendipitaceae: changing phenotype of the host plants 29 V. Endophytism in Serendipitaceae: a fungal adaptation to biotrophy 33 VI. Conclusion and future directions 35 Acknowledgements 36 Author contributions 36 References 36
MultisystemicSYNE1ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum
2016-05-19

Sir, We recently reported in Brain a large multi-centre study suggesting that truncating SYNE1 mutations are a recurrent cause of recessive ataxia also outside Quebec (23/434 = 5.3% of patients with unexplained early-onset ataxia) (Synofzik et al. , 2016). Moreover, this study indicated that SYNE1 ataxia might commonly present with complex multisystemic phenotypes rather than pure cerebellar ataxia, including in particular motor neuron and brainstem dysfunction (Synofzik et al. , 2016). However, confirmation of both the frequency estimate and the complex phenotypic spectrum is still lacking, raising the question whether these findings indeed represent systematic results rather than just exceptional or coincidental associations. Here, we now report the mutational and phenotypic findings on SYNE1 from a second, independent ataxia series of 116 patients. These findings not only confirm the high frequency of SYNE1 ataxia and extend both the mutational spectrum (seven novel index patients, 12 novel SYNE1 mutations) and the multisystemic phenotypic spectrum, including amyotrophic lateral sclerosis (ALS)-like motor neuron features, they also indicate that muscle immunohistochemistry might provide a valuable diagnostic biomarker for clarifying the pathogenic contribution of SYNE1 missense variants. This observation may have consequences for clinical SYNE1 diagnostics, as diagnostic tests are urgently needed for clarifying the role of the ubiquitous SYNE1 missense variants with unknown clinical significance (VUS), which are frequently found in neurological and non-neurological patients and controls (Synofzik et al. , 2016). Index subjects ( n = 116) with unexplained degenerative ataxia compatible with autosomal recessive inheritance (no ataxia in the parental generation) and negative for trinucleotide repeat expansions causing Friedreich’s ataxia (FRDA) were compiled from three sources: the Early Onset Ataxia Consortium ( n = 88), the ataxia centre Antwerp, Belgium ( n = 9), and the ataxia centre Milano, Italy ( n = 19). All subjects originated from European, Middle East or Mediterranean countries. This ...
Continued decay in the cyclotron line energy in Hercules X-1
2016-05-19

\\n The centroid energy Ecyc of the cyclotron line in the spectrum of the binary X-ray pulsar <ext-link ext-link-type="aoi">Her X-1</ext-link> has been found to decrease with time on a time scale of a few tens of years – surprisingly short in astrophysical terms. This was found for the pulse phase-averaged line centroid energy using observational data from various X-ray satellites over the time period 1996 to 2012, establishing a reduction of ~4 keV. Here we report on the result of a new observation by NuSTAR performed in August 2015. The earlier results are confirmed and strengthened with respect to both the dependence of Ecyc on flux (it is still present after 2006) and the dependence on time: the long-term decay continued with the same rate, corresponding to a reduction of ~5 keV in 20 yr. \\n
Reading out olfactory receptors: feedforward circuits detect odors in mixtures without demixing
2016-05-19

The olfactory system, like other sensory systems, can detect specific stimuli of interest amidst complex, varying backgrounds. To gain insight into the neural mechanisms underlying this ability, we imaged responses of mouse olfactory bulb glomeruli to single odors and hundreds of mixtures. We used this data to build a model of mixture responses that incorporated nonlinear interactions and trial-to-trial variability and explored potential decoding mechanisms that can mimic mouse performance from our previous study (Rokni et al., 2014) when given glomerular responses as input. We find that a linear decoder with sparse weights could match mouse performance using just a small subset of the glomeruli (~ 15). However, when such a decoder is trained only with single odors, it generalizes poorly to mixture stimuli due to nonlinear mixture responses. We show that mice similarly fail to generalize, although they could in principle fully decompose the mixtures. This suggests that mice learn this segregation task discriminatively by adjusting task-specific decision boundaries without taking advantage of a demixed representation of odors.