julilili42/papers huggingface dataset:
Intermittent vs continuous docetaxel therapy in patients with metastatic castration‐resistant prostate cancer – a phase III study ( PRINCE )
2018-04-10

Objective To investigate non‐inferiority of intermittent docetaxel compared to continuous docetaxel in patients with metastatic castration‐resistant prostate cancer ( mCRPC ). Patient and Methods The investigator initiated randomised phase III study included 187 chemotherapy‐naïve patients with mCRPC who were allocated to two treatment arms: intermittent docetaxel and continuous docetaxel. Docetaxel was applied in both arms as weekly (35 mg/m 2 ) or 3‐weekly (75 mg/m 2 ). The primary endpoint was 1‐year survival, which was tested for non‐inferiority (margin δ = 0.125). The secondary endpoints were: overall survival ( OS ), progression‐free survival ( PFS ), median time to treatment failure ( TTF ), and toxicity. Results Of 156 eligible patients, 78 were allocated to each arm. The intermittent treatment met the non‐inferiority criteria for 1‐year survival (two‐sided 95% confidence interval, −0.12, 18, P = 0.022), but not for OS , according to the result of a post hoc analysis. The differences between the study arms in PFS and TTF were not significant. The median (range) treatment holiday in the intermittent arm was 110 (13–486) days, or 38% of the overall treatment duration. Safety profiles of both study arms were comparable. The main limitation of this study was that the planned number of patients could not be recruited. Conclusion Intermittent docetaxel chemotherapy was non‐inferior to continuous therapy for 1‐year survival; non‐inferiority in regard to OS was not reached.
High-Resolution Infrared Body Surface Temperature and Self-Perceived Warmth Distribution in Adolescent Anorexia Nervosa Patients
2018-04-10

Abstract. Anorexia nervosa (AN) is associated with thermoregulatory disturbances such as hypothermia. However, few studies have explored body warmth in AN patients. In this study, we assessed the body surface temperature distribution in adolescent AN patients using high-resolution infrared thermal imaging and through a patient questionnaire, and explored how this differed between intervention and control group and length of treatment. Adolescent AN patients admitted to a multimodal inpatient treatment programme based on an integrative perspective were assessed at three time-points: admission (t1), 6 weeks post-admission (t2), and 3 months after t2 (t3). Healthy control participants were assessed once at baseline. In both groups we assessed participants’ surface temperature and the perception of warmth, using thermal imaging and a questionnaire, in the face, hands, abdomen, and feet. We recruited 40 AN patients and 40 healthy controls, who were admitted to the treatment programme for an average of 70 days ( SD = 24.07). The AN patients were significantly colder in all chosen body domains, except the abdomen area, at t1 compared to healthy controls at baseline. The questionnaire findings supported this result. Differences between the intervention and control groups noted at t1 were significantly reduced by t2 and t3. Our findings suggest that abnormities in the body warmth distribution of AN patients are reversible after having received an AN-specific treatment. Reducing the loss of warmth could improve therapeutic outcomes in AN patients and be a predictor of recovery, and should be investigated in further studies.
Quick Flicks: Association of Paroxysmal Kinesigenic Dyskinesia and Tics
2018-04-10

Abstract Background Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterised by brief attacks of chorea, dystonia, or mixed forms precipitated by sudden movement. Methods Observational study with a cohort of 14 PKD patients and genetic testing for PRRT2 mutations. Results In a series of 14 PKD patients seen in our clinic at the National Hospital of Neurology, Queen Square, from 2012–2017, we noted tics in 11 patients (79%), which stand in stark contrast to the estimated lifetime prevalence of tics estimated to reach 1%. Conclusions The two reasons to point out this possible association are the clinical implications and the potential opportunity of a better understanding of shared pathophysiological mechanisms of neuronal hyperexcitability.
In search of Pleistocene remains at the Gates of Europe: directed surface survey of the Megalopolis Basin (Greece)
2018-04-10

&amp;lt;p&amp;gt;The PaGE Project survey of the Megalopolis Basin (Arcadia, Greece), conducted in 2012 -&amp;lt;br&amp;gt;\\n2013 over a period of two field seasons, was an intensive, target-oriented surface survey of&amp;lt;br&amp;gt;\\nPleistocene sediments. Implementing a modified version of field methods applied in our&amp;lt;br&amp;gt;\\nsurvey of cave systems and Pleistocene cave sediments, the main goal of this systematic&amp;lt;br&amp;gt;\\nresearch focused on the identification of intact stratified remains from either stratigraphic&amp;lt;br&amp;gt;\\nsections or on remnants of exposed ancient surfaces. The project area consisted of the active&amp;lt;br&amp;gt;\\nopen-cast lignite mine of Megalopolis, where access to recently exposed sections were&amp;lt;br&amp;gt;\\nabundant, and of the alluvial fans in the surrounding uplands, where hominins exploited the&amp;lt;br&amp;gt;\\ncommanding views of the ancient lake. This paper presents the survey results and applied&amp;lt;br&amp;gt;\\nfield methods for conducting archaeological research within the remnants of an Early to&amp;lt;br&amp;gt;\\nMiddle Pleistocene ancient lake system. The project succeeded in identifying at least five&amp;lt;br&amp;gt;\\nsurface and stratified sites, the latter including the Lower Paleolithic remains of Marathousa-&amp;lt;br&amp;gt;\\n1. This site is currently under investigation, but has already yielded the oldest&amp;lt;br&amp;gt;\\nchronometrically dated archaeological remains in Greece. Therefore, PaGE has not only&amp;lt;br&amp;gt;\\nmanaged to place mainland Greece on the Lower Paleolithic map of Europe, but has also&amp;lt;br&amp;gt;\\nsuccessfully tested a methodological corpus for survey research targeting the earliest phases&amp;lt;br&amp;gt;\\nof the Paleolithic period in a Mediterranean landscape.&amp;lt;/p&amp;gt;
Long-term functional outcome in patients with acquired infections after acute spinal cord injury. (P4.322)
2018-04-10

April 25, 2018April 10, 2018Free AccessLong-term functional outcome in patients with acquired infections after acute spinal cord injury. (P4.322)Jan Schwab, Peter Martus, Ralf Watzlawick, YuYing Chen, Michael DeVivo, and Marcel KoppAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P4.322 Letters to the Editor
Release of Staphylococcus aureus extracellular vesicles and their application as a vaccine platform
2018-04-11

Abstract Secretion of extracellular vesicles (EVs), a process common to eukaryotes, archae, and bacteria, represents a secretory pathway that allows cell-free intercellular communication. Microbial EVs package diverse proteins and influence the host-pathogen interaction, but the mechanisms underlying EV production in Gram-positive bacteria are poorly understood. Here we show that EVs purified from community-associated methicillin-resistant Staphylococcus aureus package cytosolic, surface, and secreted proteins, including cytolysins. Staphylococcal alpha-type phenol-soluble modulins promote EV biogenesis by disrupting the cytoplasmic membrane; whereas, peptidoglycan cross-linking and autolysin activity modulate EV production by altering the permeability of the cell wall. We demonstrate that EVs purified from a S. aureus mutant that is genetically engineered to express detoxified cytolysins are immunogenic in mice, elicit cytolysin-neutralizing antibodies, and protect the animals in a lethal sepsis model. Our study reveals mechanisms underlying S. aureus EV production and highlights the usefulness of EVs as a S. aureus vaccine platform.
MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing
2018-04-12

Key Points Genome editing induces t(9;11) chromosomal translocations and transforms primary CD34+ human cord blood cells leading to acute leukemia. CD9 is upregulated in primary t(9;11) cells and is a useful marker for enrichment of genome-edited MLL-rearranged cells in vitro.
Homogeneous Palladium‐Catalyzed Transfer Hydrogenolysis of Benzylic Alcohols Using Formic Acid as Reductant
2018-04-12

Abstract We report the first homogeneous palladium‐based transfer hydrogenolysis of benzylic alcohols using an in situ formed palladium‐phosphine complex and formic acid as reducing agent. The reaction requires a catalyst loading as low as only 1 mol % of palladium and just a slight excess of reductant to obtain the deoxygenated alkylarenes in good to excellent yields. Besides demonstrating the broad applicability for primary, secondary and tertiary benzylic alcohols, a reaction intermediate could be identified. Additionally, it could be shown that partial oxidation of the applied phosphine ligand was beneficial for the course of the reaction, presumably by stabilizing the active catalyst. Reaction profiles and catalyst poisoning experiments were used to characterize the catalyst, the results of which indicate a homogeneous metal complex as the active species.
Magnitude or Multitude – What Counts?
2018-04-12

Recent studies revealed an association of low or high numbers (e.g., 1 vs. 9) and word semantics referring to entities typically found in upper or lower space (e.g., <i>roof</i> vs. <i>root</i>) indicating overlapping spatial representations. Another line of research revealed a similar association of grammatical number as a syntactic aspect of language and physical space: singular words were associated with left and plural words with right - resembling spatial-numerical associations of low numbers with left and high numbers with right. The present study aimed at integrating these lines of research by evaluating both types of spatial relations in one experiment. In a lexical decision task, pairs of a numerical cue and a subsequent plural noun were presented. For word with spatial associations (e.g., <i>roofs</i> vs. <i>roots</i>) number magnitude was expected to serve as a spatial cue. For spatially neutral words (e.g., <i>tables</i>) numbers were expected to cue multitude. Results showed the expected congruency-effect between the numbers and words with spatial associations (i.e., small numbers facilitate responses to down-words and high numbers to up-words). However, no effect was found for numbers and spatially neutral words. This seems to indicate that spatial aspects of word meaning may be related more closely to the magnitude of numbers than grammatical number is to the multitude reflected by numbers - at least in the current experimental setting, where only plural words were presented.
Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB
2018-04-13

Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear. Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic ( kl/kl ), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD. Results In cultured VSMCs, treatment with zinc sulfate (ZnSO 4 ) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF- κ B activation. ZnSO 4 increased the abundance of zinc-finger protein TNF- α –induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF- κ B pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO 4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO 4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO 4 ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO 4 ameliorated the osteoinductive effects of uremic serum in VSMCs. Conclusions Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF- κ B pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.
Professional burnout among medical students: Systematic literature review and meta-analysis
2018-04-14

This review underlines the burden of burnout among medical students. Future research should explicitly focus on specific context factors and student group under investigation. Such efforts are necessary to control for context-dependent confounders in research on medical students' mental health impairment to enable more meaningful comparisons and adequate prevention strategies.
Efficacy of a Gel Containing Polihexanide and Betaine in Deep Partial and Full Thickness Burns Requiring Split-thickness Skin Grafts: A Noncomparative Clinical Study
2018-04-14

Despite overall advances in burn therapy, wound infection remains one of the leading causes of morbidity and mortality in patients with severe burn injuries. This prospective, multicenter, noncomparative clinical trial was conducted to assess the efficacy and safety of Prontosan® Wound Gel X (PWX), a gel containing polihexanide and betaine, for moistening and cleansing in deep tissue burn wounds requiring split-thickness skin grafting. Patients with deep partial or full thickness burn wounds requiring split-thickness skin grafting were treated with the gel to evaluate its tolerability and safety as well as graft take and the healing of the skin graft. Target wounds were assessed clinically and by using a photo-planimetric analyzing software for re-epithelialization. From 04/2012 to 05/2015, burn patients from three burn centers in Germany were screened for the study, of which 51 patients met the inclusion criteria. Predominantly deep partial thickness burn wounds were found (88.2 %). Except for one graft failure, all patients reached complete re-epithelialization after one (n = 14), two (n = 31), or three (n = 5) administrations of the gel. The median time to complete graft take was 7 days and was below the average healing time reported in comparable studies. No wound infection or erythema occurred. This is the first study to document the outcomes of deep partial and full thickness burns treated with PWX for moistening and cleansing. The gel was shown to be efficacious, safe, and well tolerated for use in burn wounds requiring split-thickness skin grafts.
HIV prevention strategies and risk of infection: a model-based analysis
2018-04-15

Abstract Risk populations for HIV infections tend to neglect condom use, making alternative preventive approaches necessary. Accordingly, we modelled the risk of sexual HIV transmission for condom use vs. use of rapid diagnostic test (RDT) systems with subsequent exclusion of potential sexual partners with a correctly or falsely positive test from unprotected sex with and without the use of HIV pre-exposure prophylaxis (PrEP) in a bio-statistical approach. We combined a previously described model of transmission risk for HIV-exposed individuals with a newly suggested model of risk of HIV exposure for sexually active HIV-negative individuals. The model was adapted for several stages of infection and different strategies of HIV infection prevention. HIV prevention with RDTs can reduce the transmission risk by up to 97% compared with having sex without any prevention and up to 80% compared with condom use. Nevertheless, RDT-based prevention strategies demonstrate a lack of protection in several stages of infection; in particular, RNA-based RDT systems may fail under treatment. RDT-based pre-screening of potential sex partners prior to unprotected sexual contacts substantially reduces HIV transmission risk. Combination of different prevention strategies is advisable for high-risk groups.
Do the fluorescent red eyes of the marine fish Tripterygion delaisi stand out? In situ and in vivo measurements at two depths
2018-04-15

Abstract Since the discovery of red fluorescence in fish, much effort has been invested to elucidate its potential functions, one of them being signaling. This implies that the combination of red fluorescence and reflection should generate a visible contrast against the background. Here, we present in vivo iris radiance measurements of Tripterygion delaisi under natural light conditions at 5 and 20 m depth. We also measured substrate radiance of shaded and exposed foraging sites at those depths. To assess the visual contrast of the red iris against these substrates, we used the receptor noise model for chromatic contrasts and Michelson contrast for achromatic calculations. At 20 m depth, T. delaisi iris radiance generated strong achromatic contrasts against substrate radiance, regardless of exposure, and despite substrate fluorescence. Given that downwelling light above 600 nm is negligible at this depth, we can attribute this effect to iris fluorescence. Contrasts were weaker in 5 m. Yet, the pooled radiance caused by red reflection and fluorescence still exceeded substrate radiance for all substrates under shaded conditions and all but Jania rubens and Padina pavonia under exposed conditions. Due to the negative effects of anesthesia on iris fluorescence, these estimates are conservative. We conclude that the requirements to create visual brightness contrasts are fulfilled for a wide range of conditions in the natural environment of T. delaisi .
Mapping the tumour human leukocyte antigen (HLA) ligandome by mass spectrometry
2018-04-16

Summary The entirety of human leukocyte antigen ( HLA) ‐presented peptides is referred to as the HLA ligandome of a cell or tissue, in tumours often termed immunopeptidome. Mapping the tumour immunopeptidome by mass spectrometry ( MS ) comprehensively views the pathophysiologically relevant antigenic signature of human malignancies. MS is an unbiased approach stringently filtering the candidates to be tested as opposed to epitope prediction algorithms. In the setting of peptide‐specific immunotherapies, MS ‐based strategies significantly diminish the risk of lacking clinical benefit, as they yield highly enriched amounts of truly presented peptides. Early immunopeptidomic efforts were severely limited by technical sensitivity and manual spectra interpretation. The technological progress with development of orbitrap mass analysers and enhanced chromatographic performance led to vast improvements in mass accuracy, sensitivity, resolution, and speed. Concomitantly, bioinformatic tools were developed to process MS data, integrate sequencing results, and deconvolute multi‐allelic datasets. This enabled the immense advancement of tumour immunopeptidomics. Studying the HLA ‐presented peptide repertoire bears high potential for both answering basic scientific questions and translational application. Mapping the tumour HLA ligandome has started to significantly contribute to target identification for the design of peptide‐specific cancer immunotherapies in clinical trials and compassionate need treatments. In contrast to prediction algorithms, rare HLA allotypes and HLA class II can be adequately addressed when choosing MS ‐guided target identification platforms. Herein, we review the identification of tumour HLA ligands focusing on sources, methods, bioinformatic data analysis, translational application, and provide an outlook on future developments.
Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy
2018-04-16

Abstract The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.
Sleep stage dynamics in neocortex and hippocampus
2018-04-16

Mammalian sleep comprises the stages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Additionally, a transition state is often discriminated which in rodents is termed intermediate stage (IS). Although these sleep stages are thought of as unitary phenomena affecting the whole brain in a congruent fashion, recent findings have suggested that sleep stages can also appear locally restricted to specific networks and regions. Here, we compared in rats sleep stages and their transitions between neocortex and hippocampus. We simultaneously recorded the electroencephalogram (EEG) from skull electrodes over frontal and parietal cortex and the local field potential (LFP) from the medial prefrontal cortex and dorsal hippocampus. Results indicate a high congruence in the occurrence of sleep and SWS (>96.5%) at the different recording sites. Congruence was lower for REM sleep (>87%) and lowest for IS (<36.5%). Incongruences occurring at sleep stage transitions were most pronounced for REM sleep which in 36.6 per cent of all epochs started earlier in hippocampal LFP recordings than in the other recordings, with an average interval of 17.2 ± 1.1 s between REM onset in the hippocampal LFP and the parietal EEG (p < 0.001). Earlier REM onset in the hippocampus was paralleled by a decrease in muscle tone, another hallmark of REM sleep. These findings indicate a region-specific regulation of REM sleep which has clear implications not only for our understanding of the organization of sleep, but possibly also for the functions, e.g. in memory formation, that have been associated with REM sleep.
The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER
2018-04-16

ABSTRACT Tail-anchored (TA) proteins are anchored to their corresponding membrane via a single transmembrane segment (TMS) at their C-terminus. In yeast, the targeting of TA proteins to the endoplasmic reticulum (ER) can be mediated by the guided entry of TA proteins (GET) pathway, whereas it is not yet clear how mitochondrial TA proteins are targeted to their destination. It has been widely observed that some mitochondrial outer membrane (MOM) proteins are mistargeted to the ER when overexpressed or when their targeting signal is masked. However, the mechanism of this erroneous sorting is currently unknown. In this study, we demonstrate the involvement of the GET machinery in the mistargeting of suboptimal MOM proteins to the ER. These findings suggest that the GET machinery can, in principle, recognize and guide mitochondrial and non-canonical TA proteins. Hence, under normal conditions, an active mitochondrial targeting pathway must exist that dominates the kinetic competition against other pathways.