julilili42/papers huggingface dataset:
Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma
2020-12-18

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS &gt; 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS &gt; 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS &gt; 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.
c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases
2020-12-18

Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.
Specific Induction of Double Negative B Cells During Protective and Pathogenic Immune Responses
2020-12-18

Double negative (DN) (CD19 + CD20 low CD27 - IgD - ) B cells are expanded in patients with autoimmune and infectious diseases; however their role in the humoral immune response remains unclear. Using systematic flow cytometric analyses of peripheral blood B cell subsets, we observed an inflated DN B cell population in patients with variety of active inflammatory conditions: myasthenia gravis, Guillain-Barré syndrome, neuromyelitis optica spectrum disorder, meningitis/encephalitis, and rheumatic disorders. Furthermore, we were able to induce DN B cells in healthy subjects following vaccination against influenza and tick borne encephalitis virus. Transcriptome analysis revealed a gene expression profile in DN B cells that clustered with naïve B cells, memory B cells, and plasmablasts. Immunoglobulin VH transcriptome sequencing and analysis of recombinant antibodies revealed clonal expansion of DN B cells that were targeted against the vaccine antigen. Our study suggests that DN B cells are expanded in multiple inflammatory neurologic diseases and represent an inducible B cell population that responds to antigenic stimulation, possibly through an extra-follicular maturation pathway.
Connecting the dots: from nanodomains to physiological functions of REMORINs
2020-12-18

Abstract REMORINs (REMs) are a plant-specific protein family, proposed regulators of membrane-associated molecular assemblies and well-established markers of plasma membrane nanodomains. REMs play a diverse set of functions in plant interactions with pathogens and symbionts, responses to abiotic stresses, hormone signaling and cell-to-cell communication. In this review, we highlight the established and more putative roles of REMs throughout the literature. We discuss the physiological functions of REMs, the mechanisms underlying their nanodomain-organization and their putative role as regulators of nanodomain-associated molecular assemblies. Furthermore, we discuss how REM phosphorylation may regulate their functional versatility. Overall, through data-mining and comparative analysis of the literature, we suggest how to further study the molecular mechanisms underpinning the functions of REMs.
Safety and efficacy of mechanical thrombectomy in infective endocarditis: A matched case–control analysis from the German Stroke Registry–Endovascular Treatment
2020-12-18

Abstract Background and purpose Up to 30% of infective endocarditis (IE) patients have ischemic stroke as a complication. Standard treatment with mechanical thrombectomy (MT) with or without intravenous thrombolysis for large vessel occlusion (LVO) has not been evaluated formally in these patients. Methods Patients enrolled in the German Stroke Registry–Endovascular Treatment (GSR‐ET) between June 2015 and December 2019 were analyzed. Patients with stroke due to IE and patients with cardioembolic stroke and atrial fibrillation (AF) were compared using propensity score matching. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score = 2b–3. Modified Rankin Scale (mRS) = 0–2 at 3 months indicated good outcome. Results Of 6635 patients, 55 patients (age = 69.0 ± 13.3 years, 43.6% female, median premorbid mRS (pmRS) = 1, interquartile range [IQR] = 0–1, National Institutes of Health Stroke Scale [NIHSS] = 15, IQR = 10–21) presented with septic embolic stroke due to IE and were compared to 104 patients (age = 66.5 ± 13.4 years, 39.4% female, pmRS = 0, IQR = 0–2, NIHSS = 16, IQR = 10–20) with cardioembolic stroke due to AF. Successful recanalization was achieved in 74.5% of endocarditis patients compared to 87.5% of controls ( p = 0.039). Intracranial hemorrhage rates were comparable (30.9% vs. 21.6%, p = 0.175). Good functional outcome was 20.0% in patients with IE compared to 43.3% in matched patients ( p = 0.006), with a significantly higher mortality (60.0% vs. 28.8%, p &lt; 0.001). IE was strongly associated with poor outcome (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.11–0.87, p = 0.03 for good outcome) and mortality (OR = 4.49, 95% CI = 1.80–10.68, p = 0.001). Conclusions Although MT results in high successful recanalization rates with acceptable safety profile, patients with LVO stroke due to IE have poor outcome.
Organ-Based Chronological Age Estimation Based on 3D MRI Scans
2020-12-18

Individuals age differently depending on a multitude of different factors\\nsuch as lifestyle, medical history and genetics. Often, the global\\nchronological age is not indicative of the true ageing process. An organ-based\\nage estimation would yield a more accurate health state assessment. In this\\nwork, we propose a new deep learning architecture for organ-based age\\nestimation based on magnetic resonance images (MRI). The proposed network is a\\n3D convolutional neural network (CNN) with increased depth and width made\\npossible by the hybrid utilization of inception and fire modules. We apply the\\nproposed framework for the tasks of brain and knee age estimation. Quantitative\\ncomparisons against concurrent MR-based regression networks and different 2D\\nand 3D data feeding strategies illustrated the superior performance of the\\nproposed work.\\n
Tetryl‐Tetrylene Addition to Phenylacetylene
2020-12-18

Abstract Phenylacetylene adds [Ar*GeH 2 ‐SnAr’], [Ar*GeH 2 ‐PbAr’] and [Ar'SnH 2 ‐PbAr*] at rt in a regioselective and stereoselective reaction. The highest reactivity was found for the stannylene, which reacts immediately upon addition of one equivalent of alkyne. However, the plumbylenes exhibit addition to the alkyne only in reaction with an excess of phenylacetylene. The product of the germylplumbylene addition reacts with a second equivalent of alkyne and the product of a CH‐activation, a dimeric lead acetylide, were isolated. In the case of the stannylplumbylene the trans ‐addition product was characterized as the kinetically controlled product which isomerizes at rt to yield the cis ‐addition product, which is stabilized by an intramolecular Sn–H–Pb interaction. NMR chemical shifts of the olefins were investigated using two‐ and four‐component relativistic DFT calculations, as spin–orbit effects can be large. Hydride abstraction was carried out by treating [Ar'SnPhC=CHGeH 2 Ar*] with the trityl salt [Ph 3 C][Al(OC{CF 3 }) 4 ] to yield a four membered ring cation.
Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn’s Disease
2020-12-18

Abstract Background The first visible signs of Crohn’s disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of human α-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo. Methods An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA. Results There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P &amp;lt; 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P &amp;lt; 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P &amp;lt; 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls. Conclusions Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.
Implementing long‐term baselines into primate tool‐use studies
2020-12-18

Abstract Studies on primate tool‐use often involve the use of baseline conditions, as they allow for the examination of any differences in the subjects' behavior before and after the introduction of a tool‐use task. While these baseline conditions can be powerful for identifying the relative contributions of individual and social learning for the acquisition of tool‐use behaviors in naïve (usually captive) subjects, many have criticized them for being too short, and not allowing enough time for the behavior to develop spontaneously. Furthermore, some wild tool‐use behaviors such as chimpanzee nut‐cracking require animals to manipulate and familiarize themselves with the materials of the behavior within a “sensitive learning period” before it develops later on in life. One solution to this problem is to implement long‐term baselines, in which, with collaboration with zoological institutions, the materials of the behavior are left in the enclosure for an extended period. The keepers would then be asked not to demonstrate or train the animals in the target behavior, but to report back to the researchers if they observe the behavior emerge during this extended period. Alongside keeper reports, video cameras could be installed in the enclosure to minimize the chance of false negatives and to allow for coding and inter‐rater reliability to be carried out on the videos. These long‐term baselines therefore provide extended enrichment opportunities for the animals, alongside allowing the zoological institution to publicize their involvement with the study and guests to observe animals interacting with different testing apparatuses and tools. Finally, long‐term baselines can provide invaluable insight on the individual and social learning abilities of primates as well as the potential development stages and sensitive learning periods required for specific behaviors.
Organ-on-Chip: Playing LEGO® With Mini-Organs to Reduce Animal Testing and Make Medicines Safer
2020-12-18

Have you ever pictured yourself as a LEGO ® -mini-figure? That is pretty cool, right?! But now, instead of picturing yourself as an astronaut, superhero, or elf-figure, try to imagine your own body being miniature and built from LEGO ® –one brick for each of your organs. Sound weird? Let us explain why a mini LEGO ® -version of you could be extremely useful and could become reality in the future. Such technology might help end testing that uses laboratory animals and help your doctors understand your disease. We use people’s cells and small plastic housings to build mini-organs the size of small LEGO ® -bricks, such as a beating heart or energy-storing fat tissue. Similar to playing LEGO ® , we can also connect different organ-bricks and study how they talk and work with each other. In this article, we will tell you how this all works and why it is so much better than animal experiments.
H3K27me3 loss indicates an increased risk of recurrence in the Tübingen meningioma cohort
2020-12-19

Abstract Background A loss of the trimethylation of lysine 27 of histone H3 (H3K27me3) in meningioma has been recently suggested as an adjunct to identify subsets of higher risk of recurrence. The aim of the present study was to assess the prognostic value of H3K27 histone trimethylation and its potential clinical utility in the “Tübingen meningioma cohort.” Methods Patients who underwent meningioma resection between October 2003 and December 2015 at the University Hospital Tübingen were included. Immunohistochemical stainings for H3K27me3 and the proliferation marker MIB1 were assessed and correlated with clinical parameters using univariate and multivariate Cox regressions as well as Pearson's chi-squared and log-rank test. Results Overall, 1268 meningiomas were analyzed with a female to male ratio of 2.6 and a mean age of 58.7 years (range 8.3–91.0). With 163 cases lost to follow up, 1103 cases were available for further analysis with a mean follow-up of 40.3 months (range 1.1–186.3). Male gender, younger age, intracranial tumor localization, progressive tumor, subtotal resection, higher WHO grade, increased MIB1 rate, and loss of H3K27me3 were significant negative prognostic factors in the univariate analysis. H3K27me3 status and all other prognostic factors, except age and tumor location, remained significant in the multivariate model. Furthermore, adjuvant radiotherapy was an independent positive prognostic factor. Conclusions Loss of H3K27me3 combined with MIB1 labeling index are independent prognostic factors in meningioma. These data from the Tübingen meningioma cohort support the clinical utility of H3K27me3 immunohistochemical staining in meningioma and its integration into the routine histopathological workup.
Direct Medium-Chain Carboxylic Acid Oil Separation from a Bioreactor by an Electrodialysis/Phase Separation Cell
2020-12-21

Medium-chain carboxylic acids (MCCAs) are valuable platform chemicals and can be produced from waste biomass sources or syngas fermentation effluent through microbial chain elongation. We have previously demonstrated successful approaches to separate >90% purity oil with different MCCAs (MCCA oil) by integrating the anaerobic bioprocess with membrane-based liquid-liquid extraction (pertraction) and membrane electrolysis. However, two-compartment membrane electrolysis unit without pertraction was not able to separate MCCA oil. Therefore, we developed a five-compartment electrodialysis/phase separation cell (ED/PS). First, we tested an ED/PS cell <i>in series</i> with pertraction and achieved a maximum MCCA-oil flux of 1.7 × 10<sup>3</sup> g d<sup>-1</sup> per projected area (m<sup>2</sup>) (19 mL oil d<sup>-1</sup>) and MCCA-oil transfer efficiency [100% × moles MCCA-oil moles electrons<sup>-1</sup>] of 74% at 15 A m<sup>-2</sup>. This extraction system at 15 A m<sup>-2</sup> demonstrated a ∼10 times lower electric-power consumption (1.1 kWh kg<sup>-1</sup> MCCA oil) than membrane electrolysis in series with pertraction (9.9 kWh kg<sup>-1</sup> MCCA oil). Second, we evaluated our ED/PS as a stand-alone unit when integrated with the anaerobic bioprocess and demonstrated that we can selectively extract and separate MCCA oil directly from chain-elongating bioreactor broth with just an abiotic electrochemical cell. However, the electric-power consumption increased considerably due to the lower MCCA concentrations in the bioreactor broth compared to the pertraction broth.
Nidogen‐1 Mitigates Ischemia and Promotes Tissue Survival and Regeneration
2020-12-21

Abstract Ischemia impacts multiple organ systems and is the major cause of morbidity and mortality in the developed world. Ischemia disrupts tissue homeostasis, driving cell death, and damages tissue structure integrity. Strategies to heal organs, like the infarcted heart, or to replace cells, as done in pancreatic islet β ‐cell transplantations, are often hindered by ischemic conditions. Here, it is discovered that the basement membrane glycoprotein nidogen‐1 attenuates the apoptotic effect of hypoxia in cardiomyocytes and pancreatic β ‐cells via the α v β 3 integrin and beneficially modulates immune responses in vitro. It is shown that nidogen‐1 significantly increases heart function and angiogenesis, while reducing fibrosis, in a mouse postmyocardial infarction model. These results demonstrate the protective and regenerative potential of nidogen‐1 in ischemic conditions.
Nanobodies Right in the Middle: Intrabodies as Toolbox to Visualize and Modulate Antigens in the Living Cell
2020-12-21

In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular components. Traceable intracellular binding molecules provide new opportunities for real-time cellular diagnostics. Most prominently, intrabodies derived from antibody fragments of heavy-chain only antibodies of camelids (nanobodies) have emerged as highly versatile and attractive probes to study and manipulate antigens within the context of living cells. In this review, we provide an overview on the selection, delivery and usage of intrabodies to visualize and monitor cellular antigens in living cells and organisms. Additionally, we summarize recent advances in the development of intrabodies as cellular biosensors and their application to manipulate disease-related cellular processes. Finally, we highlight switchable intrabodies, which open entirely new possibilities for real-time cell-based diagnostics including live-cell imaging, target validation and generation of precisely controllable binding reagents for future therapeutic applications.
Competencies for a Healthy Physically Active Lifestyle: Second-Order Analysis and Multidimensional Scaling
2020-12-21

The physical activity-related health competence (PAHCO) model assumes that individuals require movement competence, control competence, and self-regulation competence to lead a healthy, physically active lifestyle. Although previous research has already established some measurement factors ( n = 8) of the three dimensions, no attempts have so far been made to statistically aggregate them on the sub-competence level. Therefore, the goal of the present study was to test two additional factors for PAHCO and subsequently model the second-order structure with two samples from the fields of rehabilitation and prevention. We conducted two questionnaire surveys with persons with multiple sclerosis ( n = 475) and teaching students undergoing a basic qualification course in physical education ( n = 502). After performing exploratory items analysis, we used second-order confirmatory factor analysis (CFA) and multidimensional scaling to investigate whether the scales could be bundled in accordance with the PAHCO model. The CFAs with 10 factors (42 items) demonstrated a good model fit. In contrast, the second-order analysis with a simple loading structure on the three sub-competencies revealed an unacceptable model fit. Instead, a second-order model variant was preferred [comparative fit index (CFI) = 0.926, root mean square error of approximation (RMSEA) = 0.048, standardized root mean square residual (SRMR) = 0.065] in which body awareness and self-efficacy had theory-conform cross-loadings. The results of multidimensional scaling (two-dimensional solution) were in line with the extracted second-order structure. The present results suggested that the extension of the measurement instrument to 10 first-order factors was psychometrically justified for the two populations. The results from the second-order analyses provided the basis for the creation of sum scores, representing manifest indicators of movement competence, control competence, and self-regulation competence. Future studies are needed that cross-validate the extended measurement model with other populations and that relate the sub-competencies of PAHCO to indicators of health-enhancing physical activity.
Left ventricular assist device implantation causes platelet dysfunction and proinflammatory platelet-neutrophil interaction
2020-12-21

Blood flow through left ventricular assist devices (LVAD) may induce activation and dysfunction of platelets. Dysfunctional platelets cause coagulation disturbances and form platelet-neutrophil conjugates (PNC), which contribute to inflammatory tissue damage. This prospective observational cohort study investigated patients, who underwent implantation of a LVAD (either HeartMate II (HM II) (n = 7) or HeartMate 3 (HM 3) (n = 6)) and as control patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) (n = 10). We performed platelet and leukocyte flow cytometry, analysis of platelet activation markers, and platelet aggregometry. Platelet CD42b expression was reduced at baseline and perioperatively in HM II/3 compared to CABG/AVR patients. After surgery the platelet activation marker β-thromboglobulin and platelet microparticles increased in all groups while platelet aggregation decreased. Platelet aggregation was more significantly impaired in LVAD compared to CABG/AVR patients. PNC were higher in HM II compared to HM 3 patients. We conclude that LVAD implantation is associated with platelet dysfunction and proinflammatory platelet-leukocyte binding. These changes are less pronounced in patients treated with the newer generation LVAD HM 3. Future research should identify device-specific LVAD features, which are associated with the least amount of platelet activation to further improve LVAD therapy.