gebhart/patrepeval huggingface dataset:
IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice (2000)

The development of chronic graft-versus-host disease (GVHD), which is induced by the transfer of DBA/2 spleen cells into (C57BL/6 x DBA/2)F1 (BDF1) mice, is closely related to diminished donor anti-host CTL activity and host B cell hyperactivation. Therefore, an approach which activates donor CD8+ T cells or suppresses donor CD4+ T cell-host B cell interaction may have clinical utility in the treatment of chronic GVHD. We have previously demonstrated that IL-18 induces the development of naive CD8+ T cells into type I effector cells in DBA/2 anti-BDF1 MLC. In this paper we examined the effect of IL-18 administration on the development of chronic GVHD in mice. The treatment was started before or after the onset of clinical evidence of the disease. Regardless of the treatment schedule, IL-18 significantly decreased immunological parameters indicative of chronic GVHD, such as elevated serum IgG antinuclear Abs, IgG1, and IgE levels, and host B cell numbers and their activation. Importantly, IL-18-treated mice did not show the same acute GVHD-like symptoms reported for IL-12 treatment, because there was no weight loss, death, or severe immunodeficiency as indicated by a decrease in IL-2 and IFN-gamma production by Con A-stimulated spleen cells. In contrast, IL-18 treatment partially but significantly restored the production of these cytokines. Data further suggested that these IL-18-mediated therapeutic effects may be due to the induction of donor CD8+ CTL, the decrease in donor CD4+ T cell numbers, and a down-regulation of host B cell MHC class II expression. Thus, our results suggest that IL-18 has beneficial effects in the prevention and treatment of chronic GVHD.
Assessment of Temporary Dialysis Catheter Performance on the Basis of Flow and Pressure Measurements In Vivo and In Vitro (2007)

The efficiency of hemodialysis treatments depends on catheter performance and, consequently, on effective blood flow that can be achieved at maximum extracorporeal pressures. Differences in effective and displayed flow were determined with ultrasound dilution technology, and a mathematical correction function for the MultiFiltrate hemodialysis machine was developed. This algorithm was used to calculate effective blood flow during treatment from displayed flow and arterial pressure. To assess catheter performance over time, we measured effective blood flow as function of extracorporeal pressure in 11 uncuffed, tunneled hemodialysis catheters with shotgun design. Pressure and flow profiles of the catheters were determined, and pressure symmetry was measured. To assess flow resistance over time, pressure trends of the catheters at different blood flow rates were measured for each patient over a mean period of 6.1 +/- 3.0 days. Increases in flow resistance during the study period were found to be small. Mean arterial pressure decreased from -185 mm Hg to -200 mm Hg, and mean venous pressure increased from 197 mm Hg to 215 mm Hg. Effective flow did not change significantly during the study. In conclusion, all catheters investigated easily provided effective flows above 450 mL/min over the study period at maximum extracorporeal pressures below +/-300 mm Hg.
Prospective, randomized, controlled, double-blind, multi-center, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery: study protocol for the PHOENICS study (2022)

EudraCT 2016-002162-30 . ClinicalTrials.gov NCT03278548.
Targeting PI3K signaling to ameliorate chronic graft versus host disease. (2016)

Abstract The phosphoinositide 3-kinase (PI3K) pathway is a key signaling pathway necessary for T cell activation, differentiation and metabolism. T effector cells rely on increased PI3K signaling to fuel glycolysis for their metabolic needs, while T regulatory cells downregulate PI3K and favor lipid oxidation. The metabolic processes of lymphocytes modulating chronic graft versus host disease (cGVHD) have remained largely unexamined and represent a novel therapeutic strategy for this disease. Here, we investigated the role of PI3K signaling in a murine model of cGVHD that is etiologically linked to up regulated germinal centers (GCs) and characterized by multisystem organ disease; including fibrosis of the lung, which results in pulmonary dysfunction. We hypothesized that inhibition of PI3K signaling would alter the activation and/or function of GC-facilitating T follicular helper (TFH) cells resulting in lessened disease. The findings in this study are that mice treated with a PI3Kd inhibitor had decreased pulmonary dysfunction similar to that of the control, non-cGVHD mice. The frequencies of splenic TFH cells as well as GC B cells were decreased by a PI3K delta inhibitor compared to non-treated cGVHD controls. In a similar manner, mice that received PI3K kinase delta dead Tregs also had decreased TFH frequency as well as reduced pulmonary dysfunction. Our results indicate the differential requirement for signaling through PI3K delta and suggest that targeting this pathway may be a potential new therapy for treatment of cGVHD. Additional studies are required to validate the potential therapeutic use.
The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas (2017)

Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat<sup>®</sup>, Temodal<sup>®</sup> or Temodar<sup>®</sup>) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4<sup>OE</sup>) and ATF4 knock down (ATF4<sup>KD</sup>). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4<sup>OE</sup>) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4<sup>KD</sup>) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4<sup>OE</sup> gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4<sup>KD</sup> gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4<sup>OE</sup> glioma cells is almost not affected by TMZ treatment. In contrast, ATF4<sup>KD</sup> gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas.
Human Acidic Fibroblast Growth Factor Has Trophic Effects on Cultured Neurons from Multiple Regions of Brain and Retina (1991)

Neurotrophic activities of human recombinant acidic fibroblast growth factor (haFGF) were evaluated on primary cultured neurons from various brain regions and compared with those of CS23, modified human basic fibroblast growth factor. Survival of cultured neurons from embryonic day 16 (E16) rat cortex and substantia nigra was significantly increased by the addition of more than 10 ng/ml haFGF and that from the hippocampus was increased by 100 and 1000 ng/ml. However, enhancement of viability by haFGF was observed only in 1000 ng/ml-treated neurons from the striatum, thalamus, colliculus and cerebellum; and it was not observed in septal neurons. Survival of cultured neurons from postnatal day 15 rat on glial feeder layer was significantly increased by the addition of 1000ng/ml haFGF, except for neurons from the septum. CS23 (lOng/ml) increased the survival of cultured neurons from all regions mentioned above, and its effects were stronger than those of 1000 ng/ml haFGF. Addition of more than 10 ng/ml haFGF significantly increased the survival of cultured neurons from neonatal day 2 rat retina. Addition of 1000 ng/ml haFGF increased the choline acetyltransferase activity of E16 septal neurons slightly but significantly, but didn’t increase the dopamine uptake activity of embryonic day E15 ventral midbrain. These results show that haFGF is effective on limited regions and ages of brain and retina, while CS23 is effective on all regions tested.
Electronic Health Records Exploitation Using Artificial Intelligence Techniques (2020)

The exploitation of electronic health records (EHRs) has multiple utilities, from predictive tasks and clinical decision support to pattern recognition. Artificial Intelligence (AI) allows to extract knowledge from EHR data in a practical way. In this study, we aim to construct a Machine Learning model from EHR data to make predictions about patients. Specifically, we will focus our analysis on patients suffering from respiratory problems. Then, we will try to predict whether those patients will have a relapse in less than 6, 12 or 18 months. The main objective is to identify the characteristics that seem to increase the relapse risk. At the same time, we propose an exploratory analysis in search of hidden patterns among data. These patterns will help us to classify patients according to their specific conditions for some clinical variables.
Cluster activation mapping with application to computed tomography scans of the lung (2022)

<b>Purpose:</b> An open question in deep clustering is how to explain what in the image is driving the cluster assignments. This is especially important for applications in medical imaging when the derived cluster assignments may inform decision-making or create new disease subtypes. We develop cluster activation mapping (CLAM), which is methodology to create localization maps highlighting the image regions important for cluster assignment. <b>Approach:</b> Our approach uses a linear combination of the activation channels from the last layer of the encoder within a pretrained autoencoder. The activation channels are weighted by a channelwise confidence measure, which is a modification of score-CAM. <b>Results:</b> Our approach performs well under medical imaging-based simulation experiments, when the image clusters differ based on size, location, and intensity of abnormalities. Under simulation, the cluster assignments were predicted with 100% accuracy when the number of clusters was set at the true value. In addition, applied to computed tomography scans from a sarcoidosis population, CLAM identified two subtypes of sarcoidosis based purely on CT scan presentation, which were significantly associated with pulmonary function tests and visual assessment scores, such as ground-glass, fibrosis, and honeycombing. <b>Conclusions:</b> CLAM is a transparent methodology for identifying explainable groupings of medical imaging data. As deep learning networks are often criticized and not trusted due to their lack of interpretability, our contribution of CLAM to deep clustering architectures is critical to our understanding of cluster assignments, which can ultimately lead to new subtypes of diseases.
Simple model for detection of spin accumulation in a ferromagnetic double tunnel junction (2010)

We study the effect of spin accumulation in ferromagnetic double tunnel junctions based on a simple model. The analytical results for typical cases show that spin accumulation enhances the tunnel magnetoresistance (TMR) effect and furthermore affects electric potential of the center electrode. These effects are possibly used for the detection of spin accumulation in ferromagnetic double tunnel junctions.
Solid-Phase Synthesis of 4(5),1′,5′-Trisubstituted 2,4′-Biimidazoles (2009)

A method for the synthesis of libraries of 4(5),1',5'-trisubstituted 2,4'-biimidazoles on a solid support was developed. (1) A trivalent scaffold, 2-(5'-amino-4(5)-formyl-1H,1'H-2,4'-biimidazol-1'-yl)acetic acid, was first prepared in solution by a two-step synthesis from ethyl adenin-9-ylacetate and bromomalonaldehyde. The product was coupled to an amino acid loaded Wang resin and the formyl group was subsequently derivatized either by reductive amination, oximation, or hydrazone formation. The 5'-amino group of the resin-bound biimidazole was then acylated and the products were finally released from the resin and purified. 5'-Amino-2,4'-biimidazole offers a scaffold for lead compounds of drug discovery, possibly useful in finding leads for protein kinase inhibitors.
On the Energy Impact of Transmission Reach for 100G IP-over-WDM Translucent Optical Networks (2012)

We investigate the power consumption of IP-over-WDM networks for 100G coherent systems when varying optical reach values. Benefits of optimal reach depends on the slope of the reach-related consumption function. We also show that “greening” transponders has a linear-like impact on the reduction of network power consumption.
Failure Localization &amp; Design Debug on Mixed-Mode ICs by Using the Dynamic Laser Stimulation Techniques (2007)

Abstract Soft defect localization techniques based on laser stimulation have become key techniques for a wide range of FA/debug issues. In this paper, we demonstrate the ability of these techniques to solve critical design issue in mixed-mode device for automotive application which includes analog, logic, RF and power. Utilizing a wide range of laser stimulation techniques, we have determined the most efficient approach for this device to achieve the shortest cycle time. We have established a clear link between fault isolation by laser stimulation techniques and the abnormal behavior of the device with relevant and complete simulation at transistor level.
Upregulation of Cyclooxygenase-2 (COX-2) and Microsomal Prostaglandin E <sub>2</sub> Synthase-1 (mPGES-1) in Wall of Ruptured Human Cerebral Aneurysms (2012)

COX-2/mPGES-1 are expressed in the wall of human cerebral aneurysms and more abundantly so in ruptured aneurysms than in nonruptured. We speculate that the protective effect of aspirin against rupture of cerebral aneurysms may be mediated in part by inhibition of COX-2/mPGES-1.
Book reviews (1993)

Conviction and Credence: US Policymaking in the Middle East. Melvin A. Friedlander. Boulder & London: Lynne Rienner Publishers, 1991, 125 pp. A History of the Peoples of Siberia, Russia's North Asian Colony, 1581–1990. James Forsyth. Cambridge University Press, 1992. The Soviet Nationality Reader. The Disintegration in Context. Rachel Denber (Editor). Boulder, Colorado and Oxford, UK: Westview Press, 1992, 631 pp, £14.50 paperback. Journey to Khiva. Philip Glazebrook. London: Harvill, £16, 278 pp. Veils and Words. The Emerging Voices of Iranian Women Writers. Farzaneh Milani. London: I. B. Tauris & Co, 1992, xix + 295 pp, £14.95 paperback.
176. GDF-9, BMP-15 AND ACTIVIN A CONTRIBUTE TO SEMINAL FLUID SIGNALLING IN HUMAN CERVICAL EPITHELIAL CELLS (2009)

We have previously shown that in women, as in animal species, introduction of seminal fluid at coitus induces cytokine expression and a local inflammatory-like response in the female reproductive tract. The response is characterised by induction of mRNAs encoding several pro-inflammatory cytokines including GM-CSF, IL-1α and IL-6, as well as chemokines IL-8, MIP-3α and MCP-1. Recent studies in our laboratory have focused on identifying active signalling agents present in human seminal plasma. To date we have shown that all three mammalian isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3) and 19-hydroxy PGE are key regulators of this response. The current study aimed to determine whether other members of the TGFβ superfamily including GDF-9, BMP-15 and Activin A also contribute. To investigate this we utilised immortalised Ect1 ectocervical epithelial cells, which mimic the response of primary ectocervical epithelial cells. Ect1 cells were incubated with increasing doses (0.5, 5.0, 50 or 500 ng/ml) of rGDF-9, rBMP-15 or rActivin A and production of pro-inflammatory cytokines and chemokines was assessed in 24 hour post-treatment supernatants using Luminex microbead technology. BMP-15 was found to stimulate GM-CSF production (2-fold), while GDF-9 and Activin A both stimulated IL-6 production (2.4-fold and 80% increases respectively), all acting in a dose-dependent manner. In contrast, all three factors inhibited IL-8 production by Ect1 cells. These data demonstrate that GDF-9, BMP-15 and Activin A are new seminal fluid signalling agents capable of targeting female reproductive tract epithelial cells and inducing different response profiles compared with TGFβ and 19-hydroxy PGE. The relative bioavailability of these factors in seminal fluid would therefore influence the profile of inflammatory response in the female partner, regulating immune responses to male seminal antigens as well as sexually transmitted pathogens.
Targeting WEE1/AKT Restores p53-Dependent Natural Killer–Cell Activation to Induce Immune Checkpoint Blockade Responses in “Cold” Melanoma (2022)

Immunotherapy has revolutionized cancer treatment. Unfortunately, most tumor types do not respond to immunotherapy due to a lack of immune infiltration or "cold" tumor microenvironment (TME), a contributing factor in treatment failure. Activation of the p53 pathway can increase apoptosis of cancer cells, leading to enhanced antigen presentation, and can stimulate natural killer (NK) cells through expression of stress ligands. Therefore, modulation of the p53 pathway in cancer cells with wild-type TP53 has the potential to enhance tumor immunogenicity to NK cells, produce an inflammatory TME, and ultimately lead to tumor regression. In this study, we report simultaneous targeting of the AKT/WEE1 pathways is a novel and tolerable approach to synergistically induce p53 activation to inhibit tumor development. This approach reduced the growth of melanoma cells and induced plasma membrane surface localization of the ER-resident protein calreticulin, an indicator of immunogenic cell death (ICD). Increase in ICD led to enhanced expression of stress ligands recognized by the activating NK-cell receptor NKG2D, promoting tumor lysis. WEE1/AKT inhibition resulted in recruitment and activation of immune cells, including NK cells, in the TME, triggering an inflammatory cascade that transformed the "cold" TME of B16F10 melanoma into a "hot" TME that responded to anti-programmed cell death protein 1 (anti-PD-1), resulting in complete regression of established tumors. These results suggest that AKT/WEE1 pathway inhibition is a potential approach to broaden the utility of class-leading anti-PD-1 therapies by enhancing p53-mediated, NK cell-dependent tumor inflammation and supports the translation of this novel approach to further improve response rates for metastatic melanoma.
Cover Image (2020)

COVER ILLUSTRATION Evidence for short-term, motor learning-related structural plasticity in the adult human brain was revealed using diffusion MRI. Structural changes were detectable in cortical and sub-cortical brain regions of non-musicians after only 45 minutes of pianotraining. This work highlights the dynamic nature of of the adult human brain; and the use of diffusion MRI as a rapid and sensitive biomarker for gray-matter learning-driven plasticity.
Anlotinib plus sintilimab in patients with recurrent advanced endometrial cancer: A prospective open-label, single-arm, phase II clinical trial. (2021)

5583 Background: Endometrial cancer is one of the most common gynecologic malignancies in the world. however, the effects of systemic chemotherapy are limited. The combination of targeted therapy with immunotherapy is a new research field in the treatment of malignant tumors. Anlotinib is a novel tyrosine kinase inhibitor with highly selective inhibition effects on multi-targets, especially on vascular endothelial growth factor receptor, Platelet-derived growth factor receptor and Fibroblast growth factor receptor. Sintilimab is a highly selective, fully humanized, monoclonal antibody, which blocks the interaction between Programmed death 1 and its ligands. This research aimed to evaluate the efficacy and safety of the combination of anotinib and sintilimab in patients with recurrent advanced endometrial cancer. Methods: Patients who received at least one platinum-based systemic chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1 were considered eligible for enrollment. Sintilimab was administered intravenously (200mg，q3w); anlotinib was taken orally (12mg qd, d1-14, 21 days per cycle). The treatment was continued until disease progression, death or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), overall survival and safety. Results: From November 2019 to to September 2020, 23 patients with a median age of 56 years (range: 37-70), FIGO stage IA (21.7%), IB (8.7%), II (4.4%), IIIA (13.1%)，IIIC (30.4%), IVB (21.7%) were enrolled. Among these participants, 22 patients were evaluable. The therapeutic evaluation showed the incidence of complete response, partial response, stable disease and progression disease was 13.6%, 63.7%, 13.6% and 9.1% respectively, yielding the ORR of 77.3% (95%CI: 58.3%-96.3%) and the DCR of 91.7% (95%CI: 79.8%-100%). ≥1 and ＜1 Combined Positive Score of PD-L1 expression were observed in 66.7% (14/21) and 33.3% (7/21) patients respectively, and the ORR was 92.9% (95%CI: 77.4%-100%) and 57.1% (95%CI: 18.4%-90.1%) in the two groups. The median time of the first response was 1.5 months (range, 0.7-12.8). The median PFS was not reached. Most of the occurring adverse events (AEs) were grade 1 or 2. Grade 3 AEs included ileus (4.3%), immune myocarditis (4.3%) immune peritonitis (4.3%), hand-foot syndrome (8.7%), neutropenia (4.3%), neutrophils decrease (4.3%), and hypertension (4.3%); Grade 4 AE was lymphocytosis (4.3%). Neither unexpected safety signals nor treatment-related death occurred. Conclusions: Anlotinib plus sintilimab showed a promising antitumor activity with a favorable toxicity profile for patients with recurrent advanced endometrial cancer. We will report more data in the future. Clinical trial information: NCT04157491.
Nonlinear phenomenological model of magnetic dissipation for large precession angles: Generalization of the Gilbert model (2007)

A nonlinear phenomenological model of magnetic dissipation is proposed. This model is a generalization of a standard Gilbert model, where the constant Gilbert damping parameter ${\ensuremath{\alpha}}_{G}$ is replaced by a function ${\ensuremath{\alpha}}_{G}(\ensuremath{\xi})$ of the dimensionless scalar quantity $\ensuremath{\xi}$ proportional to the square of the time rate of change of the magnetization vector ${(\ensuremath{\partial}\mathbit{M}∕\ensuremath{\partial}t)}^{2}$. The proposed model is illustrated for the example of magnetization precession excited by spin-polarized current in an in-plane magnetized nanopillar---the case where the standard Gilbert model leads to qualitatively incorrect results that contradict experiments.