gebhart/patrepeval huggingface dataset:
Left Ventricular Remodeling After Anterior-STEMI PCI: Imaging Observations in the Door-to-Unload (DTU) Pilot Trial (2022)

Immediate 3-5 day post-therapy IS by CMR correlates with 90-day echocardiographic LVEF and indices of remodeling. Patients with post-therapy IS >25% demonstrated evidence of adverse remodeling. Larger studies are needed to corroborate these findings with implications on patient management and prognosis.
Development and utility of a PAK1-selective degrader (2022)

Abstract Amplification and/or overexpression of the PAK1 gene is common in several malignancies, and inhibition of PAK1 by small molecules has been shown to impede the growth and survival of such cells. Potent inhibitors of PAK1 and its close relatives, PAK2, and PAK3, have been described, but clinical development has been hindered by recent findings that PAK2 function is required for normal cardiovascular function in adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, but has relatively modest potency in cells. Here, we report the development of BJG-05-039, a PAK1-seletive degrader consisting of the allosteric PAK1 inhibitor NVS-PAK1-1 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). BJG-05-039 induced degradation of PAK1, but not PAK2, and displayed enhanced anti-proliferative effects relative to its parent compound in PAK1-dependent, but not PAK2-dependent, cell lines. Notably, BJG-05-039 promoted sustained PAK1 degradation and inhibition of downstream signaling effects at ten-fold lower dosage than NVS-PAK1-1. Our findings suggest that selective PAK1 degradation may confer more potent pharmacological effects compared with catalytic inhibition and highlight the potential advantages of PAK1-targeted degradation.
Imaging B Cells in a Mouse Model of Multiple Sclerosis Using 64Cu-Rituximab PET (2017)

B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated <sup>64</sup>Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET. <b>Methods:</b> To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment<sub>1-125</sub> emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after <sup>64</sup>Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a γ-counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography. <b>Results:</b> Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, <i>P</i> < 0.05). <sup>64</sup>Cu-rituximab PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice, compared with 1.25 ± 0.08 and 2.24 ± 0.11 %ID/g for controls (<i>P</i> < 0.05 for all regions except striatum and thalamus at 1 h after injection). Similarly, ex vivo biodistribution results revealed notably higher <sup>64</sup>Cu-rituximab uptake in the brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased <sup>64</sup>Cu-rituximab uptake in CNS tissues corresponded with elevated B cells. <b>Conclusion:</b> B cells can be detected in the CNS of EAE mice using <sup>64</sup>Cu-rituximab PET. Results from these studies warrant further investigation of <sup>64</sup>Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the clinic.
Non‐steroidal anti‐inflammatory drug toxicity in the upper gastrointestinal tract (2000)

Non-steroidal anti-inflammatory drug (NSAID) toxicity in the upper gastrointestinal tract is the most common serious drug-induced toxicity reported to drug regulatory authorities. In the last two decades, the rediscovery of H. pylori, development of potent ulcer-healing drugs and specific Cox-II inhibitors have opened new horizons in the management of NSAID toxicity. A Working Party composed of gastroenterologists and rheumatologists in the Asia-Pacific region met in Cairns, Australia, in 1999 to review the literature and develop appropriate guidelines. Recommendations were made based on the latest existing evidence. The importance of clinical events as study endpoints was emphasized. While differences exist between NSAIDs and aspirin, most studies have shown that advanced age, history of peptic ulcer disease, serious concomitant illnesses and coprescription of NSAID/aspirin with anticoagulants and steroids are high risk factors. These patients should be considered for prophylactic anti-ulcer therapy. Helicobacter pylori infection may aggravate the toxicity of NSAIDs and, in selected cases, should be treated before NSAID/aspirin is prescribed. Proton pump inhibitors and misoprostol are the most promising agents in preventing gastric and duodenal ulcers. When NSAID/aspirin needs to be continued in patients who develop an NSAID-related ulcer, proton pump inhibitors offer the best healing effect. With the discovery of cyclo-oxygenase isoforms (Cox-I and Cox-II), preferential and specific Cox-II inhibitors have been developed. While early clinical data have suggested promising antiinflammatory effects and improved safety profile in the gastrointestinal tract, several key issues on long-term safety remain unresolved. The use of potent anti-ulcer therapy, treatment of H. pylori infection and the development of Cox-II inhibitor will change the scenario of NSAID/aspirin-related gastrointestinal toxicity in the next millennium.
Front Cover: Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity (ChemBioChem 19/2023) (2023)

PROteolysis-TArgeting Chimeras (PROTACs) are a class of molecules that eliminate proteins through the cell's degradation machinery. Here, to degrade an attractive cancer drug target known as focal adhesion kinase (FAK), the Nabet and Jiang labs developed a novel FAK PROTAC (BSJ-04-146). They show that BSJ-04-146 triggers rapid and specific FAK degradation in cancer cells and in mouse models, and induces improved biological responses compared to small molecule inhibitors. The cover picture depicts a firefly (BSJ-04-146) luring a moth (FAK) to the carnivorous plant (proteasome) and was designed by DrawImpacts. More information can be found in the Research Article by B. Jiang, B. Nabet et al.
Observation of Katrina/Rita Groove Deployment: Addressing Social and Communication Challenges of Ephemeral Groups (2006)

In order to better understand the challenges specific to the deployment of collaboration technologies in crisis situations, we conducted an informal observational study of the deployment of Groove Virtual Office to various civil and military groups at the heart of the disaster zone over the course of ten days. We summarize both general lessons learned from observations of social and communication challenges in crisis situations that impact technology adoption, and make specific recommendations for improving the deployment process of Groove to enable cross group collaboration. We generally found that dynamic, informal social networks and lightweight ephemeral work groups were essential social structures in the relief effort, and we discuss the need to innovate technologies to support these alternative types of organizations. We encourage that current technology centric innovation for ephemeral workgroups is complemented by a usage centric approach to help address emergent behaviors and opportunities.
Semantic content-based recommendation of software services using context (2013)

The current proliferation of software services means users should be supported when selecting one service out of the many which meet their needs. Recommender Systems provide such support for selecting products and conventional services, yet their direct application to software services is not straightforward, because of the current scarcity of available user feedback, and the need to fine-tune software services to the context of intended use. In this article, we address these issues by proposing a semantic content-based recommendation approach that analyzes the context of intended service use to provide effective recommendations in conditions of scarce user feedback. The article ends with two experiments based on a realistic set of semantic services. The first experiment demonstrates how the proposed semantic content-based approach can produce effective recommendations using semantic reasoning over service specifications by comparing it with three other approaches. The second experiment demonstrates the effectiveness of the proposed context analysis mechanism by comparing the performance of both context-aware and plain versions of our semantic content-based approach, benchmarked against user-performed selection informed by context.
Reparative Cell Therapy for the Heart: Critical Internal Appraisal of the Field in Response to Recent Controversies (2021)

The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.
LTE Measurements With CRS Interference Cancellation (2016)

Measurements of neighboring cells received power are one of the critical tasks of the user equipment in cellular networks. These measurements are used by the network to make decisions on user handover between cells and, therefore, have a significant impact on the network overall capacity. Recently, new requirements were added to the Long Term Evolution (LTE) specifications in order to improve the measurements accuracy in dense cellular environments by taking into account interference from neighboring base stations. In this letter, we propose a novel, low complexity and robust measurement algorithm for LTE that is capable of canceling interference from neighboring base stations and demonstrate its excellent performance through extensive simulations.
Intrinsic regulation of functional blood flow and water absorption in canine colon. (1980)

1. Autoregulation of total and absorptive site blood flow and H2O fluxes were studied in canine colon during arterial pressure decreases and venous pressure elevations. 2. Reductions in arterial pressure caused proportional decreases in total colonic blood flow indicating no autoregulatory ability. In contrast, absorptive site blood flow was constant over an arterial pressure range of 40-140 mmHg but decreased sharply below 40 mmHg. 3. Venous pressure elevation decreased total blood flow and increased resistance but had no effect on absorptive site blood flow over a range of 0-30 mmHg. 4. Net H2O absorption was unchanged by alteration of arterial or venous pressure but the unidirectional H2O fluxes decreased with arterial pressure reduction and were unchanged by venous pressure elevation. 5. Adenosine infusion increased total and absorptive site blood flow and the unidirectional H2O fluxes yet had no effect on net H2O flux. 6. It was concluded that absorptive site blood flow is very well autoregulated in the colon but total blood flow is not. Net H2O absorption is maintained during decreased blood flow by maintenance of blood flow to the mucosa and by decreasing the back flux of H2O across the mucosa.
Characterization of a DNA Aptamer with High Specificity toward Fibroblast Growth Factor Receptor 1 (2021)

Artificial ligands that recognize membrane receptors with high affinity and specificity provide a means for the precise control of receptor activity and the resulting biological functions. In the present work, we focused on a previously reported DNA aptamer that is a functional mimic of fibroblast growth factor (FGF) and evaluated its receptor specificity. It was revealed that the aptamer works as a selective agonist for FGF receptor (FGFR) 1 owing to its high specificity toward the receptor, despite the high sequence homology in the extracellular domains of the FGFR family. The excellent receptor-type specificity of the aptamer, which is distinct from that of native ligands, should offer new possibilities as a chemical tool to study the biological role of growth factor receptors. In this work, we evaluated receptor specificity of a previously reported DNA aptamer that works as a functional mimic of fibroblast growth factor (FGF). Despite the high sequence homology in the extracellular domains of the FGF receptor (FGFR) family, it was demonstrated that the aptamer works as a selective agonist for FGFR1 owing to its high specificity toward the receptor.
Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome (2006)

Early life stress has been implicated as a risk factor for irritable bowel syndrome (IBS). We studied the effect of neonatal maternal separation on the visceromotor response and the expression of c-fos, 5-HT, and its receptors/transporters along the brain-gut axis in an animal model of IBS. Male neonatal Sprague-Dawley rats were randomly assigned to a 3-h daily maternal separation (MS) or nonhandling (NH) on postnatal days 2-21. Colorectal balloon distention (CRD) was performed for assessment of abdominal withdrawal reflex as a surrogate marker of visceral pain. Tissues from dorsal raphe nucleus in midbrain, lumbar-sacral cord, and distal colon were harvested for semiquantitative analysis of c-fos and 5-HT. The expression of 5-HT expression, 5-HT3 receptors, and 5-HT transporter were analyzed by RT-PCR. Pain threshold was significantly lower in MS than NH rats. The abdominal withdrawal reflex score in response to CRD in MS rats was significantly higher with distension pressures of 40, 60, and 80 mmHg. In MS rats, the number of c-fos-like immunoreactive nuclei at dorsal horn of lumbar-sacral spinal cord increased significantly after CRD. 5-HT content in the spinal cord of MS rats was significant higher. In the colon, both 5-HT-positive cell number and 5-HT content were comparable between MS and NH groups before CRD. Post-CRD only MS rats had significant increase in 5-HT content. Protein and mRNA expression levels of 5-HT3 receptors and 5-HT transporter were similar in MS and NH rats. Neonatal maternal separation stress predisposes rats to exaggerated neurochemical responses and visceral hyperalgesia in colon mimicking IBS.
Interplay of Hydrogen Bonds and n→π* Interactions in Proteins (2013)

Protein structures are stabilized by multiple weak interactions, including the hydrophobic effect, hydrogen bonds, electrostatic effects, and van der Waals interactions. Among these interactions, the hydrogen bond is distinct in having its origins in electron delocalization. Recently, another type of electron delocalization, the n→π* interaction between carbonyl groups, has been shown to play a role in stabilizing protein structure. Here we examine the interplay between hydrogen bonding and n→π* interactions. To address this issue, we used data available from high-resolution protein crystal structures to interrogate asparagine side-chain oxygen atoms that are both acceptors of a hydrogen bond and donors of an n→π* interaction. Then we employed natural bond orbital analysis to determine the relative energetic contributions of the hydrogen bonds and n→π* interactions in these systems. We found that an n→π* interaction is worth ~5-25% of a hydrogen bond and that stronger hydrogen bonds tend to attenuate or obscure n→π* interactions. Conversely, weaker hydrogen bonds correlate with stronger n→π* interactions and demixing of the orbitals occupied by the oxygen lone pairs. Thus, these two interactions conspire to stabilize local backbone-side-chain contacts, which argues for the inclusion of n→π* interactions in the inventory of non-covalent forces that contribute to protein stability and thus in force fields for biomolecular modeling.
Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity (2017)

Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This "bounce-back" response is achieved through a unique mechanism. Nrf1 is constitutively translocated into the ER lumen, N-glycosylated, and then targeted for proteasomal degradation via the ER-associated degradation (ERAD) pathway. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Under these conditions, Nrf1 is inactive in regulating proteasome subunit gene expression in response to proteasome inhibition. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. Thus, NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis.
Solidification of concentrated pea protein–pectin mixtures as potential binder (2023)

The chemical makeup of the biopolymers and their spatial distribution determines solidification behavior in concentrated biopolymer mixtures. In general, pea protein-pectin mixtures can solidify and therefore have the potential to act as binders in meat analogues. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Innentitelbild: Green‐Solvent‐Processed Molecular Solar Cells (Angew. Chem. 52/2014) (2014)

Hochleistungssolarzellen wurden durch Abscheiden molekularer Halbleiter aus dem “grünen” Lösungsmittel 2-Methyltetrahydrofuran (2-MeTHF) hergestellt, wie G. C. Bazan et al. in ihrer Zuschrift auf S. 14606 ff. beschreiben. Die lichtsammelnde halbleitende Schicht besteht dabei aus einem molekularen Donor mittlerer Größe und einem löslichen Fullerenderivat. Die Ergebnisse weisen den Weg zu einer nachhaltigen Solarzellproduktion ohne toxische Substanzen.
Giant enhancement of high-harmonic generation in graphene-metal heterostructures (2020)

Graphene-metal heterostructures can confine the optical field down to the atomic level. We report record enhancement of high-harmonic generation and demonstrate, for the first time, that plasmons can indeed affect the graphene nonlinear optical response.
Initial assessment of a simple system for frequency domain diffuse optical tomography (1995)

Diffuse optical tomography is an imaging technique whereby spatial maps of absorption and scattering coefficients are derived from the characteristics of multiply scattered light transmitted through the object. The system described here used four intensity-modulated light sources and measurements of the intensity and phase (relative to each source) at 16 or 20 detectors on the surface of a 10 cm diameter cylinder. An iterative Newton-Raphson algorithm was used to estimate the absorption and scattering coefficients at each pixel in a 17 x 17 array minimizing the difference between measured and calculated values of the intensity and phase at the measurement sites. Forward calculations of the intensity and phase were based on a multigrid finite-difference solution of the frequency domain diffusion equation. Numerical simulations were used to examine the resolution, contrast, and accuracy of the reconstructions as well as the effects of measurement noise, systematic uncertainties in source-detector location, and accuracy of the initial estimates for the optical properties. Experimental tests also confirmed that the system could identify and locate both scattering and absorbing inhomogeneities in a tissue-simulating phantom.
Cancer Neoepitopes for Immunotherapy: Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display (2019)

Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A<sup>*</sup>02:01 epitope prediction from tumor cell lines from two HLA-A2-positive melanoma patients whose TIL displayed strong tumor reactivity. The potential neoepitopes were screened for recognition using autologous TIL by immunological assays and presentation on tumor major histocompatibility complex class I (MHC-I) molecules by Poisson detection mass spectrometry (MS). TIL from the patients recognized 5/181 and 3/49 of the predicted neoepitopes, respectively. MS screening detected 3/181 neoepitopes on tumor MHC-I from the first patient but only one was also among those recognized by TIL. Consequently, TIL enriched for neoepitope specificity failed to recognize tumor cells, despite being activated by peptides. For the second patient, only after IFN-γ treatment of the tumor cells was one of 49 predicted neoepitopes detected by MS, and this coincided with recognition by TIL sorted for the same specificity. Importantly, specific T cells could be expanded from patient and donor peripheral blood mononuclear cells (PBMC) for all neoepitopes recognized by TIL and/or detected on tumor MHC-I. In summary, stimulating the appropriate inflammatory environment within tumors may promote neoepitope MHC presentation while expanding T cells in blood may circumvent lack of specific TIL. The discordance in detection between physical and functional methods revealed here can be rationalized and used to improve neoantigen-targeted T cell immunotherapy.
Robot‐Based Tele‐Echography (2007)

Our study on 58 patients suggests that the TER system could be a reliable, acceptable, and effective robot-based system for performing remote abdominal aortic ultrasound examinations. Research is continuing to improve the equipment for general abdominal use.