gebhart/patrepeval huggingface dataset:
Phase 1 study of cemiplimab, a human monoclonal anti-PD-1, in patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Final efficacy and safety data. (2018)

9557 Background: Initial analysis of expansion cohorts (ECs) patients in a phase 1 study showed that cemiplimab (REGN2810) demonstrated a positive risk/benefit profile and produced antitumor activity in patients (pts) with advanced CSCC. We now report mature final data from the CSCC ECs of the phase 1 study (NCT02383212). Methods: Pts with distantly metastatic and locally advanced CSCC were enrolled in EC 7 and 8, respectively. All pts received cemiplimab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks for up to 48 weeks. Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate (ORR; complete response [CR] + partial response [PR]). The data cutoff date was Oct 02, 2017. Tumor response was assessed by an independent central review committee. Results: A total of 26 pts were enrolled (21 M/ 5 F; 10 in EC 7, 16 in EC 8; median age: 72.5 years [range, 55–88]; ECOG performance status 1 in 16 pts and 0 in 10 pts). Median duration of cemiplimab exposure was 36.0 weeks. The most common treatment-related adverse event (TRAE) of any grade was fatigue (26.9%). The following ≥Grade 3 TRAEs occurred once: asthenia, maculopapular rash, increased alanine aminotransferase, increased aspartate aminotransferase, adrenal insufficiency, and myalgia. ORR was 50.0% (95% CI: 29.9–70.1); 0 CR and 13 PRs. Disease control rate (DCR; ORR + stable disease [SD] + non-CR + non-progressive disease [PD]) was 76.9% (95% CI: 56.4–91.0); 6 SD and 1 non-CR/non-PD. Durable DCR (SD/non-CR/non-PD or response for ≥105 days) was 65.4% (95% CI: 44.3–82.8). 3 pts were not evaluable for response. The median duration of response has not been reached; however, for pts with PR, the duration of response exceeded 6 months in 7 pts and 12 months in 2 pts. Median time to response was 2.3 months (range, 1.7–7.3). Median duration of follow-up was 11.0 months (range: 1.1–17.0). Conclusions: In this study, cemiplimab demonstrated a positive risk/benefit profile and produced substantial antitumor activity as well as durable responses in pts with advanced CSCC. Clinical trial information: NCT02383212.
Total Synthesis of Buergerinin F via Effective Construction of the Asymmetric Quaternary Carbons Using an Enantioselective Aldol Reaction. (2005)

Abstract For Abstract see ChemInform Abstract in Full Text.
Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2 (2021)

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (<b>15</b>) through structure-guided optimization of our previously published isoindolinone lead (<b>7</b>). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.
A fast algorithm for the analysis of scattering by elongated cavities (2018)

Electromagnetic scattering from elongated, arbitrarily shaped, open-ended cavities (OEC) has been studied extensively over the years. In this paper, we introduce the fast encapsulating domain decomposition (EDD) scheme for the analysis of radar cross section (RCS) of such OEC. The EDD advantages stem from a domain decomposition along the elongated dimension, followed by a spectral representation of the fields in each segment, whereby the field is naturally separated into in- and out-going waves. This diagonalizes the translation between the cross sections, thus reducing the per segment computational complexity from to , where and are the number of aperture and wall unknowns per segment, satisfying as the segmentation is constructed to be smaller than the cross section. The results of the EDD are demonstrated on an S-shaped elongated open-ended cavity.
Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics (2019)

• Combination of B-mode ultrasound, shear-wave elastography, and contrast ultrasound radiomics through machine learning is technically feasible. • Multiparametric ultrasound demonstrated a higher prostate cancer localization ability than single ultrasound modalities. • Computer-aided multiparametric ultrasound could help clinicians in biopsy targeting.
Hydrogen adsorption in microporous hypercrosslinked polymers (2006)

A microporous hypercrosslinked polymer resin was synthesized and shown to adsorb 3.04 wt.% hydrogen at 77 K and 15 bar; this represents the highest level of hydrogen adsorption yet observed for an organic polymer.
Carer Knowledge and Experiences With Menopause in Women With Intellectual Disabilities (2010)

Abstract Overall life expectancy for women with intellectual disabilities (ID) is now significantly extended, and many will live long enough to experience menopause. Little is known about how carers support women with ID through this important stage in their lives. This study investigated carer knowledge of how menopause affects women with ID under their care and how they may help them to cope with it. One‐to‐one interviews were undertaken with 69 carers (7 male/62 female) from a range of backgrounds, all with current responsibility for the care of one or more pre‐, peri‐, and/or postmenopausal women with ID. Carers reported difficulty in disentangling the psychological and physical consequences of the menopause from behaviors and symptoms arising from other causes. There was general recognition of the transitional importance of menopause and a widespread acknowledgment of the resilience that many women with ID show in coping with it. However, carers emphasized the need for health resources to be better tailored to the women's needs and for more relevant health education training for staff. The authors conclude that additional and new demands are placed on service provision as women with ID live longer. An increased awareness of health issues relating to menopause is needed, as are more appropriate and readily available relevant health education materials for women with ID in middle age.
Structural studies in the bruceol system (1981)

Single-crystal X-ray structure determinations of the chloro- and iodo-acetates of (–)-bruceol have been carried out, confirming the structure of (–)-bruceol and allowing a probable assignment of absolute configuration. The structure of (±)-deoxybruceol has also been determined.
Conversion to Mycophenolate Mofetil Monotherapy in Liver Recipients: Calcineurin Inhibitor Levels are Key (2016)

The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow-up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.
Abstract B16: Using human patient-derived organoids to identify genetic dependencies in pancreatic cancer (2016)

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable model systems to interrogate pathways involved in pancreatic tumorigenesis and to probe individual responses to novel therapies are urgently needed. To that end, we established methods to culture normal and neoplastic pancreatic duct cells as three-dimensional organoid cultures. Pancreatic organoids can be rapidly generated from resected tumors or fine needle biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Following orthotopic transplant, neoplastic organoids recapitulated the full spectrum of tumor development by forming early-grade neoplasms that progressed to locally invasive and metastatic carcinomas, demonstrating the utility of organoids to model the stages of PDA tumorigenesis. Monolayer cell lines were generated from organoid cultures with high efficiency, creating a diverse collection of new PDA cell lines. To better understand pathways involved in PDA progression, we performed transcriptomic and proteomic analyses of murine organoids derived from normal pancreatic ducts, pancreatic intraepithelial neoplasias (PanINs), and PDAs. These datasets revealed expression changes associated with early and late pancreatic tumorigenesis. To identify genes dysregulated during pancreatic tumorigenesis whose depletion impaired human PDA cells, a CRISPR-Cas competition assay was employed. Taken together, pancreatic organoids offer a novel model system for studying pancreatic cancer biology and can be used to screen for genetic dependencies in PDA. Citation Format: Lindsey A. Baker, Hervé Tiriac, Vincenzo Corbo, Sylvia F. Boj, Chang-il Hwang, Iok In Christine Chio, Danielle D. Engle, Myrthe Jager, Mariano Ponz-Sarvise, Mona S. Spector, Ana Gracanin, Tobiloba Oni, Kenneth H. Yu, Ruben van Boxtel, Meritxell Huch, Keith D. Rivera, John P. Wilson, Michael E. Feigin, Daniel Öhlund, Abram Handly-Santana, Christine M. Ardito-Abraham, Michael Ludwig, Ela Elyada, Brinda Alagesan, Giulia Biffi, Georgi N. Yordanov, Bethany Delcuze, Brianna Creighton, Kevin Wright, Youngkyu Park, Folkert H.M. Morsink, I. Quintus Molenaar, Inne H. Borel Rinkes, Edwin Cuppen, Yuan Hao, Ying Jin, Isaac J. Nijman, Christine Iacobuzio-Donahue, Steven D. Leach, Darryl J. Pappin, Molly Hammell, David S. Klimstra, Olca Basturk, Ralph H. Hruban, George Johan Offerhaus, Robert G.J. Vries, Hans Clevers, David A. Tuveson. Using human patient-derived organoids to identify genetic dependencies in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B16.
High-performance conjugate-gradient benchmark: A new metric for ranking high-performance computing systems (2015)

We describe a new high-performance conjugate-gradient (HPCG) benchmark. HPCG is composed of computations and data-access patterns commonly found in scientific applications. HPCG strives for a better correlation to existing codes from the computational science domain and to be representative of their performance. HPCG is meant to help drive the computer system design and implementation in directions that will better impact future performance improvement.
UV Raman detection of micro-organisms and their toxins in fish tissue (2002)

It has been determined that domoic acid (DA) can be quantitated from homogenized shellfish tissue by means of resonance Raman spectra excited by 251 nm light. Detection limits have been found to be substantially below the 20 micrograms DA per grain tissue deemed by regulators to be unfit for human consumption. Clam tissue obtained from a supermarket has been prepared for analysis by direct homogenization for 2 minutes in a Waring blender. The homogenized samples were placed in a flow system and subjected to a 5-10 mw 251 nm excitation. Back-scattering collected for 20-30 seconds provided sufficient information for analysis. The method is extremely simple to use since the DA produces a single intense peak at 1652 cm<SUP>-1</SUP>. Because relatively-weak protein, nucleic acid and lipid spectra are excited from the tissue, background interference is surprisingly low. Bacteria can be detected using the same approach, but sensitivities are much lower primarily due to spectral interference from tissue nucleic acids.
Correction: Quantitative Description of Glycan-Receptor Binding of Influenza A Virus H7 Hemagglutinin (2013)

In the context of recently emerged novel influenza strains through reassortment, avian influenza subtypes such as H5N1, H7N7, H7N2, H7N3 and H9N2 pose a constant threat in terms of their adaptation to the human host. Among these subtypes, it was recently demonstrated that mutations in H5 and H9 hemagglutinin (HA) in the context of lab-generated reassorted viruses conferred aerosol transmissibility in ferrets (a property shared by human adapted viruses). We previously demonstrated that the quantitative binding affinity of HA to a2R6 sialylated glycans (human receptors) is one of the important factors governing human adaptation of HA. Although the H7 subtype has infected humans causing varied clinical outcomes from mild conjunctivitis to severe respiratory illnesses, it is not clear where the HA of these subtypes stand in regard to human adaptation since its binding affinity to glycan receptors has not yet been quantified. In this study, we have quantitatively characterized the glycan receptor-binding specificity of HAs from representative strains of Eurasian (H7N7) and North American (H7N2) lineages that have caused human infection. Furthermore, we have demonstrated for the first time that two specific mutations; Gln226RLeu and Gly228RSer in glycan receptor-binding site of H7 HA substantially increase its binding affinity to human receptor. Our findings contribute to a framework for monitoring the evolution of H7 HA to be able to adapt to human host.
Regioselective synthesis of 2‐methyl‐2,5,6,11,12,13‐hexahydro 4H indazolo[5,4‐a]pyrrolo[3,4‐c]carbazole‐4‐ones (2009)

Abstract magnified image 2‐Methyl‐2,5,6,11,12,13‐hexahydro 4H indazolo[5,4‐a]pyrrolo[3,4‐c]carbazole‐4‐one was synthesized utilizing a regioselective Diels‐Alder reaction with 5‐(1H‐indol‐2‐yl)‐2‐methyl‐6,7‐dihydro‐2H‐indazole and ethyl cis ‐β‐cyanoacrylate. Acetic acid and YtBr 3 were the best solvent and catalyst for the regioselective Diels‐Alder reaction. The chemistry was used to synthesize novel 8‐pyrimidinyloxy‐2,5,6,11,12,13‐hexahydro 4H indazolo[5,4‐a]pyrrolo[3,4‐c]carbazole‐4‐ones that were screened and found to be potent inhibitors of DLK. J. Heterocyclic Chem., (2009).
Prediction of Asphaltene Deposition in Porous Media by Systematic Upscaling from a Colloidal Pore Scale Model to a Deep Bed Filtration Model (2011)

Abstract We have successfully validated the Asphaltene Option in ECLIPSE, using an experimental data set from the literature. We compare our results with a previous Deep Bed Filtration simulation model of the same data. We find that the experimental data can be reproduced by using the surface deposition parameter α only. This provides an important simplification of the Asphaltene Option in ECLIPSE. Moreover, the values of α can be predicted from a pore scale colloid dynamics simulation model using the Stochastic Rotation Dynamics (SRD) technique. It turns out that the values for α obtained in the literature (Wang, 2001) and our own ECLIPSE results are consistent with the predictions from the SRD simulation model. This may give an advantage over other asphaltene deposition models available in the literature.
Error-resilient packet header compression (2008)

Full packet headers consume valuable bitrate, which is especially costly in satellite links and some terrestrial wireless links. This has motivated the compression of packet headers by exploiting their correlation via using finite-state machines. The drawback is that compression in the presence of channel errors (packet loss) may result in error propagation. We offer several designs by adapting error control codes for the requirements of packet header compression in uni-directional and bi-directional links, and explore the tradeoffs in complexity, delay, and system performance. For the bi-directional link, we propose a new design called predictive hybrid ARQ and evaluate its performance. Experiments show significant gains in link-layer throughput as well as improved application layer performance demonstrated via video transfer experiments.
Pre-existing Hemagglutinin Stalk Antibodies Correlate with Protection of Lower Respiratory Symptoms in Flu-Infected Transplant Patients (2020)

Hemagglutination-inhibitory antibodies are usually highly strain specific with little effect on infection with drifted or shifted strains. The significance of broadly cross-reactive non-HAI anti-influenza antibodies against conserved domains of virus glycoproteins, such as the hemagglutinin (HA) stalk, is of great interest. We characterize a cohort of 40 H1N1pmd09 influenza-infected patients and identify lower respiratory symptoms (LRSs) as a predictor for development of pneumonia. A binomial logistic regression of log10 pre-existing antibody values shows that the probability of LRS occurrence decreased with increased anti-HA full-length and stalk antibody ELISA titers. However, a multilevel logistic regression model adjusted by other potential serocorrelates demonstrates that only antibodies directed against the stalk of HA correlate with protection from lower respiratory infection, limiting disease progression. Our predictive model indicates that a threshold of protective immunity based on broadly cross-reactive HA stalk antibodies could be feasible.
Synthesis of myo-inositol 1-phosphorothioate 4,5-bisphosphate: preparation of a fluorescently labelled myo-inositol 1,4,5-trisphosphate analogue (1990)

Synthesis of myo-inositol 1-phosphorothioate 4,5-bisphosphate, a novel analogue of the second messenger myo-inositol 1,4,5-trisphosphate allows, for the first time, the attachment of a fluorescent reporter group at the 1-position.
Reliability and cost assessment methodology of medium-voltage feeders (2017)

The authors introduce a methodology which quantifies medium-voltage (MV) feeder reliability in the form of commonly used indices. The contribution of the proposed methodology focuses on the modelling not only of the grid itself but also of the detailed actual operational practices of the distribution system operator (DSO), taking into consideration the specific parameters of the examined network. By doing so, the influence of diverse reliability enhancement measures on different feeders can be evaluated and assessed. The method is tested using real (MV) feeders, considering as measures the installation of protection units and remote control capabilities to the switches. Furthermore, by considering the cost of protection and remotely controlled units, the proposed methodology performs techno-economic analyses to assess the trade-offs between enhancing grid reliability and increasing costs, serving as a decision-making tool for modern DSOs.
Plgf−/−eNos−/−mice show defective angiogenesis associated with increased oxidative stress in response to tissue ischemia (2006)

Neo-angiogenesis is a complex phenomenon modulated by the concerted action of several molecular factors. We have generated a congenic line of knockout mice carrying null mutations of both placental growth factor (PlGF) and endothelial nitric oxide synthase (eNOS), two genes that play a pivotal role in the regulation of pathological angiogenesis. In the present study, we describe the phenotype of this new experimental animal model after surgically induced hind-limb ischemia. Plgf-/-, eNos-/-, Plgf-/- eNos-/-, and wild-type C57BL/6J mice were studied. Plgf-/- eNos-/- mice showed the most severe phenotype: self-amputation, and death occurred in up to 47% of the animals studied; in ischemic legs, capillary density was severely reduced; macrophage infiltration and oxidative stress increased as compared to the other groups of animals. These changes were associated with an up-regulation of both inducible NOS (iNOS) expression and vascular endothelial growth factor (VEGF) protein levels in ischemic limbs, and to an increased extent of protein nitration. Our results demonstrate that the deletion of these two genes, Plgf, which acts in synergism with VEGF, and eNos, a downstream mediator of VEGF, determines a significant change in the vascular response to an ischemic stimulus and that oxidative stress within the ischemic tissue represents a crucial factor to maintain tissue homeostasis.
Propagermanium Suppresses Macrophage-Mediated Formation of Coronary Arteriosclerotic Lesions in Pigs in Vivo (2003)

Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.