gebhart/patrepeval huggingface dataset:
Novel 1-acyl-pyrazoline derivatives as highly selective inhibitors of c-Met-kinase (2007)

A241 The role of the receptor tyrosine kinase c-Met in the development and progression of cancer is well established and suggests that inhibitors of c-Met will emerge as important novel therapeutics in the oncology field. As a result of a high-throughput-screening of our corporate database, a series of 1-acyl-pyrazoline derivatives was identified as submicromolar inhibitors of Met-kinase, for example compound 1 with IC50(c-Met-kinase) = 330 nM. The X-ray structure of 1 with the c-Met-kinase domain revealed a unique binding mode which was advantageously used for subsequent optimization. Medicinal chemistry around these hits gave highly potent inhibitors of c-Met-kinase both in enzymatic and cellular assays, for example compound 2 with IC50(c-Met-kinase) = 3 nM and IC50(c-Met-ELISA) = 340 nM.  Several of our acyl-pyrazoline derivatives were screened for inhibition of a broad panel of kinases and they turned out to be inhibitors of c-Met-kinase exclusively.  The synthesis, structure-activity relationships and pharmacokinetic properties of this new class of c-Met-kinase inhibitors will be presented.
A new procedure for the cloning, expression and purification of the β-carbonic anhydrase from the pathogenic yeastMalassezia globosa, an anti-dandruff drug target (2015)

Malassezia yeasts are almost exclusively the single eukaryotic members of the fungal flora of the skin. Malassezia globosa and Malassezia restricta are found on the skin of practically all humans. Malassezia globosa is highly implicated in the pathogenesis of dandruff and its genome encodes for only one carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the β-class (MgCA). It has been indeed demonstrated that in many pathogenic microorganisms, CAs are essential for their life cycle and their inhibition can lead to growth impairment and defects. In the previous work, the recombinant MgCA was investigated for its inhibition profile with sulfonamides, which in models of dandruff infection were able to protect animals from the fungal infection, allowing us to propose this enzyme as a new antidandruff target. MgCA was cloned as GST-fusion protein, but the yield was rather low and the protein was often found in inclusion bodies. Here, we propose an alternative procedure consisting in cloning the recombinant MgCA as His-Tag fusion protein. This procedure resulted in a good method to express and purify the active recombinant MgCA, and the protein recovery was better with respect to that used for preparing MG-CA (β-CA cloned as GST-fusion protein).
Supplementary Figures and Legends from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy (2023)

&lt;p&gt;Supplementary Figures 1-7 and matching legends&lt;/p&gt;
S0652 Real World Exposure-Response Relationship of Vedolizumab in Inflammatory Bowel Disease: A Pooled Multicenter Observational Cohort Analysis of Clinical and Modeled Pharmacological Data (2020)

INTRODUCTION: The role of vedolizumab (VDZ) therapeutic drug monitoring in patients with ulcerative colitis (UC) or Crohn's disease (CD) is under investigation. However, a thorough understanding of the relationship between VDZ serum concentrations and clinical outcomes is lacking. METHODS: ERELATE was a retrospective cohort study conducted at 9 centers in 6 countries. Data were pooled from real-world clinical cohorts of patients with UC or CD treated with VDZ. Clinically important treatment outcomes based on definitions commonly used across centers were collected at Weeks 14, 26, and 52. Using a population pharmacokinetic model,1 VDZ dosing, baseline body weight, and albumin concentration were used to predict VDZ concentrations. A Bayesian approach incorporated observed VDZ concentrations to refine individual predicted concentrations. Relationships between predicted concentrations and observed clinically important outcomes were investigated. VDZ concentration thresholds were determined using the optimal Youden index point along the receiver operating characteristic curve. Correlation and agreement between observed and predicted concentrations were evaluated using Spearman (ρ) and intra-class correlation (ICC) coefficients, respectively. RESULTS: In total 695 patients (304 UC, 391 CD) were included; 47.9% were male. Median age was 39 years, median disease duration was 9 years, and 86.3% had prior anti-tumor necrosis factor exposure. Clinically important outcome rates for UC and CD are shown in Table 1. Significant correlation ([ρ = 0.879; P < 0.01] across all timepoints) and agreement (ICC = 0.722; P < 0.01) were noted between observed and predicted concentrations, indicating adequate Bayesian model prediction of individual VDZ concentrations. Observed exposure-response relationships were more pronounced in UC than CD. Differences in VDZ concentration and drug concentration area under the curve from Weeks 0–6 were observed between remitters and non-remitters for UC and CD combined (Table 2). Predicted VDZ concentrations of 30.8 and 33.8 µg/mL at Week 6 and 16.6 and 14.4 µg/mL at Week 14 were associated with clinical remission and deep remission, respectively, at Week 52. CONCLUSION: These real-world data confirm GEMINI trial findings of significant relationships between VDZ serum concentration and clinical outcomes. Adequate drug concentrations during induction therapy may be important predictors of short- and long-term treatment outcomes.Table 1.: Clinically Important Outcomes in Patients With UC or CDTable 2.: Predicted Vedolizumab Trough Concentrations Associated With Clinical and Deep Remission in Patients With UC or CD
Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells (2018)

The presence of persistent, latent HIV reservoirs in CD4+ T cells obstructs current efforts to cure infection. The so-called kick-and-kill paradigm proposes to purge these reservoirs by combining latency-reversing agents with immune effectors such as cytotoxic T lymphocytes. Support for this approach is largely based on success in latency models, which do not fully reflect the makeup of latent reservoirs in individuals on long-term antiretroviral therapy (ART). Recent studies have shown that CD8+ T cells have the potential to recognize defective proviruses, which comprise the vast majority of all infected cells, and that the proviral landscape can be shaped over time due to in vivo clonal expansion of infected CD4+ T cells. Here, we have shown that treating CD4+ T cells from ART-treated individuals with combinations of potent latency-reversing agents and autologous CD8+ T cells consistently reduced cell-associated HIV DNA, but failed to deplete replication-competent virus. These CD8+ T cells recognized and potently eliminated CD4+ T cells that were newly infected with autologous reservoir virus, ruling out a role for both immune escape and CD8+ T cell dysfunction. Thus, our results suggest that cells harboring replication-competent HIV possess an inherent resistance to CD8+ T cells that may need to be addressed to cure infection.
Case Report (2012)

These results demonstrate the effectiveness of the LipiFlow in restoring MG function and improving ocular comfort even in this particular case of significant MG dropout and MG truncation.
A mathematic model of a cardiovascular system regulated by the baroreflex (2006)

A dynamic, nonlinear, lumped parameter model of the cardiovascular system coupled with a baroreflex model is presented. The cardiovascular system in the model consists of the left heart (ventricle) and systemic load and is represented by a fourth order nonlinear time-varying differential equation. The baroreflex is an important internal feedback mechanism in the body whose function is to regulate and stabilize the blood pressure. It plays a major role in the circulatory system by adjusting the systemic vascular resistance (SVR), heart rate (HR), heart contractility and total blood volume based on arterial pressure. The baroreflex model is represented by seven coupled nonlinear differential equations. The response of the combined eleventh order cardiovascular and baroreflex system to single changes in model parameters in preload, afterload, left ventricular contractility, and heart rate is examined. More specifically, by changing certain parameters in the combined model, different levels of human activities can be simulated. The results of our studies show that the model is capable of reproducing coherent human hemodynamic responses which agree with real exercise experimental data reported in the literature.
Abstract 1981: MYC downregulation and chemoresistance in non-small cell lung cancer (NSCLC): Evidence from the Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program (2010)

Abstract Background: Primary or acquired resistance to platinum-based therapy remains an important issue in the treatment of unresectable non-small cell lung cancer (NSCLC). Our objective was to identify factors of resistance to platinum-based therapy. Experimental procedures: Gene expression profiling from the BATTLE program (pretreated resistant tumors stage III/IV, N=32) and a control group from 2 independent publicly available datasets (never treated tumors stage III/IV, N=45) were compared. Gene expression profiling was generated using the same platform (U133 Plus 2.0 Array). Pathway and gene set analyses were used to define networks and pathways associated with resistance. For validation, we used: i-an independent set of 38 never treated NSCLC stage III/IV, ii-a set of 53 NSCLC cell lines tested for cisplatin sensitivity with proteomic profiling generated by Reverse Phase Protein Array (RPPA) technology using 177 well-characterized antibodies, iii-the comparison of two pairs of NSCLC cell lines (H1437, H460) that were made resistant by iterative exposure to cisplatin, and iv-transfection experiments. Results: A total of 3,963 probesets were found to be differentially expressed between BATTLE samples and the control group with a p-value &amp;lt; 0.001 (two-tailed t-test). DNA repair gene sets were upregulated in BATTLE samples compared to never treated tumors. Network analysis found that MYC as well as many of its downstream regulated genes were significantly downregulated in BATTLE samples. In particular, a high proportion of MYC target genes associated with apoptosis were downregulated. Using real time PCR, MYC gene expression was significantly lower in 15 BATTLE samples compared with an independent set of 38 never treated stage III/IV NSCLC (p-value=0.01). The proteomic profiling of 53 NSCLC cell lines showed that MYC expression was one of the top proteins associated with sensitivity to cisplatin. An inverse correlation was observed between sensitivity to cisplatine (IC50) and MYC protein expression evaluated by RPPA (total MYC: r=-0.41, p-value=0.003; phosphorylated MYC: r=-0.30, p-value=0.03). MYC gene expression by real time PCR was lower in resistant H1437 and H460 cell lines compared to parental cell lines. Finally, transfection of H226 cell lines with a vector expressing MYC improved sensitivity to cisplatin compared to the control. Conclusion: This is the first gene expression profiling analysis of NSCLC samples pretreated and resistant to chemotherapy included in a prospective clinical trial. MYC down regulation may play an important role in NSCLC resistance to platinum-based chemotherapy. Mechanisms of MYC down regulation should be further explored. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1981.
Shear Wave Induced Resonance Elastography of Venous Thrombi: A Proof-of-Concept (2012)

Shear wave induced resonance elastography (SWIRE) is proposed for deep venous thrombosis (DVT) elasticity assessment. This new imaging technique takes advantage of properly polarized shear waves to induce resonance of a confined mechanical heterogeneity. Realistic phantoms (n = 9) of DVT total and partial clot occlusions with elasticities from 406 to 3561 Pa were built for in vitro experiments. An ex vivo study was also performed to evaluate the elasticity of two fresh porcine venous thrombi in a pig model. Transient shear waves at 45-205 Hz were generated by the vibration of a rigid plate (plane wavefront) or by a needle to simulate a radiation pressure on a line segment (cylindrical wavefront). Induced propagation of shear waves was imaged with an ultrafast ultrasound scanner and a finite element method was developed to simulate tested experimental conditions. An inverse problem was then formulated considering the first resonance frequency of the DVT inclusion. Elasticity agreements between SWIRE and a reference spectroscopy instrument (RheoSpectris) were found in vitro for total clots either in plane (r(2) = 0.989) or cylindrical (r(2) = 0.986) wavefront configurations. For total and partial clots, elasticity estimation errors were 9.0 ±4.6% and 9.3 ±11.3%, respectively. Ex vivo, the blood clot elasticity was 498 ±58 Pa within the inferior vena cava and 436 ±45 Pa in the right common iliac vein (p = 0.22). To conclude, the SWIRE technique seems feasible to quantitatively assess blood clot elasticity in the context of DVT ultrasound imaging.
New design strategies for ultra-specific CRISPR-Cas13a-based RNA-diagnostic tools with single-nucleotide mismatch sensitivity (2023)

ABSTRACT The pressing need for clinical diagnostics has required the development of novel nucleic acid-based detection technologies that are sensitive, fast, and inexpensive, and that can be deployed at point-of-care. Recently, the RNA-guided ribonuclease CRISPR-Cas13 has been successfully harnessed for such purposes. However, developing assays for detection of genetic variability, for example single-nucleotide polymorphisms, is still challenging and previously described design strategies are not always generalizable. Here, we expanded our characterization of LbuCas13a RNA-detection specificity by performing a combination of experimental RNA mismatch tolerance profiling, molecular dynamics simulations, protein, and crRNA engineering. We found certain positions in the crRNA-target-RNA duplex that are particularly sensitive to mismatches and establish the effect of RNA concentration in mismatch tolerance. Additionally, we determined that shortening the crRNA spacer or modifying the direct repeat of the crRNA leads to stricter specificities. Furthermore, we harnessed our understanding of LbuCas13a allosteric activation pathways through molecular dynamics and structure-guided engineering to develop novel Cas13a variants that display increased sensitivities to single-nucleotide mismatches. We deployed these Cas13a variants and crRNA design strategies to achieve superior discrimination of SARS-CoV-2 strains compared to wild-type LbuCas13a. Together, our work provides new design criteria and new Cas13a variants for easier-to-implement Cas13-based diagnostics. KEY POINTS Certain positions in the Cas13a crRNA-target-RNA duplex are particularly sensitive to mismatches. Understanding Cas13a’s allosteric activation pathway allowed us to develop novel high-fidelity Cas13a variants. These Cas13a variants and crRNA design strategies achieve superior discrimination of SARS-CoV-2 strains. GRAPHICAL ABSTRACT New strategies to improve Cas13a RNA-detection specificity developed via mismatch tolerance profiling, uncovering features that modulate specificity, and structure-guided engineering of LbuCas13a.
Pathogen enrichment sequencing (PenSeq) enables population genomic studies in oomycetes (2018)

The oomycete pathogens Phytophthora infestans and P. capsici cause significant crop losses world-wide, threatening food security. In each case, pathogenicity factors, called RXLR effectors, contribute to virulence. Some RXLRs are perceived by resistance proteins to trigger host immunity, but our understanding of the demographic processes and adaptive evolution of pathogen virulence remains poor. Here, we describe PenSeq, a highly efficient enrichment sequencing approach for genes encoding pathogenicity determinants which, as shown for the infamous potato blight pathogen Phytophthora infestans, make up < 1% of the entire genome. PenSeq facilitates the characterization of allelic diversity in pathogen effectors, enabling evolutionary and population genomic analyses of Phytophthora species. Furthermore, PenSeq enables the massively parallel identification of presence/absence variations and sequence polymorphisms in key pathogen genes, which is a prerequisite for the efficient deployment of host resistance genes. PenSeq represents a cost-effective alternative to whole-genome sequencing and addresses crucial limitations of current plant pathogen population studies, which are often based on selectively neutral markers and consequently have limited utility in the analysis of adaptive evolution. The approach can be adapted to diverse microbes and pathogens.
Fast pulse Doppler radar processing accounting for range bin migration (2002)

An airborne pulse Doppler radar depends on a combination of range selectivity and velocity selectivity to detect targets in ground clutter. At a sufficiently high bandwidth the phenomenon of range bin migration occurs, precluding the use of conventional Doppler processing. The product of the range-rate and the coherent integration period exceeds the range resolution. A fast algorithm is introduced. It performs coherent integration/Doppler filtering while explicitly accounting for range bin migration. The fast algorithm is based on an integration along a slanted line in the 2-D frequency domain.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Neutronics Analysis and Design Optimization of the Pellet Bed Reactor for Bimodal Applications (1994)

A three‐dimensional MCNP analysis of the fast spectrum Pellet Bed Reactor (PeBR) is performed to determine reactor core point designs for bimodal system concepts of 10 and 40 kWe. Design requirements include an operation lifetime of ten years in the power mode, and more than 250 hours in the propulsion mode at a specific impulse > 650 seconds and thrust of a few to tens of Newtons, maximum fuel temperature < 1600 K, that is maintained almost constant during power and propulsion modes, a fuel burnup < 2.0 atom%, negative temperature reactivity feedback, passive decay heat removal, redundancy in reactor control, and sub‐criticality during water flooding accidents. The excess reactivity at beginning‐of‐mission (BOM) is as much as $1.5 at 1600 K (keff = 1.012) for a reactor core that measures 0.32 m in diameter and 0.45 m high and is loaded with 6.0 mm, UC, TRISO‐type fuel mini‐spheres. The reactor core point design has a total negative temperature reactivity of $3.0, a desirable operation and safety feature, a total mass of 328 kg and 347 kg for the 10 kWe and 40 kWe system, respectively, and employs two independent control systems with built‐in redundancy in each system: sliding reflector segments and B4C safety rods. The sliding reflector‐safety rods in combination, ensures sub‐criticality during submersion in water or wet sand.
Cleaning up our own backyard: developing new zoSs'~~F catabolic pathways to degrade pollutants ')bJrso2 6x3 Microbial-based strategies for pollution control require metabolic pathways by which man-made compounds may be degraded. Recombination-based mutagenesis and selection procedures may be able to mimic the evolution of catabolic pathways and generate enzymes with novel specificities. (1995)

In the past century or two, industrial manufacturing has generated large quantities of new organic chemicals, ranging in function from paints and plastics to explosives and biocides. The eventual fates of these manmade compounds (xenobiotics) was of little concern while their quantities were relatively small. As economies and industries have grown, however, the spread of xenobiotics through the environment whether as a result of their intended use, accidental release or waste-disposal policies - has made it increasingly clear that neither the atmosphere nor the oceans have unlimited dilution capacities.
Oxytocin Induces Prostaglandin F2α Release in Pregnant Cows: Influence of Gestational Age and Oxytocin Receptor Concentrations1 (1996)

Brahman cows with known breeding dates received i.v. injections of either 10 or 100 IU oxytocin (OT) on Days 50, 150, 250, or 280 of gestation (n = 6 for each stage). Concentrations of the prostaglandin (PG) F2 alpha metabolite, 13,14-dihydro-15-keto-prostaglandin (PGFM), and OT were measured in samples of peripheral plasma collected at 15-min intervals for 1 h before and 1 h after treatment and then at 30-min intervals for 3 h. Plasma progesterone was measured daily for 14 days after OT injections on Days 50 and 250 of gestation. The increase in plasma OT after injection was dose-dependent (p = 0.001) but not affected by stage of gestation. Plasma PGFM increased after OT in a dose- and stage-dependent manner (p = 0.0001). At Day 280, the increase in plasma PGFM after 100 IU OT was sevenfold greater than at Day 50. Plasma progesterone declined significantly during the 7th to 12th days postinjection and returned to normal pregnancy values by the 14th day (4.4 +/- 0.3 ng/ml) except in two cows treated on Day 50 of gestation that later aborted. In these, plasma progesterone was significantly lower, 2.6 +/- 0.1 ng/ml. In a second experiment, the concentration of OT receptors was determined in endometrium collected from purebred Angus or Hereford cows slaughtered on Days 50, 150, 250, and 280 of gestation (n = 3 or 4 at each stage). Endometrial concentrations of OT receptor changed as a function of gestational age, increasing sixfold from Day 50 to Day 280, which was parallel to the increase by OT of plasma PGFM. Thus, endometrial OT receptors are functionally coupled to PGF2 alpha release during pregnancy, and their concentration determines the magnitude of OT-induced PGF2 alpha release during gestation. Consequently, endogenous OT is a factor in the regulation of PGF2 alpha release from the bovine uterus during pregnancy and parturition.
Thermal profiles during recrystallization of silicon on insulator with scanning incoherent light line sources (1985)

The classical heat equation is solved in one and two dimensions to obtain temperature profiles during recrystallization of silicon thin films on insulators with scanning incoherent light sources. The extent of the Si molten region in multilayered structures is predicted using a macroscopic approach. The enthalpy method incorporates the latent heat of fusion into the temperature-enthalpy relation for Si; the Kirchhoff transformation takes the temperature dependence of the thermal conductivities for the materials into account. The calculations yield the Si melt depths and temperatures and are intended to establish proper experimental conditions.