gebhart/patrepeval huggingface dataset:
Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC) (2021)

Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound <b>4</b> (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with <b>4</b>. Subsequent lead optimization of <b>4</b> led to amelioration of this pathway and nomination of <b>5</b> (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).
Methylation of histone H3K23 blocks DNA damage in pericentric heterochromatin during meiosis (2014)

Despite the well-established role of heterochromatin in protecting chromosomal integrity during meiosis and mitosis, the contribution and extent of heterochromatic histone posttranslational modifications (PTMs) remain poorly defined. Here, we gained novel functional insight about heterochromatic PTMs by analyzing histone H3 purified from the heterochromatic germline micronucleus of the model organism Tetrahymena thermophila. Mass spectrometric sequencing of micronuclear H3 identified H3K23 trimethylation (H3K23me3), a previously uncharacterized PTM. H3K23me3 became particularly enriched during meiotic leptotene and zygotene in germline chromatin of Tetrahymena and C. elegans. Loss of H3K23me3 in Tetrahymena through deletion of the methyltransferase Ezl3p caused mislocalization of meiosis-induced DNA double-strand breaks (DSBs) to heterochromatin, and a decrease in progeny viability. These results show that an evolutionarily conserved developmental pathway regulates H3K23me3 during meiosis, and our studies in Tetrahymena suggest this pathway may function to protect heterochromatin from DSBs.
Structure of Adsorbed Polyampholyte Layers at Charged Objects (2000)

We have developed a theory of adsorption of polyampholyte chains at a charged planar surface and a charged spherical particle from dilute low salt solutions. The adsorption is due to the polarization of polyampholyte chains in the external electric field created by charged objects. The equilibrium polymer density profile is determined by the balance of the long-range polarization-induced attraction of polyampholytes to the charged object and the monomer−monomer repulsion. We demonstrate that the long-range nature of polyampholyte adsorption leads to an adsorbed layer much thicker than the size of individual chains. Using the self-consistent mean-field and scaling approaches, we obtain the detailed structure of the adsorbed layers.
Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901 (2017)

Inhibition of the MAPK/ERK pathway by PD0325901 may be an effective therapy for reducing dispersal and growth of GBM cells.
Exponential bounds and stopping rules for MCMC and general Markov chains (2006)

We develop explicit, general bounds for the probability that the empirical sample averages of a function of a Markov chain on a general alphabet will exceed the steady-state mean of that function by a given amount. Our bounds combine simple information-theoretic ideas together with techniques from optimization and some fairly elementary tools from analysis. In one direction, motivated by central problems in simulation, we develop bounds for the general class of "geometrically ergodic" Markov chains. These bounds take a form that is particularly suited to simulation problems, and they naturally lead to a new class of sampling criteria. These are illustrated by several examples. In another direction, we obtain a new bound for the important special class of Doeblin chains; this bound is optimal, in the sense that in the special case of independent and identically distributed random variables it essentially reduces to the classical Hoeffding bound.
Real- and reciprocal-space attributes of band tail states (2017)

Band tail states are localized electronic states existing near conduction and valence band edges. Band tail states are invariably found to exhibit an exponential distribution defined by a characteristic (Urbach) energy. To a large extent, the band tail state density of states determines the electronic performance of an amorphous semiconductor (or insulator) in terms of its mobility. Real-space assessment of a suitable density of states model for extended (delocalized) conduction or valence band states and nearby localized band tail states leads to an expression for the peak density of band tail states at the mobility edge and for the total band tail state density. Assuming a continuous density of states and its derivative with respect to energy across the mobility edge, these densities are found to depend on only two parameters – the Urbach energy and an effective mass characterizing the extended state density above the mobility edge. Reciprocal-space assessment is then employed to deduce a probability density function associated with band tail states. The full width at half maximum of the resulting Gaussian probability density function is found to be equal to the average real-space distance of separation between band tail states, as estimated from the total band tail state density. This real- and reciprocal-space insight may be useful for developing new high-performance amorphous semiconductors and for modeling their electronic properties.
Effect of reduced Cu(InGa)(SeS)<inf>2</inf> thickness using three-step H<inf>2</inf>Se/Ar/H<inf>2</inf>S reaction of Cu-In-Ga metal precursor (2013)

Cu(In,Ga)(Se,S) <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> (CIGSS) absorbers with thicknesses from 1.9 to 0.25 µm have been grown using a three-step selenization/Ar-anneal/sulfization reaction ofCu-In-Ga metal precursors. Material characterization revealed changes in orientation, apparent grain size, and formation of voids at the Mo/CIGSS interface with reduced thickness. Even with absorber thickness decreased to 0.25 µm and lateral compositional nonuniformity, V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">OC</inf> and fill factor were nearly sustained, while J <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SC</inf> decreased due to incomplete absorption. With the 0.25-µm-thick absorber layer, an efficiency of 9.1% (without AR coating) with V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">OC</inf> = 612 mV, J <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SC</inf> = 21.0 mA/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> , and FF = 71.1% was obtained.
A prospective randomized study of sutured versus stapled bowel anastomoses in patients with cancer (1986)

Eighty-eight cancer patients with the presence of one or more adverse factors for healing (carcinomatosis, adhesions, prior chemotherapy and radiation therapy, bowel obstruction, anemia, and low leukocyte count or albumin value) were prospectively randomized to undergo conventional two-layer hand suturing (45 patients) or mechanical stapling with a GIA/TA instrument (U.S. Surgical Corp., Norwalk, CT) (43 patients) of the large or small bowel anastomosis. Age, sex, complete blood count findings, and all biochemical plasma values were comparable in both groups. The anastomosis took an average of 19 minutes for the sutured and 9 minutes for the stapled technique (P = 0.0001), but the average length of operation, postoperative return of bowel function, and hospital stay were comparable in both groups. Bowel fistula was seen in one case of stapled anastomosis (P = not significant). The pulmonary and wound complication rates were the same in both groups. Of the four deaths (4.5%) due to causes unrelated to bowel anastomosis, three occurred in the stapled and one in the sutured group. It was concluded that a stapled anastomosis is as safe as a sutured one in patients with advanced-stage cancer. It saves time in anastomosis, but does not save time in postoperative return of the bowel function and hospital stay.
3D image-based scatter estimation and correction for multi-detector CT imaging (2014)

The aim of this work is to implement and evaluate a 3D image-based approach for the estimation of scattered radiation in multi-detector CT. Based on a reconstructed CT image volume, the scattered radiation contribution is calculated in 3D fan-beam geometry in the framework of an extended point-scatter kernel (PSK) model of scattered radiation. The PSK model is based on the calculation of elemental scatter contributions propagating the rays from the focal spot to the detector across the object for defined interaction points on a 3D fan beam grid. Each interaction point in 3D leads to an individual elemental 2D scatter distribution on the detector. The sum of all elemental contributions represents the total scatter intensity distribution on the detector. Our proposed extended PSK depends on the scattering angle (defined by the interaction point and the considered detector channel) and the line integral between the interaction point on a 3D fan beam ray and the intersection of the same ray with the detector. The PSK comprises single- and multiple scattering as well as the angular selectivity characteristics of the anti-scatter grid on detector. Our point-scatter kernels were obtained from a low-noise Monte-Carlo simulation of water-equivalent spheres with different radii for a particular CT scanner geometry. The model allows obtaining noise-free scatter intensity distribution estimates with a lower computational load compared to Monte-Carlo methods. In this work, we give a description of the algorithm and the proposed PSK. Furthermore, we compare resulting scatter intensity distributions (obtained for numerical phantoms) to Monte-Carlo results.
Radiofrequency tumor ablation system with a wireless or implantable probe (2020)

Radiofrequency ablation (RFA) is a non-invasive image-guided procedure where tumors are heated in the body with electrical current. RFA procedures are commonly indicated for patients with limited local disease or who are not surgical candidates. Current methods of RFA use multiple cords and wires that ergonomically complicate the procedure and present the risk of cutting or shorting the circuit if they are damaged. A wireless RFA technique based on electromagnetic induction is presented in this paper. The transmitting and receiving coils were coupled to resonate at the same frequency to ensure the highest power output. The receiving coil was connected to two insulated electrodes on a catheter, which allowed the current to flow to the targeted tissue. The prototype system was tested with ex-vivo bovine tissue, which has similar thermal and electrical properties to human tissue. The setup can monitor the received power, efficiency, temperature, and ablation zone during ablation procedures. The maximum received power was 15 W, and the average maximum efficiency was 63.27%. The novel system was also able to ablate up to a 2 cm ablation zone in non-perfused tissue. This proof of concept for performing RFA wirelessly with electromagnetic induction may merit further optimization.
Placing a robot manipulator amid obstacles for optimized execution (2003)

This paper presents an efficient algorithm for optimizing the base location of a robot manipulator in an environment cluttered with obstacles, in order to execute specified tasks as fast as possible. The algorithm uses randomized motion planning techniques and exploits geometric "coherence" in configuration space to achieve fast computation. The performance of the algorithm is demonstrated on both synthetic examples and real-life CAD data from the automotive industry. The computation time ranges from under a minute for simple problems to a few minutes for more complex ones.
VHF-UHF Precipitation-Static Interference Effects on Aircraft (1979)

In early researches very occasional precipitation static was reported at VHF frequencies. With increasing IFR traffic density, even occasional interference can be serious and for military operations, interference on communications channels can present a serious hazard during ground controlled instrument approaches as well as jeopardizing possible mission success. Experimental investigations of military and commercial aircraft have disclosed that the severe interference is caused by electrically isolated metallic sections on the aircraft exterior which become charged by frictional contact with atmospheric particles and then sparkover to the airframe. This results in a severe broadband interference spectrum centered at a wavelength corresponding to the dimensions of the section which is sparking. Although this type of interference has been previously observed, the investigations again illustrate the severity of the interference and the difficulty in identifying it. Also discovered in the investigations which had not previously been found was receiver desensitization resulting from corona discharges from commercial grounded type VHFUHF antennas. This can occur without the flight crew being aware of it. This investigation indicates that all VHF-UHF antennas having corona discharges from exposed metallic extremities may suffer this desensitization while in flight without the flight crew being aware of it as the interference does not break the squelch. The magnitude of the desensitization may reach 30 db. The impact of this phenomena on commercial airline and military operations, where ground controlled approach may be the only type of instrument approach available for some aircraft, suggests a serious potential problem which needs to be identified and corrected.
Syntheses and Properties of N-Fluoropyridinium Salts (1991)

Abstract Various stable N-fluoropyridinium salts with a non- or weakly nucleophilic counter anion such as TfO−, FSO3−, BF4−, SbF6−, ClO4−, CH3SO3− etc., or with an electron-donating or -withdrawing substituent(s) on the pyridine ring were synthesized and their properties investigated. N-Fluoropyridinium-2-sulfonates, N-fluoroquinolinium triflate, and highly hindered N-fluoro-2,6-di-t-butylpyridinium salts were also synthesized. They were synthesized by counter anion displacement reactions of unstable pyridine-F2 compounds, fluorination of salts of pyridines with protonic acids or silyl esters with F2, and/ or fluorination of Lewis acid complexes of pyridines. The scope of each method was examined in detail. Each of the N-fluoropyridinium salts was assigned as the first stable 1 : 1 salt structure of the pyridine nucleus and halogen atom on the basis of the spectral and elemental analyses. The stability depended on the nucleophilicity or basicity of the counter anions and electronic nature or position of the ring substituents. These results and NMR analyses clearly showed the unstable pyridine-F2 compounds to have N-fluoropyridinium fluoride salt structure. Some N-fluoropyridinium triflates were hydrolyzed and the products were examined, suggesting a unique hydrolysis mechanism.
Harnessing Natural Modularity of Metabolism with Goal Attainment Optimization to Design a Modular Chassis Cell for Production of Diverse Chemicals (2020)

Modular design is key to achieve efficient and robust systems across engineering disciplines. Modular design potentially offers advantages to engineer microbial systems for biocatalysis, bioremediation, and biosensing, overcoming the slow and costly design-build-test-learn cycles in the conventional cell engineering approach. These systems consist of a modular (chassis) cell compatible with exchangeable modules that enable programmed functions such as overproduction of a desirable chemical. We previously proposed a multiobjective optimization framework coupled with metabolic flux models to design modular cells and solved it using multiobjective evolutionary algorithms. However, such approach might not achieve solution optimality and hence limits design options for experimental implementation. In this study, we developed the goal attainment formulation compatible with optimization algorithms that guarantee solution optimality. We applied goal attainment to design an <i>Escherichia coli</i> modular cell capable of synthesizing all molecules in a biochemically diverse library at high yields and rates with only a few genetic manipulations. To elucidate modular organization of the designed cells, we developed a flux variance clustering (FVC) method by identifying reactions with high flux variance and clustering them to identify metabolic modules. Using FVC, we identified reaction usage patterns for different modules in the modular cell, revealing that its broad pathway compatibility is enabled by the natural modularity and flexible flux capacity of endogenous core metabolism. Overall, this study not only sheds light on modularity in metabolic networks from their topology and metabolic functions but also presents a useful synthetic biology toolbox to design modular cells with broad applications.
Jejunal Infusion of Levodopa–Carbidopa Intestinal Gel Versus Oral Administration of Levodopa–Carbidopa Tablets in Japanese Subjects with Advanced Parkinson’s Disease: Pharmacokinetics and Pilot Efficacy and Safety (2015)

In Japanese subjects with advanced PD, LCIG resulted in an improved pharmacokinetic profile that appeared to be associated with reduced motor complications compared with LC-oral. These results extend previous findings in mainly Caucasian populations.
Kernel Protection Against Just-In-Time Code Reuse (2019)

The abundance of memory corruption and disclosure vulnerabilities in kernel code necessitates the deployment of hardening techniques to prevent privilege escalation attacks. As stricter memory isolation mechanisms between the kernel and user space become commonplace, attackers increasingly rely on code reuse techniques to exploit kernel vulnerabilities. Contrary to similar attacks in more restrictive settings, as in web browsers, in kernel exploitation, non-privileged local adversaries have great flexibility in abusing memory disclosure vulnerabilities to dynamically discover, or infer, the location of code snippets in order to construct code-reuse payloads. Recent studies have shown that the coupling of code diversification with the enforcement of a “read XOR execute” (R ∧ X) memory safety policy is an effective defense against the exploitation of userland software, but so far this approach has not been applied for the protection of the kernel itself. In this article, we fill this gap by presenting kR ∧ X: a kernel-hardening scheme based on execute-only memory and code diversification. We study a previously unexplored point in the design space, where a hypervisor or a super-privileged component is not required. Implemented mostly as a set of GCC plugins, kR ∧ X is readily applicable to x86 Linux kernels (both 32b and 64b) and can benefit from hardware support (segmentation on x86, MPX on x86-64) to optimize performance. In full protection mode, kR ∧ X incurs a low runtime overhead of 4.04%, which drops to 2.32% when MPX is available, and 1.32% when memory segmentation is in use.
Abstract A28: Mutational landscape of TP53 in localized prostate cancer (2017)

Abstract Background: We performed a comprehensive interrogation of the mutational landscape of TP53 in the context of localized prostate cancer using a large clinical/molecular-paired dataset from the Canadian Prostate Cancer Gene Network (CPC-GENE). We further test the associations of TP53 mutations with outcomes post-image-guided radiotherapy (IGRT) or radical prostatectomy (RadP). Methods: Copy number status (N = 284), single nucleotide variants (SNV) (N = 123), methylation status (N = 117), and mRNA abundance profiling (N = 115) were assessed using the Affymetrix Oncoscan FFPE express v3.0 assay, whole genome sequencing (up to 100-200x), Illumina 450K methylation array, and Affymetrix HuGene 2.0 array, respectively. Patient cohort comprised of NCCN-defined intermediate-risk prostate cancer who underwent either IGRT (N = 146) or RadP (N = 137). Biochemical-relapse free rate (bRFR) was assessed as the primary clinical end-point. Results: We identified 65 cases (22.9%) with mono-/bi-allelic copy number alteration (CNA) of TP53, and 7 cases (5.7%; 6 non-synonymous and 1 splice variant) with TP53 SNV in our cohort, which was comparable with the TCGA (30% CNA, 7% SNV) and MSKCC (17% CNA, 2.9% SNV) cohorts of low to high-risk localized prostate cancers. Epigenomic profiling revealed specific sites of DNA hypermethylation (β-value &amp;gt;0.7) within the body and 5' UTR gene-regions, while the TSS gene-region was unaffected. Genomic mutations (CNA and/or SNV) of TP53 were associated with global genomic instability (percent genome aberration of 9.5 vs 6.4, p = 0.001) and reduced mRNA levels (mRNA abundance Z-Score: -0.58 vs 0.22, p-value = 0.0011), but methylation status had no consequence on these indices. Neither TP53 genomic mutations (HR = 1.35, 95% CI 0.91-2.00, Wald's p = 0.14) nor mRNA abundance (HR = 1.39, 95% CI 0.71-2.75, Wald's p = 0.34) was associated with bRFR on multivariable analyses. However, stratification by combinatorial genomic and mRNA abundance indices identified an unfavorable subgroup that was associated with poorer bRFR on multivariable analysis (HR = 2.95, 95% CI 1.42-6.12, Wald's p = 0.004). Conclusions: This is the first comprehensive interrogation of the mutational landscape of TP53 in localized prostate cancer. Our findings suggest that functional TP53 loss at both the copy number and transcription level accounts for a subset of non-indolent localized prostate cancer. Citation Format: Osman Mahamud, Melvin L.K Chua, Stephane Supiot, Emilie Lalonde, Alan Dal Pra, Alejandro Berlin, Michèle Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Yves Fradet, Bernard Têtu, Gaetano Zafarana, Alice Meng, Julie Livingstone, Melania Pintilie, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Bristow G. Robert. Mutational landscape of TP53 in localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A28.
Cell‐intrinsic adenosine A 2A receptor signaling is required for T cell homeostasis and tumor surveillance (2012)

Adenosine A 2A receptors (A 2A Rs) are highly expressed in certain neuronal and immune cells and regulate locomotor activity, sleep, and immune functions. Thus, A 2A Rs are promising pharmacological targets in a wide range of conditions such as sleep disorders, inflammatory disorders and cancer. Although it is known that stimulation of A 2A Rs on T cells inhibits their activation, global deletion of A 2A Rs does not affect the growth of weakly immunogenic tumors. To study the role of A 2A Rs on T cells we generated a mouse line with T cell‐specific A 2A R deletion. Here, we report that A 2A R signaling is required to maintain normal numbers of peripheral naïve CD4 and CD8 T cells. T cell‐specific A 2A R deletion does not affect thymic T cell differentiation but inhibits naïve T cell survival in response to interleukin‐7 ex vivo. In mice injected with syngeneic B16F10 melanoma cells, T cell specific A 2A R deletion decreases T cell numbers in the periphery and in the tumor, reduces the proportion of tumor infiltrating T cells with an activated/memory phenotype, and markedly accelerates tumor growth. The results indicate that A 2A R signaling is required for T cell homeostasis and control of tumor growth.