gebhart/patrepeval huggingface dataset:
The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor (2010)

First line therapy for treatment-naïve HIV patients typically include the combination of two drugs from the nucleoside or nucleotide class (N(t)RTIs), that target the viral reverse transcriptase (RT), along with either a non-nucleoside RT inhibitor (NNRTI) or HIV protease inhibitor. The N(t)RTIs therefore play an important role as the backbone of choice in HIV regimens, prompting the initiation of a research program aimed at discovering a novel, next generation N(t)RTI. The chapter describes the medicinal strategy that was used to develop a novel nucleoside phosphonate, including structure based design rationales to improve potency, resistance and selectivity. The novel NtRTI GS-9148 (22) that was discovered demonstrated a favorable resistance profile toward many clinically relevant N(t)RTI resistant isolates, and encompassed a rationally designed fluorine group to improve selectivity. To effectively deliver 22 and its active phosphorylated metabolite into lymphoid cells harboring replicating HIV, a unique prodrug strategy was employed. Prodrugs were designed as substrates of lysosomal cathepsin A, a peptidase highly expressed in lymphoid cells, to effectively target in vivo delivery of 22 to the lymphatic system. Ethylalaninyl phosphonamidate prodrug GS-9131 (32) successfully targeted 22 to peripheral blood mononuclear cells upon oral dosing in Beagle dogs (3 mg /kg) and resulted in intracellular active metabolite levels exceeding 9.0 μM, a level 5-fold higher than the HIV RT IC50 of 22. The favorable preclinical profile of 32 led to its nomination as a clinical candidate for the treatment of HIV patients harboring N(t)RTI resistant virus.
ChemInform Abstract: Antibacterial Active Substances. Part 11. The Aminomethinylation of CH2‐Acidic Isonitriles. (1986)

Abstract Aus den Isonitrilen (I) werden durch Deprotonierung und anschlie‐ βende Umsetzung mit dem Triazin (II) die 4‐substituierten Imidazole (III) erhalten.
Improving Occupancy Grid Mapping via Dithering for a Mobile Robot Equipped with Solid-State LiDAR Sensors (2018)

Occupancy grid maps are by far the most used spatial representation of the environment for robot navigation. This paper proposes a simple and effective way to improve the occupancy grid accuracy by superimposing a small oscillation to the robot motion when a predefined path is given. The method is especially suited for range sensors with long range capabilities but poor angular resolution. The innovative solid state LiDAR technology is an example of such sensor configuration and is used in this work for the experimental evaluation of the presented dithering technique. Experimental results quantitatively demonstrated that the proposed oscillating motion is effective especially in speeding up the detection of corridor like clearances in the environment.
Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol (2009)

The genotoxins ethyl chloride (EtCl) and methyl chloride (MeCl) were generated during the preparation of the hydrochloride salts of two tertiary amines in the presence of ethanol and methanol, respectively. In EtOH five batches of a tertiary amine hydrochloride were prepared on 0.3−18 kg scale using 37% aqueous HCl; residual EtCl was detected at less than 10 ppm in each batch. The preparation of the hydrochloride salt of another tertiary amine in MeOH on a 3 kg scale produced salt with 11−12 ppm of MeCl, and these higher levels precipitated investigations into controlling the levels of residual MeCl in batches of the HCl salt of the second amine. Four rework procedures were developed to reduce the level of MeCl in one batch of HCl salt. Generating the salts at a lower temperature (10 °C) was the key parameter to minimize the concentration of these impurities in this drug candidate when HCl was charged as 37% aqueous HCl. Control of the process was demonstrated by preparing a 30 kg batch containing 1 ppm of MeCl without rework processing; this level of MeCl is well within the guideline of ≤1.5 μg for the daily dosage of this drug candidate. The analytical methods to detect EtCl and MeCl, which were critical for the development of these processes, are also described.
Notch pathway blockade inhibits glioblastoma growth by depleting CD133 positive stem-like cancer cells (2008)

5001 CD133-positive cancer stem cells (CSCs) in glioblastoma (GBM) were recently shown to be resistant to commonly used chemo- and radiation-therapies (Nature, 444:756-60, 2006; Mol Cancer, 5:67, 2006). Finding reagents that can target CSCs may therefore improve the treatment of GBM patients. It has been shown that the Notch signaling pathway regulates normal stem cells in the central nervous system, and that GBM neurosphere lines show high Notch activity (Cancer Research, 64:7011-21, 2004; Cancer Cell, 9:391-403, 2006). However, it is unknown if Notch pathway blockade could target CSCs in GBM. We have demonstrated recently that Notch pathway inhibition depletes CSCs and blocks engraftment in medulloblastomas (Cancer Research, 66:7445-52, 2006), a common malignant brain tumor in children. Recent studies have shown that GBM propagated as neurospheres more accurately replicate the infiltrating growth patterns seen in primary tumors when injected into nude mice, and contain stem-like cancer cells. In the present study, we used GBM neurosphere lines to examine the effects of Notch pathway inhibition on CSCs. We found that Notch pathway blockade by 2 µM levels of the Gamma-Secretase Inhibitor GSI-18 reduced expression of CD133 by more than 90% and inhibited tumor growth in 3 independent lines by 20 to 70% in vitro. In contrast, overexpression of an active form of Notch2 (NICD2) increased both pathway activity and tumor growth approximately 2-fold in vitro. When equal numbers of viable GSI-18 or vehicle (DMSO) treated GBM neurosphere cells were injected subcutaneously into nude mice, DMSO treated cells always formed tumors whereas GSI-18 treated cells did not. Most importantly, in vivo delivery of GSI-18 by polymer based beads two weeks after orthotopic tumor engraftment also effectively blocked the tumor growth intracranially and significantly prolonged survival. We believe that this compound is acting primarily via Notch blockade, as mice bearing orthotopic xenografts stably transfected with GSI-insensitive NICD2 formed larger tumors and had uniformly short survival when treated with GSI-18. These results suggest that depleting CSCs by Notch pathway blockade inhibits tumor growth and propagation both in vitro and in vivo. Finally, reduced proliferation was seen in GSI-18 treated GBM stem-like cells, as evidenced by decreased Ki-67 expression observed selectively in the Nestin+ population. Increased expression of cleaved caspase-3 was also seen in GBM neurospheres following Notch blockade. Reduced expression of phosphorelated Akt and STAT3 in these GBM neurosphere cells after GSI-18 application suggests that Notch pathway inhibition depletes CSCs through Akt/STAT3 mediated apoptosis. In summary, we demonstrate that Notch pathway blockade depletes stem-like cells in GBMs, suggesting that Gamma-secretase inhibitors can be used as chemotherapeutic reagents to target CSCs in malignant brain tumors.
Größen- und Dichtemessung im CT (Size and Attenuation CT - SACT) zur Interim-Evaluation von Lymphomen als zusätzlicher Surrogatparameter für ein zuverlässigeres Therapie-Response-Monitoring (2011)

Ziele: Ziel ist die retrospektive Analyse der potentiellen Bedeutung zusätzlicher Dichtemessungen im CT zur Evaluation des Therapieansprechens bei residuellen Lymphommassen von Patienten mit Morbus Hodgkin (MH) und follikulären Non-Hodgkin-Lymphomen (FL). Methode: In dieser retrospektiven Studie wiesen 39 Patienten mit MH und 35 Patienten mit FL residuelle Lymphom-Massen in der Interim-CT-Kontrolle (nach 2–4 Zyklen Chemotherapie) auf. Diese wurden mittels kontrastangehobenem CT vor, während und nach Therapie untersucht. Die Größe der Residuen wurde als Produkt von Längs- und Querdurchmesser erhoben. Eine Tumor-Dichterelation (attenuation ratio – AR) wurde als Quotient der Dichten von Tumor und Muskel zum jeweiligen Zeitpunkt gegenüber der Ausgangsuntersuchung berechnet. Die Resultate wurden mit Rezidiv-freier Überlebenszeit von mindestens 6 Monaten nach Therapieabschluss korreliert. Ergebnis: Eine Größenzunahme von >10% sowie eine Dichtezunahme im CT von >20% zeigte ein Therapieversagen mit Falsch-Positiven von 1/64 und 2/64 Patienten an. Entsprechend entsprach eine Größenabnahme von >10% sowie eine Dichteabnahme von >15% einem Therapieansprechen mit Falsch-Negativen von 0/8 Patienten. Die Sensitivität und Spezifität des Therapieversagens mittels Interim-SACT betrugen für FL und MH 88% (FL 80%, MH 100%) und 98% (FL 97%, HD 100%). Die negativen prädiktiven Werte durch SACT-Analyse waren jeweils ≥97%. Schlussfolgerung: Die Interim-Evaluation des Therapieansprechens mittels SACT bei residuellen Lymphommassen von Patienten mit MH und FL stellt einen potentiellen weiteren Surrogatparameter zur Risikostratifizierung dar.
8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist (2009)

cADPR (cyclic ADP-ribose) is a universal Ca(2+) mobilizing second messenger. In T-cells cADPR is involved in sustained Ca(2+) release and also in Ca(2+) entry. Potential mechanisms for the latter include either capacitative Ca(2+) entry, secondary to store depletion by cADPR, or direct activation of the non-selective cation channel TRPM2 (transient receptor potential cation channel, subfamily melastatin, member 2). Here we characterize the molecular target of the newly-described membrane-permeant cADPR agonist 8-Br-N(1)-cIDPR (8-bromo-cyclic IDP-ribose). 8-Br-N(1)-cIDPR evoked Ca(2+) signalling in the human T-lymphoma cell line Jurkat and in primary rat T-lymphocytes. Ca(2+) signalling induced by 8-Br-N(1)-cIDPR consisted of Ca(2+) release and Ca(2+) entry. Whereas Ca(2+) release was sensitive to both the RyR (ryanodine receptor) blocker RuRed (Ruthenium Red) and the cADPR antagonist 8-Br-cADPR (8-bromo-cyclic ADP-ribose), Ca(2+) entry was inhibited by the Ca(2+) entry blockers Gd(3+) (gadolinium ion) and SKF-96365, as well as by 8-Br-cADPR. To unravel a potential role for TRPM2 in sustained Ca(2+) entry evoked by 8-Br-N(1)-cIDPR, TRPM2 was overexpressed in HEK (human embryonic kidney)-293 cells. However, though activation by H(2)O(2) was enhanced dramatically in those cells, Ca(2+) signalling induced by 8-Br-N(1)-cIDPR was almost unaffected. Similarly, direct analysis of TRPM2 currents did not reveal activation or co-activation of TRPM2 by 8-Br-N(1)-cIDPR. In summary, the sensitivity to the Ca(2+) entry blockers Gd(3+) and SKF-96365 is in favour of the concept of capacitative Ca(2+) entry, secondary to store depletion by 8-Br-N(1)-cIDPR. Taken together, 8-Br-N(1)-cIDPR appears to be the first cADPR agonist affecting Ca(2+) release and secondary Ca(2+) entry, but without effect on TRPM2.
An Internal Fuel Efficiency Credit Market Mechanism for Meeting the CAFE Standard: Internalizing a Regulation Caused Externality (2008)

The paper develops and analyzes an internal market based mechanism that enables a decentralized enterprise to meet the conditions of the Corporate Average Fuel Economy (CAFE) regulations. Divisions that produce vehicles with fuel economy (miles per gallon fuel) above the regulatory requirement receive Fuel Efficiency Credits (FEC). These credits can be sold in an internal FEC market to divisions that produce vehicles with fuel economy levels below the regulatory requirement. The FEC available for sale by fuel efficient vehicle production and the FEC needed as a condition of production of fuel inefficient vehicles are tied to the respective fuel efficiency levels. Experimental tests demonstrate that the enterprise can achieve near profit maximum levels while continuing to operate through decentralized profit centers. The FEC market "internalizes" the externality across divisions created by the CAFE regulation. The behavioral model supported by the data suggests that the policy can be successfully crafted to include multiple firms trading FECs.
Supplementary Figure from Clinical Validation of EndoPredict in Pre-Menopausal Women with ER-Positive, HER2-Negative Primary Breast Cancer (2023)

Supplementary Figure from Clinical Validation of EndoPredict in Pre-Menopausal Women with ER-Positive, HER2-Negative Primary Breast Cancer
Texture Analysis Improves Accuracy of Computer-assisted Differentiation between Small Hepatic Cysts and Hepatocellular Carcinoma on Noncontrast CT (2011)

Background Small (< 1.5cm in diameter) liver lesions are commonly detected incidentally on non-contrast CT exams. Characterization of these lesions as cystic or solid is crucial to patient management but is frequently not possible without other imaging modalities. Evaluation This study explored whether texture analysis could increase diagnostic confidence for the differentiation of simple Hepatic Cysts (SC) and Hepatocellular Carcinoma (HCC) from normal liver parenchyma (NP) in non-contrast CT exams. Patients (42) were retrospectively selected, 21 with ultrasound confirmed SC and 21 with positive pathology for HCC. Images were resampled to 0.75mm per pixel. Circular ROIs were drawn to fit the smallest lesion and copied nearby to overlie NP. A total of 84 ROIs were defined (21 SC + 21 HCC + 42 NP). Intensity metrics (IM) were measured, and texture features extracted, using either an S-Transform (ST) or a Wavelet Transform (WT) for each ROI. A Support Vector Machine Classifier was used to solve the classification problem. A leave-one-out cross-validation was used to estimate classification accuracy. Using IM only the accuracy was 89%. The statistical power to detect a 'biomarker of tissue type' was found to be equal to 0.98 at a 95% confidence level. Using IM and either ST or WT increased accuracy to 94%. Using IM and both ST and WT increased the accuracy to 95%. SCs were identified with 100% sensitivity (SN) and 100% specificity (SP). Differentiating HCC from NP had SN=77% (SP=94%) using IM only. Using IM and ST, the SN was 83% (SP=98%). Using IM and WT, the SN was 90% (SP=95%). Using IM and both WT and ST, the SN was 87% (SP=98%). Discussion The accuracy of distinguishing SC from NP or HCC tissue is improved by adding transform based texture features to pixel intensity analysis. Due to the small number of cases not correctly classified on the basis of intensity, this texture-enabled additional accuracy did not reach statistical significance. CONCLUSION Image intensity combined with texture analysis provides a robust tool that could aid in the discrimination between SC, HCC and NP for small liver lesions on non-contrast CT, avoiding the expense and inconvenience of additional imaging.
PersistentCryptococcus neoformansPulmonary Infection in the Rat Is Associated with Intracellular Parasitism, Decreased Inducible Nitric Oxide Synthase Expression, and Altered Antibody Responsiveness to Cryptococcal Polysaccharide (2000)

Fungal pathogens are notorious for causing chronic and latent infections, but the mechanism by which they evade the immune response is poorly understood. A major limitation in the study of chronic fungal infection has been the lack of suitable animal models where the infection is controlled and yet persists. Pulmonary Cryptococcus neoformans infection in rats results in a diffuse pneumonitis that resolves without dissemination or scarring except for the persistence of interstitial and subpleural granulomas that harbor viable cryptococci inside macrophages and epithelioid cells. Infected rats are asymptomatic but remain infected for as long as 18 months after inoculation with C. neoformans. Containment of infection is associated with granuloma formation that can be partially abrogated by glucocorticoid administration. Using this model, we identified several features associated with persistent infection in the rat lung, including (i) localization of C. neoformans to discrete, well-organized granulomas; (ii) intracellular persistence of C. neoformans within macrophages and epithelioid cells; (iii) reduced inducible nitric oxide synthase expression by granulomas harboring C. neoformans; and (iv) reduced antibody responses to cryptococcal polysaccharide. The results show that maintenance of persistent infection is associated with downregulation of both cellular and humoral immune responses.
Granger causality analysis of state dependent functional connectivity of neurons in orofacial motor cortex during chewing and swallowing (2012)

Primate feeding behavior is characterized by a series of jaw movement cycles of different types making it ideal for investigating the role of motor cortex in controlling transitions between different kinematic states. We recorded spiking activity in populations of neurons in the orofacial portion of primary motor cortex (MIo) of a macaque monkey and, using a Granger causality model, estimated their functional connectivity during transitions between chewing cycles and from chewing to swallowing cycles. We found that during rhythmic chewing, the network was dominated by excitatory connections and exhibited a few “out degree” hub neurons, while during transitions from rhythmic chews to swallows, the numbers of excitatory and inhibitory connections became comparable, and more temporarily varying “in degree” hub neurons emerged. Furthermore, based on shared connections between neurons between different networks, networks from same state transitions were quantitatively shown to be more similar. These results suggest that networks of functionally connected neurons in MIo change their operative states with changes in kinematically defined behavioral states.
<title>Ultrafast High Resolution Contact Lithography Using Excimer Lasers</title> (1982)

A new technique for fine-line, high-speed photolithography using ultraviolet excimer lasers is proposed and demonstrated. Absence of speckle and resolution down to 1000 line-pairs/mm are experimentally demonstrated. Using a XeCl laser at 308 nm and a KrF laser at 249 nm, excellent quality images are obtained by contact printing in two positive photoresists. These images are comparable to state-of-the-art lithography done with conventional lamps, the major difference being that the excimer laser technique is -2 orders of magnitude faster. Preliminary results on reciprocity behavior in several resists are also presented.
Detection and review of crystal originated surface and sub surface defects on bare silicon (2007)

The continuous dimensional reduction for micro-and nano electronics is driving the technology for yield relevant defect detection. Defects originating in the crystal are always present in silicon wafers. Due to miniaturization, the size of these defects becomes comparable to the feature sizes of future technology generations. Therefore, they are identified as a future yield limiting mechanism. This paper shows that crystal originated sub surface defects impact the performance of dark Held Scanning Surface Inspection Systems with respect to defect counts, defect classification, defect sizing, and capture rate.
Deterioration of Internal Interfaces between Silicone and Epoxy Resin (2006)

Interfacial defects, such as loss of adhesion together with environmental effects, such as moisture intrusion into the defect, can cause interfaces to become weak points in an insulation system. Silicone rubber moulded onto internal epoxy components is commonly used in high voltage outdoor composite insulation systems. For evaluating the interfacial properties of such a material combination, samples containing interfacial defects were prepared. In the samples a transparent silicone rubber was moulded onto a primer pre-treated epoxy substrate, while the spots to be characterized by a loss of adhesion were left unprimed. In this way air-filled defects between the two materials were created. The samples were thereafter exposed to an electric aging test with a needle-ring electrode arrangement attached to them. The electrode arrangement provided stress characterized by a high content of tangential field component along the interface and the field strength at the needle tip was kept at high enough level to maintain corona discharge activity. The ageing was performed under normal and humid conditions. The latter was performed to secure moisture ingress into the interface area through the silicone rubber. After the testing, the defect surfaces were analysed chemically to investigate reactions involved in the ageing processes. In addition, optical microscopy was used to evaluate a risk for void growth, which could potentially be caused by hydrolysis of the primer. The defect area was chemically evaluated by infrared spectroscopy
Nanometer-scale heterogeneity in SiO2–GeO2 glass preforms and fibers prepared by vapor phase axial deposition method (1996)

Nanometer-scale heterogeneity of Ge ions in SiO2:GeO2 (10–15 mol %) glass preforms prepared by vapor phase axial deposition method and in optical fibers drawn from the preform was found by transmission electron microscopic observation. Both preforms and fibers were comprised of 8–10 nm sized Ge-rich and Si-rich phases. Observation of Ge E′ centers in the as-prepared state and the formation of Ge E′ centers with light illumination with 5 eV-light may be understood by the occurrence of these heterogeneity.
Physical effects of macrosonic standing waves in oscillating cavities (1998)

Previous work has demonstrated resonant macrosonic synthesis (RMS) for shaping pressure waves in oscillating closed cavities. Additional measurements of pressure waves are presented, with peak overpressures in excess of 400% of ambient pressure. Characteristic power consumption of various resonator shapes is presented. Resonator shape as well as pressure amplitude is shown to be important in determining power consumption. For a change in resonator geometry, one example shows a 765% increase in pressure amplitude for a fixed power delivery. The dependence on resonator geometry of hardening and softening resonance behavior is demonstrated by showing results for both different resonator shapes and different gases in the resonators. Physical effects of macrosonic pressures and particle velocities are demonstrated with pulverization of objects placed in the resonator cavity.
300m transmission over multimode fiber at 25Gb/s using a multimode launch at 1310nm (2013)

We demonstrate the transmission of 25Gb/s multimode optical signals over a record length of 300m multimode fiber designed for high modal bandwidth at 1310nm. The power penalty is 1.8 dB at 10(-12) bit error rate level.
Geoscience Laser Altimeter System (GLAS) Instrument: Flight Loop Heat Pipe (LHP) Acceptance Thermal Vacuum Test (2001)

We conclude that quantitative ADC may detect meningitis-induced hypoxia early in brain parenchyma, which may be associated with abnormal motor and mental development.
ChemInform Abstract: 1,3,2‐Oxathiaphospholane Approach to the Synthesis of P‐Chiral Stereodefined Analogues of Oligonucleotides and Biologically Relevant Nucleoside Polyphosphates (2008)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.