gebhart/patrepeval huggingface dataset:
Abstract 1140: A novel MTA non-competitive PRMT5 inhibitor (2021)

Abstract The chromosome 9p21 (chr9p21) locus is deleted in almost 10% of all cancer types. This locus includes the CDKN2A gene that encodes the critical tumor suppressors p19-ARF and p16-INK4a. Methylthioadenosine phosphorylase (MTAP), a gene proximal to CDKN2A, is co-deleted in 80%-90% of tumors with CDKN2A deletion. MTAP plays a critical role in the methionine salvage pathway, and the deletion of MTAP results in the accumulation of its substrate methythioadenosine (MTA). Accumulation of MTA partially inhibits the activity of the arginine methyltransferase PRMT5, causing MTAP deficient cancer cells to be more sensitive to the genetic knockdown of PRMT5. In contrast to genetic knockdown, sensitivity to pharmacological inhibition of PRMT5 does not appear to stratify with MTAP status. However, currently known PRMT5 inhibitors all possess SAM competitive or uncompetitive MOIs, which generally require displacement of MTA from the active site for binding. We hypothesize that leveraging the high MTA state induced by MTAP deficiency will require an inhibitor that can bind PRMT5 without disrupting bound MTA. Here we report the discovery of a PRMT5 inhibitor with a novel binding mode that is compatible with MTA binding. While this compound possesses the desired MOI, it shows only modestly increased potency toward MTAP-null cells. Mathematical simulations of different inhibitor mechanisms indicate that the degree of selectivity that can be achieved depends on the difference in MTA levels between MTAP-null and WT cells. Our in vitro data suggest that the elevation in intracellular MTA concentrations that occurs with MTAP deletion is not sufficient to confer significantly increased sensitivity to PRMT5 inhibition. We anticipate that the therapeutic index that can be achieved between MTAP-null tumor cells and PRMT5-sensitive normal tissues will be similarly limited in vivo. Citation Format: Rohit Malik, Peter K. Park, Christopher M. Barbieri, Yuval Blat, Steven Sheriff, Carolyn A. Weigelt, Lisa M. Kopcho, Muge Celiktas, Max Ruzanov, Joseph G. Naglich, Jennifer L. Price, Mary Harner, Kevin M. Omalley, JIngjing Deng, William Schmitz, Guo Li, Zheming Ruan, Lan-ying Qin, Gerald J. Duke, Iyoncy Rodrigo, Mark R. Witmer, David G. Harden, Shilpa Demes, Brian J. Arey, Matt Soars, Brian E. Fink, Ashvinikumar V. Gavai, Gregory D. Vite, Charles F. Voliva. A novel MTA non-competitive PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1140.
Micropore structure of chromium oxide gels (1971)

The adsorption of nitrogen, carbon tetrachloride and water vapour was studied on various well-characterized chromium oxide gels in an attempt to relate the adsorptive properties with the texture and surface chemistry of the gels. Standard adsorption data obtained on non-porous chromium oxides provided a basis for the analysis of the isotherms on the porous gels by the application of the αs-method. The pore structures identified were within both the micropore and the mesopore range. For the microporous gels it was possible to use the nitrogen αs-plot to assess the pore volume and the external surface area; comparison of the micropore volumes obtained with the three adsorbates gave an indication of the micropore size distribution.Certain of the gels outgassed at temperatures below 200°C exhibited molecular sieve properties; in these cases, the water sorption capacity was high, whereas the pore volume available for nitrogen and carbon tetrachloride sorption was small. It is suggested that cavities were formed in the gel in the vicinity of the Cr3+ ions through the removal of water ligands under conditions where the hydroxide, oxide-hydroxide or oxide structures were slow to develop. The molecular sieve character was not found with gels prepared at high pH, presumably because of replacement of H2O ligands by OH– ions. Heat treatment of gels in air and nitrogen at temperatures between 200 and 600°C led in some cases to the closure of micropores and in others to pore widening with the development of mesopores. The results show that the pore structure may be stabilized to higher temperatures if the formation of the thermally unstable CrO3 is prevented. Crystalline α-Cr2O3 was non-porous, but the water sorption results indicate that the surface structure was not perfected until the calcination temperature was above 900°C.
Short P‐Wave Duration is a Marker of Higher Rate of Atrial Fibrillation Recurrences after Pulmonary Vein Isolation: New Insights into the Pathophysiological Mechanisms Through Computer Simulations (2021)

Background Short ECG P-wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single-pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P-wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms-138 ms; range, 71 ms-180 ms). At Cox regression, PWD was significantly associated with AF recurrence (<i>P</i>=0.012). Patients with a PWD <110 ms (hazard ratio [HR], 2.20; 95% CI, 1.24-3.88; <i>P</i>=0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06-3.30; <i>P</i>=0.031) had a nearly 2-fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.
Structural Details of Aqueous Attack on a Phosphate Glass by 1H/31P Cross-Polarization NMR (1998)

One- and two-dimensional heteronuclear correlation solid-state nuclear magnetic resonance experiments allow a direct study of the chemistry of water incorporation into a simple phosphate glass network. One main pathway for water incorporation into phosphate glass networks is through the formation of P−OH groups, and previous 1H magic-angle-spinning NMR investigations of proton environments in silicate and phosphate glasses suggest that hydroxyl groups are involved in multiple hydrogen-bonding motifs with backbone units within the glass networks. The presence of multiple proton environments presents more complex structural issues for aqueous incorporation into glass systems, which have yet to be explained unambiguously. The spectral editing capabilities of two-dimensional cross-polarization NMR identify specific subunits in modified sodium phosphate glasses, and strong evidence is presented for the formation of intramolecular as well as weaker intermolecular hydrogen bonds. Using a combination of one- and two-dimensional 1H/31P cross-polarization NMR studies, a total of five distinct phosphate units are identified in a near-metaphosphate glass after aqueous treatment.
ChemInform Abstract: Microwave‐Induced Organometallic Reactions in Aqueous Media. Use of Ga and Bi for the Allylation of Aromatic N‐Oxides and Hydrazones. (2002)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.
Extracting the Traffic Flows and the Physical Graphs from Timetables (2005)

Timetables of mass transportation systems contain an information not only about the traffic flows in the network, but also about the topology of the physical infrastructure of the network. However, this data is not given explicitly; it requires an nontrivial preprocessing to be revealed. We propose an algorithm that extracts the physical structure and the network of traffic flows from timetables. We then apply the algorithm to the timetables of the Swiss railway system, and evaluate our approach. 1
Reverse Micelle Based Synthesis of Microporous Materials in Microgravity (2001)

Formation of zincophosphates from zinc and phosphate containing reverse micelles (water droplets in hexane) has been examined. The frameworks formed resemble that made by conventional hydrothermal synthesis. Dynamics of crystal growth are however quite different, and form the main focus of this study. In particular, the formation of zincophosphate with the sodalite framework was examined in detail. The intramicellar pH was found to have a strong influence on crystal growth. Crystals with a cubic morphology were formed directly from the micelles, without an apparent intermediate amorphous phase over a period of four days by a layer-bylayer growth at the intramicellar pH of 7.6. At a pH of 6.8, an amorphous precipitate rapidly sediments in hours. Sodalite was eventually formed from this settled phase via surface diffusion and reconstruction within four days. With a rotating cell, it was possible to minimize sedimentation and crystals were found to grow epitaxially from the spherical, amorphous particles. Intermediate pH's of 7.2 led to formation of aggregated sodalite crystals prior to settling, again without any indication of an intermediate amorphous phase. These diverse pathways were possible due to changes in intramicellar supersaturation conditions by minor changes in pH. In contrast, conventional syntheses in this pH range all proceeded by similar crystallization pathways through an amorphous gel. This study establishes that synthesis of microporous frameworks is not only possible in reverse micellar systems, but they also allow examination of possible crystallization pathways.
ChemInform Abstract: Chiral Phosphinephosphites Having Axial and Central Chirality in Asymmetric Hydroformylations. (1996)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.
IPv6 over Low-Power Wireless Personal Area Network (6LoWPAN) ESC Dispatch Code Points and Guidelines (2017)

RFC 4944 defines the ESC dispatch type to allow additional dispatch
octets in the 6LoWPAN header. The value of the ESC dispatch type was
updated by RFC 6282; however, its usage was not defined in either RFC
6282 or RFC 4944. This document updates RFC 4944 and RFC 6282 by
defining the ESC extension octet code points and listing registration
entries for known use cases at the time of writing of this document.
Formation of the outer layer of the Dictyostelium spore coat depends on the inner-layer protein SP85/PsB (2003)

The Dictyostelium spore is surrounded by a 220 microm thick trilaminar coat that consists of inner and outer electron-dense layers surrounding a central region of cellulose microfibrils. In previous studies, a mutant strain (TL56) lacking three proteins associated with the outer layer exhibited increased permeability to macromolecular tracers, suggesting that this layer contributes to the coat permeability barrier. Electron microscopy now shows that the outer layer is incomplete in the coats of this mutant and consists of a residual regular array of punctate electron densities. The outer layer is also incomplete in a mutant lacking a cellulose-binding protein associated with the inner layer, and these coats are deficient in an outer-layer protein and another coat protein. To examine the mechanism by which this inner-layer protein, SP85, contributes to outer-layer formation, various domain fragments were overexpressed in forming spores. Most of these exert dominant negative effects similar to the deletion of outer-layer proteins, but one construct, consisting of a fusion of the N-terminal and Cys-rich C1 domain, induces a dense mat of novel filaments at the surface of the outer layer. Biochemical studies show that the C1 domain binds cellulose, and a combination of site-directed mutations that inhibits its cellulose-binding activity suppresses outer-layer filament induction. The results suggest that, in addition to a previously described early role in regulating cellulose synthesis, SP85 subsequently contributes a cross-bridging function between cellulose and other coat proteins to organize previously unrecognized structural elements in the outer layer of the coat.
Flow boiling of R245fa in a microgap with integrated staggered pin fins (2016)

We present an experimental study of two phase flow of refrigerant R245fa in a pin fin enhanced microgap for a range of heat fluxes between 151 W/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> to 326 W/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> . The gap has a base surface area of 1cm × 1cm and height of 200 μm. An array of hydrofoil shaped pin fins covers from bottom to top of the microgap. The pin fins have chord length, longitudinal pitch, and transversal pitch of 75μm, 450μm and 225μm, respectively. On the back side of the chip, four platinum heaters are fabricated and electrically powered in series to enable two phase flow in the microgap, which was part of a pumped flow loop. Heater and surface temperature data were obtained versus heat flux dissipated. Flow visualization was performed using a high speed camera in the heat flux range from 151 W/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> to 326 W/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> . The amount of heat loss across the test section is also provided.
Pharmacodynamics of tepoxalin, sodium-salicylate and ketoprofen in an intravenous lipopolysaccharide inflammation model in broiler chickens (2010)

The pharmacodynamic properties of tepoxalin, Na-salicylate and ketoprofen were determined in an intravenous lipopolysaccharide (LPS) inflammation model in broiler chickens. The drugs were administered orally at a dose of 30, 50 and 3 mg/kg, respectively. LPS administration induces an increase in the intracellular expression of interleukin (IL)-1β and IL-6 and the secreted IL-6 plasma concentration. Furthermore, an elevation in body temperature is noted. Despite pretreatment with a single dose of the drugs and LPS administration on the T(max) of the drug after a second dose, no decrease was seen in systemic IL-6 levels. The intracellular expression of IL-1β in the heterophils was slightly decreased if LPS was administered in combination with each of the three drugs. Tepoxalin and Na-salicylate administration had no significant effect on the LPS-induced increase in prostaglandin E(2) plasma concentration, in contrast to ketoprofen. None of the three drugs were able to influence the elevation in body temperature after LPS administration. The pharmacokinetic properties of Na-salicylate and ketoprofen were not altered in combination with LPS administration. However, LPS significantly decreased the AUC(0→6 h) of the active metabolite of tepoxalin, RWJ-20142, indicating a perfusion-limited elimination for this molecule.
Study of FK-binding Protein:FK506-metabolite Complexes by Electrospray Mass Spectrometry: Correlation to Immunosuppressive Activity (1999)

Electrospray ionization mass spectrometry was used to study several non-covalent FK-binding protein (FKBP) immunosuppressant complexes in the gas phase. Relative FKBP binding affinities were determined from the signal ratio for the 7+ charge states of bound and unbound complexes as a function of capillary exit voltage. All complexes displayed a 1:1 binding stoichiometry. The relative gas-phase binding affinities were found to be well correlated with in vitro FKBP binding and in vitro immunosuppression (rapamycin > FK506 > or = 31-demethyl FK506 > 13-demethyl FK506 >> Cyclosporin A; CsA). The method demonstrates potential as a simple, rapid, and automatable technique for prediction of the immunosuppressive activity of FKBP:drug complexes.
Parallel 'Go with the winners' algorithms in the LogP model (2002)

The authors parallelize the 'Go with the winners' algorithm of Aldous and Vazirani (1994) and analyze the resulting parallel algorithm in the LogP-model. The main issues in the analysis are load imbalances and communication delays. The result of the analysis is a practical algorithm which, under reasonable assumptions, achieves linear speedup. Finally, they analyze the algorithm for a concrete application: generating models of amorphous chemical structures.
Identification of a Mu-9 (anti-colon-specific antigen-p)-reactive peptide having homology to CA125 (MUC16) (2005)

Mu-9, an anti-colon specific antigen-p (CSAp) monoclonal antibody (MAb), has shown excellent gastrointestinal cancer targeting in both pre-clinical and clinical trials. With the recent development of the humanized version of this MAb, Mu-9 will receive further attention as a potential therapeutic agent for colorectal cancer. Hence, we have undertaken studies to examine the nature of the CSAp antigen and the structure of the Mu-9 epitope. M13 phage displaying random 12-mer peptides were used to isolate a peptide that binds both murine and humanized Mu-9 MAbs. The peptide, Mu-9-p16, was synthesized and found to inhibit binding of Mu-9 to CSAp with a Ka for the humanized antibody of 4.28 x 10(-7) +/- 0.91 x 10(-7) M. Control peptides did not bind Mu-9, nor did they inhibit the Mu-9-CSAp interaction. Three overlapping peptides were synthesized and used to demonstrate that the last six residues were sufficient to inhibit the Mu-9-CSAp interaction. A search of GenBank revealed that the peptide sequence IHPRP, was also present within CA125, a very high molecular weight ovarian cancer-associated antigen. The sequence is present outside of the known antigenic regions identified by the Oc125, M-11 and Ov197 anti-CA125 antibodies. To demonstrate that CSAp and CA125 may be the same protein, a heterologous sandwich enzyme immunoassay was developed with anti-CA125 MAbs used as capture reagents and Mu-9 as probe. By use of this ELISA system, we were able to specifically identify CSAp. In conclusion, our results indicate that the Mu-9-p16 peptide isolated through our screen identifies a peptide epitope shared by CSAp and CA125 and suggest that these proteins are related.
Laparoscopic renal surgery. (2009)

Renal surgery, radical nephrectomy in particular, was historically the first application of laparoscopic techniques in urology. Since then, laparoscopy has been constantly evolving to claim its position in the surgical armamentarium of the urologist for the treatment of both malignant and benign diseases of the kidney and upper urinary tract. Over the years of increasing surgical experience and exposure, along with the evolution in the techniques and instruments used, laparoscopy has emerged as an equally effective and even more attractive alternative to open surgery for certain indications. The currently available load of literature is able to prove beyond any doubt the oncologic efficacy and minimal morbidity of laparoscopy for the treatment of renal masses in the form of radical or partial laparoscopic nephrectomy and nephroureterectomy. On the other hand, one can claim that laparoscopy is not far from replacing open surgery for the management of benign conditions such as ureteropelvic junction obstruction and donor nephrectomy. This review on laparoscopic renal surgery will discuss the major applications, indications, techniques and outcomes of laparoscopy in the contemporary management of benign and malignant renal diseases while focusing on its benefits and drawbacks compared to open surgery.
In Vitro and In Vivo Activity of IMGN853, an Antibody–Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers (2018)

Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRα as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The <i>in vitro</i> cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα. <i>In vivo</i> antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors (<i>P</i> < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FRα, induced twofold increase in median survival (<i>P</i> < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRα 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment. <i>Mol Cancer Ther; 17(5); 1003-11. ©2018 AACR</i>.