50 research outputs found
AI is a viable alternative to high throughput screening: a 318-target study
: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNetĀ® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNetĀ® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery
Case-control Analysis of Clostridium difficileāAssociated Diarrhea on a Gynecologic Oncology Service
Objective: The incidence, morbidity, and risk factors associated with Clostridium difficile-associated
diarrhea (CDAD) were studied in a group of gynecologic oncology patients
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Interannual Herbaceous Biomass Response to Increasing Honey Mesquite Cover on Two Soils
This study quantified herbaceous biomass responses to increases in honey mesquite (Prosopis glandulosa Torr.) cover on two soils from 1995 to 2001 in north central Texas. Vegetation was sampled randomly with levels of mesquite ranging from 0% to 100%. With no mesquite covering the silt loam soils of bottomland sites, peak herbaceous biomass averaged (6SE) X 300 +/- 210 kg ha-1 vs. ā560 +/- 190 kg ha-1 on clay loam soils of upland sites (P = 0.001). A linear decline of 14 +/- 2.5 kg ha-1 in herbaceous biomass occurred for each percent increase in mesquite cover (P = 0.001). The slope of this decline was similar between soils (P=0.135). Herbaceous biomass with increasing mesquite cover varied between years (P=0.001) as did the slope of decline (P=0.001). Warm-season herbaceous biomass decreased linearly with increasing mesquite cover averaging a 73 +/- 15% reduction at 100% mesquite cover (P = 0.001) compared to 0% mesquite cover. Cool-season herbaceous biomass was similar between soils with no mesquite, 1 070 +/- 144 kg ha-1 for silt loam vs. 930 +/- 140 kg ha-1 for clay loam soils, but averaged 340 +/- 174 kg ha-1 more on silt loam than on clay loam soils at 100% mesquite cover (P = 0.004). Multiple regression analysis indicated that each centimeter of precipitation received from the previous October through the current September produced herbaceous biomass of 51 kg ha-1 on silt loam and 41 kg ha-1 on clay loam soils. Herbaceous biomass decreased proportionally with increasing mesquite cover up to 29 kg ha-1 at 100% mesquite cover for each centimeter of precipitation received from January through September. Increasing mesquite cover reduces livestock forage productivity and intensifies drought effects by increasing annual herbaceous biomass variability. From a forage production perspective there is little advantage to having mesquite present.Ā The Rangeland Ecology & Management archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform August 202
Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers
Summary: Somatic hypermutation of immunoglobulin sequences in germinal center (GC) reactions must be optimized to elicit high-affinity, protective antibodies after vaccination. We expose natural killer (NK) cells as robust negative regulators of somatic hypermutation in antigen-reactive B cells. NK cells restrict follicular helper TĀ cell (TFH) and GC B cell frequencies and titers of antigen-specific immunoglobulin after administration of alum-adjuvanted hapten-protein conjugate vaccines. This inhibition is perforin dependent, suggesting that NK cells kill one or more cells critical for GC development. In the presence of perforin-competent NK cells, antigen-specific GC BĀ cells acquire fewer mutations, including less frequent generation of non-synonymous substitutions and mutations associated with increased antibody affinity. Thus, NK cells limit the magnitude of GC reactions and thereby restrain vaccine elicitation of high-affinity antibodies. Circumventing this activity of NK cells during vaccination has strong potential to enhance humoral immunity and facilitate vaccine-elicited prevention of disease. : Natural killer (NK) cells limit immunization-elicited follicular helper TĀ cell and germinal center B cell responses. Rydyznski etĀ al. link perforin-dependent functions of NK cells to a reduced frequency and quality of somatic hypermutation within antigen-specific BĀ cells. Strategies targeting this NK cell activity may enhance vaccination-induced generation of high-affinity protective antibodies. Keywords: natural killer cells, germinal center, vaccination, affinity maturation, perforin, somatic hypermutation, immunoglobulin, humoral immunity, innate immunit
Phase I Study of Paclitaxel, Carboplatin, and Increasing Days of Prolonged Oral Etoposide in Ovarian, Peritoneal, and Tubal Carcinoma: A Gynecologic Oncology Group Study
Limited Access Trial Using Amifostine for Protection Against Cisplatin- and Three-Hour PaclitaxelāInduced Neurotoxicity: A Phase II Study of the Gynecologic Oncology Group
Phase I Trial of Carboplatin and Gemcitabine Chemotherapy and Stereotactic Ablative Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer.
BackgroundWe conducted a phase I trial to determine the safety of systemic chemotherapy prior to abdominopelvic robotic stereotactic ablative radiotherapy (SABR) in women with persistent or recurrent gynecologic cancers.MethodsPatients were assigned to dose-finding cohorts of day 1 carboplatin (AUC 2 or 4) and gemcitabine (600 or 800 mg/m(2)) followed by day 2 to day 4 Cyberknife SABR (8 Gy Ć three consecutive daily doses). Toxicities were graded prospectively by common terminology criteria for adverse events, version 4.0. SABR target and best overall treatment responses were recorded according to response evaluation criteria in solid tumors, version 1.1.FindingsThe maximum tolerated dose of chemotherapy preceding SABR was carboplatin AUC 4 and gemcitabine 600 mg/m(2). One patient experienced manageable, dose-limiting grade 4 neutropenia, grade 4 hypokalemia, and grade 3 nausea attributed to study treatment. One patient had a late grade 3 rectovaginal fistula 16 months after trial therapy. Among 28 SABR targets, 22 (79%) showed a partial response and 6 (21%) remained stable.InterpretationSystemic chemotherapy may be given safely prior to abdominopelvic robotic SABR with further investigation warranted