Heidemartinez6290

PURPOSE The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 is the standard for oncology toxicity encoding and grading despite limited validation. We assessed inter-rater reliability (IRR) in multi-reviewer toxicity identification. METHODS AND MATERIALS Two reviewers independently reviewed 100 randomly selected notes for weekly on-treatment visits during radiotherapy from the electronic health record (EHR). Discrepancies were adjudicated by a third reviewer for consensus. Term harmonization was performed to account for overlapping symptoms in CTCAE. IRR was assessed based on unweighted and weighted Cohen's kappa coefficients. RESULTS Between reviewers, unweighted kappa was 0.68 (95% CI 0.65-0.71) and weighted kappa 0.59 (0.22-1.00). IRR was consistent between noted present or absent symptoms with kappa of 0.6 (0.66-0.71) and 0.6 (0.65-0.69), respectively. CONCLUSIONS Significant discordance suggests toxicity identification, particularly retrospectively, is a complex and error prone task. Strategies to minimize IRR, including training and simplification of the CTCAE criteria, should be considered in trial design and future terminologies. Well-hydrated phospholipid bilayers provide a near-native environment for membrane proteins. They enable the preparation of chemically-defined samples suitable for NMR and other spectroscopic experiments that reveal the structure, dynamics, and functional interactions of the proteins at atomic resolution. The synthetic polymer styrene maleic acid (SMA) can be used to prepare detergent-free samples that form macrodiscs with diameters greater than 30 nm at room temperature, and spontaneously align in the magnetic field of an NMR spectrometer at temperatures above 35 °C. Here we show that magnetically aligned macrodiscs are particularly well suited for solid-state NMR experiments of membrane proteins because the SMA-lipid assembly both immobilizes the embedded protein and provides uniaxial order for oriented sample (OS) solid-state NMR studies. We show that aligned macrodiscs incorporating four different membrane proteins with a wide range of sizes and topological complexity yield high-resolution OS solid-state NMR spectra. The work is dedicated to Michelle Auger who made key contributions to the field of membrane and membrane protein biophysics. V.BACKGROUND Aspirin Exacerbated Respiratory Disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance to medications that inhibit cyclooxygenase-1. AERD patients have more severe upper and lower respiratory tract disease compared to aspirin-tolerant CRSwNP patients. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE To utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS Single-cell RNA sequencing (10X Genomics) was utilized to compare the transcriptional profile of NP cells from AERD and CRSwNP patients and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional RT-PCR. Lipid mediators were measured in sinonasal tissue by mass spectrometry. Localization of various proteins within NP was assessed by immunofluorescence. RESULTS The gene encoding for 15-LO, ALOX15, was significantly elevated in NP of AERD compared to CRSwNP (p less then 0.05) or control (p less then 0.001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r=0.56, p less then 0.001) and were associated with asthma. 15-oxo-ETE, a downstream product of 15-LO, was significantly elevated in CRSwNP (27.93pg/mg tissue) and AERD (61.03pg/mg tissue) NP compared to control (7.17pg/mg tissue, p less then 0.001). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in AERD NP. CONCLUSIONS Epithelial and mast cell interactions, leading to the synthesis of 15-oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway, and to the enhanced sinonasal disease severity observed in AERD. In a national cohort, we demonstrate the safety and efficacy of tailored chemo-immunotherapy followed by RIC HSCT for PID-associated lymphoproliferative disorders in children. As an important DNA topoisomerase I inhibitor in oncotherapy, camptothecin (CPT) with traditional formulation only shows a limited clinical application mainly because of its poor solubility. In this study, a novel redox responsive nanoscaled delivery system was developed to overcome the inherent defect of CPT. Firstly, a CPT prodrug (CPT-LA) and two crosslinkable surfactants (SO-LA and MPEG-LA) was synthesized, all of which contained the same lipoic acid (LA) structure. In the preparation, highly core-crosslinked structure was formed by adding a thiol crosslinker, which can induce LA ring opening polymerization and disulfide crosslinking. The resulting CPT-LA core-crosslinked nanomicelles (CPT-LA CNM) were formulated with a highly crosslinked core and a PEG hydrophilic shell. Dynamic light scattering (DLS) characterization indicated that CPT-LA CNM possessed a narrow size distribution (184.6 ± 3.6 nm) and negatively charged zeta potential (-3.5 ± 1.2 mV). selleck inhibitor The storage and physiological stabilities showed that the size distribution of CPT-LA CNM was relatively stable in both conditions which were neutral PBS at 4 °C (1 week period) and PBS containing 10% serum at 37 °C (24 h period). Moreover, the effective CPT release behavior of CPT-LA CNM was confirmed in the reducing circumstances containing dithiothreitol (DTT). Under confocal laser scanning microscopy (CLSM), CPT-LA CNM demonstrated a rapid cellular uptake behavior against cancer cells when compared to CPT suspension. Finally, the enhanced anticancer efficacy of CPT-LA CNM was also detected by in vitro cytotoxicity and cell apoptosis assay. In summary, the core-crosslinked CPT-LA CNM could be a promising CPT delivery system because of high stability, effectively controlled release as well as improved anticancer activity.