Songthorpe8847

Background This work aimed to evaluate the influence of two chelators DOTA(SCN) and DOTA(NHS) on radioimmunotherapy using 177Lu-DOTA-Rituximab preparations in murine lymphoma xenograft models. Subsequently, based on animal data, the organ radiation-absorbed doses were extrapolated to humans (adult male). Materials and Methods Therapeutic efficacy of 177Lu-DOTA-Rituximab was evaluated in male nude mice bearing either Raji (B lymphocyte, CD20+) and Jurkat (T lymphocyte, CD20) xenografts, utilizing an anti-CD20 antibody-Rituximab conjugate with either DOTA(SCN) or DOTA(NHS). The DOTA-Rituximab conjugates were prepared in the form of freeze-dried kits. Results All radioimmunoconjugates were obtained with high radiolabeling yield (radiochemical purity, RCP > 95%) and specific activity of ca. this website 0.5 GBq/mg. Therapeutic effects of 177Lu-DOTA-Rituximab were observed in animals regardless whether DOTA(SCN) or DOTA(NHS) were used for conjugation. Importantly, therapy involving 177Lu-DOTA-Rituximab was more effective than use of Rituximab alone. Conclusions The degree of antitumor efficacy was dependent on the type of applied bifunctional chelators conjugated to mAb. However, this difference was not statistically significant. Dosimetry calculations showed that the absorbed radiation doses extrapolated to humans were very low for osteogenic cells regardless of the conjugates. Organs like the liver and spleen, treated with 177Lu-DOTA(SCN)-Rituximab, showed similar radiation absorbed doses when compared with 177Lu-DOTA(NHS)-Rituximab.BACKGROUND The gold-standard method for collecting patient-reported outcomes (PROs) is the prospective assessment of preoperative to postoperative change. However, this method is not always feasible because of unforeseen cases or emergencies, logistical and infrastructure barriers, and cost issues. In such cases, a retrospective approach serves as a potential alternative, but there are conflicting conclusions regarding the reliability of the recalled preoperative PROs after orthopaedic procedures. PURPOSE To assess the agreement between prospectively and retrospectively collected PROs for a common, low-risk procedure. STUDY DESIGN Cohort study (Diagnosis); Level of evidence, 3. METHODS Patients who underwent arthroscopic rotator cuff repair between May 2012 and September 2017 at the study institution were identified. All of the patients completed the American Shoulder and Elbow Surgeons (ASES) Standard Shoulder Assessment Form preoperatively at their preassessment appointment. Patients were then contacted in called PROs were almost always lower than their prospectively recorded counterparts. Recalled PROs are more likely to be accurate when reported by younger patients, those with a longer duration of symptoms, and those with more severe preoperative conditions.RATIONALE Obesity-related asthma disproportionately affects minority children, and is associated with non-atopic T helper (Th) 1 polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood. OBJECTIVES Utilize functional genomics to identify cellular mechanisms associated with non-atopic inflammation in obese asthmatic minority children. METHODS CD4+Th cells from 59 obese asthmatic and 61 normal-weight asthmatic Hispanic and African American children underwent quantification of the transcriptome and DNA methylome, and genotyping. Expression and methylation quantitative trait loci (eQTLs and meQTLs) revealed the contribution of genetic variation to transcription and DNA methylation. Adjusting for Th cell subtype proportions discriminated loci where transcription or methylation differences were driven by differences in subtype proportions from loci that were independently associated with obesity-related asthma. MEASUREMENTS AND MAIN RESULTS Obese asthmatics had more memory and fewer naïve Th cells than normal-weight asthmatics. Differentially expressed and methylated genes, and meQTLs in obese asthmatics, independent of Th cell subtype proportions, were enriched in Rho-GTPase pathways. Inhibition of CDC42, one of the Rho-GTPases associated with Th cell differentiation, was associated with downregulation of IFNγ, but not IL-4 gene. Differential expression of RPS27L gene, part of the p53-mTOR pathway, was due to non-random distribution of eQTL variants between groups. link2 Differentially expressed and/or methylated genes, including RPS27L, were associated with pulmonary function deficits in obese asthmatics. CONCLUSIONS We found enrichment of Rho-GTPase pathways in obese asthmatic Th cells, identifying them as a novel therapeutic target for obesity-related asthma, a disease that is sub-optimally responsive to current therapies.Targeted alpha therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (223Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (227Th), the progenitor nuclide of 223Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.BACKGROUND Exposure mixtures frequently occur in data across many domains, particularly in the fields of environmental and nutritional epidemiology. Various strategies have arisen to answer questions about exposure mixtures, including methods such as weighted quantile sum (WQS) regression that estimate a joint effect of the mixture components. OBJECTIVES We demonstrate a new approach to estimating the joint effects of a mixture quantile g-computation. This approach combines the inferential simplicity of WQS regression with the flexibility of g-computation, a method of causal effect estimation. We use simulations to examine whether quantile g-computation and WQS regression can accurately and precisely estimate the effects of mixtures in a variety of common scenarios. METHODS We examine the bias, confidence interval (CI) coverage, and bias-variance tradeoff of quantile g-computation and WQS regression and how these quantities are impacted by the presence of noncausal exposures, exposure correlation, unmeasured eously. https//doi.org/10.1289/EHP5838.BACKGROUND The Achilles tendon Total Rupture Score (ATRS) is a commonly used patient-reported outcome measure for patients with an acute Achilles tendon rupture. The score consists of 10 questions, the last 3 of which include activities that some patients cannot or do not do. No instruction manual has been developed for the ATRS. HYPOTHESIS/PURPOSE The purpose was to evaluate the ATRS at 4, 12, and 24 months after a rupture. The hypothesis was that the results at 4 months would be inconsistent when compared with the results at 1 year and 2 years. We also aimed to develop a manual that explains how to use the ATRS. STUDY DESIGN Cohort study (Diagnosis); Level of evidence, 3. METHODS This was a mixed-methods study. The first section was a registry study, where prospectively collected data were analyzed. Data were collected 4, 12, and 24 months after rupture. The original score based on 10 items was compared with a score based on the first 7 items adjusted to the same scale as the original score. Density plots and scatterplots were made and differences between the scores were tested using the Mann-Whitney U test. The second section of the study consisted of discussions among the authors, which resulted in a manual for the ATRS. RESULTS In total, 2790 complete ATRSs were included. The 7-item score significantly overestimated the value of the 10-item score at all time points (P less then .001), but only at 4 months was the difference clinically relevant (9.7 points). CONCLUSION When the ATRS is used for short-term evaluation, there is a risk of results being inconsistent because of the last 3 questions. A manual explaining how to use the ATRS was therefore developed. We recommend that the full ATRS together with the manual should be used in future research rather than eliminating the 3 last questions.BACKGROUND MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published. METHODS We conducted a genome-wide analysis of microRNA and mRNA in the sputum from patients with asthma and implemented Weighted gene correlation network analysis (WGCNA) to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes, and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway. RESULTS Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. link3 Multiple microRNAs in the nely module correlated with two mRNA modules enriched for toll-like receptor (TLR) and Th17 signaling, and endoplasmic reticulum stress. CONCLUSIONS This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.